Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH:2]([C:13](OCC)=O)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:18](Br)[C:19]#C.Cl>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:13]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:18]#[CH:19]
Reactant: C#CCBr
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C#CCC(C(=O)OCC)C(=O)OCC
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 180.3 %

Procedure:
To a mixed solution of triethyl methanetricarboxylate sodium salt (25.0 g) in toluene/DMF (120 mL/120 mL) was added propargyl bromide (25.0 g), and the mixture was stirred at 80° C. for 1.5 hr. After allowing to cool, dilute hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate (60 mL). The organic layer was washed with saturated brine and concentrated under reduced pressure. The residue was dissolved in THF (30 mL), sodium ethoxide (7.60 g) was added, and the mixture was stirred at room temperature for 1 hr. 1 mol/L Hydrochloric acid (150 mL) was added, and the mixed solution was extracted with chloroform (100 mL). The organic layer was concentrated, and the residue was purified by silica gel column chromatography to give the title compound (35.0 g) as an oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(O)(=O)C.[Br:16]Br.C([O-])(O)=O.[Na+]>CCOCC>[Br:16][C:9]1[CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=1[OH:11]
Reactant: BrBr
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc(O)c(Br)c1
Temperature: -10 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
To a solution of 4-(methylsulfonyl)phenol (5 g, 29.1 mmol) in ether (100 mL) at −15° C. was slowly added acetic acid (5 mL). To this cold solution was slowly added Br2 (5.1 g, 32.0 mmol) and the reaction was stirred at −10° C. for 1 h and then warmed to r.t. and stirred for further 10 h. After the reaction was completed, 100 mL of sat. NaHCO3 aq. was added and the mixture was extracted with EA (50 mL×3). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and evaporation of the solvent, 2-bromo-4-(methylsulfonyl)phenol (3.2 g, 43.6%) was obtained as a white solid.
Reaction SMILES: C(O[C:6](=[O:16])[NH:7][C:8]1[C:13]([CH:14]=O)=[CH:12][CH:11]=[CH:10][N:9]=1)(C)(C)C.C(OCC)(=O)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].N1CCCCC1>C(O)C>[CH2:22]([O:21][C:19]([C:18]1[C:6](=[O:16])[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:20])[CH3:23]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C)OC(=O)Nc1ncccc1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1cc2cccnc2[nH]c1=O
Temperature: 23 °C

Procedure:
A solution of 5-2 (1.53 g, 6.88 mmol, 1 equiv), diethyl malonate (2.09 mL, 13.8 mmol, 2.00 equiv), and piperidine (0.340 mL, 3.44 mmol, 0.500 equiv) in ethanol (20 mL) was heated at reflux for 16 h. The reaction mixture was allowed to cool to 23° C. The white crystals which formed were filtered and washed with ethanol (20 mL) to give 2-oxo-1,2-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester (5-3). 1H NMR (400 MHz, CDCl3) δ 11.9 (br s, 1H), 8.85 (dd, 1H, J=4.8, 1.7 Hz), 8.46 (s, 1H), 8.03 (dd, 1H, J=7.9, 1.6 Hz), 7.27 (dd, 1H, J=7.9, 4.8 Hz), 4.45 (q, 2H, J=7.1 Hz), 1.43 (t, 3H, J=7.1 Hz).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[S:7]([O-:10])([O-:9])=[O:8].[Na+:11].[Na+].O>COC(C)(C)C>[CH2:2]([S:7]([O-:10])(=[O:9])=[O:8])[CH2:3][CH2:4][CH:5]=[CH2:6].[Na+:11]
Reactant: C=CCCCBr
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: C=CCCCS(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 19 h

Procedure:
5-Bromo-1-pentene (199.74 g), sodium sulfite (202.67 g), and water (650 ml) were mixed at room temperature. Under reflux, the solution was stirred for 19 hours. After cooling to room temperature, t-butyl methyl ether was added thereto. The aqueous layer separated was concentrated and dehydrated azeotropically with toluene. Thus, sodium 4-pentene-1-sulfonate (1) containing inorganic substances (387.51 g) was obtained as white solid.
Reaction SMILES: [OH:1][N:2]=[C:3]([CH3:13])[C:4](=[N:10][O:11][CH3:12])[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].[CH3:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH3:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][O:1][N:2]=[C:3]([CH3:13])[C:4](=[N:10][O:11][CH3:12])[C:5]([N:7]([CH3:8])[CH3:9])=[O:6])=[CH:17][CH:16]=1
Reactant: CON=C(C(=O)N(C)C)C(C)=NO
Reactant: Cc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CON=C(C(=O)N(C)C)C(C)=NOCc1ccc(C)cc1
Yield: 96.5 %

