Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[CH3:19][N:20]1[CH:24]=[C:23]([S:25](Cl)(=[O:27])=[O:26])[N:22]=[CH:21]1>N1C=CC=CC=1>[CH3:19][N:20]1[CH:24]=[C:23]([S:25]([NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])(=[O:27])=[O:26])[N:22]=[CH:21]1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1cn(C)cn1
Reaction time: 96 h
Yield: 79.4 %

Procedure:
Pyridine (25 mL) was added to a mixture of 3-amino-4-methoxy-N-phenyl-benzamide (2.43 g, 10 mmol) and 1-methylimidazole-4-sulfonyl chloride (1.82 g, 10 mmol) and the mixture agitated then allowed to stand at room temperature. After 4 days, the mixture was partitioned between ethyl acetate (400 mL) and water (400 mL). The insoluble material was collected by filtration, washed with water, and air dried. The organic extract was washed with water (2×400 mL), 1N HCl (100 mL), and brine (100 mL), then dried over magnesium sulfate, filtered, and stripped of solvent. The residue was combined with the solid obtained above to afford the product (3.07 g); m.p. 250-252° C., after trituration in hexanes/ethyl acetate (1:1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:20]1(/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22][CH:21]=1.C1C=CC2C(=NO[N+]=2[O-])C=1.C(OCC)(=O)C>CO.C(#N)C>[CH:14]1([N:13]2[C:12]3[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=3[N:1]=[C:26]2[C:23]2[CH:24]=[CH:25][C:20](/[CH:28]=[CH:29]/[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:21][CH:22]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=Cc1ccc(/C=C/c2ccccc2)cc1
Reactant: CCOC(=O)c1ccc(NC2CCCCC2)c(N)c1
Agent: [O-][n+]1onc2ccccc21
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(/C=C/c3ccccc3)cc1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
Ethyl 3-amino-4-cyclohexylaminobenzoate (500 mg) obtained in Example 1, Step 3, was dissolved in methyl alcohol (6 ml) and trans-4-stilbenecarbaldehyde (397 mg) was added under ice-cooling. The mixture was stirred overnight at room temperature. The reaction mixture was ice-cooled and benzofuroxan (259 mg) dissolved in acetonitrile (2 ml) was added. The mixture was stirred for 7 hr at 50° C., The reaction mixture was ice-cooled. After 1N sodium-hydroxide was added, ethyl acetate was added and the mixture was extracted. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (developing solvent, n-hexane:ethyl acetate=4:1) to give the title compound (540 mg, yield 63%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[CH:5]2.[OH-].[K+].Br[CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20].Cl>CS(C)=O.O.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[N:6]=[CH:5]2
Reactant: CCOC(=O)CCCBr
Reactant: O=c1[nH]ncc2cc(Br)ccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: CCO
Product: O=C(O)CCCn1ncc2cc(Br)ccc2c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a slurry of 56 gm 6-bromophthalazin-1(2H)-one (0.25 mole) in 600 ml DMSO was added 110 ml 45% KOH followed by 58.5 gm ethyl 4-bromobutyrate. The temperature of the mildly exothermic reaction was moderated with a water bath (ca. 25° C.) and was stirred for 20 hours. Ethanol (750 ml) was added, then the mixture was acidified with 125 ml concentrated HCl, diluted with 2500 ml water over about 30 minutes, stirred an additional 30 minutes, filtered, washed with water and isopropanol and dried. The product weighed 63.6 gm. A tlc of the product showed product, Rf =0.43 plus a trace of starting material, Rf =0.63.