Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C@H:7]([CH3:13])CCCCC)[CH3:3].C[C:15]([CH3:17])=[O:16].[OH:18]S(O)(=O)=O.O=[Cr](=O)=O.O.[O-]S([O-])(=O)=O.[Na+].[Na+]>CC(C)=O.C(Cl)Cl.CCOCC>[CH3:1][C@H:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:13])[CH2:3][CH2:17][C:15]([OH:18])=[O:16]
Reactant: CC(C)=O
Reactant: O=S(=O)(O)O
Reactant: CCCCC[C@@H](C)CCC=C(C)C
Agent: O=[Cr](=O)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: CCCCC[C@@H](C)CCC(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
(R)-2,6-Dimethylundec-2-ene 153 (10.03 g, 55.03 mmol) was dissolved in acetone (270 mL) and cooled to 0° C. Jones reagent (CrO3/H2SO4) (2.7 M, 120 mL) was added dropwise, and the reaction allowed to warm to room temperature over 18 hours. The reaction was poured on to water/Na2SO4 (200 mL), and the aqueous layer extracted with ethyl acetate (4×100 mL). The combined organics were dried over MgSO4, filtered and rotovapped to give an oil. The crude oil was dissolved in CH2Cl2 (400 mL) and cooled to −78° C. Ozone was bubbled into reaction until blue to remove traces of the impurity (6E)(3S)-3,7-dimethylocta-1,6-diene. Dimethylsulfide (5 mL) was added, and the reaction stirred at room temperature for 2 hours. The solvent was removed, and the crude material chromatographed on silica eluting with 20% EtOAc/hex to give oil. The oil was dissolved in ether (100 mL) and extracted with 10% NaOH (2×25 mL). The aqueous layers were combined and extracted with ether (50 mL). The aqueous layer was cooled to 0° C. and acidified with HCl. The acidic layer was extracted with EtOAc (3×100 mL), and the combined extracts dried over MgSO4, filtered and rotovapped to give 154 as an oil (6.86 g, 54%). 1H NMR (400 MHz, CDCl3) δ 2.40-2.25 (m, 4H), 1.70-1.62 (m, 2H), 1.47-1.11 (m, 8H), 0.87-0.84 (m, 6H); [α]D=−11.4 (c1 in CHCl3).
Reaction SMILES: [CH2:1]([C:3]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[C:4]=1[N:5]([C:8](=[CH:14]O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=O)[CH3:2].Cl.C([NH2:25])=O>>[CH2:1]([C:3]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[C:4]=1[N:5]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][N:25]=[CH:6]1)[CH3:2]
Reactant: CCOC(=O)C(=CO)N(C=O)c1c(CC)cccc1CC
Reactant: NC=O
Agent: Cl
Product: CCOC(=O)c1cncn1-c1c(CC)cccc1CC

Procedure:
17.8 g (0.06 mole) of ethyl 2-(2,6-diethyl-N-formylanilino)-3-hydroxyacrylate were heated with stirring together with 10 ml of concentrated hydrochloric acid and 50 ml of formamide for 8 hours at an oil bath temperature of 160° C. (internal temperature 140° C.). After cooling, the product was extracted by shaking with a mixture of 100 ml of water and 100 ml of diisopropyl ether, the organic layer was separated off and the aqueous phase was extracted once more with diisopropyl ether. The combined organic phases were dried over sodium sulphate and evaporated. 14.8 g (90% of theory) of the title compound were obtained in the form of a colorless oil of boiling point 145° C./0.01 mm Hg.