Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C@H:13]3[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:22])[CH3:21])[CH2:15][CH2:14]3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH2:23]([OH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[H-].[Na+]>CC(N(C)C)=O>[CH2:23]([O:30][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C@H:13]3[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:22])[CH3:21])[CH2:15][CH2:14]3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)N[C@H]1CC[C@H](Oc2ccc3c(Cl)nccc3c2)CC1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)N[C@H]1CC[C@H](Oc2ccc3c(OCc4ccccc4)nccc3c2)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
975 mg (3.06 mmol) of N-[4-(1-chloro-isoquinolin-6-yloxy)-cyclohexyl]-acetamide (18) were dissolved in 20 ml of dimethyl acetamide and 992 mg (9.17 mmol) of benzyl alcohol were added. After addition of 367 mg (9.17 mmol) of sodium hydride (60%), the reaction mixture was stirred for 3 h at room temperature and for 1 h at 80° C. Then, the solvent was removed in vacuo, the residue was dissolved in dichloromethane and washed three times with water. The organic layer was dried with magnesium sulfate and evaporated. Final purification by preparative HPLC yielded 680 mg of the title compound. Rt=1.75 min (Method B). Detected mass: 391.2 (M+H+).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[C:6]([N+:21]([O-:23])=[O:22])[CH:5]=1.[CH2:24](I)[CH3:25].O>CN(C=O)C>[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([N:8]([CH2:24][CH3:25])[S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[C:6]([N+:21]([O-:23])=[O:22])[CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2[N+](=O)[O-])cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(c1ccc(Cl)cc1[N+](=O)[O-])S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 73.5 %

Procedure:
To a suspension of sodium hydride (60%, 0.05 g (1.25 mmol)) in DMF (2.0 ml), 4′-chloro-2′-nitro-p-toluenesulfonanilide (0.30 g (0.92 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, ethyl iodide (0.50 ml (6.25 mmol)) was added dropwise. After one hour's heating at 100° C. with stirring, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:3) as eluent, giving 0.24 g (74%) of the title compound as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:16][C:17](=[O:29])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([C:27]#[N:28])([CH3:26])[CH3:25])[CH:19]=3)[CH:12]=[CH:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1.[C:30]([N:35]=[C:36]=[S:37])(=[O:34])[O:31][CH2:32][CH3:33].O>CS(C)=O>[C:27]([C:24]([C:20]1[CH:19]=[C:18]([C:17]([NH:16][C:11]2[CH:12]=[CH:13][C:14]([CH3:15])=[C:9]([CH:10]=2)[O:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:36]([NH:35][C:30](=[O:34])[O:31][CH2:32][CH3:33])=[S:37])=[N:7][CH:6]=2)=[O:29])[CH:23]=[CH:22][CH:21]=1)([CH3:26])[CH3:25])#[N:28]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc(N)nc1
Reactant: CCOC(=O)N=C=S
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)NC(=S)Nc1ccc(Oc2cc(NC(=O)c3cccc(C(C)(C)C#N)c3)ccc2C)cn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of N-{3-[(6-aminopyridin-3-yl)oxy]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (4.71 g, 12.2 mmol) in dimethyl sulfoxide (100 mL) was added ethyl isothiocyanatocarbonate (1.73 mL, 14.6 mmol), and the mixture was stirred at room temperature for 6 hr. Water (300 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL, 50 mL). The combined organic layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give ethyl ({5-[5-({[3-(1-cyano-1-methylethyl)phenyl]carbonyl}amino)-2-methylphenoxy]pyridin-2-yl}carbamothioyl)carbamate as a yellow amorphous solid. The obtained compound was used in the next reaction without further purification.
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]2=[N:4][CH:3]=1.CN([CH:14]=[O:15])C.O>C1COCC1.C([Li])CCC>[CH:14]([C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]2=[N:4][CH:3]=1)=[O:15]
Reactant: CN(C)C=O
Reactant: Brc1cnc2n1CCCC2
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cnc2n1CCCC2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (2.84 g) in THF (50 ml), n-butyllithium (1.6M hexane solution, 28 ml) was added dropwise at −78° C. The mixture was stirred for 1 hour at −78° C., DMF (5 ml) was added to the mixture, and the mixture was stirred for 0.5 hour at room temperature. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:1→ethyl acetate), to give 3-formyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (1.48 g) as colorless oil.
