Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]=[C:9]=[S:10])[CH:3]=1.[NH2:11][C:12]1[S:16][C:15]([S:17]([NH2:20])(=[O:19])=[O:18])=[N:14][N:13]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[I:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[S:10])[NH:11][C:12]2[S:16][C:15]([S:17]([NH2:20])(=[O:19])=[O:18])=[N:14][N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: S=C=Nc1cccc(I)c1
Reactant: Nc1nnc(S(N)(=O)=O)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NS(=O)(=O)c1nnc(NC(=S)Nc2cccc(I)c2)s1
Temperature: 75 °C
Reaction time: 4 h
Yield: 44.9 %

Procedure:
To a solution of 1-iodo-3-isothiocyanatobenzene (0.13 g, 0.50 mmol) in acetonitrile (10 mL) was added 5-amino-1,3,4-thiadiazole-2-sulfonamide (0.108 g, 0.50 mmol) and anhydrous K2CO3 (0.40 g). The mixture was stirred at 75° C. for 4 hrs. Solvent was evaporated and diluted with water. The precipitated solid was filtered and dried over vacuum to give desired compound (99 mg, 45%) as a white solid. 1H NMR (400 MHz, DMSO) δ 8.99 (brs, 1H), 8.24 (brs, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.69 (t, J=1.8 Hz, 1H), 7.35 (m, 1H), 7.26 (t, J=7.8 Hz, 1H), 7.02 (s, 2H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:29])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH3:28])([CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=1)[CH2:9][CH2:8]2)(=[O:3])[CH3:2].[H][H]>CO.C1C=CC=CC=1.C(OCC)(=O)C.[Pd]>[C:1]([O:4][C:5]1[C:6]([CH3:29])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=1)([CH3:28])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc([N+](=O)[O-])cc1)O2
Agent: [Pd]
Solvent: c1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc(N)cc1)O2

Procedure:
24.3 g of 6-acetoxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman were dissolved in a mixture of 200 ml of methanol and 20 ml of benzene and reacted for 3 hours under a hydrogen pressure of 45-55 lb/sq. inch (3.1-3.8 bars), using Pearl's hydrogen adding apparatus, in the presence of 7 g of 10% w/w palladium-on-carbon. The palladium-on-carbon was removed by filtration from the reaction mixture and washed with a mixture of 600 ml of acetone and 60 ml of concentrated hydrochloric acid. The filtrate and the washings were combined and the mixture was neutralized with sodium bicarbonate. The solvent was then distilled off, and the crude crystals obtained were dissolved in ethyl acetate. The ethyl acetate solution was washed with water and dried over anhydrous sodium sulfate. The ethyl acetate was then distilled from the extract, and the crude substance obtained was washed with a 1:1 by volume mixture of benzene and cyclohexane, giving the desired 6-acetoxy-2-(4-aminophenoxymethyl)-2,5,7,8-tetramethylchroman, melting at 138°-140° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[C:7]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[N:8]=[C:9]([NH:12][C:13]3([C:16]([F:19])([F:18])[F:17])[CH2:15][CH2:14]3)[C:10]=2[N:11]=1.[CH3:32][S:33]([C:36]1[CH:37]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:39]=[CH:40][C:41]=1[O:42][CH3:43])(=[O:35])=[O:34].C(=O)(O)[O-].[Na+]>COCCOC>[CH3:32][S:33]([C:36]1[CH:37]=[C:38]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]=[C:7]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=4)[N:8]=[C:9]([NH:12][C:13]4([C:16]([F:18])([F:19])[F:17])[CH2:15][CH2:14]4)[C:10]=3[N:11]=2)[CH:39]=[CH:40][C:41]=1[O:42][CH3:43])(=[O:34])=[O:35]
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1S(C)(=O)=O
Reactant: NS(=O)(=O)c1ccc(CNc2nc(NC3(C(F)(F)F)CC3)c3nc(Cl)ccc3n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2ccc3nc(NCc4ccc(S(N)(=O)=O)cc4)nc(NC4(C(F)(F)F)CC4)c3n2)cc1S(C)(=O)=O
Temperature: 65 °C
Yield: 39.1 %

