Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.O.[OH-].[Li+]>CO>[C:1]([O:5][C:6]([CH:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(C2CCC(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)C1CCC(c2ccc(C(=O)O)cc2)CC1
Reaction time: 18 h
Yield: 34.2 %

Procedure:
400 mg of ethyl 4-(4-tert-butoxycarbonylcyclohexyl)benzoate (1.2 mmol, 1 eq) are placed in 6 mL of a 2/1 mixture of tetrahydrofuran and methanol. The reaction medium is cooled using an ice bath, and 202 mg of lithium hydroxide monohydrate (4.81 mmol, 4 eq.) dissolved in 2 mL are added and stirring is continued for 18 hours. The reaction medium is evaporated and acidified with aqueous 6% sulfur dioxide solution. After stirring for 1 hour, the solid obtained is filtered off by suction, and washed successively with water, ethanol and ethyl acetate. The residue is chromatographed on silica gel, eluting with a gradient of methanol in dichloromethane ranging from 3% to 5%. 125 mg of 4-(4-tert-butoxycarbonylcyclohexyl)benzoic acid are obtained.
Reaction SMILES: CI.[C:3]([O-])([O-])=O.[K+].[K+].[O:9]=[C:10]([CH3:19])[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>CC(C)=O>[CH3:3][CH:11]([C:10](=[O:9])[CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CC(=O)C(C)C(=O)OC(C)(C)C
Reaction time: 15 h
Yield: 55.5 %

Procedure:
Methyl iodide (6.86 mL, 1.1 eq) and K2CO3 (17.97 g, 1.3 eq) were added to an acetone (400 mL) solution of tert-butyl 3-oxobutanoate (15.82 g, 100 mmol) at room temperature. After 15 h, the mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate (300 mL), washed with water (30 mL) and brine (300 mL), dried (MgSO4) and concentrated. The crude residue was purified by silica gel chromatography (5-10% EtOAc-hexanes) to give tert-butyl 2-methyl-3-oxobutanoate as a colorless oil (9.56 g, 56%). MS found: (M+Na)+=195.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:27]=[CH:26][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:35]2[CH2:37][O:36]2)[CH:32]=[CH:33][CH:34]=1>C(Cl)(Cl)Cl.CO>[CH2:18]([NH:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:37][C@@H:35]([C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([Cl:28])[CH:30]=3)[OH:36])=[CH:27][CH:26]=2)[CH2:10][CH2:11]1)=[O:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Reactant: Clc1cccc([C@@H]2CO2)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)c3cccc(Cl)c3)cc2)CC1
Yield: 16.1 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-octyl-1-piperidinecarboxamide (0.50 g, 1.18 mmol) was reacted with (2R)-2-(3-chlorophenyl)oxirane (0.183 g, 1.18 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.063 g, 0.19 mmol).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([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.[F:19][C:20]([F:38])([F:37])[C:21]1[CH:36]=[CH:35][CH:34]=[CH:33][C:22]=1[CH:23](O)[C:24]1[CH:29]=[CH:28][C:27]([S:30][CH3:31])=[CH:26][CH:25]=1.C(N1CC(OC(C2C=CC(Cl)=CC=2)C2C=CC(Cl)=CC=2Cl)C1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][CH:23]([C:24]2[CH:25]=[CH:26][C:27]([S:30][CH3:31])=[CH:28][CH:29]=2)[C:22]2[CH:33]=[CH:34][CH:35]=[CH:36][C:21]=2[C:20]([F:38])([F:37])[F:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CSc1ccc(C(O)c2ccccc2C(F)(F)F)cc1
Agent: Clc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccc(Cl)cc2Cl)cc1
Product: CSc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccccc2C(F)(F)F)cc1

