Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([C:14]([OH:16])=O)=[CH:12][N:11]=[C:10]3[NH:17][CH:18]=[CH:19][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:21]1[C:25]2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.Cl.CN>CN(C)C=O.CCOC(C)=O.O>[CH:1]1([NH:7][C:8]2[C:13]([C:14]([NH:21][CH3:25])=[O:16])=[CH:12][N:11]=[C:10]3[NH:17][CH:18]=[CH:19][C:9]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cnc2[nH]ccc2c1NC1CCCCC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1cnc2[nH]ccc2c1NC1CCCCC1
Temperature: 55 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
To a solution of 4-(cyclohexylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (25 mg) in N,N-dimethylformamide (0.375 mL) were added 1-hydroxybenzotriazole (19.5 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (22.5 mg) and methylamine hydrochloride (9.8 mg). The mixture was stirred at 55° C. for 1 hour. To the solution were added water and EtOAc and the mixture was extracted with EtOAc. The extract was washed with water, dried over MgSO4, filtrated and evaporated The residue was purified by column chromatography on silica gel with chloroform and methanol (100:0 to 90:10) to give 4-(cyclohexylamino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (5 mg), as a pale yellow powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([C:14]1[N:15]=[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]2[CH:23]=1)[CH2:11][C:12]#[CH:13]>>[F:22][C:19]1[CH:20]=[CH:21][C:16]2[N:17]([CH:23]=[C:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=3)[N:15]=2)[CH:18]=1
Reactant: C#CCCc1cn2cc(F)ccc2n1
Reactant: FCc1cccc(Br)n1
Product: FCc1cccc(C#CCCc2cn3cc(F)ccc3n2)n1

Procedure:
The title compound was prepared in accordance with the general method of Example 190(F), from 2-bromo-6-(fluoromethyl)pyridine (220 mg, 1.10 mmol) and 2-(but-3-ynyl)-6-fluoro-imidazo[1,2-a]pyridine (220 mg, 1.14 mmol). The crude residue was purified over C18 chromatography (prepacked 35 g silicagel column, H2O/CH3CN: from 95/5 to 55/45 as eluent) to afford 1.55 mg of 6-fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)H-imidazo[1,2-a]pyridine (Yield: 46%) as a white powder (Mp=140-141.8° C.).
Reaction SMILES: [Si:1]([O:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1.[CH:42]1[C:51]2[C:46](=[CH:47][C:48]([C:52]3[S:56][C:55]([NH2:57])=[N:54][N:53]=3)=[CH:49][CH:50]=2)[CH:45]=[CH:44][N:43]=1.C1C2C(=CC(C(O)=O)=CC=2)C=CN=1.ClC1C=NC=C2SC(C(O)=O)=CC=12>CN(C=O)C>[Si:1]([O:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([NH:57][C:55]1[S:56][C:52]([C:48]2[CH:47]=[C:46]3[C:51](=[CH:50][CH:49]=2)[CH:42]=[N:43][CH:44]=[CH:45]3)=[N:53][N:54]=1)=[O:12])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: Nc1nnc(-c2ccc3cnccc3c2)s1
Reactant: CC(C)(C)[Si](C)(C)OC(Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)c1cc2c(Cl)cncc2s1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC(Cc1ccccc1)C(=O)Nc1nnc(-c2ccc3cnccc3c2)s1
Reaction time: 0.17 h
Yield: 25.5 %