Procedure:
4-{[6-Chloro-4-(1-trifluoromethyl-cyclopropylamino)-pyrido[3,2-d]pyrimidin-2-ylamino]-methyl}benzenesulfonamide (0.100 g, 0.23 mmol) was combined with 2-(3-methanesulfonyl-4-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.091 g, 0.34 mmol, see Scheme 7), palladium tetrakistriphenylphosphine (0.013 g, 0.011 mmol) and sodium bicarbonate (1.5 mL of a saturated aqueous solution). The mixture was suspended in DME (3 mL) and heated to 65° C. for 1 h. Crude product was precipitated by the addition of water (5 mL). The precipitate was filtered and purified by reverse phase HPLC (5-100% ACN/H2O+0.1% TFA) to give 0.056 g (40% yield) of the title compound, and was characterized by its NMR and mass spectrum as follows: 1H NMR (d6-DMSO): d 1.38-1.26 (m, 4H), 3.31 (s, 3H), 4.06 (s, 3H), 4.79 (m, 2H), 7.34 (s, 2H), 7.46 (d, J=8.7 Hz, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.78 (d, J=8.4 Hz, 2H), 8.01 (d, J=9.0 Hz, 1H), 8.45-8.41 (m, 2H), 8.90 (d, J=11.4 Hz, 1H), 9.08 (bs, 1H), 10.15 (bs, 1H): MS (m/z): 623.2 ([M+H]+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:24]([N:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)=[CH:31][C:30]([CH:40]=O)=[N:29]1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([N:28]1[C:32]([C:33]2[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=2)=[CH:31][C:30]([CH2:40][NH:21][CH2:20][CH2:19][N:16]2[CH2:15][CH2:14][N:13]([CH:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:23][CH:22]=3)[CH2:18][CH2:17]2)=[N:29]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1ccc(-c2cc(C=O)nn2C(C)(C)C)cc1
Reactant: NCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Product: Cc1ccc(-c2cc(CNCCN3CCN(C(c4ccccc4)c4ccc(Cl)cc4)CC3)nn2C(C)(C)C)cc1
Yield: 41 %

Procedure:
Compound 99 was prepared using the same method as that of Example 1 except for using 4-(4-chlorobenzhydryl)piperazin-1-ylethylamine and 1-t-butyl-5-(4-methylphenyl)pyrazole-3-carbaldehyde.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1[CH3:19])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:28][C:29]1[CH:34]=[C:33]([CH2:35]OS(C)(=O)=O)[CH:32]=[C:31]([NH:41][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)[N:30]=1.[I-].[Li+]>CN(C=O)C.C(OCC)(=O)C>[F:28][C:29]1[CH:34]=[C:33]([CH2:35][N:8]2[C:9]([O:10][C:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=3[CH3:19])=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]2=[O:20])[CH:32]=[C:31]([NH:41][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)[N:30]=1
Reactant: Cc1cc(C)c(C)c(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: COc1ccc(CNc2cc(COS(C)(=O)=O)cc(F)n2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CNc2cc(Cn3c(Oc4cc(C)cc(C)c4C)c(C(C)C)c(=O)[nH]c3=O)cc(F)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.8 %

Procedure:
5-Isopropyl-6-(2,3,5-trimethyl-phenoxy)-1H-pyrimidine-2,4-dione (39 mg, 0.135 mmol) was dissolved in 1.5 mL DMF. Potassium carbonate (31 mg, 2 eq.) was added and the reaction was stirred at room temperature for 10 minutes. Methanesulfonic acid 2-fluoro-6-(4-methoxy-benzylamino)-pyridin-4-ylmethyl ester (0.135 mmol) and lithium iodide (15 mg, 1 eq.) were added. The reaction was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, followed by washing with brine. The organic layer was concentrated down and purified (silica gel, 0-80% EtOAC/hexane) to give white powder (25 mg, 42%). LC-MS shows 533.1 (M+1). 1H NMR (300 MHz, CDCl3): δ 8.68 (b, 1H), 7.22 (d, 2H), 6.86 (d, 2H), 6.75 (s, 1H), 6.18 (s, 1H), 5.95 (d, 2H), 4.94 (d, 1H), 4.45 (d, 1H), 4.37 (s, 2H), 3.80 (s, 3H), 2.68 (m, 1H), 2.23 (s, 3H), 2.19 (s, 3H), 2.06 (s, 3H), 1.15 (dd, 6H).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C[O:10][C@@H:11]1[C@@H:15]([CH2:16][O:17]CC2C=CC(Cl)=CC=2Cl)[O:14][C@@H:13]([N:27]2[CH:40]=[C:31]3[CH:32]=[CH:33][C:34]4[C:35](=[O:39])[NH:36][N:37]=[CH:38][C:29]([C:30]=43)=[N:28]2)[C@:12]1([CH3:42])[OH:41].B(Cl)(Cl)Cl>C(Cl)Cl>[CH3:42][C@@:12]1([OH:41])[C@H:11]([OH:10])[C@@H:15]([CH2:16][OH:17])[O:14][C@H:13]1[N:27]1[CH:40]=[C:31]2[CH:32]=[CH:33][C:34]3[C:35](=[O:39])[NH:36][N:37]=[CH:38][C:29]([C:30]=32)=[N:28]1
Reactant: C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1cc2ccc3c(=O)[nH]ncc(n1)c23
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc2ccc3c(=O)[nH]ncc(n1)c23
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 77.1 %