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:55])[NH:4][C@@H:5]([CH:52]([CH3:54])[CH3:53])[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:17][C:16]2[C:18]3[C:23]([CH:24]=[CH:25][C:15]=2[N:14]=1)=[CH:22][C:21]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([NH:44]C(OC(C)(C)C)=O)[C:32]=2[NH:36]C(OC(C)(C)C)=O)[CH:27]=1)=[CH:20][CH:19]=3)=[O:7].[C:56]([OH:62])([C:58]([F:61])([F:60])[F:59])=[O:57]>ClCCl>[NH2:36][C:32]1[C:31]([NH2:44])=[CH:30][CH:29]=[C:28]2[C:33]=1[CH:34]=[CH:35][C:26]([C:21]1[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=1)[C:16]1[NH:17][C:13]([C@@H:9]4[CH2:10][CH2:11][CH2:12][N:8]4[C:6](=[O:7])[C@@H:5]([NH:4][C:3](=[O:55])[O:2][CH3:1])[CH:52]([CH3:54])[CH3:53])=[N:14][C:15]=1[CH:25]=[CH:24]3)=[CH:27]2.[C:56]([OH:62])([C:58]([F:61])([F:60])[F:59])=[O:57]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5c(NC(=O)OC(C)(C)C)c(NC(=O)OC(C)(C)C)ccc5c4)ccc3c2[nH]1)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5c(N)c(N)ccc5c4)ccc3c2[nH]1)C(C)C
Reaction time: 2 h

Procedure:
To (S)-1-((S)-2-(7-(5,6-bis(tert-butoxycarbonylamino)naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester (165 mg, 0.22 mmol) in dichloromethane (2.2 mL) was added TFA (0.5 mL) and the reaction mixture stirred for 2 hours. The solvent was removed under reduced pressure to provide title compound as TFA salts.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:13][S:14]([C:17]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=2[CH3:26])(=[O:16])=[O:15])[CH:5]=[C:6]([CH:12]=1)[O:7][CH2:8][CH2:9][CH2:10][OH:11].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([O:13][S:14]([C:17]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=2[CH3:26])(=[O:16])=[O:15])[CH:5]=[C:6]([CH:12]=1)[O:7][CH2:8][CH2:9][CH:10]=[O:11]
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cc([N+](=O)[O-])ccc2C)c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2cc([N+](=O)[O-])ccc2C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
Sulfur trioxide pyridine complex (960 mg, 6.0 mmol) was added to a solution of 3-[5-methyl-3-(2-methyl-5-nitrophenylsulfonyloxy)phenoxy]propanol (760 mg, 2.0 mmol), as prepared in the preceding step, N,N-diisopropylethylamine (0.7 mL, 5.5 mmol) and anhydrous dimethyl sulfoxide (0.4 mL, 5.6 mmol) in anhydrous dichloromethane (20 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched with 10% aqueous citric acid (70 mL). The mixture was extracted into dichloromethane (3×50 mL), and the dichloromethane solution was washed with 10% aqueous citric acid (40 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane) to give the title compound as a colorless oil (590 mg, 78%). 1H-NMR (300 MHz, CDCl3) δ 9.83 (s, 1H), 8.72 (s, 1H), 8.38 (d, J=8.4 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 6.63 (s, 1H), 6.46 (s, 1H), 6.39 (s, 1H), 4.21 (t, J=6.0 Hz, 2H), 2.89 (s, 3H), 2.87 (t, J=6.0 Hz, 2H), 2.26 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[C:4]([C:8]([F:11])=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH3:13][N:14]([CH3:28])[CH:15]1[CH2:20][CH2:19][C:18]([C:21]2[CH:22]=[C:23]([NH2:27])[CH:24]=[CH:25][CH:26]=2)=[CH:17][CH2:16]1>>[ClH:1].[Cl:1][C:2]1[C:3]([F:12])=[C:4]([C:8]([F:11])=[CH:9][CH:10]=1)[C:5]([NH:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:18]2[CH2:19][CH2:20][CH:15]([N:14]([CH3:28])[CH3:13])[CH2:16][CH:17]=2)[CH:22]=1)=[O:6]
Reactant: O=C(Cl)c1c(F)ccc(Cl)c1F
Reactant: CN(C)C1CC=C(c2cccc(N)c2)CC1
Product: CN(C)C1CC=C(c2cccc(NC(=O)c3c(F)ccc(Cl)c3F)c2)CC1
Product: Cl
Yield: 116 %

Procedure:
