Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-])=O)[C:3]=1[N+:13]([O-])=O>C1COCC1.[Ni]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([NH2:10])[C:3]=1[NH2:13]
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: COc1ccc(Br)c(N)c1N
Yield: 99.3 %

Procedure:
A solution of 1.12 g (4.04 mmol) 1-bromo-4-methoxy-2,3-dinitro-benzene in 25 ml THF is hydrogenated in the presence of 100 mg Raney-Nickel (B113W Degussa) at normal pressure for 3 h. The catalyst is filtered off and the filtrate is concentrated in vacuo to afford 871 mg of the title compound as a grey crystalline solid.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([CH3:6])[CH2:4][OH:5].[Cl:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3F)[N:18]=[CH:17][N:16]=2)[CH:11]=[CH:10][C:9]=1[OH:26]>>[Cl:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[O:5][CH2:4][C@H:3]([NH:2][CH3:1])[CH3:6])[N:18]=[CH:17][N:16]=2)[CH:11]=[CH:10][C:9]=1[OH:26]
Reactant: CN[C@H](C)CO
Reactant: Oc1ccc(Nc2ncnc3cccc(F)c23)cc1Cl
Product: CN[C@H](C)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Yield: 100 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using (2R)-2-(methylamino)propan-1-ol (obtained as described in Becker et al., J. Chem. Soc. 1957, 858) and 2-chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenol (obtained as described in Example 4.5, preparation of starting materials) to give 2-chloro-4-[(5-{[(2R)-2-(methylamino)propyl]oxy}quinazolin-4-yl)amino]phenol in >100% yield; NMR spectrum (DMSO-d6) 1.20 (d, 3H), 2.40 (s, 3H), 3.30 (m, 1H), 4.25 (dd, 1H), 4.35 (dd, 1H), 7.00 (d, 1H), 7.10 (d, 1H), 7.30 (d, 1H), 7.60 (dd, 1H), 7.70 (t, 1H), 7.90 (d, 1H), 8.50 (s, 1H); Mass spectrum MH+ 359.1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][NH:6][C:7](=[O:13])[N:8]([CH:10]([CH3:12])[CH3:11])[CH3:9].Cl[C:19]([O:21][CH3:22])=[O:20].O>O1CCCC1.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][N:6]([C:19]([O:21][CH3:22])=[O:20])[C:7](=[O:13])[N:8]([CH:10]([CH3:12])[CH3:11])[CH3:9]
Reactant: CC(C)N(C)C(=O)NOc1cc(Cl)cc(Cl)c1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N(Oc1cc(Cl)cc(Cl)c1)C(=O)N(C)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.8 %