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[O:18][C:19]([CH3:35])=[C:20]([C:22]([NH:24][CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)=[O:23])[N:21]=4)=[C:13]([NH:36][CH:37]([CH3:39])[CH3:38])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.CCOCC.Cl>C(Cl)Cl>[NH2:27][CH2:26][CH2:25][NH:24][C:22]([C:20]1[N:21]=[C:17]([C:14]2[CH:15]=[N:16][C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]4[N:3]=[CH:2][S:1][C:5]=4[CH:6]=3)=[CH:12][C:13]=2[NH:36][CH:37]([CH3:38])[CH3:39])[O:18][C:19]=1[CH3:35])=[O:23]
Reactant: Cc1oc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)nc1C(=O)NCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1oc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)nc1C(=O)NCCN
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl (2-(2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxamido)ethyl)carbamate in DCM (5 mL) was treated with ether. HCl (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min. The reaction temperature was raised to room temperature and stirred for 30 min. The reaction mixture was concentrated to dryness. The material obtained was purified by prep. HPLC to afford N-(2-aminoethyl)-2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxamide 1H NMR: 400 MHz, DMSO-d6: δ 1.35 (d, J=6.40 Hz, 6H), 2.64 (s, 3H), 2.70-2.80 (m, 2H), 3.70-3.74 (m, 1H), 6.17 (s, 1H), 7.60 (dd, J=2.00, 9.00 Hz, 1H), 7.79 (d, J=7.20 Hz, 1H), 7.96 (d, J=8.80 Hz, 1H), 8.02 (bs, 1H), 8.53 (s, 1H), 8.67 (d, J=2.00 Hz, 1H), 9.16 (s, 1H), 9.35 (s, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm, 2.7 μm; Solvent A=2% ACN: 98% H2O: 10 mM NH4COOH; Solvent B=98% ACN: 2% H2O: 10 mM NH4COOH; gradient 0-100% B over 1.5 mM; retention time: 1.646 min; LCMS (ES-API), m/z 452.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 30 min (36 min run time); Flow rate: 1.0 μL/min; Retention time: 8.956 min; Purity: 91.1%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH:12]([F:14])[F:13])[CH:8]=[C:7]([Cl:15])[CH:6]=1.[CH:17](OC)=[O:18].[Na].CO>CCOCC.O>[CH3:1][O:2][C:3](=[O:16])[CH:4]([C:5]1[CH:10]=[C:9]([O:11][CH:12]([F:13])[F:14])[CH:8]=[C:7]([Cl:15])[CH:6]=1)[CH:17]=[O:18]
Reactant: COC=O
Reactant: COC(=O)Cc1cc(Cl)cc(OC(F)F)c1
Agent: [Na]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: COC(=O)C(C=O)c1cc(Cl)cc(OC(F)F)c1
Temperature: 2 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
3-Chloro-5-difluoromethoxyphenylactic acid methyl ester (1 g, 4 mmol; see step (vi) above) and methyl formate (1 g, 16 mmol) were dissolved in ether (100 mL) and cooled in an ice-bath (ca. 2° C.). Then, finely cut sodium (180 mg, 7.8 mmol) and methanol (1 mL) were added and the mixture was left in the ice-bath with stirring overnight. Water (100 mL) was added carefully and the phases were separated. The water containing phase was acidified with hydrochloric acid (2 M) to pH 1 and extracted with ether (2×100 mL). The extract was dried over sodium sulphate, filtered and concentrated at reduced pressure. The residue was chromatographed on silica (hexane:ethyl acetate (1:1)) which gave 400 mg, 1.4 mmol (yield: 36%) of the sub-title compound.