Procedure:
To a solution of 600 mg (3.2 mmol) of 3-hydroxyimino-2-methoxyimino-N,N-dimethylbutyramide in 20 ml of acetone, 500 mg (3.5 mmol) of 4-methylbenzylchloride and 660 mg (4.8 mmol) of potassium carbonate were added and the mixture was heated under reflux for 16 hours. The reaction mixture was combined with 30 ml of water and extracted three times with 30 ml of diethylether. After washing with water and a saturated aqueous sodium chloride, the mixture was dried over with anhydrous magnesium sulfate and then the solvent was distilled off. The residue thus obtained was purified by a column chromatography on a silica gel (n-hexane/ethyl acetate) to obtain 900 mg (yield: 96%) of 3-(4-methylbenzyloxyimino)-2-methoxyimino-N,N-dimethylbutyramide as a colorless crystal.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11](=O)[C:12]([N+:17]([O-:19])=[O:18])=[CH:13][NH:14]3)=[CH:9][C:8]=2[O:21][CH3:22])=[C:5]([CH3:23])[O:4][N:3]=1.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:11]1[C:10]2[C:15](=[CH:16][C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:23])=[C:8]([O:21][CH3:22])[CH:9]=2)[N:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]
Reactant: COc1cc2c(=O)c([N+](=O)[O-])c[nH]c2cc1-c1c(C)noc1C
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2c(Cl)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 63.4 %

Procedure:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-3-nitroquinolin-4(1H)-one (for a preparation see Intermediate 6) (4.78 g, 15.16 mmol) was dissolved in POCl3 (10 ml, 107 mmol) and the mixture was heated at 110° C. for 3 h, then cooled and evaporated in vacuo, The residue was suspended in toluene (20 ml) and evaporated in vacuo, then the residue was suspended in DCM (100 ml) and saturated sodium hydrogen carbonate solution (100 ml) and stirred for 10 min. The organic layer was dried and evaporated and the residue dissolved in DCM (10 ml) and loaded onto a 100 g silica column, then eluted with 0-60% EtOAc/cyclohexane to give 4-(4-chloro-6-methoxy-3-nitroquinolin-7-yl)-3,5-dimethylisoxazole (3.21 g, 9.62 mmol, 63.4% yield) as a bright yellow powder. LCMS (formate) Rt 1.13 min, MH+ 334
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:50]=[CH:49][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][OH:26])[C:22]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]4[N:38]=[C:39]([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)[O:40][C:41]=4[CH3:42])=[CH:31][CH:30]=3)=[N:21]2)=[CH:17][CH:16]=1.C(Cl)(Cl)Cl>[O-2].[O-2].[Mn+4].O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:50]=[CH:49][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH:25]=[O:26])[C:22]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]4[N:38]=[C:39]([C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)[O:40][C:41]=4[CH3:42])=[CH:31][CH:30]=3)=[N:21]2)=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(Cc3ccc(OCc4nc(-c5ccccc5)oc4C)cc3)cc2CO)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(Cc3ccc(OCc4nc(-c5ccccc5)oc4C)cc3)cc2C=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.4 %

Procedure:
A mixture of [1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazol-4-yl]methanol (27.02 g), activated manganese dioxide (52.29 g), chloroform (50 ml), and tetrahydrofuran (300 ml) was stirred at room temperature for 3 hours. After the manganese dioxide was removed by filtration, the filtrate was concentrated. The crystals obtained were collected by filtration to yield 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazole-4-carbaldehyde (25.69 g, yield: 95%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 155–156° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[S:8][C:4]=2[CH:3]=1.[CH:12]1[CH:17]=[CH:16][C:15]([O:18][C:19](OC2C=CC=CC=2)=[N:20][C:21]#[N:22])=[CH:14][CH:13]=1>C(#N)C>[C:15]1([O:18][C:19](=[N:1][C:2]2[CH:11]=[CH:10][C:5]3[N:6]=[C:7]([SH:9])[S:8][C:4]=3[CH:3]=2)[NH:20][C:21]#[N:22])[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: Nc1ccc2nc(S)sc2c1
Solvent: CC#N
Product: N#CNC(=Nc1ccc2nc(S)sc2c1)Oc1ccccc1
Yield: 29.6 %