Procedure:
(±)-2-(tert-Butyldimethylsilyloxy)-3-phenylpropanoic acid (1.2 g, 4.3 mmol) was taken up in 18 mL of DMF. N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (1.4 g, 7.1 mmol) and HOBt (1.4 g, 11 mmol) were added. After 10 minutes, 5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-amine (0.81 g, 3.6 mmol) (prepared as shown in Scheme 5 using isoquinoline-6-carboxylic acid, commercially available from AstaTech Product List (Order Number 62874), instead of 4-chlorothieno[2,3-c]pyridine-2-carboxylic acid) was added. The mixture was stirred overnight. It was then partitioned between 50 mL of EtOAc and 50 mL of aq. NH4Cl. The aqueous portion was extracted twice with 50 mL of EtOAc. The combined organic extracts were washed with water (3×50 mL) and brine (50 mL) and dried over MgSO4. The mixture was filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluting with a gradient of 10% to 50% EtOAc in hexanes) to provide (±)-2-(tert-butyldimethylsilyloxy)-N-(5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-yl)-3-phenylpropanamide (0.45 g, 26%) as a yellow solid.
Reaction SMILES: [C:1]([O:9][C@H:10]([CH2:15][C:16]1[C:17]([CH2:26][O:27]C(=O)C)=[C:18]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[NH:21][N:20]=[CH:19]2)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.CO.C[O-].[Mg+2].C[O-]>>[C:1]([O:9][C@H:10]([CH2:15][C:16]1[C:17]([CH2:26][OH:27])=[C:18]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[NH:21][N:20]=[CH:19]2)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](Cc1cc(Cl)c2[nH]ncc2c1COC(C)=O)OC(=O)c1ccccc1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H](Cc1cc(Cl)c2[nH]ncc2c1CO)OC(=O)c1ccccc1
Reaction time: 3 h
Yield: 67 %

Procedure:
(R)-3-(4-(acetoxymethyl)-7-chloro-1H-indazol-5-yl)-1-methoxy-1-oxopropan-2-yl benzoate (8.5g, 19.73 mmol) in a mixture of chloroform (80.0 ml, 992 mmol) and methanol (60.0 ml, 1483 mmol) was added magnesium methoxide (4.18 ml, 39.5 mmol). After 3 h, quenched with 1.0 M HCl and extracted with dichloromethane (300 mL). The crude product was purified by flash chromatography using 70% EtOAc in hexane to give (R)-3-(7-chloro-4-(hydroxymethyl)-1H-indazol-5-yl)-1-methoxy-1-oxopropan-2-yl benzoate in 67% yield. 1H NMR (500 MHz, CDCl3): in δ 8.09 (s, 1H), 7.93 (d, J=7.5 Hz, 1H), 7.47 (m, 1H), 7.32 (t, J=8 Hz, 2H), 7.22 (s, 1H), 5.49 (m, 1H), 4.99 (m, 2H), 3.45-3.41 (m, 1H), 3.68 (s, 3H), 3.36-3.31 (m, 1H); MS (ESI) 389 (M+H); Rf=2.07.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:36]=[CH:35][CH:34]=[CH:33][C:7]=1[C:8]([C:10]1[CH:11]=[C:12]([NH:16][C:17]([C:19]2[CH:20]=[CH:21][N:22]3[C:26]=2[CH2:25][S:24][CH:23]3[C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[O:18])[CH:13]=[CH:14][CH:15]=1)=[O:9])=[O:5])C.[OH-].[K+].C(O)(=O)C.C>C(O)C.C(O)CCC.CN(C)C=O>[C:4]([C:6]1[CH:36]=[CH:35][CH:34]=[CH:33][C:7]=1[C:8]([C:10]1[CH:11]=[C:12]([NH:16][C:17]([C:19]2[CH:20]=[CH:21][N:22]3[C:26]=2[CH2:25][S:24][CH:23]3[C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[O:18])[CH:13]=[CH:14][CH:15]=1)=[O:9])([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccccc1C(=O)c1cccc(NC(=O)c2ccn3c2CSC3c2cccnc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(O)c1ccccc1C(=O)c1cccc(NC(=O)c2ccn3c2CSC3c2cccnc2)c1
Temperature: 20 °C
Reaction time: 3 h
Yield: 43.4 %