Procedure:
To a solution of the compound 6.5 (0.71 g, 1.1 mmol) in 30 mL of anhydrous CH2Cl2 at −78° C. was added boron trichloride (1M solution in CH2Cl2, 11 mL, 11 mmol) dropwise. The mixture was stirred at −78° C. for 2.5 h, then at −30° C. to −20° C. for 3 hr. The reaction was quenched by addition of methanolic/CH2Cl2 (1:1) (5 mL) and the resulting mixture stirred at −15° C. for 30 min., then neutralized with aqueous ammonia at 0° C. and stirred at room temperature for 15 min. The solid was filtered and washed with CH2Cl2/MeOH (1/1, 3×30 mL). Chromatography over silica gel using 5% MeOH in CH2Cl2 as eluent furnished the 282 mg of the desired compound 6.6 as a yellow solid (yield: 77.8%). 1H NMR (300 MHz, DMSO-d6) δ 10.67 (br s 1H, NH), 8.32 (s, 1H, H-4), 7.86 (s, 1H, H-1), 7.00 (d, J 12.6 Hz, H-8), 6.09 (s, 1H, H-1′), 5.63 (d, J 12.6 Hz, H-9), 5.16 (m, 3H, 3×OH), 3.95 (m, 1H, H-3′), 3.88-3.56 (m, 3H, H-4′, 2×H-5′), 0.73 (s, 3H, CH3); ES MS: 391.5 (M+CH3COO)−.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N:4]=1.[CH2:32]([N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[SH:39])[CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:32]([N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[S:39][CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N:4]=1)[CH3:33]
Reactant: CCn1ccnc1S
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(CSc2nccn2CC)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.4 %

Procedure:
A mixture of ethyl 2-chloromethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate (3.0 g), 1-ethyl-2-mercaptoimidazole (1.0 g), potassium carbonate (1.1 g) and N,N-dimethylformamide (30 ml) was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform/ethyl acetate (=3/2, v/v) gave ethyl 2-[(1-ethylimidazol-2-yl)thiomethyl]-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate (2.8 g, 78%) which was then recrystallized from ethyl acetate-hexane.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][NH:15][CH:14]([CH3:22])[CH2:13][C:12]2=1)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:22][CH:14]1[CH2:13][C:12]2[C:11]3[C:19](=[CH:20][CH:21]=[C:9]([OH:8])[CH:10]=3)[NH:18][C:17]=2[CH2:16][NH:15]1
Reactant: CC1Cc2c([nH]c3ccc(OCc4ccccc4)cc23)CN1
Agent: [Pd]
Solvent: CCO
Product: CC1Cc2c([nH]c3ccc(O)cc23)CN1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.3 %

Procedure:
A solution of 6-benzyloxy-3-methyl-2,3,4,9-tetrahydro-1H-β-carboline (60 mg) in ethanol (4 mL) was added to a suspension of 10% Pd/C (100 mg) in ethanol (10 mL). The mixture was stirred at rt for 16 h under an atmosphere of hydrogen. The mixture was filtered through celite and evaporation of the filtrate yielded 3-methyl-2,3,4,9-tetrahydro-1H-β-carbolin-6-ol (30 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.CC1C=CC(C2[O:21]C=CN=2)=CC=1>>[O:12]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH:1]=[O:21])=[CH:7][CH:6]=2)=[N:9][CH:10]=[N:11]1
Reactant: Cc1ccc(-c2ncco2)cc1
Reactant: Cc1ccc(-c2ncno2)cc1
Product: O=Cc1ccc(-c2ncno2)cc1

