Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[N:6]=[CH:5][N:4]=1.C(N(CCC)CCC)CC.[CH:24]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>N1C=CC=CC=1>[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:30]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:31])[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: Nc1ccc2ncnc(N)c2c1
Reactant: O=C(Cl)C1CCCCC1
Agent: CCCN(CCC)CCC
Agent: Cl
Solvent: c1ccncc1
Product: Nc1ncnc2ccc(NC(=O)C3CCCCC3)cc12
Reaction time: 1 h
Yield: 56.1 %

Procedure:
A mixture of 4,6-diaminoquinazoline hydrochloride (12 g) and tripropylamine (31.7 g) in dry pyridine (120 ml) was stirred in an ice-bath for 1 hour. Cyclohexanecarbonyl chloride (12.1 g) was added dropwise during 4 hours and 20 minutes to the mixture at 70° C. The mixture was stirred for additional 1 hour at 5° C. Crushed ice was added to the reaction mixture. The mixture was stirred for 1 hour and concentrated under reduced pressure. After addition of water, the mixture was adjusted to pH 8 with sodium hydrogen carbonate to give precipitates which were separated by filtration, washed with water and dried. The precipitates were dissolved in a mixture of chloroform and methanol under heating. Insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure to give crystalline 4-amino-6-cyclohexanecarboxamidoquinazoline (9.25 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[C:6]([OH:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](I)[CH3:20]>CN(C=O)C.C(OCC)C>[CH2:19]([O:8][C:6]1[CH:7]=[C:2]([I:1])[CH:3]=[CH:4][C:5]=1[O:9][CH:10]([CH3:12])[CH3:11])[CH3:20]
Reactant: CCI
Reactant: CC(C)Oc1ccc(I)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOc1cc(I)ccc1OC(C)C
Temperature: 40 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a solution of 5-iodo-2-isopropoxyphenol (2.3 g, 8.3 mmol) in DMF (20 mL), K2CO3 (2.3 g, 16.5 mmol) and ethyl iodide (0.86 mL, 10.8 mmol) were added. The mixture was stirred at 40° C. for 2.0 h. It was diluted with diethyl ether, washed with brine, dried over MgSO4. The crude was purified by chromatography (5:1 EtOAc/hexanes) to give 2-ethoxy-4-iodo-1-isopropoxybenzene (2.5 g, 96% yield) as an oil.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(SC2C=CC=CC=2C(O)=O)C=CC=CC=1.S(Cl)(Cl)=O.[OH-].[NH4+:38]>CC(C)=O>[C:1]1([S:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([NH2:38])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: O=C(Cl)c1ccccc1Sc1ccccc1
Agent: O=C(O)c1ccccc1Sc1ccccc1
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O=S(Cl)Cl
Product: NC(=O)c1ccccc1Sc1ccccc1

Procedure:
Following the procedure described in Example 1, 2-(phenylthio)benzoyl chloride is prepared from 0.065 mole of 2-(phenylthio)benzoic acid and excess thionyl chloride. A solution of the oily acid chloride in 50 ml. of acetone is added dropwise with stirring to 100 ml. of concentrated ammonium hydroxide. The mixture is heated to refluxing for 3 hours. On cooling, the product separates and is collected.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17]1([CH2:27][C:28]([OH:30])=O)[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][C:24]([OH:26])=O)[CH:18]=1>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:24](=[O:26])[CH2:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH2:27][C:28]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:30])[CH:18]=1)=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Reactant: O=C(O)Cc1cccc(CC(=O)O)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)Cc1cccc(CC(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)c1
Yield: 82.8 %