Procedure:
This material was prepared from 1-benzhydryl-3-azetidinol (1) (15 mmol) and 2-(trifluoromethyl)-4′-(methylthio)benzhydrol (116) (30 mmol) using the procedure described for compound (3) (4.68 g, 60%).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][CH3:5].Cl[C:10]([O:12][CH2:13][CH3:14])=[O:11]>[OH-].[Na+]>[CH2:13]([O:12][C:10]([NH:1][C@@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][CH3:5])=[O:11])[CH3:14]
Reactant: CCOC(=O)Cl
Reactant: CCC[C@@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCC[C@@H](NC(=O)OCC)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
D-Norvaline (10.0 g, 85.3 mmol) was dissolved in aqueous sodium hydroxide (4M, 25 mL). Ethyl chloroformate (10.6 mL, 111 mmol) and aqueous sodium hydroxide (4M, 25 mL) was added over 15 min. at 0° C. The reaction mixture was warmed to room temperature and stirred at this temperature for 4 h. The reaction mixture was washed with diethyl ether three times and then acidified with aqueous hydrochloric acid (2M). The product was extracted with diethyl ether three times. The combined organic phases were dried over magnesium sulphate and concentrated in vacuo to yield the title compound in quantitative yield.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH3:4].C(NC(C)C)(C)C.Br[C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=1>C(#N)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:19][C:17]1[CH:16]=[N:15][CH:14]=[C:13]([C:1]#[C:2][CH2:3][CH3:4])[CH:18]=1
Reactant: C#CCC
Reactant: Brc1cncc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCC#Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
But-1-yne (g) was during 5 min gently bubbled through anhydrous acetonitrile cooled in an ice-water bath. The resulting solution contained about 170 mg but-1-yne per mL. The solution of but-1-yne (4.57 mL, 14.36 mmol) and diisopropylamine (3.72 mL, 26.11 mmol) were added sequentially to a mixture of 3,5-dibromopyridine (3.09 g, 13.06 mmol), bis(triphenylphosphine)-palladium(II) chloride (0.458 g, 0.65 mmol) and CuT (0.249 g, 1.31 mmol) in acetonitrile (15 mL) under an argon atmosphere. The resulting mixture was stirred at r.t. overnight, diluted with EtOAc and passed through a short plug of silica. The solvents were evaporated and the residue was purified by flash chromatography on silica (gradient elution 0-20% EtOAc in heptane) to give 2.40 g of the title compound (87% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 1.17 (t, 4H), 2.47 (q, 3H), 8.11 (t, 1H), 8.57 (d, 1H), 8.65 (d, 1H); MS (ES+) m/z 210 [M+H]+.
Reaction SMILES: [OH-].[Na+].[I:3][C:4]1[C:9]2[C:10](=[O:15])[O:11][C:12](=O)[NH:13][C:8]=2[CH:7]=[CH:6][CH:5]=1>CO.[OH-].[Na+]>[NH2:13][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([I:3])[C:9]=1[C:10]([O:11][CH3:12])=[O:15]
Reactant: O=c1[nH]c2cccc(I)c2c(=O)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1c(N)cccc1I
Temperature: 60 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
To a stirred solution of sodium hydroxide (0.35 g, 8.8 mM) in methanol (31 mL) was added 5-iodo-2H-3,1-benzoxazine-2,4(1H)-dione (18.5 g, 64.0 mM). The mixture was heated at 60° C. for 1.5 hr. An additional quantitiy of sodium hydroxide (0.10 g, 2.5 mM) was added to the reaction mixture and stirring at 60° C. was continued for an additonal 1 hr. After cooling to room temperature, the reaction mixture was concentrated and the residue was taken up in ethyl acetate. The ethyl acetate was washed successively with water, brine, dilute aqueous sodium hydroxide, and water. After drying over MgSO4, the ethyl acetate was filtered and concentrated to leave (13.9 g, 78.4%) of the title ester as a brown oil; MS(CI): 278 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:20]=1[C:21](O)=[O:22]>>[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:20]=1[C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:22]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4c(Cl)cccc4Cl)cc3c2C1
Yield: 15.7 %

Procedure:
Beginning with 8.7 mg (0.038 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 18.0 mg (0.086 mMol) 2,6-dichlorobenzoic acid, 2.4 mg (16%) of the title compound were recovered as a beige solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[F:24][C:25]([F:40])([F:39])[C:26]1[N:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][NH:35][C:34](=[O:38])[CH:33]=2)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[CH3:11][N:8]1[C:9]2[CH:10]=[C:2]([N:35]3[CH:36]=[CH:37][C:32]([C:29]4[CH:30]=[N:31][C:26]([C:25]([F:24])([F:39])[F:40])=[CH:27][CH:28]=4)=[CH:33][C:34]3=[O:38])[CH:3]=[CH:4][C:5]=2[C:6]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CCC2
Reactant: O=c1cc(-c2ccc(C(F)(F)F)nc2)cc[nH]1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CCC2
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.11 g, 0.29 mmol), 4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (83 g, 0.35 mmol) and Cs2CO3 (0.10 g, 0.32 mmol) were suspended in DMSO (1.0 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (13 mg, 0.087 mmol) and copper iodide (72 mg, 0.38 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N2. The mixture was cooled, diluted with 5:1 MeOH/NH4OH (20 mL), and the resulting solution was stirred at ambient temperature for 30 min. The reaction was further diluted with CH2Cl2 (75 mL). The resulting solution was filtered through silica gel and the filtrate was concentrated under reduced pressure. The residue was diluted with CH2Cl2 and washed with brine (3×20 mL). The organic solution was dried over Na2SO4, filtered and concentrated to dryness. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 5 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes and held for 5 column volumes) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA) gave the title compound (67 mg, 42%) as a yellow film: 1H NMR (500 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.50-8.48 (m, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.85 (d, J=6.5 Hz, 1H), 7.54-7.51 (m, 2H), 7.03-6.99 (m, 2H), 6.78 (dd, J=7.5, 2.0 Hz, 1H), 4.60 (s, 2H), 3.69-3.65 (m, 5H), 3.00-2.99 (m, 2H), 1.96-1.90 (m, 2H), 1.36-1.30 (m, 9H); ESI MS m/z 539 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][CH3:8])=[C:5]([C:9]([O:11]CC)=[O:10])[CH:4]=[N:3]1.C(O)C.[OH-].[K+]>O>[CH3:1][N:2]1[C:6]([O:7][CH3:8])=[C:5]([C:9]([OH:11])=[O:10])[CH:4]=[N:3]1
Reactant: CCOC(=O)c1cnn(C)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1c(C(=O)O)cnn1C
Yield: 108.7 %