Procedure:
In a mixed solvent of 20 ml of tetrahydrofuran and 1.9 ml of pyridine was dissolved 2.15 g (7.76 mmoles) of 3-(3,5-dichlorophenoxy)-1-isopropyl-1-methylurea, and then 10 ml of a tetrahydrofuran solution of 1.47 g (15.5 mmoles) of methyl chloroformate was added. The mixture was stirred at 25° C. for 2 hours. Water (100 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The ethyl acetate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate/hexane) to give 1.14 g (yield 44 %) of the desired compound as the yellow crystals
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[C:6]([NH:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH2:19])[CH:16]=2)[CH2:11]1)(=[O:8])[CH3:7]>OS(O)(=O)=O>[C:6]([NH:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][C:14]([N+:1]([O-:4])=[O:2])=[C:15]([NH2:19])[CH:16]=2)[CH2:11]1)(=[O:8])[CH3:7]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)NC1Cc2ccc(N)cc2C1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)NC1Cc2cc(N)c([N+](=O)[O-])cc2C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
1.62 g of KNO3 is introduced in portions into 2.85 g (15 mmol) of 2-acetylamino-5-aminoindan in 7.5 ml of concentrated H2SO4 that has been cooled to 0° C. The whole is stirred for 3 hours at 0° C. and then poured into ice-cold 6N sodium hydroxide solution, stirred, extracted with methylene chloride and then washed, dried and evaporated. 2.8 g of a black solid are isolated, which is purified on silica (eluant:methylene chloride/methanol: 97/3). In that manner, 1.46 g of the expected product are isolated. Yield: 42%.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:23]=[CH:22][C:8]([O:9][CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:11]([O:13][CH3:14])=[O:12])=[CH:22][CH:23]=1
Reactant: COC(=O)C(Oc1ccc(CN=[N+]=[N-])cc1)c1ccccc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(Oc1ccc(CN)cc1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the product of Step E in dry tetrahydrofuran is treated protionwise with triphenylphosphine (1 equivalent). The solution is stirred under N2 at ambient temperature. After about 2 hours, when gas evolution has ceased, H2O (1 equivalent) is added, and the solution is concentrated in vacuo, and the residue is chromatographed on silica gel to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].[C:19]1([C:25]2[S:26][CH:27]=[C:28]([CH2:30][CH2:31][CH2:32]O)[N:29]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:32][CH2:31][CH2:30][C:28]2[N:29]=[C:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:26][CH:27]=2)=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c(F)c1)OCC
Reactant: OCCCc1csc(-c2ccccc2)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCCc2csc(-c3ccccc3)n2)c(F)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (example 7 a]) was reacted with 3-(2-phenyl-thiazol-4-yl)-propan-1-ol in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-{3-fluoro-4-[3-(2-phenyl-thiazol-4-yl)-propoxy]-phenyl}-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-2-ethoxy-3-{3-fluoro-4-[3-(2-phenyl-thiazol-4-yl)-propoxy]-phenyl}-propionic acid as a colorless gum.
Reaction SMILES: O[CH2:2][C:3]1[C:16]2[O:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([OH:17])[CH:13]=3)[C:8]3([C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19](=[O:26])[O:18]3)[C:7]=2[CH:6]=[CH:5][C:4]=1[OH:27].[F:28][C:29]([F:52])([F:51])[C:30]([NH:32][C@@H:33]([CH3:50])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)(=[O:43])=[O:42])=[CH:37][CH:36]=1)=[O:31].[I-].[Na+].N1C(C)=CC=CC=1C>CN(C)C=O>[OH:27][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3([C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19](=[O:26])[O:18]3)[C:9]3[C:14]([O:15][C:16]=2[C:3]=1[CH2:2][N:47]1[CH2:48][CH2:49][N:44]([S:41]([C:38]2[CH:37]=[CH:36][C:35]([CH2:34][C@@H:33]([NH:32][C:30](=[O:31])[C:29]([F:52])([F:51])[F:28])[CH3:50])=[CH:40][CH:39]=2)(=[O:42])=[O:43])[CH2:45][CH2:46]1)=[CH:13][C:12]([OH:17])=[CH:11][CH:10]=3
Reactant: C[C@@H](Cc1ccc(S(=O)(=O)N2CCNCC2)cc1)NC(=O)C(F)(F)F
Reactant: O=C1OC2(c3ccc(O)cc3Oc3c2ccc(O)c3CO)c2ccccc21
Agent: [I-]
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: C[C@@H](Cc1ccc(S(=O)(=O)N2CCN(Cc3c(O)ccc4c3Oc3cc(O)ccc3C43OC(=O)c4ccccc43)CC2)cc1)NC(=O)C(F)(F)F
Temperature: 120 °C
Yield: 35 %

Procedure:
A mixture of 61 mg (0.160 mmol) of rac-4'-(hydroxymethyl)-3',6'-dihydroxyspiro[isobenzofuran-1(3H), 9'-[9H]xanthen]-3-one (2), 125 mg (0.33 mmole) of (S)-2,2,2-trifluoro-N-[1-methyl-2-[4-(1-piperazinylsulfonyl)phenyl]ethyl]acetamide (17), 150 mg (1.0 mmol) of sodium iodide and 600 μL (5.15 mmol) of 2,6 lutidine in 4.5 mL of anhydrous dimethylformamide was heated at 120° C. for 2 hours. The reaction mixture was concentrated and 20 mL of a 1:1 mixture of methanol:THF was added. Inorganic salt was filtered off and the filtrate was concentrated. The residue was purified by thin layer chromatography using 50% chloroform in ethyl acetate to yield 41 mg of (S)-N-[2-[4-[[4-[(3',6'-dihydroxy-3-oxospiro[isobenzo-furan-1(3H),9'-[9H]xanthen]-4'-yl)methyl]-1-piperazinyl]-sulfonyl]phenyl]-1-methylethyl]-2,2,2-trifluoroacetamide (1:1 epimers) (18) (0.056 mmol, 35%) as an orange red powder. NMR, IR and MS data confirmed the compound identity.
Reaction SMILES: [CH3:1][C:2]1[NH:3][NH:4][C:5](=[O:7])[CH:6]=1.[Mg].Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.Cl>C1COCC1.CCOCC>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[CH:14]=[CH:15][C:10]([C:2]3([CH3:1])[CH2:6][C:5](=[O:7])[NH:4][NH:3]3)=[CH:11][CH:12]=2)=[CH:17][CH:18]=1
Reactant: Fc1ccc(-c2ccc(Br)cc2)cc1
Reactant: Cc1cc(=O)[nH][nH]1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(c2ccc(-c3ccc(F)cc3)cc2)CC(=O)NN1