Procedure:
Using General Procedure A with 2.0 g (8.2 mmol) D-Proline benzyl ester hydrochloride and 800 mg (4.1 mmol) 1,3-phenylenediacetic acid afforded, after flash chromatography (EtOAc), 1.93 g (84%) of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][N:10](C)C)[C:5]([N+]([O-])=O)=[CH:4][N:3]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C([O-])=O.[NH4+]>[Pd].CO.C(Cl)Cl>[N:16]1([C:4]2[CH:5]=[C:6]3[CH:8]=[CH:9][NH:10][C:7]3=[CH:2][N:3]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: CN(C)C=Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: c1cc2cc(N3CCOCC3)ncc2[nH]1
Temperature: 65 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
A solution of 450 mg (2 mmol) of [2-(2-chloro-5-nitro-pyridin-4-yl)-vinyl]-dimethyl-amine in a 20 mL of mixed solvent of MeOH-CH2Cl2 (1:1) was treated with 3 mL of morpholine. The reaction mixture was stirred at 65° C. for 8 h. Volatiles were then removed. CH2Cl2 (100 mL) and H2O (30 mL) were added. The organic layer was separated and washed with H2O (30 mL), brine (30 mL), dried over Na2SO4, and concentrated. The red powder was treated with 4.0 g (63 mmol, 32 eq) of ammonium formate and 10% Pd—C (120 mg). The reaction mixture was stirred at 65° C. for 30 min. The reaction mixture was then filtered through a pad of celite and concentrated to obtain a yellow solid. Column chromatography (silica, 5% MeOH/CH2Cl2) provided 210 mg (52% for 2 steps) of 5-morpholin-4-yl-1H-pyrrolo[2,3-c]pyridine as a yellow solid. TLC (silica, 5% MeOH/CH2Cl2): Rf=0.40. MS (electrospray): exact mass calculated for C11H13N3O, 203.11; m/z found, 204.2 [M+H]+.
Reaction SMILES: N#N.[CH2:3]([P:5]([CH2:12][CH3:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:4].[N-:14]([S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])[S:15]([C:18]([F:21])([F:20])[F:19])(=[O:17])=[O:16].[C:29](=O)(OC)OC>CO>[F:28][C:25]([F:26])([F:27])[S:22]([N-:14][S:15]([C:18]([F:19])([F:20])[F:21])(=[O:16])=[O:17])(=[O:23])=[O:24].[CH2:12]([P+:5]([CH2:3][CH3:4])([CH3:29])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:13]
Reactant: CCP(CC)c1ccccc1
Reactant: COC(=O)OC
Agent: N#N
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CO
Product: CC[P+](C)(CC)c1ccccc1
Temperature: 15 °C

Procedure:
In a reactor wherein air was replaced by N2, 200.0 g of (1.2 mol) diethylphenyl phosphine and 400 mL of methanol were added and cooled to 15° C. by a ice-bath. 338.6 g (1.2 mol) of trifluoromethanesulfonimide was then added dropwise under strong stirring, and 202.0 g (2.2 mol) of dimethyl carbonate was also added after the reaction was complete. The reaction mixture was transferred to an autoclave, wherein air was removed prior to heating. After 2 hours of reaction at temperature of 180° C. and at pressure of from 1.2 MPa to 1.5 MPa, the crude product was obtained after distilling off the unreacted materials and solvent. 507.1 g of diethyl methyl phenyl phosphonium bis(trifluoromethanesulfonyl)amide was obtained after washing and drying at 60° C. and 0.1 kPa for 4 hours.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:10]=1.[CH2:32]([S:35](Cl)(=[O:37])=[O:36])[CH2:33][CH3:34]>>[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([S:35]([CH2:32][CH2:33][CH3:34])(=[O:37])=[O:36])[CH2:28][CH2:27]2)[N:10]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: O=C(O)C(F)(F)F
Product: CCCS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3ccccc3OC)c(N)n2)CC1

