Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH2:13][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11]2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[OH:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>C(O)(=O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[C:13](=[CH:26][C:25]3[CH:28]=[CH:29][C:22]([OH:21])=[CH:23][CH:24]=3)[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11]2)=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCOC(=O)C1=NN(c2ccc(C(=O)O)cc2)C(=O)C1
Solvent: CC(=O)O
Product: CCOC(=O)C1=NN(c2ccc(C(=O)O)cc2)C(=O)C1=Cc1ccc(O)cc1
Temperature: 25 °C

Procedure:
276 g (1 mole) of 1-(p-carboxyphenyl)-3-ethoxycarbonyl-2-pyrazolin-5-one and 122 g (1 mole) of p-hydroxybenzaldehyde were dissolved in 1000 ml of acetic acid. The reaction mixture was refluxed for 3 h. The dye crystallized partially. After cooling to room temperature the dye was filtered with suction and rinsed with acetone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Br:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[Br:25])[CH:21]([CH3:26])[NH:20][CH2:19][CH2:18]2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH2:19][CH2:18][C:17]4[C:22](=[CH:23][C:24]([Br:25])=[C:15]([Br:14])[CH:16]=4)[CH:21]3[CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cc(Br)c(Br)cc21
Product: CC1c2cc(Br)c(Br)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dibromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([N:28]2[C:33](=[O:34])[NH:32][C:31](=[O:35])[CH:30]=[N:29]2)[CH:25]=[C:24]([Cl:36])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:22]C)=[C:9]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:10]=1.B(Br)(Br)Br>ClCCl>[Cl:36][C:24]1[CH:25]=[C:26]([N:28]2[C:33](=[O:34])[NH:32][C:31](=[O:35])[CH:30]=[N:29]2)[CH:27]=[C:2]([Cl:1])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([OH:22])=[C:9]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:10]=1
Reactant: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1NS(=O)(=O)c1ccc(F)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1cnn(-c2cc(Cl)c(Oc3ccc(O)c(NS(=O)(=O)c4ccc(F)cc4)c3)c(Cl)c2)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a cooled (0° C.), stirred solution of N-{5-[2,6-dichloro-4-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-phenoxy]-2-methoxy-phenyl}-4-fluoro-benzenesulfonamide (96 mg) in dichloromethane (5 mL) was added boron tribromide (64 μL) and the resulting solution was allowed to stir at ambient temperature for 4 h. The reaction mixture was poured over ice, stirred for 0.5 h and extracted with ethyl acetate. The organic phase was dried (Na2SO4), concentrated in vacuo and flash chromatographed on silica gel (40% acetone/hexanes) to afford the title compound of this EXAMPLE as a colorless foam, 68 mg. m.p. 222-225° C. (dec), MS Calc.:539.2 Found:536.8.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13]=O.[BH4-].[Na+].Cl>CO>[CH:1]1([NH:7][CH2:13][C:9]2[NH:8][CH:12]=[CH:11][N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: O=Cc1ncc[nH]1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1c[nH]c(CNC2CCCCC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of cyclohexylamine (2.4 mL, 26.8 mmole) in methanol (30 mL) was added 1H-imidazole-2-carboxaldehyde (2.00 g, 26.8 mmole). After stirring at room temperature for one hour, the solution was cooled to 0° C. Sodium borohydride (1.57 g, 41.5 mmol) was then added slowly into the reaction mixture and the reaction mixture was stirred at 0° C. for one hour. Aqueous hydrochloric acid (1 N, 30 mL) was then added. The reaction mixture washed with diethyl ether twice, and then basified by addition of solid sodium carbonate. The aqueous phase was extracted with ethyl acetate twice. The combined ethyl acetate extracts were washed with saturated sodium bicarbonate solution twice and saturated aqueous sodium chloride solution once, and then dried over magnesium sulfate. The solvent was removed to yield cyclohexyl-(1H-imidazol-2-ylmethyl)-amine as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:12][CH2:13][CH3:14])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:15]([O:22][C:23]1[CH:28]=[C:27]([O:29][CH2:30][CH2:31][CH2:32]Cl)[C:26]([CH2:34][CH3:35])=[CH:25][C:24]=1[C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].COC(C)(C)C>CS(C)=O.CN(C)C1C=CN=CC=1.O>[CH2:15]([O:22][C:23]1[C:24]([C:36]2[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=2)=[CH:25][C:26]([CH2:34][CH3:35])=[C:27]([CH:28]=1)[O:29][CH2:30][CH2:31][CH2:32][O:1][C:2]1[C:3]([CH2:12][CH2:13][CH3:14])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCCc1c(O)cccc1C(=O)OC
Reactant: CCc1cc(-c2ccc(F)cc2)c(OCc2ccccc2)cc1OCCCCl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Solvent: O
Product: CCCc1c(OCCCOc2cc(OCc3ccccc3)c(-c3ccc(F)cc3)cc2CC)cccc1C(=O)OC
Temperature: 60 °C
Reaction time: 87 h
Yield: 107.3 %

