Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:9][CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[B-](F)(F)(F)F.C1C=C[CH+]C=CC=1.C(=O)(O)[O-].[Na+]>CO>[CH3:1][O:2][CH:3]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=[CH:4]1
Reactant: COC1=CC=CC=CC1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC1C=CC=CC=C1

Procedure:
An improved multi-step process for synthesizing the liquid irritant 1-methoxycycloheptatriene through the steps of reacting cycloheptatrienyl tetrafluoroborate in aqueous solution with methanol and sodium bicarbonate to produce 7-methoxycycloheptatriene, thermally isomerizing the 7-methoxycycloheptatriene to 3-methoxycycloheptatriene by heating at 150° C. for 2 hours and isomerizing the 3-methoxycycloheptatriene to 1-methoxycycloheptatriene by acid, catalyzed rearrangement employing methanolic hydrogen chloride followed by neutralization with sodium bicarbonate, filtration and fractional distillation to give the final product the improvement comprising the step of utilizing a polymerization/condensation inhibitor to increase the overall yield and purity of the 1-methoxycycloheptatriene product. The overall yield and purity of the product can further be increased through the step of conducting the thermal isomerization of 7-methoxy to 3- and 1-methoxycycloheptatriene at 180° C. under reduced pressure, e.g., by heating in a sealed reactor.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]2=[CH:15][S:16][CH:17]=[C:6]2[C:5]1=[O:18].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:19]([N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:4]([CH3:3])[C:5](=[O:18])[C:6]2=[CH:17][S:16][CH:15]=[C:7]12)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN1C(=O)c2cscc2Nc2ccccc21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)c2cscc2N(Cc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of 0.18 g. of 57% sodium hydride-mineral oil dispersion in 25 ml. of dimethylformamide is added 0.92 g. of 4,9-dihydro-9-methyl-10H-thieno[3,4-b][1,5]-benzodiazepin-10-one and 0.8 ml. of benzyl bromide. The mixture is stirred at room temperature for 3.5 hours, quenched by dropwise addition of water, diluted with 200 ml. of water and extracted several times with chloroform. The chloroform extracts are dried over magnesium sulfate and concentrated under reduced pressure to give an amber oil, which crystallizes on trituration with methanol. Recrystallization from aqueous methanol and then from ethyl acetate gives off-white crystals, m.p. 151.5°-153° C.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[C:8](=[S:13])([S:11][CH3:12])[S:9][CH3:10].[F:14][B-:15]([F:18])([F:17])[F:16].[H+]>C(#N)C>[F:14][B-:15]([F:18])([F:17])[F:16].[CH3:10][S:9][C:8](=[S+:13][CH3:5])[S:11][CH3:12]
Reactant: COS(=O)(=O)OC
Reactant: CSC(=S)SC
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CC#N
Product: CSC(SC)=[S+]C
Temperature: 90 °C
Yield: 83 %

Procedure:
Dimethyl sulfate (22.84 mL, 240 mmol) and dimethyl trithiocarbonate (26.48 mL, 240 mmol) were added to acetonitrile (80 mL). The resultant dark yellow solution was heated to 90° C. for 2 hours. The mixture was then allowed to cool to 55° C. and then a solution of tetrafluoroboric acid (54% in diethyl ether, 48 mL) was added over 5 min time. The resultant solution was stirred for an additional 15 min, followed by pouring it into a solution of ice-cold diethyl ether (600 mL). The white solid that formed was collected and washed with diethyl ether (3×50 mL) and dried in a vacuum oven to provide (bis-methylsulfanyl-methylene)-methyl-sulfonium tetrafluoroborate salt (47.3 g, 83%) as a colorless solid.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:32])[C:4]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:9][CH2:8][C:7]([C:10]2[NH:11][C:12]3[C:17]([C:18]=2[CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:6][CH2:5]1.[Sn]>Br.O>[CH:20]1([CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:7]2[CH2:6][CH2:5][C:4]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([N:3]([CH3:2])[CH3:32])[CH2:9][CH2:8]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CN(C)C1(c2ccccc2)CC=C(c2[nH]c3ccccc3c2CC2CCCCC2)CC1
Agent: Br
Agent: Cl
Agent: [Sn]
Solvent: O
Product: CN(C)C1(c2ccccc2)CCC(c2[nH]c3ccccc3c2CC2CCCCC2)CC1
Reaction time: 0.33 h