Procedure:
A solution of 9.8 g of 3-methyl-pyrazolin-5-one in 100 ml of THF is added dropwise with stirring and cooling, to a Grignard solution prepared from 4.8 g of magnesium and 20.3 g of 4-bromo-4'-fluoro-biphenyl in 800 ml of absolute ether. After stirring for 2 hours at 10°-25°, the mixture is decomposed with ice and dilute hydrochloric acid and worked up in the usual manner to give 3-(4'-fluoro-4-biphenylyl)-3-methyl-pyrazolidin-5-one, m.p. 194°-196°.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].[OH-].[Na+].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:64])(=O)=O)=CC=1.C(Cl)Cl>C(O)(=O)C.O>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@:9]([F:64])([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@](C)(F)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Reaction time: 2 h
Yield: 95.8 %

Procedure:
Erythromycin A (5 g, 6.813 mmole) was dissolved in glacial acetic acid (20 mL) at room temperature and stirred for 2 hours. The pH of the mixture was adjusted to 4.3 with 6N sodium hydroxide (approx. 12.5 mL) while the temperature was maintained below 20° C. N-fluorobenzenesulfonimide (2.2 g, 6.813 mmole) was added and stirring continued for an additional 18 hours at 22° C. Methylene chloride (100 mL) was added, the solution was placed in an ice bath while the pH of the mixture was adjusted to 9 with 6N sodium hydroxide (approx. 85 mL) and the temperature was maintained below 20° C. Next, water (100 mL) was added, the layers separated and the aqueous layer washed an additional two times with methylene chloride (100 mL each). The methylene chloride serves as an extractant for the flurithromycin product. The combined organic phases were washed 2 to 4 times with 5 percent sodium hydroxide (100 mL each) and dried over magnesium sulfate. After filtration, the organic phase was concentrated under vacuum at room temperature to afford 4.91 g of crude flurithromycin. The crude material was dissolved in ethanol concentrated to 20 mL. This process was repeated two more times. After standing at 0° C. for one night, the product was filtered under vacuum, washed with 5 mL cold ethanol and dried under vacuum at 40° C. to afford 3.48 g (68% yield) of flurithromycin ((8S)-8-fluoroerythromycin).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:14][CH2:13][CH2:12][N:11]2C(OC(C)(C)C)=O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[ClH:22].O1CCOCC1>>[ClH:22].[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([CH:10]2[CH2:14][CH2:13][CH2:12][NH:11]2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(C2CCCN2C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)N1CCC(C2CCCN2)CC1
Yield: 100 %

Procedure:
A solution of tert-butyl 2-(1-isopropylpiperidin-4-yl)pyrrolidine-1-carboxylate (302 mg, 1.02 mmol) in 4N HCl/dioxane (5 mL) was stirred at room temperature for 8 h. Removal of the solvent gave the desired product (232 mg, 100% yield) as a yellow solid. LCMS m/z [M+H]+ 197.2
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[N-:26]=[C:27]=[O:28]>>[F:25][C:3]([F:2])([F:24])[C:4]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:27]([NH:26][CH:4]([CH2:5][CH3:6])[CH3:3])=[O:28])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: Fc1ccc(C(OC2CNC2)c2ccc(Cl)cc2)c(C(F)(F)F)c1
Reactant: [N-]=C=O
Agent: Cl
Product: CCC(C)NC(=O)N1CC(OC(c2ccc(Cl)cc2)c2ccc(F)cc2C(F)(F)F)C1

