Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][C@H:15]([CH3:25])[C@:16]2([OH:24])[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:27])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:26])[CH:6]=[CH:5]1.[C:28](OC)(OC)([O:32]C)[CH:29]([CH3:31])[CH3:30].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.CC(C)=O.O>[Cl:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][C@H:15]([CH3:25])[C@:16]2([O:24][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:27])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:26])[CH:6]=[CH:5]1
Reactant: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](Cl)C[C@]2(C)[C@@]1(O)C(=O)CO
Reactant: COC(OC)(OC)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CC(C)=O
Product: CC(C)C(=O)O[C@]1(C(=O)CO)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](Cl)C[C@@]21C
Reaction time: 0.5 h

Procedure:
A solution of 11β-chloro-17,21-dihydroxy-16β-methylpregna-1,4-diene-3,20-dione (214 mg.) in dioxan (7 ml.) was treated with trimethyl orthoisobutyrate (0.22 ml.) and toluene p-sulphonic acid (23 mg.) at room temperature. After 45 minutes a little sodium bicarbonate was added and the mixture was then poured into a dilute solution of sodium bicarbonate. The oily product was extracted into ethyl acetate and washed with water. Evaporation of the organic solent gave an oil which was dissolved in acetone (10 ml.) and treated with 0.08 N-sulphuric acid (2.4 ml.). After keeping at room temperature for 30 minutes, the solution was diluted with water and the precipitated oil was extracted with ethyl acetate and washed with water. Evaporation of the organic solvent afforded the crude product which, on crystallization from ether-petroleum ether, gave the title compound, m.p. 163°-164° (K), [α]D + 108.5 (c 0.6 chloroform) λmax 240 nm (ε 15,460) (Found: C, 67.7; H, 7.7; Cl, 7.4. C26H35Cl O5 requires C, 67.45; H, 7.6; Cl, 7.65%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=2)[O:10][CH:11]([CH2:15][CH2:16][CH3:17])[C:12](Cl)=[O:13])[N:3]=1.[N:21]1([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>CN(C)C1C=CN=CC=1.ClCCl>[N:21]1([C:27]2[CH:28]=[CH:29][C:30]([NH:31][C:12](=[O:13])[CH:11]([O:10][C:9]3[CH:18]=[CH:19][CH:20]=[C:7]([C:4]4[N:3]=[C:2]([CH3:1])[O:6][N:5]=4)[CH:8]=3)[CH2:15][CH2:16][CH3:17])=[CH:32][CH:33]=2)[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: CCCC(Oc1cccc(-c2noc(C)n2)c1)C(=O)Cl
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCC(Oc1cccc(-c2noc(C)n2)c1)C(=O)Nc1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
200 mg of 4-dimethylaminopyridine on polystyrene are added to a solution of 100 mg (0.339 mmol) of 2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]pentanoyl chloride and 60.4 mg (0.339 mmol) of 4-morpholin-4-ylaniline in 6 ml of dichloromethane, and the mixture is stirred at room temperature for 18 hours. The reaction mixture is filtered, and the filtrate is evaporated, giving N-(4-morpholin-4-ylphenyl)-2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]pentanoamide as a colourless solid, ESI 437.
Reaction SMILES: [N:1]([C:4]1[N:9]=[CH:8][N:7]=[C:6]([O:10][CH2:11][CH2:12][OH:13])[CH:5]=1)=[N+]=[N-]>[C].[Pd].C(O)C>[NH2:1][C:4]1[N:9]=[CH:8][N:7]=[C:6]([O:10][CH2:11][CH2:12][OH:13])[CH:5]=1
Reactant: [N-]=[N+]=Nc1cc(OCCO)ncn1
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(OCCO)ncn1
Reaction time: 1 h
Yield: 79 %

Procedure:
A mixture of 2-(6-azidopyrimidin-4-yloxy)ethanol (1.64 g), 10% palladium-carbon (0.25 g) and ethanol (20 ml) is subjected to catalytic hydrogenation at room temperature for one hour under hydrogen atmosphere (1 atm). The catalyst is removed by filtration, and the filtrate is concentrated. The residue is recrystallized from ethanol/diethyl ether to give 2-(6-aminopyrimidin-4-yloxy)ethanol (1.11 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([CH:13]([CH3:15])[CH3:14])[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CN([CH:24]=[O:25])C.[Cl-].[NH4+]>C1COCC1>[CH:24]([C:2]1[CH:3]=[C:4]([C:8]2([CH:13]([CH3:15])[CH3:14])[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1)=[O:25]
Reactant: CC(C)C1(c2cccc(Br)c2)OCCO1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C1(c2cccc(C=O)c2)OCCO1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
110 mg of 2-(3-bromophenyl)-2-isopropyl-1,3-dioxolane was dissolved in 1 mL of THF, and cooled to −78° C., and 0.36 mL of n-butyl lithium (1.5 M hexane solution) was added thereto, followed by stirring for 15 minutes. Thereafter, DMF (0.53 mL) was added thereto, followed by stirring at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction liquid, followed by extraction with diethyl ether. The organic layer was then washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 57 mg (yield 61%) of a title compound as a pale yellow oily substance.
