Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13]O)=[CH:5][CH:4]=1.S(Cl)([Cl:17])=O>ClCCl.C(OCC)(=O)C>[Cl:17][CH2:13][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc2cccc(CO)c2c1
Reactant: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc2cccc(CCl)c2c1
Yield: 84 %

Procedure:
To a solution of the compound obtained in Step A (100 g) in dichloromethane (5 ml/g) there are added 2 equivalents of thionyl chloride (126.35 g). The mixture is heated to reflux and maintained at reflux for 2 hours. After returning to ambient temperature, the solvent is evaporated off under reduced pressure. The oil obtained is taken up in ethyl acetate and washed with water and then with saturated NaCl solution. The solvent is evaporated off under reduced pressure and the crude product is purified by passing over a pad of silica (eluant: heptane). The title compound is obtained in the form of a yellow solid in a yield of 84%.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2]O.[Cl:6][C:7]1[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH:13]=[O:14])=[C:9]([CH3:17])[CH:8]=1.B(F)(F)F.CCOCC>CCOCC.O1CCCC1>[Cl:6][C:7]1[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH:13]2[O:5][C:1](=[O:4])[CH2:2][O:14]2)=[C:9]([CH3:17])[CH:8]=1
Reactant: O=C(O)CO
Reactant: Cc1cc(Cl)ccc1OCC=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1OCC1OCC(=O)O1
Reaction time: 24 h
Yield: 62.6 %

Procedure:
A solution containing 2.5g (0.033 mole) of glycolic acid, 4.2g (0.025 mole) of 4-chloro-2-methylphenoxyacetaldehyde and 10g (0.07 mole) of boron trifluoride etherate in 50 ml of ether and 30 ml of tetrahydrofuran was allowed to stand at room temperature for 24 hours. The dark solution was washed with aqueous sodium bicarbonate, dried and concentrated to dryness. Recrystallization from ether-hexane gave 3.8g of 2-(4-chloro-2-methylphenoxymethyl)-1,3-dioxolan-4-one having a melting point of 42°-44°.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)[CH2:4][CH2:3]1.[CH3:36][S:37]([CH3:39])=O.C(OC(=O)C)(=O)C>O>[CH3:36][S:37][CH2:39][O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)[CH2:4][CH2:3]1
Reactant: CS(C)=O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCSC)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (2.0 g), dimethyl sulfoxide (30 mL) and acetic anhydride (10 mL) was stirred at room temperature for 14 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.3 g, 59%).
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH3:8])=[O:6].[C:9](=O)([O-])[O-:10].[Ca+2]>CO>[CH3:9][O:10][CH2:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)/C=C/CBr
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Product: COC/C=C/C(=O)OC
Yield: 77.9 %

Procedure:
A mixture of 54 g of methyl 4-bromocrotonate and 30.2 g of calcium carbonate in 200 mL of methanol was refluxed for 5 days. The mixture was filtered and the solvent was removed from the filtrate. The residue was dissolved in ether and washed with water containing a trace of hydrochloric acid. The ether solution was dried over magnesium sulfate. The solvent was removed and the residue was distilled to give 30.6 g of methyl 4-methoxycrotonate. This material was stirred in 170 mL of 1N sodium hydroxide for 3 min. The solution was washed with ether and the aqueous layer was acidified with sulfuric acid. The mixture was extracted several times with ether. The combined extracts were washed with brine and dried over magnesium sulfate. The solvent was removed to give 4-methoxycrotonic acid as a crystalline solid. A 10 g portion of this acid was stirred in 50 mL of benzene at 0° C. and 8.3 mL of oxalyl chloride was added. The mixture was stirred at room temperature for 6 hr. The solvent was removed and the residue was distilled to give 4-methoxycrotonyl chloride as a colorless liquid.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[C:17]2[C:18]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[O:28])[C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:4][CH2:3]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:15])([F:14])[F:16])=[CH:9][C:8]=2[C:17]2[C:18]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:31][CH2:32][N:33]([C:36](=[O:39])[CH2:37][CH3:38])[CH2:34][CH2:35]4)=[O:28])[C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:3][CH2:4]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)(F)F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f31) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[NH2:32][C@H:33]([C:36]([O:38][CH3:39])=[O:37])[CH2:34][OH:35]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([NH:32][C@H:33]([C:36]([O:38][CH3:39])=[O:37])[CH2:34][OH:35])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](N)CO
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: -70 °C