Procedure:
The same procedure as described in Example 28 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 11, and propanesulfonyl chloride (Aldrich), to give [4-amino-2-[1-(propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone. HRMS, observed: 434.1860; Calcd for (M+H)+: 434.1857.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[OH:24])[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33]([CH3:42])([CH3:41])[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>CN(C)C=O>[C:37]([O:36][C:34](=[O:35])[C:33]([CH3:42])([CH3:41])[CH2:32][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:2]([F:1])[CH:3]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)C(C)(C)CBr
Reactant: O=C(OCc1ccccc1)c1ccc(-c2ccccc2O)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)COc1ccccc1-c1ccc(C(=O)OCc2ccccc2)c(F)c1
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
To an N,N-dimethylformamide solution (200 ml) of benzyl 3-fluoro-2′-hydroxybiphenyl-4-carboxylate (14.8 g) was added at room temperature cesium carbonate (37.5 g), followed by stirring for 30 minutes. To this was added an N,N-dimethylformamide solution (200 ml) of tert-butyl 3-bromo-2,2-dimethylpropanoate (27.2 g), followed by stirring at 60° C. for 3 days. After the reaction solution was concentrated under reduced pressure, water and ethyl acetate were added to the residue, and the solution was separated. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford benzyl 2′-(3-tert-butoxy-2,2-dimethyl-3-oxopropoxy)-3-fluorobiphenyl-4-carboxylate (15.0 g).
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:12])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:11])[CH2:9][CH3:10].[OH:13][C:14]1[CH:22]=[CH:21][C:17]2[CH2:18][CH2:19][O:20][C:16]=2[CH:15]=1>>[CH3:12][C:4]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:11])[CH2:9][CH3:10])=[CH:3][CH2:2][O:13][C:14]1[CH:22]=[CH:21][C:17]2[CH2:18][CH2:19][O:20][C:16]=2[CH:15]=1
Reactant: CCC(C)=CCCC(C)=CCBr
Reactant: Oc1ccc2c(c1)OCC2
Product: CCC(C)=CCCC(C)=CCOc1ccc2c(c1)OCC2

Procedure:
1-bromo-3,7-dimethyl-2,6-nonadiene and 6-hydroxy-2,3-dihydrobenzofuran are reacted to form 6-[(3,7-dimethyl-2,6-nonadienyl)-oxy]-2,3-dihydrobenzofuran of boiling point 138° C./0.002 mmHg; nD20 = 1.5382;
Reaction SMILES: [C:1]1(=[O:7])[O:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18].C1(=O)OCC1.C([NH-])C=C>>[CH2:18]([CH:2]1[CH2:3][CH2:4][CH2:5][O:6][C:1]1=[O:7])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=[CH2:9]
Reactant: C=CCCCCCCCCBr
Reactant: O=C1CCCCO1
Agent: C=CC[NH-]
Agent: O=C1CCO1
Product: C=CCCCCCCCCC1CCCOC1=O
Yield: 60 %

Procedure:
14.30 g of tetrahydro-3-(9-decenyl)-2H-pyrane-2-one of interest was prepared in the same manner as in Example 1 except that 10.01 g (100.0 mmol) of δ-valerolactone and 26.30 g (110.0 mmol) of 10-bromo-1-decene were used instead of β-propiolactone and allyl amide described in Preparation Example 1.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)=[O:12].[CH:22]1[CH:23]=[CH:24][C:25]2[N:30](O)N=[N:28][C:26]=2[CH:27]=1.C(Cl)CCl.C1(N)C=CC=CC=1N>CN(C=O)C>[NH2:28][C:26]1[CH:27]=[CH:22][CH:23]=[CH:24][C:25]=1[NH:30][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)=[O:12]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)CCCCCCC(=O)c1ccc2ccccc2c1
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Nc1ccccc1NC(=O)CCCCCCC(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.3 %