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([N:11]2[CH2:32][CH2:31][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-:33].[Na+]>>[OH:33][C:2]1[C:7]([S:8]([N:11]2[CH2:32][CH2:31][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: [OH-]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1Cl)CC2
Agent: [Na+]
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1O)CC2

Procedure:
The title compound was prepared in analogy to example 189 from 8-(2-chloro-pyridine-3-sulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 188) and 6N NaOH. White solid. MS (ESI): 472.2 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37](O)(=[O:39])[CH3:38].CCCCCC>CN(C)C1C=CN=CC=1.ClCCl>[C:37]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])(=[O:39])[CH3:38]
Reactant: CC(=O)O
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(=O)OC(CC=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3 ml of dry dichloromethane. To the resulting solution was added 60 mg (1 mmole) of acetic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. 20 ml of n-hexane was added to the reaction solution. The mixture was filtered to remove the insoluble materials. The filtrate was dried and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (n-hexane: ethylacetate=20:1-5:1) to obtain 247 mg (Yield: 75%) of the title compound having the following structure as a red precipitate.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)[C:11]3[N:16]=[CH:15][S:14][C:12]=3[N:13]=2)[CH2:4]1.[N:28]1[CH:33]=[CH:32][N:31]=[CH:30][C:29]=1[C:34](O)=[O:35].CCN=C=NCCCN(C)C.CN1C=CN=C1>C(Cl)Cl>[CH3:27][O:26][C:20]1[CH:19]=[C:18]([NH:17][C:10]2[C:11]3[N:16]=[CH:15][S:14][C:12]=3[N:13]=[C:8]([N:5]3[CH2:6][CH2:7][CH:3]([NH:2][C:34]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][N:28]=4)=[O:35])[CH2:4]3)[N:9]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: O=C(O)c1cnccn1
Reactant: COc1ccc(Nc2nc(N3CCC(N)C3)nc3scnc23)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COc1ccc(Nc2nc(N3CCC(NC(=O)c4cnccn4)C3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.1 %

Procedure:
A mixture of 5-(3-aminopyrrolidin-1-yl)-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine hydrochloride (40 mg, 0.1 mmol), pyrazine-2-carboxylic acid (14 mg, 0.11 mmol), EDCI (38 mg, 0.2 mmol) and N-methylimidazole (25 mg, 0.3 mmol) in 3 mL of DCM was stirred at room temperature for 15 hours. The mixture was washed with water (5 mL), the organic layer was dried over Na2SO4. After filtration and concentration, the residue was purified by preparative TLC (Silica gel, 20 cm×20 cm, separated by EtOAc, eluted by DCM:MeOH=1:20, v/v) to give N-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-yl)pyrazine-2-carboxamide (35 mg, 73%) as white solid. 1H NMR (300 MHz, DMSO): δ 9.56 (s, 1H), 9.18 (s, 1H), 9.12 (d, 1H, J=7.8 Hz), 8.86 (d, 1H, J=2.4 Hz), 8.80 (s, 1H), 8.71 (s, 1H), 7.85 (s, 1H), 7.50-7.27 (m, 1H), 6.90 (d, 1H, J=8.4 Hz), 4.64-4.62 (m, 1H), 3.75-3.64 (m, 10H), 2.27-2.16 (m, 2H). LC-MS: 479 [M+H]+, 477 [M−H]−, tR=1.39 min. HPLC: 97.06% at 214 nm, 96.92% at 254 nm, tR=4.63 min.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[F:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>[I-].[Na+]>[F:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:2][CH2:3][CH2:4][S:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:22]4[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:21]=4)[NH:16][CH:15]=3)[CH2:10][CH2:9]2)(=[O:7])=[O:6])=[CH:35][CH:34]=1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCOc4ccc(F)cc4)CC3)c[nH]c12
Yield: 38.6 %

Procedure:
Following the general procedure of example 159, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indole-7-carboxamide (40.0 mg, 0.087 mmol), 4-fluorophenol (112 mg, 0.87 mmol), K2CO3 (35.0 mg, 0.35 mmol) and sodium iodide (0.5 mg) were reacted to give the title compound (18.0 mg, 39%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[C:13]3=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=[C:12]3[C:11]2=[O:21])=[C:6]([CH2:22]I)[CH:5]=1)([O-:3])=[O:2].[C:24]([OH:27])(=[O:26])[CH3:25]>C([O-])(=O)C.[Ag+]>[C:24]([O:27][CH2:22][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=1[N:10]1[C:14](=[O:15])[C:13]2=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=[C:12]2[C:11]1=[O:21])(=[O:26])[CH3:25]
Reactant: O=C1c2ccc(Cl)cc2C(=O)N1c1ccc([N+](=O)[O-])cc1CI
Reactant: CC(=O)O
Agent: [Ag+]
Agent: CC(=O)[O-]
Product: CC(=O)OCc1cc([N+](=O)[O-])ccc1N1C(=O)c2ccc(Cl)cc2C1=O

Procedure:
The starting material is prepared as follows: The solution of 1.77 g of N-(4-nitro-2-iodomethylphenyl)-4-chlorophthalimide and 1.0 g of silver acetate in 32 ml of acetic acid is refluxed for one hour with protection from light. It is filtered, the filtrate evaporated and the residue recrystallized from ethyl acetate-diethyl ether, to yield the N-(2-acetoxymethyl-4-nitrophenyl)-4-chlorophthalimide melting at 124°-125°.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C([O-])([O-])=O.[K+].[K+].CN(C)C=O.[SH:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1OCCOCCOCCOCCOCCOC1.O>[CH2:8]([C:7]1[C:3]2[S:4][CH:5]=[CH:6][C:2]=2[S:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCOC(=O)CS
Reactant: CCCCCC(=O)Cc1sccc1Br
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCc1c(C(=O)OCC)sc2ccsc12
Reaction time: 8 h
Yield: 83.3 %

Procedure:
Compound 59 (35.4 g, 0.13 mol) and K2CO3 (27.6 g, 0.2 mol) were mixed with N,N-dimethylformamide (100 mL). A catalytic amount (˜25 mg) 18-crown-6 was added, and to this mixture, ethyl 2-mercaptoacetate (14.0 mL, 0.13 mol) was added dropwise at 60° C. The mixture was stirred overnight and poured into water (500 mL). The organic component was extracted with ethyl acetate (3×80 mL). The combined organic layers were washed with brine (2×100 mL) and water (100 mL). Organic layer was then dried over MgSO4. After evaporation of the solvent, the crude compound 61 was obtained and purified by column chromatography (SiO2/5% ethyl acetate in hexanes) to yield pure compound 61 (32.1 g, 84.5%). GC/MS: 296 g/mol (M). 1H NMR (CD2Cl2) δ 7.56 (d, 1H), 7.24 (d, 1H), 4.34 (q, 2H), 3.15 (t, 2H), 1.71 (m, 2H), 1.32 (m, 6H), 0.88 (m, 6H), 13C NMR: 163.24, 143.31, 141.85, 141.09, 131.13, 128.44, 120.35, 61.25, 31.99, 29.72 (overlap), 22.98, 14.52, 14.23.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[N:43][N:44]([CH2:46][CH2:47]OS(C)(=O)=O)[CH:45]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[N:43][N:44]([CH2:46][CH2:47][N:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)[CH:45]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cnn(CCOS(C)(=O)=O)c4)c4ccccc43)cn12
Solvent: C1CCOC1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cnn(CCN5CCOCC5)c4)c4ccccc43)cn12
Temperature: 50 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
To a solution of Intermediate 187c (0.19 mmol) in THF (3 mL) was added morpholine (166 μL, 1.9 mmol) and the reaction stirred at 50° C. overnight. The crude reaction mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 2.5-10% (2M NH3 in MeOH) in DCM followed by MDAP (Method 7) purification, to give the title compound (49 mg, 35%). LCMS (Method 5): Rt 3.53 min, m/z 722 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.87 (3H, d, J=6.4 Hz), 1.20 (9H, s), 1.43-1.51 (2H, m), 1.58-1.69 (2H, m), 1.70-1.88 (3H, m), 1.88-1.96 (1H, m), 1.96-2.12 (2H, m), 2.37 (4H, t, J=4.5 Hz), 2.69 (2H, t, J=6.5 Hz), 2.87 (1H, ddd, J=12.6, 9.1, 3.9 Hz), 3.12 (1H, dt, J=12.1, 4.2 Hz), 1H UNDER SOLVENT, 3.50 (4H, t, J=4.6 Hz), 4.20 (2H, t, J=6.5 Hz), 4.80 (1H, td, J=8.5, 5.8 Hz), 5.48 (1H, t, J=4.3 Hz), 6.22 (1H, s), 7.11 (1H, d, J=8.5 Hz), 7.15 (1H, dd, J=9.9, 2.2 Hz), 7.21-7.26 (1H, m), 7.28-7.35 (3H, m), 7.60 (1H, d, J=9.8 Hz), 7.60 (1H, s), 7.66 (1H, d, J=2.1 Hz), 7.96 (1H, s), 8.02 (1H, s), 8.12 (0.5H, s).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=1.[CH:21](=[O:23])[CH3:22]>C1COCC1>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[C:19]=1[CH:21]([OH:23])[CH3:22]