Procedure:
Into a 200 mL round bottomed flask are added 6-amino-1,3-benzothiazole-2-thiol (2.26 g, 12.4 mmol), diphenylcyanocarbonimidate (4.43 g, 18.6 mmol) and acetonitrile (50 mL). The reaction mixture is refluxed under nitrogen atmosphere for 16 hrs. The precipitates are collected by filtration and washed with acetonitrile (15 mL). Recrystalization of the solid from ethanol affords the intermediate of N-cyano-N′-(2-mercapto-benzothiazol-6-yl)carbamimidic acid phenyl ester as white solid (1.2 g, 30%). 1H NMR (DMSO-d6) δ 7.20-7.42 (m, 8H), 7.78 (s, 1H), 10.88 (b, 1H); ESIMS: m/z 324.8 (M−H).
Reaction SMILES: [CH2:1](C1C=C2C(COC2=O)=CC=1)[CH3:2].Br[C:14]1[C:15]([O:36][CH3:37])=[C:16]([C:22]([CH2:25][S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])(=[O:28])=[O:27])=[CH:23][CH:24]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(B(CC)CC)C>>[CH2:1]([C:14]1[C:15]([O:36][CH3:37])=[C:16]([C:22]([CH2:25][S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])(=[O:28])=[O:27])=[CH:23][CH:24]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:2]
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2C)ccc(Br)c1OC
Reactant: CCc1ccc2c(c1)C(=O)OC2
Agent: CCB(CC)CC
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2C)ccc(CC)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 18, starting from ethyl 3-bromo-2-methoxy-6-(2-methylbenzenesulphonylmethyl)benzoate (Intermediate 62) and triethyl borane.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]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>[CH3:18][N:19]1[CH:23]=[C:22]([C:2]2[N:7]=[N:6][C:5]([N:8]3[CH2:17][CH2:16][C:11]4([O:15][CH2:14][CH2:13][O:12]4)[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH:21]=[N:20]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Clc1ccc(N2CCC3(CC2)OCCO3)nn1
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: Cn1cc(-c2ccc(N3CCC4(CC3)OCCO4)nn2)cn1
Temperature: 100 °C

Procedure:
In a two-neck flask was placed 8-(6-chloropyridazin-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane, prepared as in STEP 1 above (3.07 g, 12 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (3.24 g, 15.6 mmol), K2CO3 (6.62 g, 48 mmol), and Pd(PPh3)4 (693 mg, 0.6 mmol). The resulting mixture was degassed and refilled with N2 (3 times). 1,4-Dioxane/H2O (15 mL/5 mL) was added and the resulting mixture was heated at 100° C. for 4 h. The resulting mixture was then poured into EtOAc/H2O (100 mL/100 mL). The organic layer was washed with brine (100 mL), dried (Na2SO4), and filtered. The solvent was removed by roto-evaporator and the resulting residue purified by column using EtOAc as the eluent to yield 8-(6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(N(CC)CC)C.Cl.[Cl:17][C:18]1[C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1>O1CCCC1>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:24]([C:23]1[C:18]([Cl:17])=[N:19][CH:20]=[CH:21][CH:22]=1)=[O:25]
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Nc1ccccc1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.1 %