Reaction SMILES: [NH3:1].C(=O)=O.CC(C)=O.Cl[C:10]1[C:11]2[N:12]([C:16]([CH:29]3[CH2:32][CH2:31][CH2:30]3)=[N:17][C:18]=2[C:19]2[CH:28]=[C:27]3[C:22]([CH:23]=[CH:24][CH:25]=[N:26]3)=[CH:21][CH:20]=2)[CH:13]=[CH:14][N:15]=1>N.CC(O)C>[CH:29]1([C:16]2[N:12]3[CH:13]=[CH:14][N:15]=[C:10]([NH2:1])[C:11]3=[C:18]([C:19]3[CH:28]=[C:27]4[C:22]([CH:23]=[CH:24][CH:25]=[N:26]4)=[CH:21][CH:20]=3)[N:17]=2)[CH2:32][CH2:31][CH2:30]1
Reactant: Clc1nccn2c(C3CCC3)nc(-c3ccc4cccnc4c3)c12
Reactant: N
Agent: O=C=O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: Nc1nccn2c(C3CCC3)nc(-c3ccc4cccnc4c3)c12
Temperature: 110 °C

Procedure:
Gaseous NH3 was condensed into a cooled (dry ice/acetone) solution of 7-(8-chloro-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-quinoline (203.2 mg, 0.607 mmol) in 2M NH3/iPrOH (6 mL) in a pressure tube until the volume was doubled, then the tube was sealed and heated to 110° C. (bath temp.) for 19 h. The ammonia was evaporated, the crude material was adsorbed onto Hydromatrix and chromatographed on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with CH2Cl2 1:1 (1-6)→2% MeOH in CH2Cl2 (7-27)→4% MeOH in CH2Cl2 (28-37)→5% MeOH in CH2Cl2 (38-53)→7% MeOH in CH2Cl2 (54-67)], yielding the title compound as a yellow solid, >98% pure by HPLC, mp. 94-96° C.; 1H NMR (CDCl3, 400 MHz) δ 2.00-2.10 (m, 1H), 2.12-2.25 (m, 1H), 2.47-2.57 (m, 2H), 2.61-2.73 (m, 2H), 3.85 (quint, J=8.4 Hz, 1H), 5.23 (brs, 2H), 7.10 (d, J=4.4 Hz, 1H), 7.16 (d, J=4.4 Hz, 1H), 7.44 (dd, J=4.2, 8.2 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 8.00 (d, J=8.4 Hz, 1H), 8.22 (d, J=8.2 Hz, 1H), 8.36 (s, 1H), 8.95-9.00 (m, 1H); MS (ES+): m/z 316.2 (30) [MH+].