Using a method similar to example 1, using 3-chloro-2,6-difluorobenzoyl chloride (142 mg, 0.67 mmol) and 3-(4-dimethylamino-cyclohex-1-enyl)-phenylamine (preparation 2, 121 mg, 0.56 mmol) provides the title compound (free base 166 mg, 76%). Free base: MS (ES): m/z=391.2 (M+H)+; 1H NMR (CDCl3): δ 7.79 (s, br, 1H), 7.68 (br, 1H), 7.49 (m, 2H), 7.34 (t, 1H), 7.22 (d, 1H), 7.00 (dt, 1H), 6.12 (m, 1H), 2.46 (m, 4H), 2.38 (s, 6H), 2.15 (m, 2H), 1.59 (m, 1H). Hydrochloride salt: Anal. cal'd for C21H21ClF2N2O.HCl 0.25H2O: C, 58.41; H, 5.25; N, 6.49. Found: C, 58.65; H, 5.16; N, 6.51.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13]([OH:16])(=[O:15])=[O:14])[CH:8]=1.C(N(CC)CC)C.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C([O-])([O-])=O.[K+].[K+]>CO.C1(C)C=CC=CC=1>[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13]([Cl:2])(=[O:16])=[O:14])[CH:8]=1.[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)(=[O:15])=[O:16])[CH:8]=1
Reactant: C1COCCN1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=S(=O)(Cl)c1cccnc1
Product: O=S(=O)(c1cccnc1)N1CCOCC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
Pyridine-3-sulfonyl chloride was prepared from phosphorus pentachloride (17.82 g, 0.112 mol) and pyridine-3-sulfonic acid (12.36 g, 77.7 mmol) according to the procedure described by P. Breant et al. Synthesis, 1983, 822. Anhydrous toluene (20 mL) was added to the product and this solution added slowly to a mixture of toluene (100 mL), triethylamine (4 eq, 43 mL) and morpholine (1.5 eq, 10.3 mL) with cooling in ice water. A thick precipitate was formed. The mixture was stirred for 16 hr and then shaken with a saturated K2CO3 solution, dried over anhydrous sodium sulfate and evaporated to give a yellowish brown solid. Trituration with methanol gave 4-(pyridine-3-sulfonyl)-morpholine as a pale yellow solid (14.29 g, 81%).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[N:20]1[CH:25]=[C:24](B(O)O)[CH:23]=[N:22][CH:21]=1>>[CH3:17][C:7]1[C:6]2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=[C:2]([C:24]3[CH:25]=[N:20][CH:21]=[N:22][CH:23]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]=12
Reactant: OB(O)c1cncnc1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Product: Cc1c2n(c3c(-c4cncnc4)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, light yellow solid (19 mg, 24%), MS (ISP) m/z=318.6 [(M+H)+], mp 304° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available pyrimidin-5-ylboronic acid (40.3 mg, 0.325 mmol).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[CH:11]=2)=[C:5]([CH3:7])[N:6]=1.Cl.[NH2:20][OH:21].C(N(CC)CC)C>O1CCCC1.CO>[Br:1][C:2]1[S:3][C:4]([CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]([NH:20][OH:21])=[NH:15])=[C:12]([Cl:18])[CH:11]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(Br)sc1COc1ccc(C#N)c(Cl)c1
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1nc(Br)sc1COc1ccc(C(=N)NO)c(Cl)c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
4-(2-Bromo-4-methyl-thiazol-5-ylmethoxy)-2-chloro-benzonitrile (200 mg, 0.6 mmol) was dissolved in a mixture of 4 ml tetrahydrofuran and 4 ml methanol. Hydroxylamine hydrochloride (1.0 g, 14.6 mmol) was added followed by the addition of 2.1 ml triethylamine. The reaction mixture was stirred at 65° C. overnight. The solvents were removed in vacuo and the resulting residue poured into water and extracted five times with ethylacetate. The combined organic extracts were washed with brine, dried over MgSO4 and the solvent was evaporated in vacuo to obtain 199 mg 4-(2-Bromo-4-methyl-thiazol-5-ylmethoxy)-2-chloro-N-hydroxy-benzamidine as an oil.