Procedure:
The title compound is prepared by a procedure analogous to Step B of Reference Example 73 by substituting the 5-(4-methylphenyl)-1,2,4-oxadiazole from Step A above for the 2-(4-methylphenyl)oxazole of Step B of Reference Example 73. MS 175 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][N:14]=[C:13]([N:18]3[CH:22]=[C:21]([CH2:23][O:24][CH3:25])[N:20]=[CH:19]3)[CH2:12][CH:7]12.CO[C:28]1C=CC=C(OC)[C:33]=1[C:34]1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C1(B(O)O)CC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:34]1([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][N:6]2[C:16](=[O:17])[CH2:15][N:14]=[C:13]([N:18]4[CH:22]=[C:21]([CH2:23][O:24][CH3:25])[N:20]=[CH:19]4)[CH2:12][CH:7]23)[CH2:33][CH2:28]1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: COCc1cn(C2=NCC(=O)N3CCc4c(Br)cccc4C3C2)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: COCc1cn(C2=NCC(=O)N3CCc4c(C5CC5)cccc4C3C2)cn1
Temperature: 100 °C
Reaction time: 0.05 h
Yield: 70.4 %

Procedure:
Example 143. 9-bromo-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-1,7,8,12b-tetrahydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (148 mg, 0.367 mmol) was dissolved in toluene (3.6 mL) and S-Phos (49 mg, 0.117 mmol), cyclopropylboronic acid (66 mg, 0.734 mmol) and K3PO4 (164 mg, 0.771 mmol) were added. The suspension was degassed, Pd(OAc)2 (17 mg, 0.073 mmol) was added under Argon and the mixture was heated at 100° C. for 1.5 h. The mixture was allowed to warm to RT and filtered through a pad of celite and the solvent was removed under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (Biotage Isolera Four, eluent: 1% MeOH in DCM for 3 min, then from 1% MeOH in DCM to 4% MeOH in DCM in 12 min, 4% MeOH in DCM for 3 min) to yield a yellow foam. Further purification by SFC (column: 2-Ethylpyridine 5 μm, 250×30 mm, 60A, Princeton; eluent: 11% MeOH/CO2 for 1 min, then from 11% MeOH/CO2 to 16% MeOH/CO2 in 6 min; flow 100 mL/min; UV detection at 220 nm) gave the title compound as white foam (30 mg). UPLC-MS: MS 365.3 (M+H+); UPLC rt 0.85 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.51-0.66 (m, 2 H), 0.86-0.98 (m, 2 H), 1.86-2.00 (m, 1 H), 2.97-3.09 (m, 2 H), 3.21 (s, 3 H), 3.54-3.66 (m, 1 H), 3.67-3.77 (m, 1 H), 4.11-4.30 (m, 3 H), 5.26 (d, J=15.31 Hz, 1 H), 5.73 (dd, J=9.91, 4.89 Hz, 1 H), 6.95 (d, J=7.28 Hz, 1 H), 7.12-7.21 (m, 1 H), 7.21-7.27 (m, 1 H), 7.57 (s, 1 H), 8.10 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:6]([C:7](O)=[O:8])=[C:5]([N+:20]([O-:22])=[O:21])[CH:4]=1.C(Cl)(=O)C(Cl)=O.O.[OH-].[NH4+:31]>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:6]([C:7]([NH2:31])=[O:8])=[C:5]([N+:20]([O-:22])=[O:21])[CH:4]=1
Reactant: [NH4+]
Reactant: COc1cc([N+](=O)[O-])c(C(=O)O)cc1OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])c(C(N)=O)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
To a suspension of 4-methoxy-5-benzyloxy-2-nitrobenzoic acid (10.0 g, 33.3 mmol) in anhydrous THF (100 mL) was added oxalyl chloride (4.90 mL, 56.2 mmol) followed by one drop of anhydrous DMF. The mixture was stirred at RT for 16 h, upon which the mixture was poured into water (300 mL) and ammonium hydroxide (50 mL). A solid was separated out, which was collected by filtration and dried under vacuo. The solid was taken up in refluxing methanol (500 mL) and the insoluble solid was collected via filtration and dried under vacuum to give 4-methoxy-5-benzyloxy-2-nitrobenzamide (6.50 g, 21.5 mmol, 65%). HPLC retention time 6.154 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:9]([O-])([OH:11])=[O:10]>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[C:7]([OH:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1cccnc1Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1ccnc(Cl)c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
A solution of 2-chloro-3-pyridinol (11.3 g, 87.2 mmol) in concentrated sulfuric acid (25 mL) was cooled in an ice-bath and a 1:1 mixture of nitric acid and sulfuric acid (25 mL) was added slowly. After everything was added, solution was stirred at 0° C. for 1 hour and then at room temperature for another hour. Mixture was diluted with water and extracted with methylene chloride. Organic phases were dried over magnesium sulfate, filtered, and concentrated. Residue was purified by column chromatography on silica gel (ethyl acetate/hexane 2:1→3:1) to give 2-chloro-4-nitro-pyridin-3-ol as a tanned solid (3.58 g, 24%). 1HNMR (CDCl3, 400 MHz) δ 10.5 (s, 2H), 8.14-8.13 (d, J=5.5 Hz, 1H), 7.88-7.87 (d, J=5.5 Hz, 1H).
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:11]([C:12]([O:14]C)=[O:13])=[C:10]([C:16]([O:18]C)=[O:17])[S:9][N:8]=2)[CH:2]=1.[OH-].[Na+]>O>[C:1]1([CH3:20])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:11]([C:12]([OH:14])=[O:13])=[C:10]([C:16]([OH:18])=[O:17])[S:9][N:8]=2)[CH:2]=1
Reactant: COC(=O)c1snc(-c2cccc(C)c2)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc(-c2nsc(C(=O)O)c2C(=O)O)c1

