Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([Cl:31])=[C:12]([CH:30]=2)[C:13]([NH:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([NH2:29])=[O:28])[CH:17]=2)=[O:14])[C:5]([F:32])=[CH:4][CH:3]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].O.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[C:33]([NH:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([Cl:31])=[C:12]([CH:30]=2)[C:13]([NH:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([NH2:29])=[O:28])[CH:17]=2)=[O:14])[C:5]([F:32])=[CH:4][CH:3]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1cc(NC(=O)c2cc(-c3nc(N)ccc3F)ccc2Cl)n(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(F)c(-c2ccc(Cl)c(C(=O)Nc3cc(C(N)=O)nn3-c3ccccc3)c2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40 %

Procedure:
To a solution of 5-(5-(6-amino-3-fluoropyridin-2-yl)-2-chlorobenzamido)-1-phenyl-1H-pyrazole-3-carboxamide (Preparation 1, 23 mg, 0.05 mmol) in acetic acid (2 mL) was added acetic anhydride (0.5 mL) and the reaction was stirred at room temperature for 18 hours. The reaction was poured into water (50 mL) and basified by the addition of solid potassium carbonate. The aqueous solution was extracted with ethyl acetate (50 mL) and the organic layer was washed with brine (50 mL), dried over magnesium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 40-60% EtOAc in heptanes followed by trituration in TBME to afford the title compound as a white solid (10 mg, 40%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[F:12].[F:13][C:14]([F:34])([F:33])[O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:26][CH2:25][C:24]3([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:23]2=[O:32])=[CH:18][CH:17]=1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[F:12][C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[N:29]1[CH2:30][CH2:31][C:24]2([C:23](=[O:32])[N:22]([C:19]3[CH:18]=[CH:17][C:16]([O:15][C:14]([F:33])([F:13])[F:34])=[CH:21][CH:20]=3)[CH2:26][CH2:25]2)[CH2:27][CH2:28]1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(c1ccc(C(F)(F)F)cc1F)CC2
Temperature: 80 °C
Yield: 65.6 %

Procedure:
A sealed tube was charged with 4-bromo-3-fluorobenzotrifluoride (40 mg, 0.16 mmol), 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (50 mg, 0.16 mmol), sodium tert-butoxide (17 mg, 0.18 mmol), tris(dibenzylidene acetone)dipalladium-(0) (15 mg, 0.02 mmol), BINAP (5 mg, 0.01 mmol) and toluene (2) under argon. The sealed tube was closed and immersed in an oil bath and heated to 80° C. for 15 h. The reaction mixture was allowed to cool to room temperature, diluted in ethyl acetate, filtered, and concentrated in vacuo to give a crude residue which was purified by flash column chromatography to yield the title compound as a light yellow solid (50 mg, 66%). MS (ESI): 477.1 (MH+)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.Cl[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:24][C:25]1[CH:30]=[N:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1
Reactant: COc1ccc(CCl)cn1
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c3c(c(=O)n2-c2ccc(F)cc2F)[C@@H]2CC[C@@]3(C)C2(C)C)cn1
Temperature: 100 °C
Yield: 8.7 %

Procedure:
A mixture of (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 42; 480 mg, 1.6 mmol), 5-chloromethyl-2-methoxy-pyridine (Intermediate 50; 995 mg, 6.3 mmol) and tetrabutylammonium iodide (583 mg, 1.6 mmol) in dimethylformamide (63 mL) was heated at 100° C. for 48 h. The solvent was evaporated and dichloromethane (150 mL) was added. The solution was washed with saturated aqueous sodium thiosulfate (200 mL), saturated aqueous sodium hydrogen carbonate (200 mL) and brine (200 mL), dried (sodium sulfate), filtered, evaporated and purified using a Biotage 40M system, eluting with 20-50% ethyl acetate/hexanes and then 2% methanol/dichloromethane, to give a crude product that contains some tetrabutylammonium iodide. This material was taken up in dichloromethane (50 mL) and washed with 5% dimethylformamide in water (2×100 mL) and water (5×100 mL). The organic phase was dried (sodium sulfate), filtered and evaporated to give (4R,7S)-2-(2,4-difluoro-phenyl)-1-(6-methoxy-pyridin-3-ylmethyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (59 mg, 9%). APCI(+)-MS (M+H) 426.
Reaction SMILES: [N:1]1([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5][CH2:4][CH2:3][NH:2]1.[C:13](C1CC(=O)NC1=O)([O:15][CH2:16][CH:17]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14]>ClCCl>[N:2]1([C:13]([O:15][CH2:16][CH:17]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[C:24]3[C:29]2=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:14])[CH2:3][CH2:4][CH2:5][N:1]1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCCN1
Reactant: O=C1CC(C(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 94 %

