Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:13]([CH3:15])[CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:16][CH:17]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18]1>>[CH2:22]([N:19]1[CH2:20][CH2:21][CH:17]([NH:16][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[C:3]([N:13]([CH3:15])[CH3:14])=[CH:4][C:5]=2[O:11][CH3:12])[CH2:18]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1cc(N(C)C)c(Cl)cc1C(=O)O
Reactant: NC1CCN(Cc2ccccc2)C1
Product: COc1cc(N(C)C)c(Cl)cc1C(=O)NC1CCN(Cc2ccccc2)C1

Procedure:
By following general method A using 0.85 g. of 5-chloro-4-dimethylamino-2-methoxybenzoic acid and 0.65 g. of 3-amino-1-benzylpyrrolidine, 0.8 g. of N-(1-benzyl-3-pyrrolidinyl)-5-chloro-4-dimethylamino-2-methoxybenzamide was obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].Cl[S:27]([C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33]([OH:35])=[O:34])(=[O:29])=[O:28]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:27]([C:30]4[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=4)[C:33]([OH:35])=[O:34])(=[O:29])=[O:28])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cccc(C(=O)O)c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 3-(chlorosulfonyl)benzoic acid as starting compounds. Instead of using the work-up procedure described for GP1, the following procedure is used. After the reaction has been quenched with 1 M aqueous sodium carbonate solution, the phases are separated and the aqueous phase is slightly acidified with aqueous hydrochloric acid. The aqueous phase is extracted with DCM, the organic phase dried with MgSO4 and the solvent is removed under reduced pressure to yield the title compound.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[C:13]([O:17][C:18](=[O:26])[N:19]([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][CH3:22])([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[C:13]([O:17][C:18](=[O:26])[N:19]([CH2:23][CH2:24][O:25][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([O:8][CH3:9])[N:7]=1)[CH2:20][CH2:21][CH3:22])([CH3:14])([CH3:15])[CH3:16]
Reactant: CCCN(CCO)C(=O)OC(C)(C)C
Reactant: COc1nc(Br)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCN(CCOc1ccc([N+](=O)[O-])c(OC)n1)C(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 4 h
Yield: 36.8 %

Procedure:
A mixture of 6-bromo-2-methoxy-3-nitropyridine (5 g, 21.46 mmol), (2-hydroxy-ethyl)-propyl-carbamic acid tert-butyl ester (4.36 g, 21.46 mmol) and K2CO3 (2.97 g, 21.46 mmol) in dimethylformamide (DMF) (60 ml) was stirred at room temperature for 24 h and at 40° C. for 4 h. After evaporation of the solvent under reduced pressure the residue was purified by silica gel chromatography with dichloromethane/methanol (10:0; 9:1; 7:3; 0:10) as eluent to provide 2.81 g (36.9%) of the product.
Reaction SMILES: [CH:1]([NH:3][C@H:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]#[N:6])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>C1C=CC=CC=1>[NH2:6][C:5]1[S:21][CH:1]=[N:3][C:4]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)[C@H](C#N)NC=O
Solvent: c1ccccc1
Product: CCOC(=O)c1ncsc1N