Procedure:
To a solution of 7-(2-naphthoyl)heptanoic acid 50 g (1.00 g, 3.52 mmol) in DMF (15 mL) were added HOBT (950 mg, 7.04 mmol) and EDC (1.00 g, 5.28 mmol). The mixture was stirred at room temperature for 1 hour, after which 1,2-phenylenediamine (760 mg, 7.04 mmol) was added and the solution was stirred at room temperature for 16 hours. The DMF was evaporated under high vacuum, deionized water was added, and the mixture was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with saturated sodium bicarbonate (20 mL), washed with brine (20 mL), and dried (MgSO4). The solvents were removed in vacuo and the title compound 63 (558 mg, 42%) was isolated by recrystallization from acetone and dichloromethane. 1H NMR (300 MHz, 20% CD3OD in CDCl3): δ 8.47 (s, 1H), 8.10-7.85 (m, 4H), 7.63-7.50 (m, 2H), 7.14-6.70 (m, 4H), 3.11 (t, J=7.2 Hz, 2H), 2.39 (t, J=7.5 Hz, 2H), 1.77 (m, 4H), 1.46 (m, 4H). 13C NMR (75 MHz, 20% CD3OD in CDCl3): δ 23.99, 25.40, 28.66, 28.74, 36.08, 38.23, 117.69, 119.09, 123.45, 124.01, 125.34, 126.53 126.86, 127.45, 128.19, 128.23, 129.28, 129.56, 132.23, 133.85, 135.32, 140.58, 172.81, 201.11.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([Cl:18])[C:3]=1[NH:19][C:20]([C:22]1[O:26][N:25]=[C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:23]=1)=O.O>CC(O)=O>[C:27]([C:24]1[CH:23]=[C:22]([C:20]2[NH:19][C:3]3[C:4]([Cl:18])=[N:5][C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=4[C:14]([F:17])([F:16])[F:15])=[CH:7][C:2]=3[N:1]=2)[O:26][N:25]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)c1cc(C(=O)Nc2c(N)cc(-c3ccccc3C(F)(F)F)nc2Cl)on1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1cc(-c2nc3cc(-c4ccccc4C(F)(F)F)nc(Cl)c3[nH]2)on1
Temperature: 100 °C

Procedure:
3-tert-Butyl-isoxazole-5-carboxylic acid [4-amino-2-chloro-6-(2-trifluoromethyl-phenyl)-pyridin-3-yl]-amide (73.9 mg, 0.168 mmol, prepared as in the previous step) was dissolved in AcOH (1 mL) and the resulting solution was heated to 100° C. for 14 h. The resulting mixture was cooled to room temperature and poured into H2O (20 mL). The aqueous phase was extracted with DCM (3×10 mL) and the combined extracts were washed with sat NaHCO3 solution (20 mL). The organic layer was dried over MgSO4, filtered and the solvent was removed under reduced pressure. The residue was dissolved in POCl3 (1 mL) and heated for 16 h at 100° C. The resulting mixture was cooled to room temperature and poured onto ice (˜20 mL). After the POCl3 had been consumed, the precipitate was isolated by filtration and washed with H2O (2×20 mL). The solid was dissolved in DCM (25 mL) and the solution was dried over MgSO4 and filtered. The solvent was removed under reduced pressure and the crude product was chromatographed on a 24-g SiO2 pre-packed column eluting with 0:1-2:3 EtOAc/hexanes to yield 2-(3-tert-butyl-isoxazol-5-yl)-4-chloro-6-(2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]pyridine. 1H-NMR (400 MHz, CD3OD) δ: 7.84 (d, J=7.8 Hz, 1H), 7.69-7.77 (m, 1H), 7.62-7.68 (m, 2H), 7.59 (d, J=7.6 Hz, 1H), 7.30 (s, 1H), 1.43 (s, 9H). Mass Spectrum (LCMS, ESI pos.): Calculated for C20H16ClF3N4O: 421.1 (M+H). Measured: 421.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:18][C@H:17]([OH:19])[CH2:16][C@H:12]2[C:13]([OH:15])=[O:14])=[O:10])=[CH:5][CH:4]=1.[N+](=[CH2:24])=[N-]>CO.O1CCCC1>[CH3:24][O:14][C:13](=[O:15])[C@@H:12]1[CH2:16][C@@H:17]([OH:19])[CH2:18][N:11]1[C:9]([O:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=1)=[O:10]
Reactant: C=[N+]=[N-]
Reactant: COc1ccc(COC(=O)N2C[C@H](O)C[C@H]2C(=O)O)cc1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc(OC)cc1
Reaction time: 8 h