Reactant: Fc1cncc(Br)c1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(O)c1c(F)cncc1Br
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
n-BuLi (1.6M in hexanes) (19.60 ml, 31.4 mmol) was added dropwise to a solution of diisopropylamine (4.84 ml, 34.0 mmol) in THF (87 ml) at −78° C. under N2. The resulting mixture was warmed up to −40° C. and stirred for 10 min and recoiled to −78° C. 3-bromo-5-fluoropyridine (4.6 g, 26.1 mmol) in 5 mL THF was added dropwise at this temperature. After 30 min, acetaldehyde (2.95 ml, 52.3 mmol) was added dropwise and the resulting mixture was stirred for 30 min at −78° C., and then for another 30 min at 0° C. The mixture was quenched with saturated NH4Cl solution and extracted with EtOAc two times, dried over magnesium sulfate, filtered, concentrated. The residue was purified via Biotage (SNAP50, 0-30% AcOEt/heptane, v/v) giving the title compound 4a (2.869 g, 50%) as yellow oil. LC-MS (M+1) 221.9, t=1.01 min.
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:34])[CH:12]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)[CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[N:6][CH:5]=1.[OH-].[Na+]>CO.O>[CH3:29][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:35])=[O:2])=[CH:5][N:6]=2)=[O:34])=[CH:21][C:22]=1[C:30]([F:31])([F:33])[F:32])(=[O:28])=[O:27]
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCCO2)c2ccc(S(C)(=O)=O)c(C(F)(F)F)c2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCCCO2)C(=O)Nc2ccc(C(=O)O)cn2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
A solution of 6-[2-(4-methylsulfonyl-3-trifluoromethyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionylamino]-nicotinic acid methyl ester (prepared as in Example 15, 21 mg, 0.04 mmol) in methanol (0.40 mL) was treated with a 1N aqueous sodium hydroxide solution (0.20 mL, 0.20 mmol). The reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was then diluted with water and concentrated in vacuo to remove methanol. The resulting aqueous residue was acidified to pH=2 with a 1N aqueous hydrochloric acid solution and then extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford pure 6-[2-(4-methylsulfonyl-3-trifluoromethyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionylamino]-nicotinic acid (15 mg, 75%) as a colorless gum: EI-HRMS m/e calcd for C22H23F3O6S (M+H)+ 501.1302. found 501.1305.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](=[S:8])[NH2:7].Br[CH2:17][C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)C>[CH3:15][O:14][C:10]1[CH:9]=[C:5]([C:6]2[S:8][CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:7]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:11]=1[O:12][CH3:13]
Reactant: COc1cc(C(N)=S)cc(OC)c1OC
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(-c2cc(OC)c(OC)c(OC)c2)n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
3,4,5-Trimethoxybenzothioamide (2.5 g) and 90% ethyl bromopyruvate (2.62 g) were added to ethanol (20 mL), and the mixture was stirred at 80° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was then purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) and further recrystallized from ethyl acetate-hexane to obtain the title compound.