Procedure:
Ethyl N-formyl-3-nitriloalaninate (11.22 g, 71.86 mmol) is dissolved in anhydrous benzene (220 mL). Following the addition of Lawesson's reagent (14.53 g, 35.93 mmol), the suspension is refluxed for 24 h. Most of the solvent is removed in vacuo, and the viscous red residue is absorbed on silica gel and loaded to a silica gel column (elution solvent: EtOAc:hexanes=50:50). The title compound is obtained as yellow solids. 1H NMR (400 MHz, CDCl3) 7.87 (1H, s), 7.26 (1 H, s), 6.01 (2H, broad s), 4.38 (2H, q), 1.41 (3H, t).
Reaction SMILES: [CH2:1]([O:8][C:9](N1C(=O)CCC1=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:19][CH:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:19][CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1C(=O)OCc1ccccc1
Reactant: CCOC(=O)C(N)C(=O)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
N-(Benzyloxycarbonyl)succinimide (5.6 g, 22.4 mmol) was dissolved in CH2Cl2 (25 mL) and the solution was added to a cooled (0° C.) and stirred solution of diethyl aminomalonate hydrochloride (5.0 g, 23.6 mmol) and triethylamine (13.4 mL, 95 mmol) in CH2Cl2 (125 ml). The resulting solution was stirred at 0° C. for 10 min and then at rt for 1 h. The solution was washed with 10% citric acid (2×50 mL),10% sodium hydrogen carbonate (2×50 mL), and water (50 mL) and was then dried (Na2SO4) and evaporated to afford diethyl N-benzyloxycarbonylaminomalonate as a colorless oil, which crystallized upon standing at 0° C. (6.3 g) (LC/Mass + ion): 310 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(N(CC)CC)C.Br[CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[N:23][CH:24]=1>C(O)C>[CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[N:23][CH:24]=2)[N:5]=[C:4]([OH:9])[CH:3]=1
Reactant: BrCc1cncnc1
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2cncnc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 1.5 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (483 mg, 3.4 mmol) was dissolved in absolute ethanol (70 mL), and triethylamine (1.4 mL, 10.2 mmol) and 5-(bromomethyl)pyrimidine (882 mg, 5.1 mmol) were added. The mixture was stirred overnight at room temperature. The solid was filtered. The filtrate was evaporated. The residue was triturated in water, filtered, and washed with water followed with diethyl ether. The solid was dissolved in DCM and purified on silica gel using 10% DCM/MeOH to afford 6-methyl-2-[(pyrimidin-5-ylmethyl)sulfanyl]pyrimidin-4-ol (12 mg, 2% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.19 (s, 3H), 4.34 (s, 2H), 6.02 (bs, 1H), 8.88 (s, 2H), 9.05 (s, 1H); LRMS (ES) m/z 235 (100%, M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)=O.[C:19]([C:22]1[CH:23]=[CH:24][C:25]([OH:31])=[C:26]([CH:30]=1)[C:27]([OH:29])=[O:28])(=[O:21])[CH3:20]>[OH-].[Na+].O.C(O)(=O)C>[OH:31][C:25]1[CH:24]=[CH:23][C:22]([C:19](=[O:21])[CH:20]=[CH:1][C:3]2[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)(=[O:11])=[O:10])=[CH:5][CH:4]=2)=[CH:30][C:26]=1[C:27]([OH:29])=[O:28]
Reactant: CC(=O)c1ccc(O)c(C(=O)O)c1
Reactant: O=Cc1ccc(S(=O)(=O)Nc2ccccn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(C=Cc1ccc(S(=O)(=O)Nc2ccccn2)cc1)c1ccc(O)c(C(=O)O)c1

Procedure:
4-Formyl-N-(2-pyridinyl)benzenesulfonamide (5.7 g, 0.022 mol), 5-acetyl-2 -hydroxybenzoic acid (6.64 g, 0.044 mol) in 5M sodium hydroxide (20 ml) were stirred for 3 days at room temperature. The solution was diluted with water (100 ml) and acetic acid added dropwise in excess. The precipitate was collected by filtration and washed with water. After drying, the material was recrystallized from acetic acid and dried at 120° C. in vacuo. Yield 6.4 g, 66%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([N:11]2[C:15](=[O:16])[CH2:14][C@@H:13]([CH:17]=[O:18])[CH2:12]2)[CH3:10])=[CH:5][CH:4]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C[Si](C)(C)[C:39]([F:42])([F:41])[F:40]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([N:11]2[CH2:12][C@H:13]([CH:17]([OH:18])[C:39]([F:42])([F:41])[F:40])[CH2:14][C:15]2=[O:16])[CH3:10])=[CH:5][CH:4]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H](C=O)CC2=O)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: Cc1ccccc1
Product: COc1ccc([C@@H](C)N2C[C@H](C(O)C(F)(F)F)CC2=O)cc1
Temperature: -60 °C