Procedure:
21.5 g of t-butoxycarbonylproline are dissolved in 500 ml of methylene chloride. The solution is cooled to -70° C. 20.2 g of N-methylmorpholine are added, followed by the addition of 13.7 g of isobutylchloroformate. The reaction mixture is warmed up to -15° C. and again cooled to -70° C. 15.6 g of methyl serinate hydrochloride are added to the reaction mixture which is stirred for sixteen hours at room temperature. The reaction mixture is extracted three times with 1 M potassium bisulfate, three times with a saturated solution of potassium bicarbonate and two times with brine. The methylene chloride solution is dried over anhydrous sodium sulfate, filtered and stripped of solvent. The product is purified by chromatography on silica gel to give methyl t-butoxycarbonylprolylserinate.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:8]3[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:13][C:9]=3[N:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.C(#N)C>[CH2:19]([O:18][C:16]([C:14]1[NH:13][C:9]2[N:10]=[CH:11][N:12]=[C:7]([O:6][C:5]3[CH:21]=[CH:22][C:2]([NH:1][C:31]([NH:30][C:27]4[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=4)=[O:32])=[CH:3][CH:4]=3)[C:8]=2[CH:15]=1)=[O:17])[CH3:20]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CCOC(=O)c1cc2c(Oc3ccc(N)cc3)ncnc2[nH]1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ncnc2[nH]1
Reaction time: 1 h