Reaction SMILES: CN(C)C=O.[C:6]([O:10][C:11]([C@H:13]1[CH2:15][C@H:14]1[CH:16]1[CH2:20][CH2:19][NH:18][C:17]1=[O:21])=[O:12])([CH3:9])([CH3:8])[CH3:7].[H-].[Na+].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH2:24]([N:18]1[CH2:19][CH2:20][CH:16]([CH:14]2[CH2:15][CH:13]2[C:11]([O:10][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:12])[C:17]1=[O:21])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@H]1C1CCNC1=O
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C1CC1C1CCN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34.8 %

Procedure:
To 30 ml of a dimethylformamide solution of 2.288 g (10.2 mmol) of 3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidin-2-one was added 406.2 mg (10.2 mmol) of sodium hydride under cooling with ice, followed by stirring at room temperature for 1.5 hours. Then, 1.81 ml (15.3 mmol) of benzyl chloride was added thereto dropwise, followed by stirring for 2.5 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and the organic layer was washed with water and a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to give 1.121 g (35.0%) of 1-benzyl-3-(2-t-butoxycarbonylcyclopropyl)pyrrolidin-2-one (isomer A: an isomer attributed to the steric configuration of the cyclopropyl group bonded to the carbon atom of the pyrrolidine ring) as a colorless solid. The column was then eluted with hexane:ethyl acetate=1:1 to give 670.9 mg (20.9%) of 1-benzyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidin-2-one (isomer B: an isomer attributed to the steric configuration of the cyclopropyl group bonded to the carbon atom of the pyrrolidine ring) as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13](COCC[Si](C)(C)C)[C:12]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:24][CH2:23]3)=[N:11][C:10]=2[C:38](O)=[O:39])=[CH:5][CH:4]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[CH:79]([N:82]1[CH2:87][CH2:86][NH:85][CH2:84][CH2:83]1)([CH3:81])[CH3:80]>C(Cl)Cl>[CH:79]([N:82]1[CH2:87][CH2:86][N:85]([C:38]([C:10]2[N:11]=[C:12]([N:22]3[CH2:23][CH2:24][N:25]([C:28]4[C:33]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:26][CH2:27]3)[NH:13][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:41])([F:42])[F:1])=[CH:4][CH:5]=2)=[O:39])[CH2:84][CH2:83]1)([CH3:81])[CH3:80]
Reactant: CC(C)N1CCNCC1
Reactant: C[Si](C)(C)CCOCn1c(N2CCN(c3ncccc3C(F)(F)F)CC2)nc(C(=O)O)c1-c1ccc(C(F)(F)F)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2-c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 70 h

Procedure:
A mixture of 5-(4-(trifluoromethyl)phenyl)-2-(4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid from step (e) above (200. mg, 0.325 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (216 mg, 0.488 mmol, Aldrich), DIEA (0.17 mL, 0.98 mmol, Aldrich), and 1-isopropylpiperazine (62 mg, 0.49 mmol, Aldrich) in DCM (2 mL) was stirred at RT for 70 h. The solvents were removed and the residue was purified on silica gel using ISCO Combiflash® system with DCM/2M methanolic ammonia gradient to give the title compound, which was used in the next step. MS (ESI, positive ion) m/z: 726 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:9]=3[C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[C:19](Cl)(=[O:21])[CH3:20]>N1C=CC=CC=1>[Cl:16][C:13]1[CH:14]=[CH:15][C:9]2[C:8](=[O:17])[NH:7][C:6]3[CH:18]=[C:2]([NH:1][C:19](=[O:21])[CH3:20])[CH:3]=[CH:4][C:5]=3[NH:11][C:10]=2[CH:12]=1
Reactant: CC(=O)Cl
Reactant: Nc1ccc2c(c1)NC(=O)c1ccc(Cl)cc1N2
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)NC(=O)c1ccc(Cl)cc1N2
Reaction time: 8 h
Yield: 55.8 %

Procedure:
A solution of Example 7C (100 mg, 0.38 mmol) in pyridine (10 mL) at 0° C. was treated with acetyl chloride (32 mg, 0.40 mmol), stirred overnight, and concentrated. The residue was purified by flash column chromatography on silica gel with ethyl acetate to provide 64 mg (56%) of the desired product. MS (DCI) m/e 302 (M+H)+, 319 (M+NH4)+; 1H NMR (500 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.81 (s, 1H), 7.93 (s, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.25 (d, J=1.9 Hz, 1H), 7.16 (dd, J=8.4, 2.2 Hz, 1H), 7.05 (d, J=1.9 Hz, 1H), 6.90 (dd, J=8.4, 1.9 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 1.99 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:26][N:27]([CH:35]=[O:36])[O:28]C2CCCCO2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[N:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][NH:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.O>C(O)(=O)C>[CH:1]1([CH2:6][C@H:7]([CH2:26][N:27]([CH:35]=[O:36])[OH:28])[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[N:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][N:23]=3)=[O:16])[CH2:13][CH2:12][NH:11]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cnc(NC(=O)[C@@H]2CCNN2C(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)nc1
Solvent: O
Solvent: CC(=O)O
Product: COc1cnc(NC(=O)[C@@H]2CCNN2C(=O)[C@H](CC2CCCC2)CN(O)C=O)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
A mixture of (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoyl)-N-[5-(methyloxy)-2-pyrimidinyl]-3-pyrazolidinecarboxamide (67 mg, 0.133 mmol) in acetic acid (7 ml)/water (1.8 ml) was stirred at ambient temperature for overnight. The solvent was removed to give a residue which was purified by RP-HPLC to give (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(hydroxy)amino]methyl}propanoyl)-N-[5-(methyloxy)-2-pyrimidinyl]-3-pyrazolidinecarboxamide (27 mg, 0.061 mmol, 46% yield). MS (ES+) m/z 421.1 (MH+).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[I:7]I.[NH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:20])[N:11]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C.O>[NH2:9][C:10]1[C:19]([I:7])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:20])[N:11]=1
Reactant: COC(=O)c1ccc(N)nc1C
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(I)c(N)nc1C
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
Sodium periodate (4.05 g, 18.9 mmol) and iodine (9.62 g, 37.9 mmol) were added to a solution of methyl 6-amino-2-methylnicotinate (8.40 g, 50.5 mmol) in DMF (45 ml), and the mixture was then stirred at 50° C. for 1.5 hours. The reaction mixture was added to a cold solution of 250 ml of saturated sodium thiosulphate solution in 150 ml of water. The solid formed was filtered off with suction, washed with water and dried. This gave 13.4 mg (88.9% of theory) of methyl 6-amino-5-iodo-2-methylnicotinate. HPLC-MS: log P=1.55; mass (m/z): 293.0 (M+H)+; 1H-NMR (D6DMSO) 2.50 (s, 3H), 3.74 (s, 3H), 6.81 (br. s, 1H), 8.25 (s, 1H).
Reaction SMILES: C(O[CH:4](OCC)[N:5]([CH3:7])[CH3:6])C.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([CH3:26])[C:20]([NH:22][N+:23]([O-:25])=[O:24])=[NH:21])=[CH:14][N:13]=1.CCCCCC>O1CCOCC1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([CH3:26])[C:20]([N:21]=[CH:4][N:5]([CH3:7])[CH3:6])=[N:22][N+:23]([O-:25])=[O:24])=[CH:14][N:13]=1
Reactant: CN(Cc1ccc(Cl)nc1)C(=N)N[N+](=O)[O-]
Reactant: CCOC(OCC)N(C)C
Solvent: CCCCCC
Solvent: C1COCCO1
Product: CN(C)C=NC(=N[N+](=O)[O-])N(C)Cc1ccc(Cl)nc1
Temperature: 130 °C

Procedure:
Variant a): 1.5 g of N,N-dimethylformamide-diethyl-acetal are added to 2.43 g of N-(2-chloropyrid-5-ylmethyl)-N-methyl-N'-nitroguanidine in 75 ml of dioxane. The mixture is heated at 130° C. for 45 minutes and is then freed of solvent using a rotary evaporator. The crude product is chromatographed over silica gel using first ethyl acetate and then ethyl acetate/ethanol (5:1). A viscous oil is formed which, after the addition of hexane, yields crystals of the desired product (m.p.: 85°-89° C.).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:44])[NH:14][CH2:15][C:16]([N:18]2[CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[CH:21]([C:30]([N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])=[O:31])[CH2:20][CH:19]2[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:17])[CH:9]=[CH:10][CH:11]=1)=[O:5])C.[OH-].[K+]>O.CO>[C:40]([O:39][C:37]([CH:19]1[CH2:20][CH:21]([C:30]([N:32]([CH2:33][CH3:34])[CH2:35][CH3:36])=[O:31])[CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[N:18]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:44])[NH:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:4]([OH:5])=[O:3])=[O:38])([CH3:42])([CH3:43])[CH3:41]