Procedure:
Ethyl 1-methyl-5-methoxypyrazole-4-carboxylate (1.4 g) was stirred at room temperature for 2 hours together with 30 ml of ethanol, 10 ml of water and 2 g of potassium hydroxide. Ethanol was removed from the reaction solution under reduced pressure. From the aqueous layer, 1.29 g (yield 99%) of the desired 1-methyl-5-methoxypyrazole-4-carboxylic acid was obtained by acid precipitation.
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([CH3:20])([CH3:19])[CH2:13][C:14](=[O:18])[O:15]2)=[CH:10][CH:9]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O>[OH:18][CH2:14][CH2:13][C:12]([C:11]1[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:17][C:16]=1[OH:15])([CH3:20])[CH3:19]
Reactant: COc1ccc2c(c1)OC(=O)CC2(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(C)(C)CCO)c(O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
To a tetrahydorofran (THF) (20 ml) solution of 7-methoxy-4,4-dimethylchroman-2-one (4.1 g, 19.7 mmol) was added lithium aluminum hydride (750 mg, 19.7 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour. To the mixture was added H2O (1 ml) carefully to form a white prepicitate. The organic layer was dried over magnesium sulfate. After filtration to separate solvent and magnesium sulfate and precipitate, the solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with ethyl acetate/hexane=¼ to furnish 3.0 g (76% yield) of the title compound as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[NH2:13].C(OCC)(=O)C>CO.[Pd]>[NH2:13][C:5]1[C:6]([NH2:10])=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:14]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(N)c1N

Procedure:
2-Amino-3-nitro-benzoic acid methyl ester (50.7 g, 258.7 mmol) was suspended in methanol (441 ml) and ethyl acetate (441 ml) with palladium-on-active charcoal 10% (1.93 g, 1.81 mmol). The suspension was hydrogenated at room temperature under an H2 pressure of 2.5 bar. When the reaction was complete, the suspension was filtered over Celite and the residue was rinsed with ethyl acetate. The filtrate was concentrated to dryness under reduced pressure, the residue was dissolved in ethyl acetate (50 ml) and hexane (50 ml) was added. After addition of starting crystals, a precipitate precipitated out. Hexane (200 ml) was added to the suspension and the precipitate was filtered off, washed with hexane and dried in vacuo. Methyl 2,3-diaminobenzoate (D-01) was obtained (35.8 g, 83%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:15][CH2:16][CH2:17][O:18][CH3:19])[N:3]=1>[Pd].C1COCC1.CO>[NH2:12][C:11]1[C:2]([NH2:1])=[N:3][C:4]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COCCOc1nc(N)c([N+](=O)[O-])cc1C(=O)OC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COCCOc1nc(N)c(N)cc1C(=O)OC

Procedure:
Prepared analogously to example 154d by hydrogenation of the product obtained in (800d) using palladium on charcoal in THF and methanol.
Reaction SMILES: [C:1]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH:10]2[CH2:13][N:12]([CH:14](C3C=CC=CC=3)C)[CH2:11]2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>[Pd].C(O)C>[C:1]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH:10]2[CH2:13][N:12]([CH3:14])[CH2:11]2)[C:8]#[N:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(c1ccccc1)N1CC(C(C#N)(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN1CC(C(C#N)(c2ccccc2)c2ccccc2)C1
Reaction time: 24 h