Reaction SMILES: [NH3:1].[O:2]=O.[CH3:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH3:11])[C:6]1=O>CO>[C:6]([CH:5]([CH3:4])[CH2:10][CH2:9][CH2:8][C:7](=[O:2])[CH3:11])#[N:1]
Reactant: CC1CCCC(C)C1=O
Reactant: N
Reactant: O=O
Solvent: CO
Product: CC(=O)CCCC(C)C#N

Procedure:
A solution of 2 ml of NH3 in 50 ml of methanol is charged into a round bottom flask fitted with a gas inlet tube and a mechanical stirrer. Fitted to the gas inlet tube is an oxygen buret graduated in mls and containing oxygen gas. To this solution is added with stirring 0.015 g of CuCl2 2H2O and 1.5 g of 2,6-dimethyl cyclohexanone. Stirring is continued until all solids had dissolved. A steady stream of oxygen is bubbled into the solution for approximately 16 hours, while the solution is stirred at room temperature. Total oxygen uptake is 63 ml. The methanol solvent is removed by rotary evaporator and the product extracted in by rotary evaporator and the product extracted in ether. The ether layer is concentrated. IR and NMR analysis confirmed the presence of 1-cyano-1-methyl-5-ketohexane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=2)[C:10]2[N:14]([CH3:15])[C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Li+].[OH-].CCOC(C)=O.Cl>O1CCOCC1.O>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]([CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)[C:10]2[N:14]([CH3:15])[C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[N:11]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COC(=O)c1ccc(CN(c2cc(Cl)cc(Cl)c2)c2nc3ccccc3n2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(N(Cc2ccc(C(=O)O)cc2)c2cc(Cl)cc(Cl)c2)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the title compound of Example 223 Step B (0.2 mmol, 85 mg) in 1.6 mL of dioxane was added a solution of LiOH (0.8 mmol, 19 mg) in 0.8 mL of H2O. The reaction was allowed to stir at ambient temperature overnight. The crude reaction mixture was poured into pH 7 buffer/EtOAc, which was acidified with 2 N HCl until two clear layers formed after agitation. The organic phase was collected and the aqueous phase was extracted twice with EtOAc. The combined organic phase was dried over MgSO4, then concentrated under reduced pressure to afford the product as a white foam. MS (ESI): m/z 426 (M+H). HPLC A: 1.79 min.
Reaction SMILES: FC1C=CC(NC(=O)NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=CC=2)=CC=1.[C:35]([C:37]1[CH:38]=[C:39]([NH:43][C:44](=[O:70])[NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:60]=[C:59]4[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:69])[CH3:68])[C:63]([O:65]C)=[O:64])[C:58]4=[O:61])=[CH:54][CH:53]=3)=[CH:48][CH:47]=2)[CH:40]=[CH:41][CH:42]=1)#[N:36]>>[C:35]([C:37]1[CH:38]=[C:39]([NH:43][C:44](=[O:70])[NH:45][C:46]2[CH:47]=[CH:48][C:49]([C:52]3[CH:60]=[C:59]4[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:68])[CH3:69])[C:63]([OH:65])=[O:64])[C:58]4=[O:61])=[CH:54][CH:53]=3)=[CH:50][CH:51]=2)[CH:40]=[CH:41][CH:42]=1)#[N:36]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C#N)c4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C#N)c4)cc3)cc2C1=O
Yield: 84 %

Procedure:
The compound of example 42 was prepared analogous to compound of example 8 by hydrolysis of compound of example 41.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:9]=[N:10][C:11]([C:14]([OH:16])=O)=[N:12][CH:13]=1.Cl.[NH:18]1[CH2:21][CH2:20][CH2:19]1.C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl>[N:18]1([C:14]([C:11]2[N:12]=[CH:13][C:8]([Br:7])=[CH:9][N:10]=2)=[O:16])[CH2:21][CH2:20][CH2:19]1
Reactant: O=C(O)c1ncc(Br)cn1
Reactant: C1CNC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1ncc(Br)cn1)N1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.4 %

Procedure:
Oxalyl chloride (1.50 mL, 16.79 mmol), followed by DMF (2 drops), were added to a mixture of 5-bromopyrimidine-2-carboxylic acid (2.86 g, 14.0 mmol) in DCM (40 mL). The reaction was stirred at RT for 2 hours, the volatiles removed in vacuo and the residue dissolved in DCM (40 mL). Azetidine hydrochloride (1.44 g, 15.39 mmol), followed by triethylamine (4.29 mL, 30.78 mmol), were added and the mixture stirred at RT for 72 hours. The mixture was concentrated in vacuo and ethyl acetate (100 mL) added to the residue. The organics were washed with water (100 mL), citric acid (50 mL), saturated sodium bicarbonate solution (50 mL), brine (50 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give a yellow solid. The solid was chromatographed on silica, eluting with a gradient of 50-100% ethyl acetate in isohexane, to give the desired compound as a yellow solid (0.86 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C([O-])([O-])=O.[K+].[K+].[CH:22]1[CH:27]=[CH:26][C:25]([CH2:28]Br)=[CH:24][CH:23]=1>CN(C=O)C>[CH2:28]([O:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])[C:25]1[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)cc(C(=O)OC)c1
Temperature: 60 °C
Yield: 93.3 %

Procedure:
A mixture of 1.98 g (9.42 mmol) of dimethyl 5-hydroxyisophthalate 3.0 g (21.7 mmol) of K2CO3 and 1.8 mL (15.1 mmol) of BnBr in 30 mL of DMF was heated at 60° C. for 18 h. After the mixture was filtered through cotton, water and CHCl3 were added. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (15% EtOAc/hexanes) provided the 2.64 g of dimethyl 5-(benzyloxy)isophthalate as a colorless solid in 93% yield.