Procedure:
Tert-butyl pyrazolidine-1-carboxylate (39) (1.39 g, 8.08 mmoles) was acylated with Fmoc succinimide (3.27 g, 9.69 mmoles, 1.2 eq.) in dry dichloromethane (20 mL). The reactive mixture was left stirring overnight. The volatiles were removed using a rotary evaporator and the residue was dissolved in EtOAc. The organic layer was extracted three times, respectively, with 5% citric acid, 5% NaHCO3 and brine, dried over Na2SO4, filtered and concentrated to a white foam which was purified by column chromatography using 7:3 EtOAc:Hexane as eluant. Evaporation of the collected fractions afforded 1-(9H-fluoren-9-yl)methyl 2-tert-butyl pyrazolidine-1,2-dicarboxylate as a white solid in a 94% yield. Pyrazolidine-1,2-dicarboxylate (1.34 g, 3.4 mmoles) was treated with 25 mL of a 1:1 TFA:DCM solution and stirred for one hour. Removal of the volatiles by rotary evaporation gave a residue that was dissolved in 1N HCl, stirred for 1 hour and freeze-dryed to yield hydrochloride (9H-fluoren-9-yl)methyl-1-carboxylate: mp (143.2-148.1° C.), 1H NMR (DMSO) δ 7.89 (d, J=7.32 Hz, 2H), 7.72 (d, J=7.33 Hz, 2H), 7.43 (ddd, J=7.36 Hz, 0.57 Hz, 2H), 7.33 (ddd, J=7.42 Hz, 1.14 Hz, 2H), 4.44 (d, J=6.90 Hz, 2H), 4.33 (t, J=6.56 Hz, 1H), 3.58 (t, J=6.96 Hz, 2H), 3.43 (t, J=6.96 Hz, 2H), 2.20 (m, 2H). 13C (DMSO) δ 154.57, 144.64, 142.11, 129.26, 126.54, 121.67, 69.89, 47.50, 25.50.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[C:17]([C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=2)=[O:11])=[N:27][CH:28]=1
Reactant: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Reactant: Clc1ccc(Br)nc1
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(Cl)cn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone and 2-bromo-5-chloropyridine. ESI-MS (m/z): 437 [M+1]+.
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26].C(N(CCCC)CCCC)CCC>C(#N)C>[CH2:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:26])[O:27][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: O=C(O)CCCCCCCCCCCCCCO
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCCCN(CCCC)CCCC
Solvent: CC#N
Product: O=C1CCCCCCCCCCCCCCO1
Yield: 74 %

Procedure:
To a refluxing solution of 510 mg (2.0 mmol) of 2-chloro-1-methylpyridinium iodide in 50 ml of acetonitrile, there was added a solution of 134 mg (0.5 mmol) of 15-hydroxypentadecanoic acid and 740 mg (4.0 mmol) of tri-n-butylamine in 40 ml of acetonitrile over a period of 8 hours at a continuous and uniform rate, and the reaction mixture was refluxed for an additional 30 minutes after the addition was completed. After evaporation of the solvent, the residue was separated chromatographically on a silica gel column. 1,15-pentadecanolide was obtained in 74% yield.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].CS(O[CH2:30][CH:31]1[CH2:35][CH2:34][O:33][CH2:32]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O.O.[Cl-].[Na+].O>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:30][CH:31]2[CH2:35][CH2:34][O:33][CH2:32]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Reactant: CS(=O)(=O)OCC1CCOC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCCCOc1nc(N)c2nc(OC)n(CC3CCOC3)c2n1
Temperature: 60 °C
Yield: 101.5 %