Procedure:
As described in J. Med. Chem., 37, 519 (1994), a solution of 1.09 g of 2-aminophenol in 15 ml of tetrahydrofuran is added dropwise to a mixture of 2.1 g of triethylamine and 2.33 g of 2-chloropyridine-3-carbonyl chloride hydrochloride in 10 ml of tetrahydrofuran. The mixture is stirred at room temperature for one hour under argon and then refluxed for one hour. The solvent is removed under vacuum and the residue triturated with water: The solid is filtered off and washed with water to give 1.02 g of solid. Recrystallization from 2-propanol gives crystals, m.p. 145°-146° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10]([Br:13])=[CH:11][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[N:19][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Br:13][C:10]1[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]([C:17]2[CH:18]=[N:19][CH:20]=[C:15]([CH3:14])[CH:16]=2)=[N:12][CH:11]=1
Reactant: CCOC(=O)c1cc(Br)ncc1Br
Reactant: Cc1cncc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2cncc(C)c2)ncc1Br
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution ethyl 2,5-dibromoisonicotinate (1-2, 1.5 g, 4.86 mmol) in degassed dimethylformamide (24 mL) at 25° C. was added (5-methylpyridin-3-yl)boronic acid (0.665 g, 4.86 mmol), PdCl2dppf (0.355 g, 0.486 mmol), cesium carbonate (4.75 g, 14.6 mmol) and water (0.262 mL, 14.57 mmol). The reaction flask was purged with nitrogen, sealed and stirred at 50° C. overnight. The crude reaction mixture was partitioned between water and EtOAc, separating layers and washing the organic layer with saturated sodium bicarbonate solution and brine. The solvent was removed by rotary evaporation and the crude product was purified by normal phase column chromatography (0 to 50% EtOAc in hexanes) to afford the product (1-3) as a white solid. ESI+MS[M]+C14H13BrN2O2=321.0.
Reaction SMILES: [C:1]([C:4]1[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C:6]2[C:11]([C:12]=1[C:13]#[N:14])=[CH:10][CH:9]=[CH:8][CH:7]=2)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+]>CO.C(#N)C>[NH2:28][CH:1]([C:4]1[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C:6]2[C:11]([C:12]=1[C:13]#[N:14])=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1c(C#N)c2ccccc2n1-c1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC(N)c1c(C#N)c2ccccc2n1-c1cccc(F)c1
Temperature: 65 °C
Yield: 102.6 %

Procedure:
A mixture of 2-acetyl-1-(3-fluorophenyl)-1H-indole-3-carbonitrile (43 mg, 0.15 mmol) and ammonium acetate (0.119 g, 1.54 mmol) in methanol (1.5 mL) and acetonitrile (1.5 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, sodium cyanoborohydride (29 mg, 0.46 mmol) was added to the resultant mixture. The reaction was heated at 65° C. overnight. The reaction was then cooled to room temperature, quenched with saturated NaHCO3 solution, and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product (43 mg), which was used directly in the next step. LCMS calculated for C17H15FN3(M+H)+: m/z=280.1. Found: 280.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=1.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][N:8]([CH2:19][C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=3)[C:5]2=[N:6][CH:7]=1
Reactant: Fc1cccnc1CBr
Reactant: Fc1cnc2[nH]nc(I)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cnc2c(c1)c(I)nn2Cc1ncccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.291 g (23.921 mmol) of 5-fluoro-3-iodo-1H-pyrazolo[3,4-b]pyridine and 8.573 g (26.313 mmol) of caesium carbonate were put in DMF (10 ml) and then 5.00 g (26.313 mmol) of 2-(bromomethyl)-3-fluoropyridine dissolved in DMF (20 ml) was added dropwise. The mixture was stirred overnight at RT. Then it was left to cool and was poured into 200 ml water. A precipitate was filtered off with suction, it was washed with water and dried overnight under high vacuum. 6.28 g (70% of theor.) of the title compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH3:18])=[N:15][CH:16]=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:29]N1C(=O)CCC1=O>CC#N.CC(=O)OCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH3:18])=[N:15][C:16]([Cl:29])=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCc1ncc2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C#N)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C#N)cc1
Temperature: 70 °C