Procedure:
To a solution of methyl 3-hydroxy-2-propyl-benzoate (40.0 g, 206 mmol) and 1-benzyloxy-5-(3-chloropropoxy)-4-ethyl-2-(4-fluorophenyl)benzene (prepared according to Org. Process Res. Dev. (2009), 13: 268-275) (82.15 g, 206 mmol) in dimethylsulfoxide (240 mL) add potassium carbonate (30.2 g, 219 mmol) and N,N-dimethylpyridin-4-amine (2.0 g, 16 mmol) in succession. Stir the suspension for 87 h at 60° C. and then allow it to cool. Dilute the mixture with water (600 mL) and with methyl-tert-butylether (100 mL) and stir for 15 min. Separate the phases and wash the aqueous portion with methyl-tert-butylether (3×30 mL). Wash the combined organic extracts with water and brine. Concentrate the organic portion in vacuo to yield the title compound (123.0 g, quantitative) as a brown oil. ES/MS m/z 557 (M+1).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH:26]([C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH2:39][CH:40]=O)[C:34](=[O:42])[CH:33]=[CH:32]2)([CH3:28])[CH3:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:40][CH2:39][N:35]4[C:36]5[C:31](=[CH:30][C:29]([CH:26]([CH3:28])[CH3:27])=[CH:38][CH:37]=5)[CH:32]=[CH:33][C:34]4=[O:42])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: CC(C)c1ccc2c(ccc(=O)n2CC=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)c1ccc2c(ccc(=O)n2CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Yield: 44 %

Procedure:
To 4 mL of a chloroform solution containing 0.62 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 0.41 g of (6-isopropyl-2-oxoquinolin-1(2H)-yl)acetaldehyde and 40 μL of acetic acid were added, then, to the reaction mixture, 0.57 g of sodium triacetoxyborohydride was added and stirred at room temperature for 2 nights. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; ethyl acetate], to give 0.44 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(6-isopropyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white foam.
Reaction SMILES: F[C:2]1C=C(C(N)C)C=C(F)C=1.[ClH:12].[NH2:13][C:14]1([C:19]([O:21][CH3:22])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15]1.NC1(C(O)=O)CCCCC1>>[ClH:12].[NH2:13][C:14]1([C:19]([O:21][CH3:22])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:2]1
Reactant: CC(N)c1cc(F)cc(F)c1
Reactant: COC(=O)C1(N)CCCC1
Agent: Cl
Agent: NC1(C(=O)O)CCCCC1
Product: COC(=O)C1(N)CCCCC1

Procedure:
Essentially following the procedures described in Intermediate 1 for methyl 1-aminocyclopentanecarboxylate hydrochloride, but using 1-aminocyclohexanecarboxylic acid in place of 1-aminocyclopentanecarboxylic acid, the title compound was obtained. MS: m/z=158 (M+1).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][OH:15])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[NH4+]>N1C=CC=CC=1>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][OH:15]
Reactant: [N-]=[N+]=NCCOCCOCCOCCO
Agent: [NH4+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: NCCOCCOCCOCCO
Reaction time: 1 h

Procedure:
To a solution of Compound XXV (15.94 g; 72.7 mmole) in 100 ml of pyridine was added triphenylphosphine (29 g; 111 mmole). After stirring for one hour, at which time gas evolution had subsided, 50 ml of concentrated aqueous ammonium hydroxide was added and the mixture stirred overnight. The reaction mixture was concentrated under vacuum and the residue partitioned between 200 ml of water and 200 ml of ether (aqueous layer at pH 2). The aqueous layer was adjusted to pH 11 with solid sodium hydroxide and extracted three times with 150 ml n-butanol each time. The butanol extract was dried over sodium sulfate, filtered and concentrated. The residue was taken up in tetrahydrofuran and filtered. The filtrate was evaporated to a syrup which was azeotroped with toluene.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.Br[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[CH3:30][O:29][CH2:28][CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)=[CH:21][CH:22]=1
Reactant: COCCOc1ccc(Br)cc1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
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+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCOc1ccc(-c2cnc3[nH]ccc3c2)cc1
Yield: 67.8 %