Reaction SMILES: O.[CH3:2][O:3][C:4]1[C:13]2[NH:12][C:11]3=[CH:14][C:15]([C:17]([OH:19])=[O:18])=[N:16][N:10]3[C:9](=[O:20])[C:8]=2[CH:7]=[CH:6][CH:5]=1.[C:21](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH3:2][O:3][C:4]1[C:13]2[N:12]([CH3:21])[C:11]3=[CH:14][C:15]([C:17]([OH:19])=[O:18])=[N:16][N:10]3[C:9](=[O:20])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cccc2c(=O)n3nc(C(=O)O)cc3[nH]c12
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c(=O)n3nc(C(=O)O)cc3n(C)c12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4,9-dihydro-5-methoxy-9-oxo-pyrazolo-[5,1-b]quinazoline-2-carboxylic acid, hydrate (1:0.25) (2.64 g; 0.01 mole), anhydrous potassium carbonate (5.52 g; 0.04 mole) and methyl iodide (15 ml) in dimethyl formamide (75 ml) is stirred at room temperature for 2 days. Water is added and the grey solid is filtered off and taken up in 2(N) sodium hydroxide solution (50 ml) and methanol (50 ml). The mixture is heated under reflux for 2 hrs and the methanol is distilled off in vacuo. The aqueous solution is acidified with conc. HCl and the yellow precipitate is collected and recrystallized from methanol (275 ml), water (5 ml). Yield 0.33 g; mp 255° (d).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8]2[C:12]([N+:13]([O-])=O)=[CH:11][N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:9]=2)[CH:7]=1.O.[Cl-].[NH4+]>C(O)C.ClCCl.[Fe]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8]2[C:12]([NH2:13])=[CH:11][N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:21])[CH3:23])[N:9]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1nn(COCC[Si](C)(C)C)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: COc1ccc(Cl)cc1-c1nn(COCC[Si](C)(C)C)cc1N
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 99.6 %

Procedure:
To a solution of 3-(5-chloro-2-methoxyphenyl)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (5.97 g, 15.6 mmol) in 25 mL ethanol was added 50 mL water, ammonium chloride (3.37 g, 62.9 mmol), and iron powder (4.367 g, 78.2 mmol). The reaction mixture was stirred at 75° C. for 1.5 hours. After cooling to room temperature, the reaction was diluted with dichloromethane and filtered through a celite pad, rinsing with more dichloromethane. The filtrate was added to 150 mL saturated aqueous sodium bicarbonate and extracted twice with dichloromethane. The combined organic extracts were dried over magnesium sulfate and concentrated to yield 5.50 g (100%) of 3-(5-chloro-2-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine, which was carried forward without purification. LCMS (ESI) m+H=354.3; 1H NMR (400 MHz, CDCl3) δ: 7.44 (d, 1H), 7.34 (d of d, 1H), 7.28 (s, 1H), 6.92 (d, 1H), 5.24 (s, 2H), 3.52 (t, 2H), 0.85 (t, 2H), −0.04 (s, 9H).