Procedure:
trans-1-(p-Methoxybenzyloxycarbonyl)-4-hydroxy-L-proline (5.0 g) was dissolved in 50 ml of methanol and 50 ml of tetrahydrofuran. An ethereal solution of diazomethane was added thereto under ice-cooling until nitrogen gas evolution stopped. The mixture was allowed to stand overnight and distilled to obtain trans-1-(p-methoxy-benzyloxycarbonyl)-4-hydroxy-L-proline methyl ester.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.CCN(CC)CC.[Cl:15][CH2:16][C:17](Cl)=[O:18]>C(Cl)Cl>[Cl:15][CH2:16][C:17]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:3]1[CH2:2][OH:1])=[O:18]
Reactant: O=C(Cl)CCl
Reactant: OC[C@@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1CCC[C@H]1CO
Temperature: -20 °C
Reaction time: 18 h

Procedure:
To a solution of 2(S)-hydroxymethylpyrrolidine (25.32 g, 0,250 mol) in CH2Cl2 (720 mL) under argon was added Et3N (38.0 mL, 0,273 mol). After cooling this mixture to -20° C., chloroacetyl chloride (20.0 mL, 0.251 mol) was added dropwise over 0.75 h maintaining the reaction temperature at -20°±3° C. The reaction was stirred at ambient temperature for 18 h and evaporated in vacuo. An impurity which precipitated during concentration was removed by filtration. The crude product was purified by chromatography (silica gel, 1:39 to 1:19 MeOH/CH2Cl2) to give the title compound as a yellow oil. 1H NMR (CDCl3, 400 MHz): δ 4.37 (dd, J=8,3 Hz, 1H), 4.22 (qd, J=7,3 Hz, 1H), 4.08 (s, 2H), 3.71 (td, J=8, 3 Hz, 1H), 3.68-3.50 (m, 3H), 2.14-1.86 (m, 3H), 1.72-1.62 (m, 1H).
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:16][C@:14]2([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:34]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[C:1]([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[CH2:16][C@:14]2([C:29]2[S:30][C:31]([Br:34])=[CH:32][CH:33]=2)[N:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1=N[C@@]2(c3cccs3)CN(C(=O)OCc3ccccc3)C[C@H]2CS1)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NC1=N[C@@]2(c3ccc(Br)s3)CN(C(=O)OCc3ccccc3)C[C@H]2CS1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 91.9 %

Procedure:
To a stirred clear and colorless solution of benzyl(4aR,7aR)-2-benzamido-7a-(2-thienyl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate (1.67 g, 3.50 mmol) in dimethylformamide (35 mL) at room temperature, under an atmosphere of nitrogen is added N-bromosuccinimide (747 mg, 4.20 mmol). The resulting pale yellow solution is stirred at room temperature for 50 minutes. The solution is diluted with ethyl acetate (150 mL) and washed with water (3×50 mL) and brine (50 mL). The organic phase is separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel flash chromatography eluting with a hexanes/ethyl acetate, gradient from 80:20 to 0:100, to give the title compound (1.79 g, 92%) as a white solid: ES/MS (m/z): 557.8 (M+H).
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1[N:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([C:29](O)=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][C:18]=2[F:32])=[CH:13][N:12]=1.[F:33][C:34]([F:39])([F:38])[C@@H:35]([NH2:37])[CH3:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:10][C:11]1[N:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([C:29]([NH:37][C@@H:35]([CH3:36])[C:34]([F:39])([F:38])[F:33])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][C:18]=2[F:32])=[CH:15][N:16]=1
Reactant: C[C@H](N)C(F)(F)F
Reactant: Nc1ncc(-c2ccc(-c3ccccc3C(=O)O)cc2F)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1)C(F)(F)F