Procedure:
A solution of 800 ml. of ethanol and 59 g. (0.13 mole) of α,α-diphenyl-α-[1-(1-phenylethyl)-3-azetidinyl]acetonitrile methobromide was treated with 7.12 g. (0.13 mole) of potassium hydroxide and 0.25 g. of 10% palladium on carbon. The mixture was shaken under initial hydrogen pressure of 45 p.s.i. at ambient temperature for 24 hours. The mixture was filtered and the filtrate concentrated. The residue was crystallized from isooctane to give 21.7 g. (64%) of product melting 112°-115° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[CH:7]=1.[C:15]1([C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN1C(=O)CCC1>[N+:12]([C:5]1[CH:4]=[CH:3][C:2]([N:26]2[CH2:27][CH2:28][N:23]([C:21]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:22])[CH2:24][CH2:25]2)=[CH:7][C:6]=1[NH:8][CH2:9][CH2:10][CH3:11])([O-:14])=[O:13]
Reactant: O=C(c1ccccc1)N1CCNCC1
Reactant: CCCNc1cc(Br)ccc1[N+](=O)[O-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCNc1cc(N2CCN(C(=O)c3ccccc3)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 213.7 %

Procedure:
A solution of 5-bromo-2-nitro-N-propylbenzenamine (250 mg, 1.02 mmol) and phenyl(piperazin-1-yl)methanone (578 mg, 3.06 mmol) in NMP (2 mL) was heated to 110° C. for 16 h. The solution was cooled to room temperature to which was slowly added H2O (5 mL). The resulting yellow precipitate was filtered, washed with 2 mL of water, dried (high vacuum, 14 h) to furnish (4-(4-nitro-3-(propylamino)phenyl)piperazin-1-yl)(phenyl)methanone (520 mg, 2.18 mmol), 56% yield. 1H NMR (500 MHz, DMSO-D6) d (ppm) 8.83 (m, 1H), 7.93 (d, J=9.5 Hz, 1H), 7.50-7.45 (m, 5H), 6.41 (dd, J=2.5 Hz, 10 Hz, 1H), 6.00 (d, J=2.5 Hz, 1H), 3.72-3.40 (m, 8H), 3.29 (q, J=7 Hz, 2H), 1.66 (m, 2H), 0.96 (t, J=7 Hz, 3H).+ESI HRMS (calcd for C20H24N4NaO, M+Na) 391.1746. found 391.1741
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:16]=[CH:17][CH:18]=[N:19][C:20]=2[C:21]([O:36]C(C2C=CC=CC=2)C2C=CC=CC=2)=[C:22]2[C:26](=[O:27])[N:25]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:24][C:23]=12)=[O:13])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C>ClCCl>[F:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][N:25]2[C:26](=[O:27])[C:22]3[C:23](=[C:14]([C:12]([NH:11][CH2:10][CH2:9][P:4](=[O:3])([OH:5])[OH:8])=[O:13])[C:15]4[CH:16]=[CH:17][CH:18]=[N:19][C:20]=4[C:21]=3[OH:36])[CH2:24]2)=[CH:34][CH:33]=1
Reactant: CCOP(=O)(CCNC(=O)c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: O=C(NCCP(=O)(O)O)c1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.2 %