Procedure:
Dimethyl 3-(m-tolyl)-4,5-isothiazoledicarboxylate (14.03 g, 0.0548 mol) was hydrolyzed in NaOH (10.96 g, 0.274 mol) and 50 ml H2O for 0.5 hours at reflux. Acidification with HCl, extraction with ether and recrystallization gave a light yellow solid, m.p. 166.5°-167° with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH2:35][CH2:36][CH3:37])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[C:34]([NH:33][C:29]1[CH:28]=[C:27]([CH:24]2[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][CH2:18][NH:17][C:14]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]3)=[O:16])[CH2:22][CH2:23]2)[CH:32]=[CH:31][CH:30]=1)(=[O:38])[CH2:35][CH2:36][CH3:37]
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCCC1
Reactant: CCCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CCCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCCCC3)CC2)c1

Procedure:
Example 99 was prepared from 1-(4-chlorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.52 (s, 1H), 7.38–7.35 (m, 2H), 7.30–7.22 (m, 4H), 6.93 (d, 1H, J=7.6 Hz), 6.87 (br s, 1H), 3.28 (dd, 2H, J=6.0, 12.0 Hz), 2.92 (d, 2H, J=11.6 Hz), 2.45 (m, 1H), 2.36–2.30 (m, 6H), 1.96–1.33 (m, 18H), 1.00 (t, 3H, J=7.6 Hz); ESMS m/e: 524.3 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].CN(C)C(N(C)C)=N.[CH:19]#[C:20][CH3:21].[Na+].[Cl-]>CN(C=O)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[CH:19]=[C:20]([CH3:21])[O:10][C:3]=2[CH:4]=1
Reactant: C#CC
Reactant: COc1ccc(I)c(O)c1
Agent: CN(C)C(=N)N(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2cc(C)oc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
A pressure tube was charged with a stir bar 2-Iodo-5-methoxyphenol (500 mg, 2.0 mmol) (prepared according to Heterocycles 45, (6), 1997, 1137), Cl2Pd(PPh3)2 (70 mg, 0.1 mmol), Cul (19 mg, 0.1 mmol), 1,1,3,3-Tetramethylguanidine (2.5 ml, 20.0 mmol) and DMF (10 ml), then cooled to −78° while propyne gas was condensed. The tube was sealed and allowed to warm to room temperature. After 18 hours, the contents of the tube were poured into sat NaCl solution and extracted with EtOAc (2×). The combined organic layers were washed with brine (3×), dried (MgSO4) and concentrated under reduced pressure. The residue was flash chromatographed on silica gel eluting 3:1 (hexanes/ethyl acetate) to give 239 mg (74%) of an amber liquid. 1H NMR (DMSO-d6) δ 7.31 (1H, d, J=8.3 Hz), 6.95 (1H, d, J=2.2 Hz), 6.80 (1H, dd, J=2.2, 8.3 Hz), 6.27 (1H, s), 3.85 (3H, s), 2.40 (3H, s). Anal. Calcd for C10H10O2.0.05 hexanes: C, 74.30; H, 6.48. Found: C, 74.63; H, 6.48.
Reaction SMILES: [CH:1]([O:14][C:15]([CH:17]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:18]([NH:20][CH:21]1[C:40](=[O:41])[N:23]2[C:24]([C:29]([O:31][CH2:32][O:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:30])=[C:25]([CH3:28])[C:26](=[O:27])[C@H:22]12)=[O:19])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(C(C1C=CC=CC=1)C(NC1C(=O)N2C(C(OCOC(=O)C(C)(C)C)=O)C(C)C(=O)[C@H]12)=O)=O)C1C=CC=CC=1.CC1C(C([O-])=O)N2C(=O)C(NC(=O)C(C(OCC3C=CC4C(=CC=CC=4)C=3)=O)C3C=CC=CC=3)[C@H]2C1=O>>[CH:1]([O:14][C:15]([CH:17]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:18]([NH:20][CH:21]1[C:40](=[O:41])[N:23]2[CH:24]([C:29]([O:31][CH2:32][O:33][C:34](=[O:39])[C:35]([CH3:37])([CH3:38])[CH3:36])=[O:30])[CH:25]([CH3:28])[C:26](=[O:27])[C@H:22]12)=[O:19])=[O:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)C(C(=O)OC(c3ccccc3)c3ccccc3)c3ccccc3)[C@H]2C1=O
Agent: CC1C(=O)[C@@H]2C(NC(=O)C(C(=O)OCc3ccc4ccccc4c3)c3ccccc3)C(=O)N2C1C(=O)[O-]
Agent: CC1C(=O)[C@@H]2C(NC(=O)C(C(=O)OCc3ccccc3)c3ccccc3)C(=O)N2C1C(=O)OCOC(=O)C(C)(C)C
Product: CC1C(=O)[C@@H]2C(NC(=O)C(C(=O)OC(c3ccccc3)c3ccccc3)c3ccccc3)C(=O)N2C1C(=O)OCOC(=O)C(C)(C)C