Procedure:
To a solution of DIPEA (47 mg, 0.36 mmol) in DMF (2 mL) were added 4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid (75 mg, 0.24 mmol), (S)-1,1,1-trifluoropropan-2-amine (30 mg, 0.27 mmol) and HATU (110 mg, 0.290 mmol).
Reaction SMILES: [CH2:1]([C:15]1[NH:16][CH:17]=[CH:18][CH:19]=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][CH3:14].C[Mg]Br.[C:23](Cl)(=[O:27])[O:24][CH2:25][CH3:26].[Cl-].[NH4+]>CCOCC>[CH2:1]([C:15]1[NH:16][C:17]([C:23]([O:24][CH2:25][CH3:26])=[O:27])=[CH:18][CH:19]=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][CH3:14]
Reactant: CCOC(=O)Cl
Reactant: CCCCCCCCCCCCCCc1ccc[nH]1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCCCCCCCCCCCCc1ccc(C(=O)OCC)[nH]1
Temperature: 25 °C
Yield: 37.6 %

Procedure:
Into 20 ml of anhydrous ether was dissolved 4.00 g (15 mmol) of 2-tetradecylpyrrole obtained in Synthetic Example 2, and then 7 ml (21 mmol) of ca. 3M ethereal solution, of methylmagnesium bromide was added thereto at room temerature. The resulting mixture was heated under reflux for 30 minutes. Under cooling with ice water, 2 ml (21 mmol) of ethyl chlorocarbonate was added to the mixture. After heating under reflux for 10 hours, the resulting mixture was cooled to room temperature, poured into ice water containing ammonium chloride, and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous megnesium sulfate. After removing the solvent under reduced pressure, the residue was purified by subjecting it to column chromatography (eluent: ethyl acetate/hexane=1/10) to obtain 1.89 g (37% yield) of ethyl 5-tetradecylpyrrole-2-carboxylate, m.p. 60°-63° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=1.CCCCCC.[Li]CCCC.[C:32](=[O:34])=[O:33]>C(OCC)C>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=[C:2]([C:32]([OH:34])=[O:33])[CH:7]=1
Reactant: O=C=O
Reactant: COc1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)O)c1
Reaction time: 0.17 h

Procedure:
3.00 g (0.0086 mol) of 2-bromo-4-methoxy-6-{3-(trifluoromethyl)phenoxy} pyridine was suspended in about 30 ml of diethyl ether. While cooling the obtained suspension in a dry ice-acetone bath in an argon atmosphere, 5.9 ml of a 1.6M-hexane solution of BuLi (0.0086×1.1 mol) was added thereto, followed by stirring the obtained solution for about 10 minutes. After an interior of reactor was replaced with carbon dioxide gas, the reaction solution was removed from the bath and stirred at room temperature for about one hour. The reaction solution was mixed with about 10 ml of a 1N-hydrochloric acid aqueous solution, and then distributed in ethyl acetate-water, followed by washing with saturated sodium bicarbonate water and saturated brine. The organic phase of the obtained solution was dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][N:9]([CH3:29])[C@H:10]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])[C:11]([O:13][C@H](C1C=CC=CC=1)C)=[O:12]>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:8][N:9]([CH3:29])[C@H:10]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])[C:11]([OH:13])=[O:12]
Reactant: C[C@H](OC(=O)[C@@H](c1ccccc1F)N(C)C)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CN(C)[C@@H](C(=O)O)c1ccccc1F
Reaction time: 4 h
Yield: 84.7 %

Procedure:
A mixture of (R)—((S)-1-phenylethyl) 2-(dimethylamino)-2-(2-fluorophenyl)acetate TFA salt (1.25 g, 3.01 mmol) and 20% Pd(OH)2/C (0.125 g) in ethanol (30 mL) was hydrogenated at room temperature and atmospheric pressure (H2 balloon) for 4 hours. The solution was then purged with Ar, filtered through diatomaceous earth (Celite®), and concentrated in vacuo. This gave the title compound as a colorless solid (0.503 g, 98%). 1HNMR (400 MHz, CD3OD) δ 7.53-7.63 (m, 2H), 7.33-7.38 (m, 2H), 5.36 (s, 1H), 2.86 (s, 6H). LCMS: Anal. Calcd. for C10H12FNO2: 197. found: 198 (M+H)+.