Procedure:
A solution of N-[3-(2-ethoxycarbonylbenzoyl)phenyl]- 3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (4.4 g) and potassium hydroxide pellets (1.8 g) in a mixture of ethanol (100 cc) and distilled water (50 cc) is stirred at a temperature in the vicinity of 20° C. for 3 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. The residue is dissolved in distilled water (350 cc) and the solution obtained is adjusted to a pH in the region of 4 by adding an aqueous 4N acetic acid solution. The crystals formed are separated by filtration, washed 5 times with distilled water (500 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. A crude product (3.5 g) is thereby obtained, which is dissolved in a boiling mixture (200 cc) of butan-1-ol and dimethylformamide (35:65 by volume). Decolourizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 4° C. for 3 days. The crystals formed are separated by filtration, washed 3 times with a mixture (30 cc in total) of butan-1-ol and dimethylformamide (35:65 by volume), 3 times with ethanol (90 cc in total) and 3 times with diethyl ether (90 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-[3-(2-carboxybenzoyl) phenyl]-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (1.8 g) in the form of white crystals, m.p. 315° C. is thereby obtained.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH3:26][O:27][C@H:28]([CH3:32])[C:29](O)=[O:30]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:29](=[O:30])[C@H:28]([O:27][CH3:26])[CH3:32])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: CO[C@H](C)C(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: CO[C@H](C)C(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (19 mg, 65.2%), MS (ISP) m/z=417.5 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25.7 mg, 0.070 mmol) and (R)-2-methoxypropanoic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=1.C([Li])CCC.[CH2:18]([O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH:29]=[O:30])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(C)C>C1COCC1.O>[CH2:18]([O:25][C:26]1[CH:27]=[C:28]([CH:29]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=2)[OH:30])[CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Reactant: CCOc1cc(Br)ccc1OC
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CCOc1cc(C(O)c2ccc(OC)c(OCc3ccccc3)c2)ccc1OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 89.3 %

Procedure:
A stirred mixture of 4-bromo-2-ethoxy-1-methoxy-benzene (5.25 g, 22.7 mmol) and dry THF (50 mL) was cooled to −78° C., evacuated and refilled with nitrogen for 10 cycles. To this clear solution was slowly added n-butyllithium (9.1 mL, 22.7 mmol) and stirred for 20 min. Then a mixture of 3-benzyloxy-4-methoxy-benzaldehyde (5.0 g, 20.6 mmol) in dry THF (20 mL) was added and stirred for 1 hour at −78° C. The mixture was quenched with isopropanol (9.4 mL, 248 mmol) and added water (50 mL). The mixture was extracted with EtOAc (3×80 mL). The combined organic phases were washed with water (2×80 mL), dried over MgSO4 and concentrated to oil, which was purified by flash column chromatography (EtOAc/Hexane) to give (3-benzyloxy-4-methoxy-phenyl)-(3-ethoxy-4-methoxy-phenyl)-methanol as an off-white solid (7.26 g, 89% yield): 1H NMR (CDCl3) δ 1.43 (t, J=7 Hz, 3H, CH2CH3), 2.09 (d, J=3 Hz, 1H, OH), 3.86 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 4.00 (q, J=7 Hz, 2H, CH2CH3), 5.10 (s, 2H, CH2), 5.68 (d, J=3 Hz, 1H, CH), 6.80-6.92 (m, 6H, Ar), 7.26-7.41 (m, 5H, Ar). The product was used in the next step without further purification.
Reaction SMILES: [N:1]1[C:9]2[CH2:8][CH2:7][N:6]([C:10]([O-])=O)[CH2:5][C:4]=2[S:3][CH:2]=1.[N:13]([CH2:16][CH2:17][CH2:18][C:19]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:23](C(=S)N)[N:22]=[C:21]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[F:34])[S:20]1)=[N+]=[N-].BrC1C(=O)CCN(C(OC(C)(C)C)=O)C1.CCN(C(C)C)C(C)C>C(O)C>[F:34][C:28]1[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=1[C:21]1[S:20][C:19]([CH2:18][CH2:17][CH2:16][NH2:13])([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:23]([C:2]2[S:3][C:4]3[CH2:5][N:6]([CH3:10])[CH2:7][CH2:8][C:9]=3[N:1]=2)[N:22]=1
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(N)=S
Reactant: O=C([O-])N1CCc2ncsc2C1
Agent: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCCN)c3ccccc3)sc2C1
Reaction time: 8 h