Procedure:
Ex. 40 (913 mg, 2.033 mmol) was dissolved in hydrogen bromide/glacial acetic acid (33% HBr, 46 ml). Tin powder (2.415 g, 20.344 mmol) was then added to the mixture in portions at room temperature in the course of 40 min and the mixture was stirred for a further 20 min. The mixture was then diluted with water (300 ml). The mixture was stirred at 5° C. for 1 h. The product precipitated out as the hydrobromide. This was filtered off and washed with water (2×5 ml). 1 N NaOH (50 ml) was added to the pink-coloured wet solid (5.7 g). The mixture was extracted with methylene chloride (3×30 ml). The combined organic phases were dried with Na2SO4 and filtered and the volatile constituents were removed completely in vacuo. A yellow solid (776 mg) remained. After separation of this mixture by chromatography [silica gel 60 (80 g); ethyl acetate (500 ml), ethyl acetate/methanol 20:1 (525 ml), ethyl acetate/methanol 5:1 (600 ml), ethyl acetate/methanol 2:1 (600 ml)], 4-(3-(cyclohexylmethyl)-1H-indol-2-yl)-N,N-dimethyl-1-phenylcyclohexanamine less polar diastereoisomer) (472 mg, contaminated) and the more polar diastereoisomer (269 mg, 32%, m.p.: 195-198° C.) were obtained as white solids.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:9]([OH:11])=O)[NH:7][N:8]=2)[CH2:3][CH2:2]1.CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.[C:30]([O:34][C:35](=[O:48])[NH:36][CH:37]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([NH2:47])[CH:42]=1)[CH2:38][CH2:39][OH:40])([CH3:33])([CH3:32])[CH3:31]>C1COCC1>[C:30]([O:34][C:35](=[O:48])[NH:36][CH:37]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([NH:47][C:9]([C:6]2[NH:7][N:8]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[CH:5]=2)=[O:11])[CH:42]=1)[CH2:38][CH2:39][OH:40])([CH3:33])([CH3:31])[CH3:32]
Reactant: O=C(O)c1cc(C2CC2)n[nH]1
Reactant: CC(C)(C)OC(=O)NC(CCO)c1cccc(N)c1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CCO)c1cccc(NC(=O)c2cc(C3CC3)n[nH]2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
529 mg (3.4 mmol) 5-Cyclopropyl-2H-pyrazole-3-carboxylic acid were suspended in 9 ml THF and 834 mg (3.4 mmol) EEDQ were added. The mixture was stirred for 10 min at room temperature and subsequently 900 mg (3.4 mmol) [1-(3-Amino-phenyl)-3-hydroxy-propyl]-carbamic acid tert-butyl ester dissolved in 9 ml THF were added. The mixture was stirred overnight at room temperature, evaporated to dryness. The residue was dissolved in ethyl acetate and washed with 1 N NaOH, 10% citric acid and brine. The organic layer was dried over Na2SO4 and evaporated to dryness. 1.37 g, clear oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([N:11]2[C:15]([CH:16]=[CH2:17])=[CH:14][N:13]=[CH:12]2)[CH2:3]1>CO.[Pd]>[CH3:1][C:2]1([CH3:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([N:11]2[C:15]([CH2:16][CH3:17])=[CH:14][N:13]=[CH:12]2)[CH2:3]1
Reactant: C=Cc1cncn1C1CC(C)(C)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CCc1cncn1C1CC(C)(C)c2ccccc21
Reaction time: 2 h

Procedure:
To a solution of 1-(3,3-dimethyl-indan-1-yl)-5-vinyl-1H-imidazole (210 mg, 0.882 mmol), which can be prepared as described in Example 27, in methanol (10 mL) under a nitrogen atmosphere is added 5 wt % palladium on carbon (˜200 mg, ˜0.09 mmol). The atmosphere of the reaction vessel is evacuated of and backfilled with hydrogen gas (balloon pressure). The reaction is permitted to stir under a hydrogen atmosphere for 2 hours and is then diluted with ethyl acetate and filtered through a pad of Celite®. The reaction mixture is concentrated and the residue is purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 1:19 to 1:4) to provide 1-(3,3-dimethyl-indan-1-yl)-5-ethyl-1H-imidazole; HRMS: (ESI) m/z 241.1716 [(M+H)+; calcd for C16H21N2: 241.1705]; 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (s, 3 H), 1.31 (t, J=7.6 Hz, 3 H), 1.42 (s, 3 H), 2.04 (dd, J=12.9, 8.3 Hz, 1 H), 2.51-2.68 (m, 3 H), 5.59 (t, J=8.0 Hz, 1 H), 6.85 (d, J=1.0 Hz, 1 H), 7.04 (d, J=6.8 Hz, 1 H), 7.21-7.29 (m, 3 H), 7.33-7.38 (m, 1 H); The HCl salt of the title compound can be prepared by dissolution in diethyl ether followed by treatment with an excess of 1N HCl in diethyl ether. The resulting heterogeneous solution is concentrated to furnish the HCl salt of 1-(3,3-dimethyl-indan-1-yl)-5-ethyl-1H-imidazole.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[C:13]([Cl:14])=[C:12]([C:15]([F:18])([F:17])[F:16])[N:11]([CH3:19])[N:10]=2)=[CH:4][C:3]=1[NH:20][CH:21]([CH3:24])[CH2:22][OH:23].[N:25]([O-])=O.[Na+].C(OCC)(=O)C>C(O)(=O)C.O>[Cl:14][C:13]1[C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]3[N:1]=[N:25][N:20]([CH:21]([CH3:24])[CH2:22][OH:23])[C:3]=3[CH:4]=2)=[N:10][N:11]([CH3:19])[C:12]=1[C:15]([F:18])([F:17])[F:16]
Reactant: CC(CO)Nc1cc(Oc2nn(C)c(C(F)(F)F)c2Cl)ccc1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(CO)n1nnc2ccc(Oc3nn(C)c(C(F)(F)F)c3Cl)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.9 %