Procedure:
A solution of 2-butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt (4.5 g), tetrahydro-3-furanylmethyl methanesulfonate (2.77 g) and potassium carbonate (5.31 g) in dimethyl sulfoxide (45 ml) was stirred and heated at 60° C. for 1.5 hours, followed by heating at 90° C. for 2.5 hours. The reaction was allowed to cool and the mixture diluted with water and brine, and shaken with ethyl acetate. The insoluble solid present was filtered (209 mg of product) and the organic layer separated. The aqueous layer was further extracted four times with ethyl acetate. The combined organic layers were washed with water and then brine. The organic layer was dried by passing through a hydrophobic frit and concentrated in vacuo to yield a light brown solid (4.18 g). This was recrystallised from acetonitrile (25 ml) to afford the product (2.28 g). This was further purified by dissolving in dichloromethane and washing with 1M hydrochloric acid, brine and saturated sodium hydrogencarbonate. The organic layer was dried through a hydrophobic frit and concentrated in vacuo to yield the product as a cream coloured solid (2.03 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Br:11][C:12]1[C:13]([F:22])=[C:14]2[C:20]([NH2:21])=[CH:19][NH:18][C:15]2=[N:16][CH:17]=1>N1C=CC=CC=1>[Br:11][C:12]1[C:13]([F:22])=[C:14]2[C:20]([NH:21][C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:19][NH:18][C:15]2=[N:16][CH:17]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.3 %

Procedure:
4-Fluorobenzoyl chloride (0.15 mL, 1.30 mmol) was added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.87 mmol, Example 1, Step H) in pyridine (5 mL). The reaction was stirred at room temperature for 10 minutes, and then the pyridine was removed. THF (5 mL) and 2N LiOH (3 mL) were added and stirred for 20 minutes. The THF was removed, and water (20 mL) was added. The solid formed was collected by filtration and dried to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-fluorobenzamide (0.24 g, 77% yield) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Cl:11])[C:3]=1[S:12][C:13](=[O:17])[N:14]([CH3:16])[CH3:15].O>C(O)(=O)C.CC(O)C.[Fe]>[NH2:8][C:6]1[CH:5]=[C:4]([Cl:11])[C:3]([S:12][C:13](=[O:17])[N:14]([CH3:16])[CH3:15])=[C:2]([Cl:1])[CH:7]=1
Reactant: CN(C)C(=O)Sc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CN(C)C(=O)Sc1c(Cl)cc(N)cc1Cl
Temperature: 50 °C
Yield: 92.9 %

Procedure:
A mixture of dimethyl-thiocarbamic acid S-(2,6-dichloro-4-nitro-phenyl) ester (80) (1.6 g, 5.4 mmol) in glacial acetic acid (24 mL), 2-propanol (48 mL), and water (24 mL) heated to 50° C. was treated with iron powder (2.1 g, 37.8 mmol). The resulting mixture was heated to 95° C. for 2 h. At this time, the reaction was filtered hot through a pad of celite and was washed with water and ethyl acetate. The filtrates were concentrated to remove the majority of organics. The remaining solution was diluted with water (500 mL) and was then brought to pH=8 with a concentrated ammonium hydroxide solution. The solution was extracted with ethyl acetate (3×200 mL). The combined organics were dried with magnesium sulfate, filtered and concentrated under vacuum. The resulting residue was slurried with diethyl ether and was cooled in the freezer for 30 min. The solid that formed was collected by filtration and was washed with cold diethyl ether to afford dimethyl-thiocarbamic acid S-(4-amino-2,6-dichloro-phenyl) ester (81) (1.33 g, 93%) as a white solid; EI(+)-HRMS m/e calcd for C9H10Cl2N2OS (M+H)+ 264.9964, found 264.9964. Exact Mass=263.9891; Molecular weight=265.16
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26]([CH:28]([C:34]#[N:35])[O:29][Si](C)(C)C)[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1>CO.C1COCC1>[F:36][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26]([CH:28]([OH:29])[CH2:34][NH2:35])[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)OC(C#N)c1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1
Solvent: CO
Solvent: C1CCOC1
Product: NCC(O)c1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1
Reaction time: 8 h