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of (3R)-1-[(1R)-1-(4-methoxyphenyl)ethyl]-5-oxopyrrolidine-3-carbaldehyde 1.07 (7 g, 28.31 mmol, 1.00 equiv) in toluene (100 mL), trimethyl(trifluoromethyl)silane (2.9 mL), followed by the addition of tetrabutylammonium fluoride (1 mol/L in tetrahydrofuran) (1.53 mL) dropwise with stirring at −60° C. The resulting solution was stirred overnight at room temperature, quenched by the addition of 100 mL of water/ice and extracted with 3×300 mL of ethyl acetate. The organic layers were combined, washed with 3×300 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluting with dichloromethane: methanol (200:1-80:1) to afford (4R)-1-[(1R)-1-(4-methoxyphenyl)ethyl]-4-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-2-one. The diastereomers were separated by chiral HPLC (CHIRALPAK IC), and the later eluting diastereomer was collected to afford (R)-1-((R)-1-(4-methoxyphenyl)ethyl)-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-2-one 1.29. This compound is the earlier diastereomer under RP-HPLC conditions (Gemini column, water/acetonitrile/TFA).
Reaction SMILES: [CH:1]1([N:4]([C:9]2[C:10]3[CH2:31][NH:30][CH2:29][CH2:28][C:11]=3[N:12]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][N:24]=[C:23]4[CH3:27])=[CH:18][CH:17]=3)[N:14]=2)[CH2:5][CH2:6][C:7]#[N:8])[CH2:3][CH2:2]1.[C:32](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[CH:1]1([N:4]([C:9]2[C:10]3[CH2:31][N:30]([CH3:32])[CH2:29][CH2:28][C:11]=3[N:12]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][N:24]=[C:23]4[CH3:27])=[CH:18][CH:17]=3)[N:14]=2)[CH2:5][CH2:6][C:7]#[N:8])[CH2:2][CH2:3]1
Reactant: CC(=O)O
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(N(CCC#N)C4CC4)n2)CNCC3)cc1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(N(CCC#N)C4CC4)n2)CN(C)CC3)cc1
Yield: 3.6 %

Procedure:
3-(Cyclopropyl(2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)propanenitrile (94 mg, 0.23 mmol) was dissolved in methanol (2 mL). Acetic acid (0.013 mL, 0.23 mmol) was added followed by formaldehyde (0.017 mL, 0.23 mmol). The reaction mixture was stirred at room s temperature for 15 minutes and sodium cyanoborohydride (14.25 mg, 0.23 mmol) was added. The reaction mixture was concentrated under reduced pressure, filtered and purified by preparative HPLC (acidic system) yielding 3-(cyclopropyl(6-methyl-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)propanenitrile (3.50 mg, 3.16%) as acetate salt.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][C:5]2[S:8][C:9]([C:11]([O-:13])=O)=[N:10][C:4]=2[CH2:3]1.[Li+].Cl.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH:32]([C:36](=[O:47])[NH:37][CH2:38][C:39]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[O:40])[CH2:31]1)(=[O:29])=[O:28])[CH:21]=[CH:20]2>>[ClH:16].[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][N:33]([C:11]([C:9]3[S:8][C:5]4[CH2:6][NH:7][CH:2]([CH3:1])[CH2:3][C:4]=4[N:10]=3)=[O:13])[CH:32]([C:36](=[O:47])[NH:37][CH2:38][C:39]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[O:40])[CH2:31]1)(=[O:29])=[O:28])[CH:21]=[CH:20]2
Reactant: O=C(NCC(=O)N1CCOCC1)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1
Reactant: CC1Cc2nc(C(=O)[O-])sc2CN1
Agent: Cl
Agent: [Li+]
Product: CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3C(=O)NCC(=O)N3CCOCC3)sc2CN1

Procedure:
Starting materials : lithium 6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate, 1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-[N-[[(morpholin-4-yl)carbonyl]methyl]carbamoyl]piperazine hydrochloride
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(O)C>O>[NH2:1][C:4]1[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(C(F)(F)F)cc1N
Temperature: 50 °C

Procedure:
A mixture of methyl 2-nitro-4-(trifluoromethyl)benzoate (2.49 g 0.01 mol), sodium hydrosulfite (8.71 g, 0.05 mol), ethanol (20 ml) and water (20 ml) was heated at 50° C. for 3 h. Water was added and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with a 5% ethyl acetate/n-hexane to give 1.46 g (6.67 mmol 67%) of the title compound as a white powder.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.[CH:19]([P:22](Cl)(Cl)=[O:23])([CH3:21])[CH3:20]>>[CH:19]([P:22]1(=[O:23])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:10][N:9]1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:17])([F:18])[F:1])[CH:4]=1)([CH3:21])[CH3:20]
Reactant: CC(C)P(=O)(Cl)Cl
Reactant: FC(F)(F)c1cccc(NCc2ccccc2)c1
Product: CC(C)P1(=O)c2ccccc2CN1c1cccc(C(F)(F)F)c1