Reactant: CCOC(=O)c1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CC(C(=O)N(CC)CC)C2c2ccccc2F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCN(CC)C(=O)C1CC(C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc2cccc(C(=O)O)c2)C1c1ccccc1F
Yield: 29.9 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 3, but from 1.75 g of tert-butyl (2RS,4SR,5SR)-1-{2-[3-(3-(ethoxycarbonyl)phenyl)ureido]acetyl}-4-diethylaminocarbonyl-5-(2-fluorophenyl)pyrrolidine-2-carboxylate and 2.8 cm3 of a normal aqueous potassium hydroxide solution in a mixture of 15 cm3 of distilled water and 65 cm3 of methanol. After treatment, there is obtained 0.50 g of (2RS,4SR,5SR)-3-{3-[2-(2-tert-butoxycarbonyl-4-diethylaminocarbonyl-5-(2-fluorophenyl)-1-pyrrolidinyl)-2-oxoethyl]ureido}-benzoic acid, melting at 150° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[O:10][CH3:11].C([Li])CCC.CON(C)[C:20]([C:22]1[C:23]([NH2:31])=[N:24][C:25]([S:28][CH2:29][CH3:30])=[N:26][CH:27]=1)=[O:21]>CCCCC.O1CCCC1.O1CCCC1>[NH2:31][C:23]1[C:22]([C:20]([C:2]2[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=2[O:10][CH3:11])=[O:21])=[CH:27][N:26]=[C:25]([S:28][CH2:29][CH3:30])[N:24]=1
Reactant: COc1cc(F)c(F)cc1Br
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCSc1ncc(C(=O)c2cc(F)c(F)cc2OC)c(N)n1
Temperature: -72 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-bromo4,5-difluoro-anisole (1.95 g, 8.75 mmol, Astatech) in a mixture of pentane/tetrahydrofuran (5 mL/17 mL) was cooled to −72° C. and treated with n-butyl lithium (2.5 M in hexane, 3.6 mL, 9.0 mmol). After stirring for 10 minutes, a solution of 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide (0.78 g, 3.21 mmol, Example 1) in tetrahydrofuran (3 mL) was added. The temperature was slowly raised to −35° C. for ˜2 hours. The reaction was quenched at −35° C. with 5% aqueous ammonium chloride solution and the mixture was diluted with ethyl acetate/hexane (100 mL). The organic phase was separated, washed with 1:1 water/saturated aqueous sodium chloride solution and dried (Na2SO4). The residue after solvent removal was purified by HPLC chromatography (Waters Prep 500 eluting with 35% ethyl acetate/hexane) to give, in approximately 1:1 ratio, the two positional isomers (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone identical to material prepared in Example 102, and (4-Amino-2-ethylsulfanyl-pyrimidin-5-yl)-(4,5-difluoro-2-methoxy-phenyl)-methanone as a white solid after evaporation. HRMS, observed: 326.0772; Calcd for M+: 326.0770.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[NH2:8])(=[O:3])[CH3:2].Br[CH:14]([CH3:18])[C:15](=O)[CH3:16]>CN(C)C=O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:9]([C:14]([CH3:18])=[C:15]([CH3:16])[NH:8]2)=[C:10]([CH3:12])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)C(C)Br
Reactant: CC(=O)Nc1cc(C)cc(N)c1
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(C)c2c(C)c(C)[nH]c2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
9 g of 3-acetamido-5-methylaniline are dissolved in 20 ml of dimethylformamide and 3.2 ml of 3-bromobutan-2-one are then added. The mixture is left at ambient temperature for 1 hour and the temperature is then raised to 100°-110° C. for one hour. The mixture is cooled and poured into 100 ml of ice-water. The precipitate is drained and washed successively with 50 ml of distilled water, 20 ml of ethanol and 20 ml of isopropyl ether. 4.2 g of white precipitate are obtained.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][SH:15])=[CH:10][CH:9]=1.CS([C:20]1[C:24]([C:25]([NH2:27])=[O:26])=[C:23]([NH:28][C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[S:22][N:21]=1)(=O)=O>C1COCC1.O>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][S:15][C:20]2[C:24]([C:25]([NH2:27])=[O:26])=[C:23]([NH:28][C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)[S:22][N:21]=2)=[CH:10][CH:9]=1