Procedure:
Ranney-Ni (20 mg) is washed with MeOH (3×5 mL) before a solution of (±)-5-[6-(cyano-trimethylsilanyloxy-methyl)-pyrimidin-4-yloxy]-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (100 mg, 0.19 mmol) in MeOH (5 mL) and THF (3 mL) is added. The mixture is stirred under H2 atmosphere (ballon) overnight. The mixture is filtered through Celite® and the filtrate is concentrated. The residue is then separated by FCC (0-10% MeOH/EtOAc) to provide the title compound. MS (ESI) m/z 458.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.60-8.70 (m, 1H), 8.36 (d, J=8.59 Hz, 1H), 8.06 (br. S., 1H), 7.90 (d, J=7.58 Hz, 1H), 7.95 (d, J=3.28 Hz, 2H), 7.73 (d, J=4.55 Hz, 1H), 7.57 (t, J=7.83 Hz, 1H), 7.37-7.47 (m, 3H), 7.12 (d, J=8.59 Hz, 2H), 7.04 (s, 1H), 6.75 (br. S., 1H), 4.89 (d, J=5.05 Hz, 1H), 3.67 (dd, J=12.25, 7.71 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:67])[N:7](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:6][CH2:5][N:4]([C:21]([C@@H:23]2[CH2:27][C@H:26]([S:28][C:29]3[C@H:30]([CH3:53])[C@@H:31]4[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]4[C:33]=3[C:34]([O:36]CC3C=CC([N+]([O-])=O)=CC=3)=[O:35])[CH2:25][N:24]2C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)=[O:22])[CH2:3]1.[ClH:68]>O1CCCC1.O>[ClH:68].[CH3:67][C:2]1([CH3:1])[NH:7][CH2:6][CH2:5][N:4]([C:21]([C@@H:23]2[CH2:27][C@H:26]([S:28][C:29]3[C@H:30]([CH3:53])[C@@H:31]4[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]4[C:33]=3[C:34]([OH:36])=[O:35])[CH2:25][NH:24]2)=[O:22])[CH2:3]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)C(C)(C)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CCNC(C)(C)C4)C3)[C@H](C)[C@H]12

Procedure:
205 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[3,3-dimethyl-4-(4-nitrobenzyloxycarbonyl)-1-piperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 5 ml of a 1:1 by volume mixture of tetrahydrofuran and water, after which 0.23 ml of 1N aqueous hydrochloric acid was added, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 200 mg of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 7(b), to give 35 mg of the title compound as a powder.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[I:13]Cl>CC(O)=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][C:12]=1[I:13]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: ClI
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(O)c(I)c1
Temperature: 65 °C
Reaction time: 6 h
Yield: 73.7 %

Procedure:
Dissolve ethyl 4-hydroxy-benzoate (102.2 g, 0.61 mol) in AcOH (200 mL) at 65° C. Add dropwise a solution of ICl (100 g, 0.61 moles) in AcOH (500 mL). After the addition, stir the mixture at 65° C. for 6 hours. Pour the mixture into ice/water, filter and wash the solid with water. Dissolve the solid in CH2Cl2, dry it over MgSO4, filter and concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with CH2Cl2 to obtain 131.3 g of ethyl 4-hydroxy-3-iodo-benzoate (74% yield).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[C:5]([N+]([O-])=O)[CH:4]=1)#[N:2].[SH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].C(N(CC)CC)C.C(O)(=O)C>CS(C)=O>[C:1]([C:3]1[CH:10]=[CH:9][C:6]2[CH:7]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[S:14][C:5]=2[CH:4]=1)#[N:2]
Reactant: COC(=O)CS
Reactant: N#Cc1ccc(C=O)c([N+](=O)[O-])c1
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2ccc(C#N)cc2s1
Temperature: 0 °C

Procedure:
4.08 g (23.2 mmol) of 4-cyano-2-nitrobenzaldehyde, 2.46 g (23.2 mmol) of methyl mercaptoacetate and 6.46 ml (46.4 mmol) of triethylamine are heated in 12.3 ml of DMSO at 80° C. for 2.5 h. The reaction solution is added to 400 ml of ice-water. The precipitate resulting after addition of 4 ml of acetic acid is filtered off with suction, washed twice with water and dried in vacuo at 50° C. overnight. 4.19 g (83.2% of theory) of the title compound are obtained.
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([CH3:14])=[C:7]([CH3:13])[C:8]=1[C:9]([O:11]C)=O)=[C:2]=[S:3].[CH3:15][C:16]1[N:17]=[CH:18][N:19]([CH2:21][CH2:22][CH2:23][NH2:24])[CH:20]=1>>[CH3:13][C:7]1[C:8]2[C:9](=[O:11])[N:24]([CH2:23][CH2:22][CH2:21][N:19]3[CH:20]=[C:16]([CH3:15])[N:17]=[CH:18]3)[C:2](=[S:3])[NH:1][C:4]=2[S:5][C:6]=1[CH3:14]
Reactant: COC(=O)c1c(N=C=S)sc(C)c1C
Reactant: Cc1cn(CCCN)cn1
Product: Cc1cn(CCCn2c(=S)[nH]c3sc(C)c(C)c3c2=O)cn1