Procedure:
By the same method the other carbapen-2-em esters of Example 52 are reduced to the corresponding pivaloyloxymethyl 6-(2-benzyloxycarbonyl-2-phenylacetamido)-2-methyl-1-oxocarbapenam-3-carboxylate and 2-methyl-6-[2-(2-naphthylmethoxycarbonyl)-2-phenylacetamido]-1-oxocarbapenam-3-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:14]([NH2:16])=O>>[CH:11]([C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:16][CH:14]=[N:1]2)=[CH:7][CH:8]=1)([CH3:13])[CH3:12]
Reactant: NC=O
Reactant: CC(C)c1ccc(C(=O)O)c(N)c1
Product: CC(C)c1ccc2c(=O)[nH]cnc2c1
Yield: 34 %

Procedure:
The product of Example 431D (0.579 g, 3.231 mmol) was reacted with formamide (1.3 mL) under a nitrogen atmosphere in a microwave (Personal Chemistry Emrys Creator, 300 W) at 150°C for 30 minutes. The cooled reaction gave a solid mass which was recrystallized from absolute ethanol (2 mL) to afford the title compound as an off-white solid (0.208 g, 1.105 mmol, 34%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.26 (d, J=6.99 Hz, 6 H) 2.91-3.21 (m, 1 H) 7.44 (dd, J=8.27, 1.65 Hz, 1 H) 7.50 (d, J=1.84 Hz, 1 H) 8.02-8.07 (m, 2 H) 12.15 (s, 1 H); MS (APCI) m/z 189 (M+H)+, 211 (M+Na)+.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:6]2[S:14][CH:13]=[C:12]([CH3:15])[C:7]=2[N:8]=[C:9](Cl)[N:10]=1)[CH:2]=[CH2:3].[CH2:16]([NH2:19])[CH2:17][CH3:18].C(=O)([O-])O.[Na+]>>[CH2:1]([NH:4][C:5]1[C:6]2[S:14][CH:13]=[C:12]([CH3:15])[C:7]=2[N:8]=[C:9]([NH:19][CH2:16][CH2:17][CH3:18])[N:10]=1)[CH:2]=[CH2:3]
Reactant: CCCN
Reactant: C=CCNc1nc(Cl)nc2c(C)csc12
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NCCC)nc2c(C)csc12
Yield: 40 %

Procedure:
288 mg (1.2 mmol) of 4-allylamino-2-chloro-7-methylthieno[3,2-d]pyrimidine and 1.13 mg (19.2 mmol) of propylamine were heated in a sealed tube at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate solution thereto and extraction with ethyl acetate (50 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by a silica gel chromatography (eluent: ethyl acetate-hexane=1/2) to give 126 mg (yield: 60.0%) of the title compound.