Procedure:
The procedure of Example 1 was employed utilizing N-(3-trifluoromethylphenyl)-N-benzylamine and isopropyl phosphonic dichloride. The crude product produced as a result of the chromatographic separation was crystallized from methylcyclohexane to yield a tan precipitate. The tan precipitate was recrystallized from toluene and petroleum ether to yield 1-isopropyl-2-(3-trifluoromethylphenyl)-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide as beige plates. A second crop was obtained to give a total yield of 5.9 g, (29% yield) of 1-isopropyl-2-(3-trifluoromethylphenyl)-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide having a melting point of 117°-119° C. and the following analysis:
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.C(N(CC)C(C)C)(C)C.Cl.Cl.[OH:54][CH2:55][CH2:56][N:57]1[CH2:62][CH2:61][CH:60]([C@@H:63]2[CH2:67][C@H:66]([SH:68])[CH2:65][NH:64]2)[CH2:59][CH2:58]1>C(#N)C>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:18]([S:68][C@@H:66]3[CH2:65][NH:64][C@H:63]([CH:60]4[CH2:59][CH2:58][N:57]([CH2:56][CH2:55][OH:54])[CH2:62][CH2:61]4)[CH2:67]3)[C@H:19]([CH3:42])[C@H:20]12)[CH3:39]
Reactant: OCCN1CCC([C@@H]2C[C@H](S)CN2)CC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@@H]3CN[C@H](C4CCN(CCO)CC4)C3)[C@H](C)[C@H]12
Reaction time: 19 h
Yield: 55.3 %

Procedure:
To a solution of p-nitrobenzyl (1R, 5S, 6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (8.92 g, 15 mmol) in acetonitrile (600 ml), N,N-diisopropylethylamine (10.7 ml, 61.5 mmol) was added under cooling with ice and (2S, 4S)-2-[N-(2-hydroxyethyl)piperidin-4-yl]-4-mercaptopyrrolidine dihydrochloride (4.80 g, 15.8 mmol) was further added in limited amount. After the mixture was stirred at the same temperature for 19 hours, the reaction solution was concentrated to a volume of 300 ml and stirred under cooling with ice for 2 hours. Precipitates were collected by filtration and washed with acetonitrile, followed by drying to obtain p-nitrobenzyl (1R, 5S, 6S)-6-[(R)-1-hydroxyethyl]-2-[(2S, 4S)-2-[N-(2-hydroxyethyl)piperidin-4-yl]pyrrolidin-4-ylthio]-1-methyl-1-carbapen-2-em-3-carboxylate (4.77g, yield: 55.4%).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:8])[C:6]=1Br.C[CH2:10][O:11]CC.C([Li])CCC.CN(C)C=O>CCCCCC>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:8])[C:6]=1[CH:10]=[O:11]
Reactant: Cc1csc(C)c1Br
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cc1csc(C)c1C=O
Temperature: -20 °C
Reaction time: 8 h

Procedure:
A solution of 15 g. (79.0 mmol) of 2,4-dimethyl-3-bromothiophene in 120 ml. of dry ether was cooled to -70° C. and 36 ml. of a hexane solution of n-butyl lithium (2.4 molar, 86.4 mmol) were added dropwise. The reaction mixture was allowed to warm up to -20° C. for 10 min., cooled again to -70° C. and then quenched by adding dropwise 15 g. (0.205 mol) of dimethylformamide. The mixture was stirred at room temperature overnight, poured into ice water, stirred for 15 min. and extracted four times with ether. The ether phase was washed with saturated sodium chloride solution, dried and evaporated. The resulting oily residue was distilled to yield 2,4-dimethylthiophene-3-carboxaldehyde, b.p. 50°-55° C./0.1 mm.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[OH:12].[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[N:22]([CH3:23])[CH:21]=[CH:20][C:18]=2[N:19]=1>CN1C(=O)CCC1.O>[Cl:13][C:14]1[N:15]=[C:16]([O:12][C:5]2[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=2[CH3:3])[C:17]2[N:22]([CH3:23])[CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: Cn1ccc2nc(Cl)nc(Cl)c21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(C)c(Oc2nc(Cl)nc3ccn(C)c23)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To a stirred suspension of NaH (8.9 mg, 0.22 mmol) in dry NMP (1.0 mL) was added 2,4,6-trimethyl phenol (30.2 mg, 0.22 mmol) and stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 2,4-dichloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (44.6 mg, 0.22 mmol) in dry NMP (1.0 mL) and heated at 90° C. for 16 h. After completion of the reaction, the resulting mixture was cooled, diluted with water and washed with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (5:1-2:1), to give the product as a light yellow solid (52.7 mg, 80%).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[C:18]([O:22][C:23](=[O:44])[NH:24][CH2:25][C:26]1([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)[CH2:28][CH2:27]1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23](=[O:44])[NH:24][CH2:25][C:26]1([C:29]2[CH:30]=[CH:31][C:32]([C:2]3[C:3]4[C:4]5[CH:17]=[CH:16][S:15][C:5]=5[C:6](=[O:14])[NH:7][C:8]=4[CH:9]=[CH:10][C:11]=3[O:12][CH3:13])=[CH:33][CH:34]=2)[CH2:27][CH2:28]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C2(CNC(=O)OC(C)(C)C)CC2)cc1
Yield: 52.1 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (830 mg, 2.7 mmol) was reacted with tert-butyl(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropyl)methylcarbamate (1.5 g, 4.0 mmol) to afford the desired product (670 mg, 52%) as a light brown solid: ESI MS m/z 477 [C27H28N2O4S+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[C:12](O)(=[O:14])[CH3:13].C(OC(=O)C)(=O)C>O>[C:12]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11])(=[O:14])[CH3:13]
Reactant: CC(=O)O
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc([N+](=O)[O-])cc1O
Reaction time: 1 h