Procedure:
To a solution of 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (1.1 g, 4.3 mmol) in tetrahydrofuran (40 mL) was added 1 bromo-4-(2-methoxy-ethoxy)-benzene (647, 1.50 g, 6.49 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.25 g, 0.21 mmol). The reaction mixture was stirred with potassium carbonate solution (10 mL, 1.0 M) and warmed to reflux overnight. The biphasic reaction mixture was diluted with ethyl acetate (50 mL) and saturated sodium carbonate solution (20 mL). The organic layer was separated, washed with brine, dried over magnesium sulfate and purified by silica gel column chromatography (50-100% ethyl acetate in hexanes) to give the desired compound as a colorless solid (648, 782 mg, 67%). MS (ESI) [M+H+]+=267.4.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:8][C:9](=[O:19])[NH:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:18])[CH2:6][CH3:7].C(O)(=O)C.N([O-])=O.[Na+]>O>[CH2:5]([O:8][C:9](=[O:19])[NH:10][C:11]1[C:12]([CH3:18])=[CH:13][C:14]([N+:1]([O-:4])=[O:2])=[CH:15][C:16]=1[CH3:17])[CH2:6][CH3:7]
Reactant: O=[N+]([O-])O
Reactant: CCCOC(=O)Nc1c(C)cccc1C
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCOC(=O)Nc1c(C)cc([N+](=O)[O-])cc1C
Temperature: 0 °C
Yield: 42 %

Procedure:
To a solution of concentrated nitric acid (6.4 mL) in water (30 mL) was added (2,6-dimethyl-phenyl)-carbamic acid propyl ester (2.72 g), acetic acid (30 mL) and sodium nitrite (1.0 g). The reaction mixture was refluxed for 16 hours, water (200 mL) was added and the mixture was cooled to 0° C. The product was collected by filtration and dried in vacuo to furnish 1.40 g (42% yield) of the title compound as a yellow solid. The crude product was used without further purification. 1H NMR (500 MHz, DMSO-d6): 0.92 (t, 3H), 1.63 (m, 2H), 2.29 (s, 6H), 4.04 (t, 2H), 7.98 (s, 2H), 9.11 (b, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[C:9]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22]O)[CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([O:8][CH2:22][CH:19]2[CH2:20][CH2:21][N:16]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:17][CH2:18]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Oc1ccc(Cl)nc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(Cl)nc2)CC1
Yield: 54.3 %

Procedure:
1,1-Dimethylethyl 4-{[(6-chloro-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (0.80 g, 54%) was prepared as a white solid from 2-chloro-5-hydroxypyridine (0.60 g, 4.51 mmol), N-Boc-4-piperidinemethanol (1.0 g, 4.51 mmol) and Ph3P (1.20 g, 4.51 mmol) in THF (25 mL) followed by diisopropyl azodicarboxylate (0.97 g, 94%, 4.51 mmol) in THF (8 mL) in a manner similar to Example 1, Step 2. 1H NMR (400 MHz, CDCl3): δ 8.04 (bs, 1H), 7.25-7.15 (m, 2H), 4.20-4.10 (m, 2H), 3.82 (d, 2H, J=6.1 Hz), 2.80-2.70 (m, 2H), 2.05-1.90 (m, 1H), 1.85-1.75 (m, 2H), 1.46 (s, 9H), 1.35-1.20 (m, 2H); LRMS (ESI), m/z 327 (M+H).
Reaction SMILES: C[C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])O1.N1C=CC=CC=1.[F:17][C:18]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:19]=1[CH2:20][O:21][C:22]1[CH:31]=[CH:30][C:25]([CH2:26]C(Cl)=O)=[CH:24][CH:23]=1.Cl>ClCCl>[F:17][C:18]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:19]=1[CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][C:4](=[O:5])[CH2:6][C:7]([O:9][CH2:2][CH3:10])=[O:8])=[CH:30][CH:31]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(Cl)Cc1ccc(OCc2c(F)cccc2F)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CC(=O)Cc1ccc(OCc2c(F)cccc2F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of Meldrum's acid (0.846 g, 5.8 mmol) in dichloromethane (5 ml) was added pyridine (2 ml) over a period of 10 minutes at 0° C. To this solution was added 4-(2,6-Difluorobenzyloxy)benzylcarbonyl chloride (Step D, 1.71 g, 5.7 mmol) in dichloromethane (5 ml), which resulted in an orange solution. The dark orange solution was stirred for 1 hour at 0° C., allowed to warm to room temperature and stirred for an additional hour. The reaction mixture was diluted with dichloromethane and poured onto 2M HCl and ice. The phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic layers were washed twice with 2M HCl and brine, dried over Na2SO4, filtered and concentrated to a solid. The solid was suspended in abs EtOH (15 ml) and refluxed for 2.5 hours. The solvent was removed in vacuo to give a dark oil. The residue was purified by flash chromatography on silica gel column (hex:ethyl acetate, 2:1) to provide the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:34])[N:4]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=2[CH3:33])[C:27](O)=[O:28])[C:5]([CH3:23])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[CH2:17][NH:18][C:19]([O:21][CH3:22])=[O:20].ClC(OCC(C)C)=O.[CH3:43][N:44]1CCOCC1.CN.C1COCC1>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:34])[N:4]([C:24]2[CH:25]=[C:26]([C:27]([NH:44][CH3:43])=[O:28])[CH:30]=[CH:31][C:32]=2[CH3:33])[C:5]([CH3:23])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[CH2:17][NH:18][C:19](=[O:20])[O:21][CH3:22]
Reactant: COC(=O)NCc1cc(F)ccc1COc1cc(C)n(-c2cc(C(=O)O)ccc2C)c(=O)c1Br
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: CN
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3CNC(=O)OC)c(Br)c2=O)c1
Reaction time: 0.25 h