Procedure:
The diamine obtained in Step C (1.08 g) was dissolved in glacial acetic acid (20 cm3) and water (2 cm3) and cooled to below 5° C. in an ice/salt bath. A solution of sodium nitrite (0.41 g, 5.9 mmol) in water (5 cm3) was added dropwise, at such a rate that the internal temperature was maintained below 5° C., and when the addition was complete the reaction mixture was stirred for 4 hours, during which it was allowed to warm to room temperature. The mixture was poured into ethyl acetate (100 cm3) and washed successively with water (2×100 cm3) and saturated aqueous sodium bicarbonate solution (100 cm3). The organic phase was dried (MgSO4), filtered and the filtrate evaporated under reduced pressure. The residue was further purified by flash column chromatography on silica gel, eluting with diethyl ether, to give compound 9, DL 2-[6-(4-chloro-1-methyl-5-trifluoromethyl-1H-pyrazol-3-yloxy) benzotriazol-1-yl]-propan-1-ol (0.90 g) as an off white solid m.p. 153°-154° C.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[N:15]2[C:16]3[C:12]([CH:13]=[CH:14]2)=[C:11]([CH:17]=[O:18])[CH:10]=[CH:9][C:8]=3[CH2:7][NH:6][CH2:5]1>CCO>[OH:18][CH2:17][C:11]1[CH:10]=[CH:9][C:8]2[CH2:7][NH:6][CH2:5][C:4](=[O:3])[N:15]3[C:16]=2[C:12]=1[CH:13]=[CH:14]3
Reactant: O=Cc1ccc2c3c1ccn3C(=O)CNC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C1CNCc2ccc(CO)c3ccn1c23
Temperature: 25 °C
Yield: 88 %

Procedure:
Sodium borohydride (0.018 g, 0.466 mmol) was added to a suspension of 1-oxo-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole-7-carbaldehyde (Example 45, 0.050 g, 0.233 mmol) in 15 mL EtOH. The reaction mixture was refluxed for 1.5 h, cooled to rt and the solvent was evaporated. The residue was partitioned between 1% aq NaOH and EtOAc. The organic extract was dried over anhydrous MgSO4, filtered and evaporated to give a pale-yellow solid (88%): 1H NMR (DMSO-d6) δ 3.52-3.55 (m, 2H), 4.31 (bs, 2H), 4.63 (d, 2H, J=5.0 Hz), 4.84 (t, 1H, J=5.0 Hz), 7.12 (t, 1H, J=7.5 Hz), 7.29 (s, 1H), 7.80-7.83 (m, 2H), 8.24-8.26 (m, 1H). HRMS calcd for C12H12N2O2 (M+) 216.0899, found 216.0908. Anal. (C12H12N2O2.0.2H2O) C, H, N.
Reaction SMILES: [NH2:1][N:2]=[CH:3][NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.CS([O-])(=O)=O.[ClH:19].[C:20]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29]([CH:33]=[CH:34][C:35](=[O:37])[NH2:36])=[C:28](O)[CH:27]=[CH:26]2)(=[NH:22])[NH2:21].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[ClH:19].[ClH:19].[NH2:1][N:2]=[CH:3][NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][C:28]2[CH:27]=[CH:26][C:25]3[C:30](=[CH:31][CH:32]=[C:23]([C:20](=[NH:21])[NH2:22])[CH:24]=3)[C:29]=2[CH:33]=[CH:34][C:35](=[O:37])[NH2:36])=[O:10])=[CH:7][CH:6]=1
Reactant: NN=CNc1ccc(C(=O)O)cc1
Reactant: N=C(N)c1ccc2c(C=CC(N)=O)c(O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)[O-]
Solvent: c1ccncc1
Product: N=C(N)c1ccc2c(C=CC(N)=O)c(OC(=O)c3ccc(NC=NN)cc3)ccc2c1
Reaction time: 2 h
Yield: 180.2 %