Reaction SMILES: Cl[CH:2]1[N:7]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:5][C:4](Cl)=[N:3]1.[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=1.CC[N:22]([CH:26]([CH3:28])[CH3:27])C(C)C>O1CCOCC1>[C:13]1([CH3:12])[CH:18]=[CH:17][C:16]([NH:19][CH:2]2[N:7]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:5][C:4]([NH:22][C:26]3[CH:27]=[CH:18][C:13]([CH3:14])=[CH:12][CH:28]=3)=[N:3]2)=[CH:15][CH:14]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=[N+]([O-])N1C=CC(Cl)=NC1Cl
Reactant: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(NC2=NC(Nc3ccc(C)cc3)N([N+](=O)[O-])C=C2)cc1
Temperature: 200 °C
Reaction time: 0.33 h
Yield: 94.6 %

Procedure:
A mixture of 2,6-dichloro-3-nitropyrimidine (194 mg, 1 mmol), p-tolylamine (236 mg, 2.2 mmol) and DIEA (524 μL, 3 mmol) in 3 mL dioxane was stirred in microwave at 200° C. for 20 min. After removal of the solvent, the residue was dissolved in chloroform and subjected to silica gel column purification to give 319 mg (yield: 95%) title compound. Calculated mass=335. Observed mass=336.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9](=[N:11][OH:12])[CH3:10])[CH:3]=1.[H-].[Na+].[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19]Cl>CN(C)C=O>[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19][O:12][N:11]=[C:9]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=1)[CH3:10]
Reactant: CC(=NO)c1cc(C)cc(C)n1
Reactant: COc1ccc(CCl)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CON=C(C)c2cc(C)cc(C)n2)c(OC)c1
Reaction time: 0.5 h

Procedure:
On the other hand, 0.50 g (3.05 mmol) of 1-(4,6-dimethyl-2-pyridinyl)ethanone oxime was dissolved in 5 ml of N,N-dimethylformamide, and the resultant solution was added with 0.12 g (3.00 mmol) of sodium hydride (60%, oiliness) while cooling the solution with ice. The obtained solution was stirred for 30 min. at a temperature below 0° C. and subsequently added with the whole amount of the toluene solution of 2,4-dimethoxybenzyl chloride prepared previously under cooling with ice. The resultant solution was stirred for 1.5 hours while cooling with ice, and the reacted solution was then poured into icewater, and the ice water containing the reacted solution was extracted with diethyl ether. The resultant nonaqueous layer was separated and washed with water and then dried with anhydrous magnesium sulfate. The dried layer was then condensed under reduced pressure to obtain a crude product. Then, said crude product was purified by means of silica gel column chromatography (eluate; hexane:ethyl acetate=7:3 (v/v)) to obtain the target compound in an amount of 0.62 g. nD20.7; 1.5722
Reaction SMILES: C(S([NH:7][CH:8]([C:13]1([CH3:17])[CH2:16][O:15][CH2:14]1)[C:9]([NH2:12])=[N:10][OH:11])=O)(C)(C)C.CO[C:20](OC)(N(C)C)[CH3:21].Cl.O1CCOCC1>C(O)(C)C.C(OCC)(=O)C>[CH3:20][C:21]1[O:11][N:10]=[C:9]([CH:8]([C:13]2([CH3:17])[CH2:14][O:15][CH2:16]2)[NH2:7])[N:12]=1
Reactant: COC(C)(OC)N(C)C
Reactant: CC1(C(NS(=O)C(C)(C)C)C(N)=NO)COC1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1nc(C(N)C2(C)COC2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.1 %

Procedure:
To a solution of 2-(tert-butylsulfinylamino)-N′-hydroxy-2-(3-methyloxetan-3-yl)acetamidine (example 254a, 0.25 g, 949 μmol) in isopropanol (5.00 ml) was added 1,1-dimethoxy-N,N-dimethylethanamine (506 mg, 3.8 mmol) and the reaction mixture was stirred at room temperature overnight. A solution of 4M hydrochloric acid in dioxane (1.19 ml, 4.75 mmol) was added to the reaction mixture cooled down to 0° C. and the reaction was stirred at 0° C. for 2 hours. The reaction mixture was diluted with ethyl acetate and extracted with a 2M aqueous solution of sodium carbonate. The organic phase was collected and the aqueous phase was back-extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a dichloromethane-methanol gradient to yield the title compound (35 mg, 20%) as a yellow oil which was not totally pure and was used without any further purification. MS (ESI, m/z): 184.1 (M+H+).