Procedure:
To 400 g of 2-amino-5-nitrophenol in a 5-L multi-necked flask equipped with a mechanical stirrer, reflux condenser, nitrogen inlet, 500-mL addition funnel, heating mantle, and a thermocouple attached to a temperature controller was added 1.6 L of acetic acid. The mixture was stirred at 60° C. as 398 g of acetic anhydride was added over 1.5 hours. After 1 hour, another 37 g of acetic anhydride was added. After another 1 hour, the mixture was cooled and diluted with 2 L of water. Solid was collected by filtration and washed with water and heptane. The solid was dried in a vacuum oven to give 509 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)OC(C)(C)C)=[CH:4][C:3]=1[O:16][C:17]([F:20])([F:19])[F:18].[C:21]([Cu])#[N:22].Cl>CN(C=O)C.O>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:21]#[N:22])=[C:3]([O:16][C:17]([F:18])([F:19])[F:20])[CH:4]=1
Reactant: N#C[Cu]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)c(OC(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 10 h
Yield: 45.9 %

Procedure:
1,1-Dimethylethyl {4-bromo-3-[(trifluoromethyl)oxy]phenyl}carbamate (Intermediate 50, 1.0 g, 2.8 mmol) was dissolved in dry DMF (25 mL). To this solution was added CuCN (1.0 g, 11.1 mmol), and the reaction mixture was heated to reflux for 5 h. A second portion of CuCN (500 mg, 5.6 mmol) was added and heating at reflux was continued for 10 h. The reaction mixture was cooled to room temperature, and FeCl3 was added. This was followed by 1N HCl at 0° C. and the mixture was stirred for 2 hr at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product. This was purified by column chromatography (60-120 silica gel), eluting with 30% ethyl acetate/pet ether to give the title compound (260 mg).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]4)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:30]O>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([S:13]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]4)=[O:30])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CCc2cc(OCCCCSc3ccc(C4CCCCC4)cc3)ccc2N1
Reactant: OO
Product: O=C1CCc2cc(OCCCCS(=O)c3ccc(C4CCCCC4)cc3)ccc2N1

Procedure:
Prepared analogous to Example 123 from 6-[4-(4-cyclohexylphenyl-mercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [C:1]1([C:7]2[C:8]([OH:32])=[C:9]([C:24]([NH:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)=[O:25])[C:10]([CH:19]([O:22]C)[CH2:20][CH3:21])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.B(Br)(Br)Br>O>[C:1]1([C:7]2[C:8]([OH:32])=[C:9]([C:24]([NH:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)=[O:25])[C:10]([CH:19]([OH:22])[CH2:20][CH3:21])=[N:11][C:12]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCC(OC)c1nc(-c2ccccc2)c(-c2ccccc2)c(O)c1C(=O)Nc1nccs1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCC(O)c1nc(-c2ccccc2)c(-c2ccccc2)c(O)c1C(=O)Nc1nccs1
Reaction time: 24 h
Yield: 47.7 %

Procedure:
A solution of 8.65 g of the product of Step F and 86 ml of methylene chloride was cooled to -70° C. to -60° C. and while maintaining this temperature, 116 ml of a solution of boron tribromide were added. After stirring for 24 hours, the temperature was allowed to return to ambient. The solution was poured into 180 ml of iced water and extracted with methylene chloride. The extracts were washed with water, dried and concentrated under reduced pressure. After chromatography under pressure (methylene-chloride - ethyl acetate 8-2), 4 g of the expected product were obtained which after crystallization from ethyl acetate melted at 232° to 234° C.