Procedure:
To (2-{[9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo [3,4-g]quinoline-5-carbonyl]-amino}-ethyl)-phosphonic acid diethyl ester 214 (16 mg, 0.023 mmol) dissolved in dichloromethane (0.30 ml) was added trimethylsilylbromide (TMS-Br, 39 mg, 0.25 mmol). After 4 hours of stirring at room temperature, more trimethylsilylbromide (24 mg, 0.16 mmol) was added and the reaction mixture stirred for another 2 hours. The reaction mixture was cooled to 0° C., quenched with methanol (1.0 ml), and concentrated in vacuo. It was then triturated three times (3/1—hexane/ether) and the remaining residue in the flask and filter was dissolved in methanol, combined, and concentrated in vacuo. The residue was dissolved in dimethysulfoxide (0.40 ml), filtered through a glass plug, and purified by reverse-phase preparatory HPLC to provide (2-{[7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carbonyl]-amino}-ethyl)-phosphonic acid 314 (7 mg, 0.012 mmol, 52%). 1H NMR (CD3OD) δ 8.96 (d, 1H), 8.77 (d, 1H), 7.78 (m, 1H), 7.42 (m, 2H), 7.10 (t, 2H), 4.80 (s, 2H), 4.63 (s, 2H), 3.72 (m, 2H), 2.16 (m, 2H). 31P δ 25.0. 19F δ−78.0, −116.0. MS: 460.1 (M+1).
Reaction SMILES: CCN(CC)CC.[N:8]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[N+:9]=[N-:10].C(Cl)(=O)C(C)(C)C.[CH2:24]([C@H:31]1[CH2:35][O:34][C:33](=[O:36])[NH:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[N:8]([CH2:11][CH2:12][CH2:13][C:14]([N:32]1[C@@H:31]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:35][O:34][C:33]1=[O:36])=[O:16])=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=NCCCC(=O)O
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: [N-]=[N+]=NCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
NEt3 was added to a stirred mixture of 4-azidobutanoic acid in THF (0.3 M) cooled to −78° C. and stirring was continued at this temperature for 10 min. Pivaloyl chloride (1.3 eq) was added dropwise. The resulting mixture was warmed to 0° C. and stirred for 1 h before re-cooling to −78° C. In a separate flask, (4S)-4-benzyl-1,3-oxazolidin-2-one was dissolved in THF (0.8 M) and cooled to −78° C. before dropwise addition of N-BuLi (1.6M, 1.35 eq.) over 10 min. The mixture was stirred at −78° C. for 1 h and then transferred into the −78° C. solution of mixed anhydride using a syringe. The reaction was stirred at −78° C. for 1 h, then at RT for a further 1 h. The reaction was quenched by addition of sat. aq. NH4Cl before partitioning between H2O and EtOAc. The layers were separated and the aqueous phase re-extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by FC eluting with 10 to 30% EtOAc/PE to give the product as a colourless oil (74%). (ES+) m/z 289 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8](=[O:15])[CH2:9][N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)=[N:6][CH:7]=1.[Cl:16][C:17]([Cl:22])([Cl:21])[C:18](Cl)=[O:19].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:16][C:17]([Cl:22])([Cl:21])[C:18]([C:14]1[N:10]([CH2:9][C:8]([C:5]2[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=2)=[O:15])[CH:11]=[CH:12][CH:13]=1)=[O:19]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cc1cnc(C(=O)Cn2cccc2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(C(=O)Cn2cccc2C(=O)C(Cl)(Cl)Cl)cn1
Reaction time: 8 h

Procedure:
To a chilled (0° C.) solution of 1-(5-methylpyrazin-2-yl)-2-(1H-pyrrol-1-yl)ethanone (318 mg, 1.58 mmol) in CH2Cl2 (21 mL) was added 2,2,2-trichloroacetyl chloride (400 μL, 3.56 mmol). The solution was allowed at room temperature and stirred until complete (overnight, monitored by LCMS). A chilled saturated solution of NaHCO3 (15 mL) was then added and the mixture extracted with CH2Cl2 (3×15 mL). The organic were dried (Na2SO4), filtrated and concentrated in vacuo to give a residue that is purified by flash chromatography (Biotage SP4, 4 g cartridge, gradient 1 CV hexane, 0-50% EtOAc in hexanes 10 CV; 50-100% 3CV). The compound 2,2,2-Trichloro-1-{1-[2-(5-methylpyrazin-2-yl)-2-oxoethyl]-1H-pyrrol-2-yl}ethanone was isolated as a crystalline solid (260 mg, yield 38%). 1H-NMR (400 MHz, CDCl3): δ 2.70 (s, 3H), 5.91 (2H, s), 6.45 (dd, 1H, J 4.4, 2.5, Hz), 7.02 (dd, 1H, J 2.4, 1.6 Hz), 7.64 (dd, 1H, J 4.4, 1.5 Hz), 8.53-8.55 (m, 1H), 9.15 (d, 1H, J 1.3 Hz).
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(O)C>C1COCC1>[CH2:1]([NH:9][C@@H:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11]1[OH:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1CCc2ccccc2C1=O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: O[C@@H]1c2ccccc2CC[C@H]1NCc1ccccc1
Temperature: 25 °C
Yield: 897.1 %

Procedure:
A solution of 2-benzamido-3,4-dihydronaphthalen-1(2H)-one (3.0 g, 1.1 mmole) in THF (150 ml) was added dropwise to a suspension of LiAlH4 (2.0 g) in THF (50 ml). The reaction was heated at reflux for 2 hr and then cooled to room temperature. Enough ethanol was added to destroy excess LiAlH4 followed by 150 ml of Rochell's salt solution (20%). The resulting mixture was extracted with ethyl acetate, the ethyl acetate layer was washed with brine and dried over Na2SO4. Evaporation of the solvent afforded 2.5 g (88%) of the product, m.p. 110°-114° C. After recrystallization from cyclohexane it had m.p. 112°-115° C.