Reaction SMILES: [CH2:1]([N:6]1[CH:10]=[C:9]([C:11](=[O:16])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH:8]=[C:7]1[C:17]([C:19]1[CH:20]=[CH:21][C:22]([O:35][CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[C:23]([CH2:25][CH2:26][C:27]([O:29]CCC(C)C)=[O:28])[CH:24]=1)=[O:18])[CH2:2][CH:3]([CH3:5])[CH3:4].[OH-].[Na+].O.Cl>C(O)C.C(Cl)(Cl)Cl>[CH2:1]([N:6]1[CH:10]=[C:9]([C:11](=[O:16])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH:8]=[C:7]1[C:17]([C:19]1[CH:20]=[CH:21][C:22]([O:35][CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[C:23]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:24]=1)=[O:18])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CCOC(=O)CCc1cc(C(=O)c2cc(C(=O)CC(C)C)cn2CCC(C)C)ccc1OCCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCO
Product: CC(C)CCOc1ccc(C(=O)c2cc(C(=O)CC(C)C)cn2CCC(C)C)cc1CCC(=O)O
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a solution of 0.67 g of isopentyl 3-[5-{[1-isopentyl-4-(3-methylbutanoyl)-1H-pyrrol-2-yl]carbonyl}-2-(isopentyloxy)phenyl]propanoate in 14 ml of ethanol is added 3.6 ml of 1 mol/L sodium hydroxide solution. The mixture thus obtained is stirred at 50° C. for one hour. Water and chloroform are added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Thus, 0.56 g of 3-[5-{[1-isopentyl-4-(3-methylbutanoyl)-1H-pyrrol-2-yl]carbonyl}-2-(isopentyloxy)phenyl]propanoic acid is obtained as a white solid product.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14]([C:16]1[C:17]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[C:18]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[NH:19][CH:20]=1)=O)C>C1(C)C=CC=CC=1.O1CCCC1>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:18]2[NH:19][CH:20]=[C:16]([CH2:14][OH:13])[C:17]=2[C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.5 %

Procedure:
121.4 ml (121.4 mmol) of a 1M solution of diisobutylaluminium hydride in toluene were slowly added dropwise to a solution of 12.56 g (40.47 mmol) of 4-ethoxycarbonyl-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole [which was obtained in step (i) above] in 630 ml of tetrahyrofuran with ice-cooling. After completing the addition, the cooling bath was removed and the mixture was stirred at room temperature for 5 hours. At the end of this time, a saturated aqueous solution of ammonium chloride was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure to give 10.80 g (yield 99%) of the title compound as a pale orange powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C@@H:8]([NH2:10])[CH3:9])[N:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1.[F:21][C@H:22]([C@H:24]1[CH2:28][O:27][C:26](=[O:29])[N:25]1[C:30]1[CH:35]=[CH:34][N:33]=[C:32](F)[N:31]=1)[CH3:23].CCN(C(C)C)C(C)C>CS(C)=O>[F:21][C@H:22]([C@H:24]1[CH2:28][O:27][C:26](=[O:29])[N:25]1[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([NH:10][C@H:8]([C:6]2[N:5]=[CH:4][C:3]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=3)=[C:2]([CH3:1])[CH:7]=2)[CH3:9])[N:31]=1)[CH3:23]