Procedure:
The compound was synthesized starting from methyl 2-isothiocyanato-4,5-dimethylthiophene-3-carboxylate (0.100 g. 0.44 mmol) and 3-(4-methyl-1H-imidazol-1-yl)propan-1-amine (9) (0.061 g, 0.44 mmol) as described above.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[C:6]=2[N:7]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CS(C)=O>[CH2:15]([NH:14][C:4]1[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[C:6]=2[N:7]=[C:2]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:3]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCNc1nc(Cl)nc2c(SC)ncnc12
Reactant: C1CNCCN1
Solvent: CS(C)=O
Product: CCCCCCNc1nc(N2CCNCC2)nc2c(SC)ncnc12

Procedure:
Prepared analogously to Example 2 from 2-chloro-4-n-hexylamino-8-methylthio-pyrimido[5,4-d]pyrimidine and piperazine in dimethylsulphoxide.
Reaction SMILES: [Na].[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].Cl[CH2:11][C:12]1[N:16]=[CH:15][O:14][N:13]=1>C(O)C>[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:11][C:12]1[N:16]=[CH:15][O:14][N:13]=1
Reactant: ClCc1ncon1
Reactant: Nc1ccccc1S
Agent: [Na]
Solvent: CCO
Product: Nc1ccccc1SCc1ncon1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium (1.27 g; 0.055 mol) was dissolved in absolute ethanol (50 ml) and to this was added 2-aminothiophenol (7.38 g; 0.059 mol). To the resulting solution was added 3-chloromethyl-1,2,4-oxadiazole (6.59 g; 0.055 mol) dropwise over 10 minutes. The resulting mixture was then stirred at ambient temperature for 30 minutes, sodium chloride removed by filtration and the filtrate was evaporated to dryness under reduced pressure to give 3-(2-aminophenylthiomethyl)-1,2,4-oxadiazole which was re-crystallised from isopropanol; m.p. 57°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]1[NH:23][N:22]=[CH:21][CH:20]=1.[C:27]([O:31][CH3:32])(=[O:30])[CH:28]=[CH2:29].N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]1[CH:20]=[CH:21][N:22]([CH2:29][CH2:28][C:27]([O:31][CH3:32])=[O:30])[N:23]=1
Reactant: C=CC(=O)OC
Reactant: Cc1nnc2ccc3c(cc(-c4ccn[nH]4)n3Cc3cccc(Cl)c3)n12
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CCn1ccc(-c2cc3c(ccc4nnc(C)n43)n2Cc2cccc(Cl)c2)n1
Reaction time: 1.17 h

Procedure:
6-(3-Chlorobenzyl)-1-methyl-7-(1H-pyrazol-5-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (25 mg, 0.069 mmol, from Example 103, Step 5) in acetonitrile (0.90 mL) was treated with methyl acrylate (19 μL, 0.21 mmol, Aldrich) and 1,8-diazabicyclo[5.4.0]undec-7-ene (10. μL, 0.069 mmol, Aldrich) and stirred for 70 minutes. Purification via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) followed by evaporation of eluent afforded methyl 3-(3-(6-(3-chlorobenzyl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-pyrazol-1-yl)propanoate. The ester intermediate was dissolved in THF (0.45 mL) and was treated with 1.0 M NaOH in water (0.45 mL, 0.45 mmol). After 25 minutes, the reaction was acidified to pH 3-4 by the addition of 1 N HCl. Water was added (3 mL), and the precipitated product was isolated by filtration and air dried. Yield: (21 mg, 70%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:19])=[C:11]([F:18])[C:12]=3[O:14][CH:15]([F:17])[F:16])[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.[N+:26]([O-])([O-:28])=[O:27].[K+]>S(=O)(=O)(O)O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:26]([O-:28])=[O:27])[C:10]([F:19])=[C:11]([F:18])[C:12]=3[O:14][CH:15]([F:16])[F:17])[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC(F)F)c(F)c(F)cc2c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)c1cn(C2CC2)c2c(OC(F)F)c(F)c(F)c([N+](=O)[O-])c2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.2 %

Procedure:
The preparation comprises dissolving ethyl 1-cyclopropyl-6,7-difluoro-8-difluoromethoxyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (target product of embodiment 3, 1.0 g, 2.8 mmol) in concentrated sulfuric acid (10 mL), slowly adding potassium nitrate (2.0 g, 19.8 mmol), reacting for 1 h at 40° C., cooling down to room temperature, charging the reaction mixture into ice water (100 mL), stirring, filtering, treating obtained filter cake with ethanol (20 mL), refluxing for 0.5 h, cooling down to room temperature, filtering, and drying obtained filter cake to give ethyl 1-cyclopropyl-6,7-difluoro-8-difluoromethoxyl-5-nitro-1,4-dihydro-4-oxoquinoline-3-carboxylate (0.5 g, 45.5%).