Procedure:
To a cooled (−10° C.) solution of 3-[3-bromo-4-[(4-fluoro-2-{[(methoxycarbonyl)amino]methyl}benzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid (0.07 g, 0.13 mmol) in DMF (2.0 mL) was added isobutyl chloroformate (0.02 mL, 0.16 mmol) and 4-methylmorpholine (0.02 mL, 0.16 mmol). After 15 min, 2.0M methylamine in THF (0.01 mL, 0.20 mmol) was added. Solvent removed by distillation after 30 min. Crude product purified by preparatory HPLC. Acetonitrile was evaporated and the solution washed with 5% NaHCO3 (30 mL) and extracted in DCM (3×25 mL). The organic extracts were dried over Na2SO4, filtered, concentrated, and dried in vacuo to give a white foam, (0.061 g, 86%). 1H NMR (CD3OD/400 MHz) δ7.85 (m, 1H), 7.54 (m, 3H), 7.14 (m, 1H), 7.05 (m, 1H), 6.68 (s, 1H), 5.40 (s, 2H), 4.43 (s, 2H), 3.64 (s, 3H), 2.89 (s, 3H), 2.08 (s, 3H), 1.99 (s, 3H). ESHRMS m/z 546.0987 and 548.1018 (M+H calculated for C25H26BrFN3O5 requires 546.1034 and 548.1018).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1.[CH3:26][N:27]([CH3:32])[C:28](=[O:31])[CH2:29]Cl>CN(C)C=O>[CH3:26][N:27]([CH3:32])[C:28](=[O:31])[CH2:29][O:13][CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4](=[O:3])[N:5]1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1
Reactant: CN(C)C(=O)CCl
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)N(C)C)nc2n1
Temperature: 70 °C
Reaction time: 3 h
Yield: 50.5 %

Procedure:
Sodium hydride (0.25 g) is added in small portions at a temperature in the region of 0° C. to a solution, maintained under an argon atmosphere, of 3-hydroxy-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (3.1 g) in anhydrous dimethylformamide (50 cc). The suspension obtained is stirred for 45 minutes at a temperature in the region of 0° C., and N,N-dimethyl-2chloroacetamide (1.3 g) is then added. The reaction mixture is heated with stirring to a temperature of 70° C. for 3 hours, then cooled to a temperature in the region of 10° C., poured into distilled water (200 cc) and extracted with dichloromethane (3×70 cc). The organic phases are combined, washed with distilled water (2×40 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in ethyl acetate, N,N-dimethyl-2-[2-(7-methoxy-1,8-naphthyridin-2-yl)- 3-oxo-1 -isoindolinyloxy]acetamide (2 g), m.p. 166° C., is obtained.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:17]([O-:19])=[O:18])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[F:20]C1C=C(O)C=CC=1[N+]([O-])=O.FC1C=C(C=CC=1)CBr>>[F:20][C:5]1[CH:6]=[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:2]=[CH:3][C:4]=1[N+:17]([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)c(F)c1
Agent: Fc1cccc(CBr)c1
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)cc1F