Procedure:
After dissolving 90 mg of ethyl 4-(4-aminophenoxy)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate in 3 ml of toluene and 1 ml of acetonitrile at 110° C., 16.6 μl of 4-fluorophenyl isocyanate was added and the mixture was stirred for 1 hour under reflux. After standing at room temperature, the precipitated crystals were filtered out and dried to obtain 110 mg of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4]([Cl:11])[N:3]=1.[NH2:12][C:13]([CH3:17])([CH3:16])[C:14]#[N:15].[OH-].[Na+]>CC(C)=O.O>[Cl:11][C:4]1[C:5]([C:9]#[N:10])=[C:6]([Cl:8])[N:7]=[C:2]([NH:12][C:13]([C:14]#[N:15])([CH3:17])[CH3:16])[N:3]=1
Reactant: N#Cc1c(Cl)nc(Cl)nc1Cl
Reactant: CC(C)(N)C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C#N)Nc1nc(Cl)c(C#N)c(Cl)n1
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
A stirred solution of 6.3 grams of 2,4,6-trichloro-5-pyrimidinecarbonitrile in 25 ml of acetone was cooled to -10°, and 2.5 grams of 2-amino-2-methylpropionitrile was added. With the reaction mixture at -10°, a solution of 1.3 grams of sodium hydroxide in 3.5 ml of water was added dropwise. Upon complete addition, the reaction mixture was stirred at -10° for 30 minutes. The acetone was removed under reduced pressure; the residue was extracted with diethyl ether, and the extract was separated and dried over magnesium sulfate. The extract was filtered, and the filtrate was evaporated under reduced pressure, yielding a residue. The residue was recrystallized from methylcyclohexane to give 3.1 grams of 4,6-dichloro-2-(1-cyano-1-methylethylamino)-5-pyrimidinecarbonitrile; mp, 154-158°.
Reaction SMILES: I[C:2]1[C:6]2[C:7]([O:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][CH:9]=[CH:10][C:5]=2[N:4](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:3]=1.[N:37]1[C:46]2[C:41](=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[O:15]1[CH2:16][CH2:17][CH:12]([O:11][C:7]2[C:6]3[C:2]([C:42]4[CH:43]=[CH:44][CH:45]=[C:46]5[C:41]=4[CH:40]=[CH:39][CH:38]=[N:37]5)=[N:3][NH:4][C:5]=3[CH:10]=[CH:9][N:8]=2)[CH2:13][CH2:14]1
Reactant: OB(O)c1cccc2ncccc12
Reactant: Ic1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccnc(OC3CCOCC3)c12
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: c1cc(-c2n[nH]c3ccnc(OC4CCOCC4)c23)c2cccnc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
To a microwave tube was added 3-iodo-4-(tetrahydro-2H-pyran-4-yloxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine (120 mg, 0.20 mmol), quinolin-5-ylboronic acid (43 mg, 0.25 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (14 mg, 0.02 mmol), a 2 M aqueous solution of sodium carbonate (0.20 mL) and acetonitrile (1.5 mL, 0.029 mmol). The tube was then sealed and the reaction was irradiated in a microwave reactor at 140° C. for 30 minutes. The reaction mixture was filtered through Celite® and concentrated. The crude residue was then dissolved in DCM (3 mL) and cooled to 0° C. To the cooled reaction mixture was added triethylsilane (0.13 mL, 0.80 mmol) and trifluoroacetic acid (3.0 mL, 0.039 mmol). The mixture was stirred at room temperature for 30 minutes before concentrated under vacuum. The resulting residue was re-suspended in methanol and filtered to remove insoluble solids. The filtrate was concentrated and purified by reverse-phase HPLC to give the title compound (30 mg, 43%). LC-MS (Method G): m/z=347.1 [M+H]+; 2.98 min. 1H-NMR (400 MHz, DMSO): δ 13.69 (s, 1H), 8.94 (s, 1H), 8.23 (d, J=8.4, 1H), 8.14 (d, J=8.3, 1H), 7.89 (m, 2H), 7.78 (d, J=6.8, 1H), 7.49 (m, 1H), 7.22 (m, 1H), 5.28 (m, 1H), 3.24 (m, 2H), 3.06 (m, 2H), 1.69 (m, 2H), 1.17 (m, 3H).
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.Cl[C:33]1[O:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1>O1CCCC1>[O:34]1[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=[C:33]1[N:13]1[CH2:14][CH2:15][N:10]2[C:9](=[O:16])[O:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:11]2[CH2:12]1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Reactant: Clc1nc2ccccc2o1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C1OC(c2ccccc2)(c2ccccc2)C2CN(c3nc4ccccc4o3)CCN12
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
To a solution of hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (60 mg, 0.2 mmol) in tetrahydrofuran (2 mL) were sequentially added diisopropylethylamine (0.3 mL) and 2-chlorobenzoxazole (45 mg, 0.29 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure. Then, the residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1) and recrystallized from diisopropyl ether to obtain the title compound (51 mg, yield 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([S:15]([OH:17])=[O:16])=[C:7]1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[Cl:27]N1C(=O)CCC1=O.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([S:15]([Cl:27])(=[O:17])=[O:16])=[C:7]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1c(S(=O)O)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(S(=O)(=O)Cl)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Yield: 51.9 %