Procedure:
To a solution of 8-[2-(4-cyano-phenyl)-ethyl]-3-ethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (0.700 g; 1.840 mmol) in anhydrous MeCN (20 ml) was added dropwise, at rt, a solution of N-chlorosuccinimide (0.250 g; 1.840 mmol; 1 eq.) in anhydrous MeCN (5 ml). The resulting solution was then heated to 70° C., under nitrogen, for 4 h. Concentration to dryness afforded an oily residue which was dissolved in EA (80 ml), and this organic layer was washed with aq. sat. NaHCO3 (2×100 ml), was then dried over anh. MgSO4, filtered, and finally concentrated to dryness under reduced pressure. Purification by FC (heptane/EA=2/3) gave the expected 1-chloro-8-[2-(4-cyano-phenyl)-ethyl]-3-ethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow solid (0.417 g; 55%). LC-MS: tR=1.00 min.; [M+H]+=414.94 g/mol.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:50][C@@H:51]1[CH2:56][NH:55][CH2:54][CH2:53][N:52]1C(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:55]6[CH2:54][CH2:53][NH:52][C@H:51]([CH3:50])[CH2:56]6)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(C=O)c3)c2)c1
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN[C@H](C)C4)c3)c2)c1
Reaction time: 1.5 h

Procedure:
A mixture of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (100 mg, 0.000152 mol) in 1,2-dichloroethane (4 mL) with 1,1-dimethylethyl (2R)-2-methyl-1-piperazinecarboxylate (48 mg, 0.00024 mol) and sodium triacetoxyborohydride (68 mg, 0.00032 mol) and AcOH (12 μL) was placed on an oscillating shaker overnight at room temperature. The reaction was quenched with sat. aq. NaHCO3, then extracted with 1,2-dichloroethane (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. The crude product was taken up in 1,2-dichloroethane (10 mL) containing 25% TFA and allowed to stand at room temperature for 1.5 h. LC-MS showed the reaction to be complete and the solution stripped to dryness. Purification was carried out on Gilson HPLC instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP Column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of 1,2-dichloroethane and transferred to a vial and pumped down to afford the title compound as an ivory colored solid [62.1 mg (53%)]. LC-MS m/z 747.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:6]([C:7]([OH:9])=O)[CH:5]=1.C(Cl)(C(Cl)=O)=O.[CH2:23]([NH:26][CH2:27][CH2:28][CH3:29])[CH2:24][CH3:25]>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:6]([C:7]([N:26]([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:24][CH3:25])=[O:9])[CH:5]=1
Reactant: COC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: CCCNCCC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.6 %

Procedure:
A suspension of 5-nitro-isophthalic acid monomethyl ester (D77) (1.0 g, 4.44 mmol, 1 equiv) in CH2Cl2 (40 ml) was treated with (COCl)2 (655 mg, 5.2 mmol, 1.2 equiv) followed by a few drops of DMF. The resulting mixture was stirred for 1 h at room temperature and then dipropylamine (1.65 g, 15 mmol, 3.4 equiv) was added and the resulting solution stirred for a further 30 min. The solution was then washed with 2N aqueous HCl solution (50 ml), saturated aqueous NaHCO3 solution (50 ml), dried over MgSO4 and concentrated in vacuo to give 5-nitro-N,N-dipropyl-isophthalamic acid methyl ester (D87) (1.5 g, 110%) as a pale yellow oil.
Reaction SMILES: C[N:2]([CH:11]1[CH2:23][C:22]2[C:21]3[C:16](=[C:17]([F:25])[CH:18]=[C:19](F)[CH:20]=3)[NH:15][C:14]=2[CH2:13][CH2:12]1)[C:3](=O)[C:4]1C=CC=CC=1.C(NC1CC2C3C(=C(F)C=CC=3)NC=2CC1)(=O)C>>[CH2:3]([NH:2][CH:11]1[CH2:23][C:22]2[C:21]3[C:16](=[C:17]([F:25])[CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH2:13][CH2:12]1)[CH3:4]
Reactant: CN(C(=O)c1ccccc1)C1CCc2[nH]c3c(F)cc(F)cc3c2C1
Agent: CC(=O)NC1CCc2[nH]c3c(F)cccc3c2C1
Product: CCNC1CCc2[nH]c3c(F)cccc3c2C1

Procedure:
Following a reductive procedure similar to that described in Example 260 but substituting for 3-(N-methylbenzamido)-6,8-difluoro-1,2,3,4-tetrahydrocarbazole an equivalent amount of 3-acetamido-8-fluoro-1,2,3,4-tetrahydrocarbazole there can be obtained 3-(ethylamino)-8-fluoro-1,2,3,4-tetrahydrocarbazole.