Procedure:
Prepared in analogy to 3-fluoro-4-(3-fluoro-benzyloxy)-nitrobenzene, starting from 3-fluoro-4-nitrophenol and 3-fluorobenzyl bromide. Yield after recrystallisation from diethyl ether/hexane: 100% of a white solid. MS: m/e=265.0 (M+).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([N:12]=[CH:13][C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][OH:25].C([Li])CCC>C1C=CC=CC=1>[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][O:25][C:2]1[C:3]2[N:4]([N:12]=[CH:13][C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CCOC(=O)c1cnn2c1c(Cl)nc1ccccc12
Reactant: CN(C)CCCO
Agent: [Li]CCCC
Solvent: c1ccccc1
Product: CCOC(=O)c1cnn2c1c(OCCCN(C)C)nc1ccccc12

Procedure:
A solution of 2.76 g. of 4-chloropyrazolo[1,5-a]quinoxaline-3-carboxylic acid, ethyl ester in benzene is added dropwise, at 10° to a stirred soluttion of 1.03 g. of 3-dimethylamino-1-propanol and 0.64 g. of butyl lithium in 30 ml. of benzene. The reaction mixture is heated under reflux for 3 hours and is then filtered and concentrated under reduced pressure. The oily residue is dissolved in petroleum ether, treated with carbon and cooled for 12 hours in the refrigerator. The product, 4-[3-(dimethylamino)propoxy]pyrazolo[1,5-a]quinoxaline-3-carboxylic acid, ethyl ester, crystallizes in the form of white needles, m.p. 78°-81°.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:17]>ClCCl>[O:17]1[CH2:3][CH:2]1[CH2:1][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: C=CCNC(=O)OC(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a solution of 28.9 g (184 mmol) of tert-butyl allylcarbamate in 400 mL of dichloromethane was added 103 g (460 mmol) of 77% 3-chloroperoxybenzoic acid at room temperature. The reaction mixture was stirred at room temperature overnight. The solid was filtered and the filtrate was concentrated. The residue was taken up in diethyl ether and washed with 5% sodium hydrosulfite (3×), saturated sodium bicarbonate (3×), brine (3×), and dried over anhydrous magnesium sulfate. Removal of solvent gave 21 g (66%) of tert-butyl 2-oxiranylmethylcarbamate as a liquid. 1H-NMR (400 MHz, CDCl3): δ 4.73 (br s, 1H), 3.53 (br s, 1H), 3.21 (m, 1H), 3.08 (br s, 1H), 2.77 (t, J=4 Hz, 1H), 2.58 (m, 1H), 1.43 (s, 9H).
Reaction SMILES: N1CCC[CH2:2]1.CC(=O)CC.[C-]#N.[K+].[CH3:14][C:15]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)([CH3:18])[C:16]#[N:17]>O>[CH3:14][C:15]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)([CH2:18][CH3:2])[C:16]#[N:17]
Reactant: CC(C)(C#N)N1CCCC1
Reactant: C1CCNC1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCC(C)(C#N)N1CCCC1
Yield: 63 %

Procedure:
The title compound (9.6 g, 63%) was prepared from pyrrolidine (8.35 ml, 0.1 mol), 2-butanone (8.96 g, 0.1 mol) and potassium cyanide (6.51 g, 0.1 mol) in water (50 ml) in a similar manner to that described in D4. 1H NMR (CDCl3) δ: 1.06 (3H, t, J=7.2 Hz), 1.45 (3H, s), 1.66-1.93 (6H, m), 2.70-2.75 (4H, m).
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:14]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([Cl:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc(OC)c1N
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)cc(OC)c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
To methyl 2-amino-3-methoxybenzoate (750 mg, 4.1 mmol) in anhydrous N,N-dimethylformamide (15 mL) was added N-chlorosuccinimide (580 mg, 4.35 mmol) and this mixture was stirred at ambient temperature for 2 hours. The temperature was increased to 60° C. for 4 hours. The deep red solution was cooled, diluted with ethyl acetate, washed with saturated sodium bicarbonate, water, then brine, dried with sodium sulfate, decanted and concentrated to yield crude methyl 2-amino-5-chloro-3-methoxybenzoate (0.85 g, 95%). MS (m/z): 216.1 (M+H)+.