Procedure:
Preparation of tert-butyl 24243-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate: To a solution of 2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothioamide (0.300 g, 0.717 mmol) in 10 mL of ethanol was added tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (0.239 g, 0.860 mmol) followed by DIEA (0.25 mL, 1.43 mmol). The mixture was allowed to stir overnight at reflux, then treated with tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (100 mg) and stirred at reflux for a further 3 hours. The cooled mixture was partitioned between a saturated NaHCO3 solution (30 mL) and EtOAc (30 mL), and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (5-10% ethyl acetate/hexanes) to afford the desired product as a bright yellow foam, 0.313 g, 73%.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2=[C:7]([CH:11]=O)[CH:8]=[CH:9][CH:10]=[C:4]2[O:3]1.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16]>>[CH3:1][CH:2]1[CH2:6][C:5]2[C:7](/[CH:11]=[CH:14]/[C:15]([OH:17])=[O:16])=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1
Reactant: O=C(O)CC(=O)O
Reactant: CC1Cc2c(C=O)cccc2O1
Product: CC1Cc2c(/C=C/C(=O)O)cccc2O1
Yield: 92 %

Procedure:
2-Methyl-2,3-dihydrobenzofuran-4-carboxaldehyde was reacted with malonic acid by the above procedures to give the desired acid (92%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:18][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)([CH2:14][CH2:15][CH2:16][CH3:17])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.[CH2:24](I)[CH3:25].CO>CN(C)C=O.C(OCC)(=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:18][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)([CH2:14][CH2:15][CH2:16][CH3:17])[C:11]([O:13][CH2:24][CH3:25])=[O:12])=[CH:6][CH:5]=1
Reactant: CCCCC(Cn1cncn1)(C(=O)O)c1ccc(Cl)cc1
Reactant: CCI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCC(Cn1cncn1)(C(=O)OCC)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
To a 250 mL 3 neck flask stirring under N2 was charged 1.0 g of 60% sodium hydroxide (prewashed with hexanes) in 50 mL of dimethyl formamide (DMF). To the slurry was charged 6.14 g (0.020 mole) of 2-(4-chlorophenyl)-2-[(1,2,4-triazol-1yl)methyl]hexanoic acid in 50 mL of dimethyl formamide. The mixture was stirred at room temperature and 3.74 g (0.024 mole) of ethyl iodide was added. The reaction was monitored by thin layer chromatography (TLC) in a one to 19 mixture of methanol and ethyl acetate. Upon completion the reaction was quenched with water extracted with ether, and washed with saturated sodium bicarbonate. After drying and removal of the solvent, 5.9 g (88% yield) of a thick oil remained, Example 18 of Table 1.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH:3]1[CH2:8][CH2:7][C:6]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH2:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH2:4]1>CO.[Pd]>[F:20][C:2]([F:1])([F:19])[CH:3]1[CH2:4][CH2:5][CH:6]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH2:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:7][CH2:8]1
Reactant: Nc1nc2c(C3=CCC(C(F)(F)F)CC3)cccn2n1
Agent: [Pd]
Solvent: CO
Product: Nc1nc2c(C3CCC(C(F)(F)F)CC3)cccn2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a solution 8-(4-trifluoromethyl-cyclohexenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamine (CAS 1329673-42-8, US 20110201605) (30 mg, 0.106 mmol) in methanol (5 mL) was added 10% Pd/C (30 mg), and the reaction mixture was allowed to stir at 25° C. for 2 hours under hydrogen balloon atmosphere. The reaction mixture was filtered through a bed of celite and the filtrate was evaporated off in vacuo yield the title compound as a white solid (30 mg, 99%) which was used in the next step without further purification. MS ISP (m/e): 285.2 (100) [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[CH2:14][CH2:13][C:12]3[NH:11][C:10](=[O:16])[CH2:9][C:8]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][C:10](=[O:16])[NH:11]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1CCC1=C2CC(=O)N1
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c1CC[C@@H]1NC(=O)C[C@H]21
Yield: 80.9 %