Procedure:
This material was prepared 3-[2-(trifluoromethyl)-4-fluoro-4′-chlorobenzhydryloxy]azetidine hydrochloride (125) and the corresponding isocyanate using the procedure described for compound (10).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11]C(=O)C)[O:8][C@@H:7]([N:15]2[C:19]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[C:18]([C:25](=[O:30])[CH2:26][N:27]=[N+:28]=[N-:29])[N:17]=[CH:16]2)[C@@H:6]1[F:31])(=O)C.C[O-].[Na+].C(C(O)(C([O-])=O)CC([O-])=O)C([O-])=O.C(C(O)(C([O-])=O)CC([O-])=O)C([O-])=O.O.[Na+].[Na+].[Na+].[K+].[K+].[K+]>CO>[N:27]([CH2:26][C:25]([C:18]1[N:17]=[CH:16][N:15]([C@@H:7]2[O:8][C@H:9]([CH2:10][OH:11])[C@@H:5]([OH:4])[C@H:6]2[F:31])[C:19]=1[N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[O:30])=[N+:28]=[N-:29]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)CN=[N+]=[N-])c2N=CN(C)C)[C@H](F)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CN(C)C=Nc1c(C(=O)CN=[N+]=[N-])ncn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1F
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
The compound (22) (130 mg) obtained in item (11) above was dissolved in methanol (6 ml), to which was added a 0.2M sodium methylate solution (0.5 ml) in methanol and the resulting mixture was allowed to stand at room temperature for 30 minutes. The reaction solution as formed was neutralized with addition of ion-exchange resin, Amberlite CG-120 (H+ form) (100-200 mesh), filtered and the filtrate was concentrated to give a solid material which was then washed with diethylether to afford the titled compound (23) (63 mg) as an insoluble substance. Yield: 60%.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH:9]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH:10]2[CH:21]=1)(=O)=O.C([O-])(=O)C.[K+].Cl[C:30]1[N:35]=[C:34]2[N:36]([CH3:47])[S:37](=[O:46])(=[O:45])[N:38]([CH2:39][CH:40]3[CH2:42][C:41]3([F:44])[F:43])[C:33]2=[CH:32][CH:31]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCOCC1>[F:44][C:41]1([F:43])[CH2:42][CH:40]1[CH2:39][N:38]1[C:33]2[C:34](=[N:35][C:30]([C:7]3[CH2:8][CH:9]4[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:11][CH:10]4[CH:21]=3)=[CH:31][CH:32]=2)[N:36]([CH3:47])[S:37]1(=[O:45])=[O:46]
Reactant: CC(C)(C)OC(=O)N1CC2C=C(OS(=O)(=O)C(F)(F)F)CC2C1
Reactant: CN1c2nc(Cl)ccc2N(CC2CC2(F)F)S1(=O)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd+2]
Solvent: C1COCCO1
Solvent: O
Product: CN1c2nc(C3=CC4CN(C(=O)OC(C)(C)C)CC4C3)ccc2N(CC2CC2(F)F)S1(=O)=O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
tert-Butyl 5-{[(Trifluoromethyl)sulfonyl]oxy}-3,3a,4,6a-tetrahydrocyclo-penta[c]pyrrole-2(1H)-carboxylate (8-2, 1.3 g, 3.64 mmol, 1.0 equiv), bis(pinocolato)diboron (1.0 g, 4.0 mmol, 1.1 equiv), potassium acetate (1.1 g, 10.91 mmol, 3.0 equiv) and PdCl2(dppf) (0.19 g, 0.26 mmol, 0.07 equiv) were added to anhydrous 1,4-dioxane (4.6 mL) and heated to 60° C. After 18 h, the reaction contents were cooled to RT, followed by the subsequent addition of water (0.93 mL), 5-chloro-1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-1,3-dihydro[1,2,5]-thiadiazole[3,4-b]pyridine 2,2-dioxide (23-2, 1.1 g, 3.64 mmol, 1.0 equiv), K3PO4 (1.9 g, 9.09 mmol, 2.5 equiv), (S)-Phos (0.15 g, 0.36 mmol, 0.10 equiv) and palladium(II) acetate (4.1 mg, 0.18 mmol, 0.05 equiv). The resulting mixture was heated to 70° C. for 9 h. Following this duration, LCMS showed consumption of starting material. The contents were then cooled to room temperature, diluted with ethyl acetate (20 mL), filtered through Celite and rinsed with ethyl acetate (3×5 mL) and water (1×5 mL). The filtrate layers were separated and the combined organics were washed with saturated NaHCO3 (10 mL). The combined aqueous layers were then back-extracted with ethyl acetate (3×5 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give a dark orange oil. Purification by normal-phase chromatography (0-50% EtOAc:Hex) afforded 24-1 as a tan solid. MS m/z (M+H): calculated=482.5; observed=482.1.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1)(=O)=O.C([Li])CCC.[CH2:38]([OH:43])[CH2:39][CH2:40][CH2:41][CH3:42]>>[CH2:38]([O:43][C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1)[CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCO
Reactant: CS(=O)(=O)c1nc(Oc2cccnc2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: [Li]CCCC
Product: CCCCCOc1nc(Oc2cccnc2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
2-Methylsulfonyl-4-(3-pyridyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine from Example 86 (30 mg, 0.06 mmol) was reacted with 2 equivalents each of n-butyl lithium and n-pentanol by the procedure described in Reference Examples 6 and 7 to afford the title compound: HPLC/MS: m/e=514 (M++1); Rt'4.48 min. 1H-NMR 400 MHz (CDCl3): δ 0.89-0.91 (t, 3H), 1.26-1.40 (m, 4H), 1.69-1.76 (m, 2H), 4.19-4.22 (t, 2H), 7.15-7.28 (m, 6H), 7.35 (d, J=2 Hz, 1H), 7.40-7.43 (m, 1H), 7.58-7.61 (m, 1H), 8.52-8.55 (m, 2H).
Reaction SMILES: [N:1]1([CH2:6][C@H:7]2[NH:11][CH2:10][C@H:9]([NH:12][C:13]([C:15]3[S:16][C:17]([Cl:20])=[CH:18][CH:19]=3)=[O:14])[CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.BrC([C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]2=[O:38])=[CH:28][C:27]=1[F:39])C(N)=O>>[F:39][C:27]1[CH:28]=[C:29]([N:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]2=[O:38])[CH:30]=[CH:31][C:26]=1[NH:12][C:13]([CH2:15][N:11]1[C@H:7]([CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:8][C@@H:9]([NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[CH2:10]1)=[O:14]
Reactant: NC(=O)C(Br)c1ccc(-n2ccccc2=O)cc1F
Reactant: O=C(N[C@H]1CN[C@H](CN2CCCC2)C1)c1ccc(Cl)s1
Product: O=C(CN1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1CN1CCCC1)Nc1ccc(-n2ccccc2=O)cc1F