Reaction SMILES: [CH2:1]([NH:7][CH2:8][C:9]1[S:13][C:12](B(O)O)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[C:18]1[CH:19]=[C:20]2[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=1)[NH:23][CH:22]=[C:21]2[CH:30]1[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:39]([S:36]([N:33]1[CH2:32][CH2:31][CH:30]([C:21]2[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=[C:18]([C:12]4[S:13][C:9]([CH2:8][NH:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:10][CH:11]=4)[CH:19]=3)[NH:23][CH:22]=2)[CH2:35][CH2:34]1)(=[O:38])=[O:37])[CH3:40]
Reactant: CCCCCCNCc1ccc(B(O)O)s1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Yield: 16 %

Procedure:
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), hexylamine (33 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude {5-[(hexylamino)methyl]-2-thienyl}boronic acid. The crude {5-[(hexylamino)methyl]-2-thienyl}boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). The crude product was purified once on an Agilent MDAP using the procedure shown in preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide to give 13 mg of the title compound (16%).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:34])[CH2:7][S:8][C:9]1[N:18]=[C:17]([CH3:19])[CH:16]=[C:15]2[C:10]=1[C:11](=[O:33])[CH:12]=[C:13]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[N:14]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)C>CCO>[NH:26]([C:13]1[N:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]2[C:10]([C:11](=[O:33])[CH:12]=1)=[C:9]([S:8][CH2:7][C:6]([OH:34])=[O:5])[N:18]=[C:17]([CH3:19])[CH:16]=2)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)CSc1nc(C)cc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc2c(c(SCC(=O)O)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Reaction time: 4 h
Yield: 58.3 %

Procedure:
Aqueous NaOH (2N, 1 mL) was added to a stirred solution of ethyl[(2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)sulfanyl]acetate (100 mg, 0.23 mmol) in EtOH (8 mL) at room temperature. The mixture was allowed to stir for 4 h and was concentrated in vacuo. The reaction mixture was acidified with 1N HCl and extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification by reverse-phase preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) provided [(2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)sulfanyl]acetic acid (56 mg, 60%): LCMS RT: 2.61 min, MH+: 418.2.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][N:5]([C:7]2[CH2:8][C@@H:9]3[CH2:26][C:25](=[O:27])[N:10]3[C:11]=2[C:12]([O:14]CC2C=CC([N+]([O-])=O)=CC=2)=[O:13])[CH:6]=1.[CH3:28][C:29]1[N:33]([C:34]2[CH2:35][C@@H:36]3[CH2:53][C:52](=[O:54])[N:37]3[C:38]=2[C:39]([O:41]CC2C=CC([N+]([O-])=O)=CC=2)=[O:40])[N:32]=[N:31][CH:30]=1.N1(CCCS(O)(=O)=O)CCOCC1>O1CCOCC1.O.C(O)C.[Pd]>[CH3:1][C:2]1[N:3]=[N:4][N:5]([C:7]2[CH2:8][C@@H:9]3[CH2:26][C:25](=[O:27])[N:10]3[C:11]=2[C:12]([OH:14])=[O:13])[CH:6]=1.[CH3:28][C:29]1[N:33]([C:34]2[CH2:35][C@@H:36]3[CH2:53][C:52](=[O:54])[N:37]3[C:38]=2[C:39]([OH:41])=[O:40])[N:32]=[N:31][CH:30]=1
Reactant: Cc1cnnn1C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C[C@H]2C1
Reactant: Cc1cn(C2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)C[C@H]3C2)nn1
Agent: [Pd]
Agent: O=S(=O)(O)CCCN1CCOCC1
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: Cc1cn(C2=C(C(=O)O)N3C(=O)C[C@H]3C2)nn1
Product: Cc1cnnn1C1=C(C(=O)O)N2C(=O)C[C@H]2C1
Reaction time: 0.5 h

Procedure:
A solution of a mixture of p-nitrobenzyl 2-(4-methyl-1,2,3-triazol-1-yl)-carbapen-2-em-3-carboxylate and p-nitrobenzyl 2-(5-methyl-1,2,3-triazol-1-yl)-carbapen-2-em-3-carboxylate (0.7 mg) in dioxane (100 microliter), deionized water (60 microliter), absolute ethanol (8.3 microliter), and pH 7.0 0.5M aqueous 4-morpholinepropanesulfonic acid (10.2 microliter) was shaken with 10% (w/w) palladium on charcoal (1.0 mg) under hydrogen (50 psig) at ambient temperature. After 30 min. the mixture was centrifuged and the pellet was washed with deionized water (5×0.5 ml). The combined supernate and washes were extracted with ethyl acetate (3×0.5 ml) and concentrated under vacuum at 0° C. to provide 2.0 ml of a solution of 2-(4-methyl-1,2,3-triazol-1-yl)-carbapen-2-em-3-carboxylic acid and 2-(5-methyl-1,2,3-triazol-1-yl)-carbapen-2-em-3-carboxylic acid, UV λmax 295 nm quenched by addition of hydroxylamine hydrochloride and dipotassium hydrogen phosphate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:16])=[CH:4][C:5]2[CH:6]3[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][CH:7]3[NH:8][C:9]=2[CH:10]=1.[H-].[Na+].[CH3:19][C:20]1([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH2:22][O:21]1>CN(C=O)C>[Cl:1][C:2]1[C:3]([Cl:16])=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][C:7]=3[N:8]([CH2:19][C:20]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)([OH:21])[CH3:22])[C:9]=2[CH:10]=1
Reactant: CN1CCC2Nc3cc(Cl)c(Cl)cc3C2C1
Reactant: CC1(c2ccncc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(c3cc(Cl)c(Cl)cc3n2CC(C)(O)c2ccncc2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A flask was charged with 7,8-dichloro-2-methyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (1 g, 3.9 mmol) in DMF (10 mL) and stirred for 5 min. To this was added NaH (60% in hexane) (470 mg, 11.7 mmol) and the mixture stirred at RT for 10 min. 4-(2-Methyloxiran-2-yl)pyridine (795 mg, 5.8 mmol) was added and the mixture stirred at RT for 16 h. The progress of reaction was monitored by TLC. The reaction mixture was poured into ice water and filtered. The filtrate was washed with water and concentrated. The residue was recrystallized from ether to get pure product. 1H NMR (CD3OD, formate salt) δ (ppm): 8.38 (d, 2H), 7.56 (s, 1H), 7.48 (d, 2H), 7.30 (s, 1H), 4.60 (m, 2H), 4.30 (m, 2H), 3.58 (m, 1H), 3.50 (m, 1H), 3.35 (m, 1H), 3.10 (m, 1H), 3.0 (s, 3H), 1.70 (s, 3H).
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][P:7]([CH2:27][NH2:28])([CH2:9][CH:10]([C:15](=[O:26])[NH:16][C@H:17]([C:22](=[O:25])[NH:23][CH3:24])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8].[N+:29]([C:32]1[CH:42]=[CH:41][CH:40]=[C:34]2[C:35]([O:37][C:38](=O)[C:33]=12)=[O:36])([O-:31])=[O:30]>>[CH3:5][O:6][P:7]([CH2:9][CH:10]([C:15](=[O:26])[NH:16][CH:17]([C:22](=[O:25])[NH:23][CH3:24])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:11][CH:12]([CH3:14])[CH3:13])([CH2:27][N:28]1[C:38](=[O:37])[C:33]2=[C:32]([N+:29]([O-:31])=[O:30])[CH:42]=[CH:41][CH:40]=[C:34]2[C:35]1=[O:36])=[O:8]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN)OC
Solvent: CC(=O)O
Product: CNC(=O)C(CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN1C(=O)c2cccc([N+](=O)[O-])c2C1=O)OC
Yield: 35.9 %

Procedure:
In a manner analogous to that described in Example 3(A), from 0.23 g of (aminomethyl)[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid methyl ester acetate and 0.105 g of 3-nitrophthalic anhydride, there was obtained 0.105 g of [4-methyl-2-[[3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl][(3-nitrophthalimido)methyl]phosphinic acid methyl ester in the form of a pale yellow foam.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:17][OH:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=1)(C)(C)C.Cl>CO.O1CCOCC1>[NH2:7][C@@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=1)[CH2:17][OH:18]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1cccc(Br)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@H](CO)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (S)-[2-(3-bromo-phenyl)-1-hydroxymethyl-ethyl]-carbamic acid tert-butyl ester (400 mg, 1.21 mmol) in methanol (30 mL) was added 4 N HCl in dioxane (2 mL, excess). The reaction mixture was stirred at room temperature for 14 h. After concentration in vacuo, the residue was used for the next step without purification. LCMS (M+H)+ m/z 230 (t=0.78 min.)