Procedure:
A suspension of 150 g (0.7 mol) of 1,3,4,5-tetrahydro-6-methoxy-2H-benzo[e]indol-2-one in 1.5 l of methylene chloride was treated with 333 ml (2.1 mol) of triethylsilane and then slowly dropwise at 0° and while stirring with 240 ml of trifluoroacetic acid. After stirring for three hours 400 ml of 20% sodium hydroxide solution were added slowly while cooling until a pH of 14 had been reached. Subsequently, the mixture was poured into water and extracted with methylene chloride. The organic phase was washed with sodium chloride solution, dried with sodium sulphate, filtered and evaporated. The residue was treated with 500 ml of ether, whereupon the solid was filtered off and dried at 50°/20 Torr. There were obtained 123 g (81%) of rac-cis-1,3,3a,4,5,9b-hexahydro-6-methoxy-2H-benzo[e]indol-2-one with m.p. 192°-194°. The material showed a Rf value of 0.14 in a thin-layer chromatogram (silica gel, ethyl acetate).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][C:4]1([F:7])[F:6].C([O-])([O-])=O.[K+].[K+].[Cl:14][C:15]1[N:20]=[CH:19][C:18]([OH:21])=[CH:17][N:16]=1>CN(C=O)C>[Cl:14][C:15]1[N:20]=[CH:19][C:18]([O:21][CH2:2][CH:3]2[CH2:5][C:4]2([F:7])[F:6])=[CH:17][N:16]=1
Reactant: Oc1cnc(Cl)nc1
Reactant: FC1(F)CC1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC1(F)CC1COc1cnc(Cl)nc1
Temperature: 80 °C

Procedure:
295 mg (1.72 mmol) 1-bromomethyl-2,2-difluorocyclopropane and 318 mg (2.30 mmol) K2CO3 are added to a mixture of 150 mg (1.15 mmol) 2-chloro-5-hydroxypyrimidine in 2 mL DMF. The mixture is stirred at 80° C. over night. Then the reaction mixture is quenched by the addition of water and extracted with DCM. The organic layer is dried with Na2SO4 and the solvent is removed in vacuo. The residue is purified by HPLC (MeOH/H2O/NH3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([NH:12][C:13]([C:15]2[C:16](=[O:33])[C:17]([O:31][CH3:32])=[C:18]([C:27]([O:29][CH3:30])=[O:28])[N:19]([CH2:21][CH:22]([O:25]C)[O:23]C)[CH:20]=2)=[O:14])[CH2:11][CH2:10]1.CS(O)(=O)=O>C(#N)C.C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([NH:12][C:13]([C:15]2[C:16](=[O:33])[C:17]([O:31][CH3:32])=[C:18]([C:27]([O:29][CH3:30])=[O:28])[N:19]([CH2:21][CH:22]([OH:23])[OH:25])[CH:20]=2)=[O:14])[CH2:10][CH2:11]1
Reactant: COC(=O)c1c(OC)c(=O)c(C(=O)NC2(c3ccc(F)cc3F)CC2)cn1CC(OC)OC
Agent: CS(=O)(=O)O
Solvent: CC#N
Solvent: CC(=O)O
Product: COC(=O)c1c(OC)c(=O)c(C(=O)NC2(c3ccc(F)cc3F)CC2)cn1CC(O)O
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Methyl 5-(1-(2,4-difluorophenyl)cyclopropylcarbamoyl)-1-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate (27-1B, 0.150 g, 0.32 mmol) in acetonitrile (1.5 mL) and acetic acid (0.2 mL) was treated with methanesulfonic acid (0.05 mL), sealed with a yellow cap, and heated to 70° C. After 16 hours, the mixture was cooled to afford a crude solution of methyl 5-(1-(2,4-difluorophenyl)cyclopropylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate 27-C. LCMS-ESI+ (m/z): [M+H]+ calculated for C18H19F2N2O7: 439; found: 439.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[O:15][C:16]3[CH:21]=[C:20]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:29])[CH3:28])[CH3:25])[N:19]=[CH:18][C:17]=3[N:30]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH:11]([OH:13])[CH3:12].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:14]2[O:15][C:16]3[CH:21]=[C:20]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:29])[CH3:28])[CH3:25])[N:19]=[CH:18][C:17]=3[N:30]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][C:11](=[O:13])[CH3:12]
Reactant: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCCC(C)O)c(F)c3)nc2cn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)CCOc1ccc(-c2nc3cnc(OC[C@H](C)NC(C)=O)cc3o2)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.3 %