Reactant: C[C@H](F)[C@H]1COC(=O)N1c1ccnc(F)n1
Reactant: Cc1cc([C@H](C)N)ncc1-c1ccnc(C(F)(F)F)c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc([C@H](C)Nc2nccc(N3C(=O)OC[C@@H]3[C@H](C)F)n2)ncc1-c1ccnc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 28.5 %

Procedure:
A solution of (S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethanamine (28.1 mg, 0.1 mmol), (R)-4-((S)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (22.9 mg, 0.100 mmol) and DIPEA (52.4 μl, 0.300 mmol) in DMSO (Volume: 500 μl) was heated at 110° C. for 1 hr. The solution was then cooled to rt, and RP-HPLC (acetonitrile:water) purification provided a white solid. This material was purified again with flash column chromatography (0-10% MeOH/EtOAc) to give 14 mg (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a white solid. 1H NMR (400 MHz, MeOD) δ 8.81 (d, J=5.0 Hz, 1H), 8.41 (s, 1H), 8.18 (s, 1H), 7.86 (s, 1H), 7.69 (dd, J=5.0, 1.6 Hz, 1H), 7.44 (s, 1H), 7.41 (d, J=5.8 Hz, 1H), 5.08 (br s, 1H), 4.73 (br d, J=26.0 Hz, 1H), 4.56-4.27 (m, 3H), 2.32 (s, 3H), 1.58 (d, J=7.1 Hz, 3H), 1.12 (br s, 3H); HRMS (B) m/z 491.1782 (M+H)+. Anal. RP-HPLC tR=3.42 min. Purity 100%/100%.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4]1[CH:9]=[CH:8][C:7]([S:10](CCCCC(O)=O)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].[C:22]([O-:25])(=O)[CH3:23].[Na+]>C(OC(=O)C)(=O)C>[CH2:20]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:3]2[CH2:4][CH2:5][CH2:6][CH2:23][C:22]2=[O:25])(=[O:11])=[O:12])=[CH:8][CH:9]=1)[CH3:21]
Reactant: CCN(CC)c1ccc(S(=O)(=O)CCCCC(=O)O)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)c1ccc(S(=O)(=O)N2CCCCC2=O)cc1
Temperature: 25 °C
Yield: 121.2 %

Procedure:
2 g of product obtained in Stage A are heated to reflux for 2 hours with 2 g of sodium acetate in 20 cm3 of acetic anhydride. The mixture is cooled to room temperature and evaporated to dryness, the residue is taken up in a mixture of chloroform and water, the organic phase is separated and dried and, after removal of the solvents, 1.8 g of expected crude product are obtained. M.p. 118°-120° C. After crystallization in isopropanol, 1.2 g of pure product are obtained. M.p. 122°-123° C.
Reaction SMILES: C(O[C:4]([CH:6]1[N:13]2[CH:9]([CH2:10][CH2:11][C:12]2=[O:14])[CH2:8][CH2:7]1)=[O:5])C.CCCN[N:19]([CH2:24][CH3:25])NCCC>>[CH3:4][CH:6]([N:13]([CH2:25][CH2:24][NH:19][C:4]([CH:6]1[N:13]2[CH:9]([CH2:10][CH2:11][C:12]2=[O:14])[CH2:8][CH2:7]1)=[O:5])[CH:9]([CH3:10])[CH3:8])[CH3:7]
Reactant: CCOC(=O)C1CCC2CCC(=O)N21
Reactant: CCCNN(CC)NCCC
Product: CC(C)N(CCNC(=O)C1CCC2CCC(=O)N21)C(C)C
Temperature: 80 °C

Procedure:
A solution of hexahydro-5-oxo-1H-pyrrolizine-3-carboxylic acid ethyl ester (5.0 g, 0.0254 mol) in N,N-di-(2-methylethyl)aminoethylamine (10 g, 0.0693 mol) is stirred at room temperature 24 hours and heated at 80° C. for 24 hours. The solution is concentrated at reduced pressure and distilled to yield N-[2-[N,N-bis(1-methylethyl)amino]ethyl]-hexahydro-5-oxo-1H-pyrrolizine3-carboxamide, bp 155°-165° C. at 0.025 Torr.