Procedure:
N-(3,4-Dichlorobenzyl)-2-ethoxycarbonylindole-3-sulphinic acid (0.48 g), N-chlorosuccinimide (0.16 g) and triethylamine (0.16 ml) were stirred in dichloromethane for 4 hours. The reaction was then concentrated in vacuo and the residue purified by chromatography using iso-hexane:10% ethyl acetate as eluent to give the product as a white crystalline solid (0.27 g, 52%); NMR d (CD3SOCD3) 1.43 (t, 3H), 4.48 (q, 2H), 5.53 (s, 2H), 6.98 (m, 1H), 7.30-7.50 (m, 5H), 8.22 (m, 1H); M/z (−) 444 (M−H+), 426, 410.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[NH:10][N:9]=2)=[CH:4][C:3]=1[CH3:14].[H-].[Na+].I[CH3:18].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:18])[C:11]([CH3:13])=[N:10][N:9]=2)=[CH:4][C:3]=1[CH3:14]
Reactant: Cc1nc(-c2ccc(Br)c(C)c2)n[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2nnc(C)n2C)ccc1Br
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
3-(4-Bromo-3-methylphenyl)-5-methyl-1,2,4-triazole (D62, 0.60 g, 2.4 mmol) was stirred under Ar in dry DMF (6 ml) as sodium hydride (80% dispersion, 0.21 g, 7.2 mmol) was added. After stirring for 30 min, iodomethane (0.3 ml, 4.8 mmol) was added. This mixture was stirred for 1 h, and treated with water (30 ml), giving a beige precipitate. This was filtered off and dried, giving the title compound (0.49 g, 77%) as a beige solid. 1H NMR (250 MHz, d6DMSO) δ(ppm): 7.92 (s, 1H), 7.65 (m, 2H), 3.80 (s, 3H), 2.44 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:6])=O.[NH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][NH:25][S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]2[C:44]3[C:39](=[C:40]([Cl:46])[CH:41]=[C:42]([Cl:45])[CH:43]=3)[CH2:38][N:37]([CH3:47])[CH2:36]2)[CH:30]=1)(=[O:28])=[O:27]>>[Cl:45][C:42]1[CH:43]=[C:44]2[C:39](=[C:40]([Cl:46])[CH:41]=1)[CH2:38][N:37]([CH3:47])[CH2:36][CH:35]2[C:31]1[CH:30]=[C:29]([S:26]([NH:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][NH:13][C:4](=[O:6])[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1]([NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][NH:25][S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]3[C:44]4[C:39](=[C:40]([Cl:46])[CH:41]=[C:42]([Cl:45])[CH:43]=4)[CH2:38][N:37]([CH3:47])[CH2:36]3)[CH:30]=2)(=[O:28])=[O:27])=[O:12])(=[O:28])=[O:27])[CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)c1ccccc1C(=O)O
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN)c2)C1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCNC(=O)c3ccccc3C(=O)NCCOCCOCCOCCNS(=O)(=O)c3cccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)c3)c2)C1
Yield: 59.8 %

Procedure:
Compound 230 was prepared by following the procedure outlined in Example 215 using phthalic acid (8.0 mg, 0.0484 mmol) and N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (Compound 28, 75 mg, 0.0968 mmol). Purification by preparative HPLC gave the title compound (35.4 mg) as a TFA salt. 1H-NMR (400 MHz, CD3OD): δ 7.87 (d, 2H), 7.76 (s, 2H), 7.63 (t, 2H), 7.50 (m, 8H), 6.79 (s, 2H), 4.83-4.73 (m, 4H), 4.65 (d, 2H), 3.85 (q, 2H), 3.62-3.39 (m, 36H), 3.10 (s, 6H), 3.02 (t, 4H). MS (m/z): 1223.00 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].C1(C)C(S(O[CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)(=O)=O)=CC=CC=1>>[CH:32]1([CH2:31][N:7]2[C:8]([C:9](=[O:18])[C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]2=[O:19])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: Cc1ccccc1S(=O)(=O)OCC1CCCC1
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(CC2CCCC2)c(=O)[nH]c1=O
Yield: 56.4 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and (cyclopentyl)-methyl toluenesulfonate were reacted by the same method with example 20 to obtain the titled compound. (80 mg)
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[CH:20]1([NH:23][CH2:24][C@@H:25]2[C@H:29]([F:30])[CH2:28][NH:27][CH2:26]2)[CH2:22][CH2:21]1>>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:27]4[CH2:28][C@@H:29]([F:30])[C@@H:25]([CH2:24][NH:23][CH:20]5[CH2:21][CH2:22]5)[CH2:26]4)[N:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: F[C@@H]1CNC[C@@H]1CNC1CC1
Product: O=C(O)c1cn(C2CC2)c2nc(N3C[C@H](CNC4CC4)[C@H](F)C3)c(F)cc2c1=O
Yield: 19.6 %

Procedure:
Using 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (283 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (190 mg), the same procedure was followed as in Example 23 to give 1-cyclopropyl-7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid as a white powder (79.4 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([NH:7][CH:8]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:17]=1)[C:9]1[C:14]([Cl:15])=[N:13][CH:12]=[CH:11][N:10]=1)=O)[CH3:2]>O=P(Cl)(Cl)Cl.CN(C=O)C>[CH2:1]([O:3][C:4]([C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:14]([Cl:15])[C:9]2=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:17]=2)[N:7]=1)=[O:30])[CH3:2]
Reactant: CCOC(=O)C(=O)NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(-c2cccc(OCc3ccccc3)c2)c2c(Cl)nccn12
Temperature: 75 °C