Reactant: SCc1ccc(Cl)cc1
Reactant: CS(=O)(=O)c1nsc(Nc2ccncc2)c1C(N)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1c(SCc2ccc(Cl)cc2)nsc1Nc1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.4 %

Procedure:
Potassium tertbutoxide (318 mg, 2.84 mmol) is dissolved in anhydrous THF (5 mL) and (4-Chlorophenyl)-methanethiol (0.375 mL, 2.84 mmol) is then added and stirred for 30 min room temperature. This resulting solution is then added to a solution of crude 9 (170 mg) dissolved in anhydrous THF (3 mL). The reaction is stirred for 4 hours at room temperature and then heated to 60° C. for 18 hours. The reaction is diluted with water and extracted with a solution containing 5% methanol and 95% methylene chloride (10 mL×3). The combined organics are dried over sodium sulfate, filtered and then concentrated in vacuo. Chromatography (3% MeOH/methylene chloride) provides 3-(4-Chloro-benzylsulfanyl)-5-(pyridin-4-ylamino)-isothiazole-4-carboxylic acid amide (18 mg, 2.5%-2 steps). 1H NMR (d6 DMSO): δ 8.17 (2H, broad s), 7.45 (2H, d, J=8.4 Hz), 7.37 (2H, d, J=8.4 Hz), 6.99 (2H, broad s), 4.32 (2H, s); LRMS (M+): 376.9, (M−): 375.0.
Reaction SMILES: IC.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([I:11])[CH:5]=1.[C:12](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:12])=[C:6]([I:11])[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Br)cc1I
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(Br)cc1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Iodomethane (103 μL, 1.65 mmol) was added to a solution of 4-bromo-2-iodophenol (450 mg, 1.51 mmol) and potassium carbonate (271 mg, 1.96 mmol) in acetone (10 mL). The resulting mixture was stirred at room temperature for 16 hours.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1)=[O:4].[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH2:17]Cl)[CH:16]=1.[H-].[Na+]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:17][C:15]1[CH:14]=[N:13][CH:12]=[C:11]([Br:10])[CH:16]=1)=[O:4]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: ClCc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)[C@@H]1CCCN1Cc1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of intermediates A-12 [B], (S)-pyrrolidine-2-carboxylic acid methyl ester was reacted with 3-bromo-5-chloromethyl-pyridine (intermediate A-12 [A]) in presence of NaH to give the title compound as a light yellow oil. MS: 299.2, 301.1 (M+H+).
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([OH:21])[CH:14]=[C:15](F)[CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(=O)([O-])[O-].[Cs+].[Cs+].[O:28]1[C:30]2([CH2:36][CH2:35][CH2:34][N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32][CH2:31]2)[CH2:29]1>CN(C=O)C>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:21][CH2:29][C:30]4([OH:28])[CH2:36][CH2:35][CH2:34][N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32][CH2:31]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Oc1cc(F)cc2ccc(-c3nnc4ccccn34)nc12
Reactant: CC(C)(C)OC(=O)N1CCCC2(CC1)CO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(O)(COc2cccc3ccc(-c4nnc5ccccn45)nc23)CC1
Temperature: 72 °C
Yield: 60.5 %

Procedure:
2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-ol (0.065 g, 0.25 mmol), cesium carbonate (0.16 g, 0.50 mmol) and tert-butyl 1-oxa-6-azaspiro[2.6]nonane-6-carboxylate (0.068 g, 0.30 mmol) were added to 1 mL of DMF and heated to 72° C. overnight. The reaction mixture was concentrated, and DCM was added to the residue. Solids were removed by filtration and the filtrate was purified on Silica gel using 6% NH4OH in MeOH and DCM to yield 74 mg of the desired product as an off-white foam. MS ESI (+) m/z 490 (M+1) detected.