Procedure:
A solution of N-((2S)-1-((2-(3-fluoro-4-(3-hydroxybutoxy)phenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide (300 mg) and Dess-Martin reagent (914 mg) in DMF (30 mL) was stirred at room temperature for 15 hr. To the mixture was added saturated aqueous sodium thiosulfate solution, and the mixture was stirred at room temperature for 10 min. Water was added thereto, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (165 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].CC(C)([O-])C.[K+].[CH3:12][C:13]([C:16]1[CH:17]=[C:18]([CH:27]=[C:28]2[S:32][C:31](SC)=[N:30][C:29]2=[O:35])[CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])([CH3:15])[CH3:14]>C(O)C>[CH3:15][C:13]([C:16]1[CH:17]=[C:18]([CH:27]=[C:28]2[S:32][C:31](=[N:1][CH2:2][C:3]([OH:5])=[O:4])[NH:30][C:29]2=[O:35])[CH:19]=[C:20]([C:23]([CH3:24])([CH3:25])[CH3:26])[C:21]=1[OH:22])([CH3:12])[CH3:14]
Reactant: NCC(=O)O
Reactant: CSC1=NC(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)S1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)c1cc(C=C2SC(=NCC(=O)O)NC2=O)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.2 %

Procedure:
A mixture of glycine (2.25 g, 0.03 mole), potassium-t-butoxide (2.81 g, 0.025 mole), and ethanol (700 mL) is stirred at room temperature for 15 minutes. 5-[(3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl)methylene]-2-(methylthio)-4(5H)-thiazolone (7.27 g, 0.02 mole) is added to it and the mixture is refluxed with stirring for 20 hours. The mixture is then filtered and the solvent removed at 40° C. under reduced pressure. The residue is treated with ice-water, acidified with 1N aqueous hydrochloric acid and extracted with ether. The organic layer is washed with water, dried, and the solvent removed to give 7.75 g of a solid. The crude solid is recrystallized from tetrahydrofuran-ether to give 2.95 g (38%) of pure N-[5-[3,5-[bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-4-oxo-2-thiazolidinylidene]glycine, (Z)-, mp 260° C. (dec).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18](=[O:29])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+].CC(C)(C(=O)CC(=O)C(C)(C)C)C>CN1CCCC1=O.O.[Cu]Cl>[CH3:16][O:17][C:18](=[O:29])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)=[CH:23][C:22]=1[CH3:28]
Reactant: COC(=O)CCc1ccc(O)cc1C
Reactant: Brc1cccc(OCc2ccccc2)c1
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)CCc1ccc(Oc2cccc(OCc3ccccc3)c2)cc1C
Temperature: 120 °C
Yield: 50.7 %

Procedure:
A mixture of 3-benzyloxy-1-bromobenzene (14.53 g, 55.2 mmol), 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (10.72 g, 55.2 mmol), cesium carbonate (21.59 g, 66.3 mmol), and 2,2,6,6-tetramethyl-3,5-heptanedione (2.54 g, 13.8 mmol) in 1-methyl-2-pyrrolidinone (100 mL) is purged with N2 and then copper (I) chloride (2.73 g, 27.6 mmol) is added. The reaction mixture is heated to 120° C. for 18 hours under N2. The mixture is then diluted with water and extracted with Et2O. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using a gradient of 19/1 to 9/1 hexanes/ethyl acetate to afford 10.54 g (51%) of the titled compound. Rf=0.53 (100% hexanes). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C24H24O4 376, found 377 (M+1, 100%).