Procedure:
17.5 Using general procedure A 5-chloro-thiophene-2-carboxylic acid ((3R,5S)-5-pyrrolidin-1-ylmethyl-pyrrolidin-3-yl)-amide was reacted with 2-bromo-[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenyl]-acetamide (example 11.3) to give 5-chloro-thiophene-2-carboxylic acid ((3R,5S)-1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-5-pyrrolidin-1-ylmethyl-pyrrolidin-3-yl)-amide. Light yellow solid. MS 558.2 ([M+H]+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:20]([F:23])([F:22])[F:21])=[N:15][C:16]([C:17](O)=[O:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.[N:31]1(OC(N(C)C)=[N+](C)C)[C:35]2[CH:36]=[CH:37][CH:38]=CC=2N=N1.C1(CN)CC1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:36]1([CH2:35][NH:31][C:17]([C:16]2[N:15]=[C:14]([C:20]([F:22])([F:23])[F:21])[N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][C:10]=23)=[O:18])[CH2:38][CH2:37]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1
Agent: F[P-](F)(F)(F)(F)F
Agent: NCC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)NCC3CC3)c2C1
Reaction time: 12 h
Yield: 77.2 %

Procedure:
7-Tert-butoxycarbonyl-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxylic acid 20a (330 mg, 1 mmol) was dissolved in 5 mL of N, N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (756 mg, 2 mmol), cyclopropylmethylamine (142 mg, 2 mmol) and N,N-diisopropylethylamine (0.5 mL, 3 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and added with 50 mL of ethyl acetate and washed successively with saturated ammonium chloride (15 mL×3) and saturated sodium chloride solution (10 mL). The organic phase was collected, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain crude tert-butyl 1-(cyclopropylmethylc arb amoyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate 24a (300 mg) as a brown-red oil. The product was used directly in the next reaction without purification.
Reaction SMILES: [C:1]1([C:6]([NH:8][CH2:9][C:10]([O-:12])=O)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[Na+].[CH2:14](O)C.O.Cl>N1C=CC=C(C)C=1.C(OC(=O)C)(=O)C>[C:1]1([C:6]([NH:8][CH2:9][C:10](=[O:12])[CH3:14])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: O=C([O-])CNC(=O)c1cccs1
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: Cc1cccnc1
Product: CC(=O)CNC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 44.0 ml of a suspension of 16.70 g of sodium 2-(2-thenoylamino)acetate in β-picoline, 42.7 ml of acetic anhydride was added, and stirred for 3 hours at room temperature. After ice-cooling, 26.3 ml of ethanol, 129.7 ml of water and 45.2 ml of conc. hydrochloric acid were slowly added dropwise in sequence, and the mixture was stirred for 15 minutes as it is. After removal of ice-bath, the mixture was stirred for another 15 minutes at room temperature. Water (250 ml) was added and the precipitated crystals were collected, and washed with water. To the crystals was added 37.0 ml of water, and the mixture was heated to reflux for 1 hour. After 14.0 g of sodium chloride was added, the mixture was heated to reflux for another 1 hour. The reaction solution was extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. After addition of activated carbon (Kyoryoku-sirasagi® MOIWY433), the mixture was stirred for 30 minutes at room temperature. The solvent was distilled off under reduced pressure. The residue was crystallized by addition of t-butyl methyl ether to provide 7.15 g of the objective compound as pale brown crystals.