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][C:17]1[N:21]([C@@H:22]2[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[C@@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:23]2[O:24][C:25](=[O:27])[CH3:26])[CH:20]=[N:19][C:18]=1[C:40]([OH:42])=[O:41]>C(Cl)Cl>[C:1]1([CH:7]([O:42][C:40]([C:18]2[N:19]=[CH:20][N:21]([C@@H:22]3[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[C@@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:23]3[O:24][C:25](=[O:27])[CH3:26])[C:17]=2[NH2:16])=[O:41])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)O)c2N)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)OC(c3ccccc3)c3ccccc3)c2N)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
Diphenyldiazomethane (2.0 g, 10.3 mmol) was added to the suspension of 5-amino-1-(2,3,5-tris-O-acetyl-β-D-ribofuranosyl)-1H-imidazole-4-carboxylic acid (3.86 g, 10 mmol) in CH2Cl2 (50 mL). The mixture was stirred at room temperature for 16 h, by which time all the reactants had dissolved. The reaction mixture was poured onto the top of a column of silica gel (100 g, packed in CH2Cl2, collected 100-mL fractions), and the column was washed with 5% EtOAc in CH2Cl2 (300 mL), then the product was eluted with 40% EtOAc in CH2Cl2. Fractions 5 to 10 were combined and concentrated, then pumped under high vacuum overnight to give 5-amino-1-(2,3,5-tris-O-acetyl-β-D-ribofuranosyl)-1H-imidazole-4-carboxylic acid diphenylmethyl ester as a pale yellow foam: 4.86 g (88% yield); IR (CHCl3) 3445, 3345, 1752, and 1678 cm-1 ; HRMS (EI) m/z found 551.1870 [calcd for C28H29N3O9, 551.1904 (M+)]; NMR (CDCl3) δ2.13 (s, 9), 4.32 (d of d, 1,J=12 and 3 Hz), 4.40 (m, 1), 4.47 (d of d, 1,J=12 and 3 Hz), 5.30 (m, 1), 5.45 (t, 1, J=5 Hz), 5.48 (s, 2), 5.67 (d, 1, J=5 Hz), 7.08 (s, 1), 7.25 (m, 3), 7.32 (t, 4,J=7 Hz), UV max (CH3OH) 267 nm (ε12510).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][C:11]=2[F:24])[C:5]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:4][C:3]=1[CH3:29].[O:30]1[C:34]2[CH:35]=[CH:36][C:37](B(O)O)=[CH:38][C:33]=2[CH2:32][CH2:31]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:25]([C:5]1[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][C:11]=2[F:24])[C:7](=[O:8])[C:2]([C:37]2[CH:36]=[CH:35][C:34]3[O:30][CH2:31][CH2:32][C:33]=3[CH:38]=2)=[C:3]([CH3:29])[N:4]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Reactant: OB(O)c1ccc2c(c1)CCO2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCCc1nc(C)c(-c2ccc3c(c2)CCO3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Temperature: 90 °C
Reaction time: 12 h
Yield: 79.2 %

Procedure:
To a solution of 4′-[(5-bromo-2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile (0.5 g) and 2,3-dihydro-1-benzofuran-5-ylboronic acid (0.27 g) in 1,4-dioxane (10 mL) were added 2 M aqueous cesium carbonate solution (2 mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.05 g), and the mixture was stirred at 90° C. for 12 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was washed successively with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.43 g, 79%) as a colorless solid.