Procedure:
A solution of N-[(3-benzyloxy-phenyl)-(3-chloro-pyrazin-2-yl)-methyl]-oxalamic acid ethyl ester (50 mg, 0.12 mmol) in POCl3 (2 mL) was heated to 55° C. for 17.5 h. Very little reaction occurred therefore DMF (3 drops) was added to reaction mixture and heated to 75° C. overnight. The brown reaction mixture was allowed to cool to rt, concentrated in vacuo and then quenched with 2M NH3 in i-PrOH at 0° C. until the pH was basic. The reaction mixture was concentrated in vacuo and the crude material was purified by chromatography on silica gel [eluting with 2% EtOAc in DCM], resulting in the title compound as an off-white solid; 1H NMR (CDCl3, 400 MHz) δ 1.48 (t, J=7.2 Hz, 3H), 4.56 (q, J=7.2 Hz, 2H), 5.13 (s, 2H), 7.05-7.09 (m, 1H), 7.22-7.29 (m, 2H), 7.29-7.47 (m, 6H), 7.67 (d, J=5.2 Hz, 1H), 9.15 (d, J=5.2 Hz, 1H); MS (ES+): m/z=408.07 (100) [MH+], HPLC: tR=3.88 min (MicromassZQ, polar—5 min).
Reaction SMILES: [N+:1]([C:4]1[CH:38]=[CH:37][C:7]([CH2:8][O:9][C:10]([O:12][C@@H:13]([C@H:15]2[C:21](=[O:22])[N:20]3[C@@H:16]2[CH2:17][C:18](=O)[C@@H:19]3[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[NH2:63][C:64]1[S:65][CH:66]=[C:67]([C@@H:69]2[CH2:73][C@H:72]([SH:74])[CH2:71][N:70]2[C:75]([O:77][CH2:78][C:79]2[CH:84]=[CH:83][C:82]([N+:85]([O-:87])=[O:86])=[CH:81][CH:80]=2)=[O:76])[N:68]=1>ClCCl>[NH2:63][C:64]1[S:65][CH:66]=[C:67]([C@@H:69]2[CH2:73][C@H:72]([S:74][C:18]3[CH2:17][C@H:16]4[N:20]([C:21](=[O:22])[C@@H:15]4[C@H:13]([O:12][C:10]([O:9][CH2:8][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:38][CH:37]=4)=[O:11])[CH3:14])[C:19]=3[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])[CH2:71][N:70]2[C:75]([O:77][CH2:78][C:79]2[CH:84]=[CH:83][C:82]([N+:85]([O-:87])=[O:86])=[CH:81][CH:80]=2)=[O:76])[N:68]=1
Reactant: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Reactant: Nc1nc([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cs1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](c4csc(N)n4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)C[C@H]12
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of 4-nitrobenzyl (2R,5R,6S)-6-[(1R)-1- (4-nitrobenzyloxycarbonyloxy)ethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate (1.92 g) in dichloromethane (50 ml) were added N,N-diisopropyl-N-ethylamine (0.76 ml) and trifluoromethanesulfonic anhydride (0.73 ml) at -30° C., and the solution was stirred at the same temperature for 30 minutes. To this solution was added (2S, 4S)-2-(2-aminothiazol-4-yl)-4-mercapto-1- (4-nitrobenzyloxycarbonyl)pyrrolidine (1.13 g) in dichloromethane (20 ml) at -30° C. and the solution was stirred at 0° C. for 3 hours. The mixture was washed in turn with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The oily residue was chromatographed on silica gel (60 g) eluting with a mixture of dichloromethane and acetone (5:1 V/V) to give 4-nitrobenzyl (5R,6S)-3-[(2S,4S)-2-(2-aminothiazol-4-yl) -1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(1R)-1-(4-nitrobenzyloxycarbonyloxy) ethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (1.85 g).