Procedure:
90 Milliliters of 20% hydrous pyridine was added to 5.08 g of 4-aminoiminomethylaminobenzoic acid.methanesulfonate, 4.5 g of 6-amidino-1-(2-carbamoylvinyl)-2-naphthol.hydrochloride, 6.34 g of DCC and 80 mg of DMAP, followed by stirring for 2 hours under cooling with ice and then 48 hours at room temperature. Then, the precipitate was collected by filtration and washed twice with 160 ml of warm 20% hydrous pyridine. The above-obtained reaction filtrate and the warm hydrous pyridine wash liquid were combined and the resulting solution was added to 1 liter of acetone, followed by stirring for 24 hours under cooling with ice. The precipitate was collected by filtration and thereto was added 70 ml of warm DMF to dissolve the precipitate. Then, 0.5 g of active carbon was added, followed by stirring for 30 minutes at room temperature. Insoluble matter was filtered and 8.4 ml of concentrated hydrochloric acid was added to the filtrate. The resulting solution was added dropwise to 600 ml of acetone, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain 6.8 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([CH3:13])[CH:3]=1.[H-].[Na+].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.CCOC(C)=O>[C:16]1([S:22]([N:8]2[C:9]3[C:5](=[C:4]([CH3:13])[CH:3]=[C:2]([Cl:1])[C:10]=3[O:11][CH3:12])[CH:6]=[N:7]2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1c(Cl)cc(C)c2cn[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1c(Cl)cc(C)c2cnn(S(=O)(=O)c3ccccc3)c12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
6-Chloro-7-methoxy-4-methyl-1H-indazole (1.55 g, 9.2 mmol) is dissolved in THF (50 mL) and cooled to 0° C. Sodium hydride (60% in mineral oil, 0.40 g, 10 mmol) is added and the reaction is stirred 10 min. Benzenesulfonyl chloride (1.2 mL, 9.7 mmol) is added and the reaction is stirred 20 min. The reaction is diluted with EtOAc, washed with a solution of NH4Cl, water, brine and dried with MgSO4. The solution is concentrated and triturated with hexane to provide 1-benzenesulfonyl-6-chloro-7-methoxy-4-methyl-1H-indazole which is used without further purification.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[C:14]([OH:16])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[NH2:22][C:23](=[O:32])[CH:24]([OH:31])[CH:25]([NH3+:30])[CH2:26][CH2:27][CH2:28][CH3:29]>>[NH2:22][C:23](=[O:32])[CH:24]([OH:31])[CH:25]([NH:30][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[C:10]1[N:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[S:8][CH:9]=1)[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCC([NH3+])C(O)C(N)=O
Reactant: O=C(O)c1ccccc1-c1csc(-c2ccccc2)n1
Agent: [Cl-]
Product: CCCCC(NC(=O)c1ccccc1-c1csc(-c2ccccc2)n1)C(O)C(N)=O
Yield: 87.7 %

Procedure:
Coupling of 2-(2-phenylthiazol-4-yl)benzoic acid (200 mg, 0.711 mmol) and 1-amino-2-hydroxy-1-oxoheptan-3-aminium chloride (145 mg, 0.737 mmol) in an analogous manner as described for example 1.2 afforded 264 mg of the title compound as white solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].[K].[CH:16]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1)([CH3:18])[CH3:17]>>[CH2:1]([C:5]1[CH:6]=[C:7]([CH2:11][C:12]([O:14][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([O:19][CH:16]([CH3:18])[CH3:17])=[CH:21][CH:22]=2)=[O:13])[CH:8]=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)Oc1ccc(CCl)cc1
Reactant: CCCCc1cccc(CC(=O)O)c1
Agent: [K]
Product: CCCCc1cccc(CC(=O)OCc2ccc(OC(C)C)cc2)c1

Procedure:
3-Butylphenylacetic acid, potassium salt, is reacted with 4-isopropoxybenzyl chloride to obtain 4-isopropoxybenzyl 3-butylphenylacetate;
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[C:18]1([CH2:24][CH2:25][CH2:26][NH2:27])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>O1CCCC1>[N+:8]([C:5]1[CH:4]=[N:3][C:2]([NH:27][CH2:26][CH2:25][CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:7][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Reactant: NCCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc(NCCCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.7 %

Procedure:
2-Chloro-5-nitropyrimidine (100 mg, 0.627 mmol) and triethylamine (96 μL, 0.690 mmol) were added successively to a solution of 3-phenylpropylamine (98 μL, 0.690 mmol) in tetrahydrofuran, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and 0.5 mol/L hydrochloric acid and dried over anhydrous magnesium sulfate. Thereafter, the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to afford 5-nitro-N-(3-phenylpropyl)pyrimidin-2-amine as a colorless solid (108 mg).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11](=[O:30])[C:12](=[CH:20][C:21]1[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[NH:23][CH:22]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>C1COCC1>[CH3:9][O:10][C:11](=[O:30])[CH:12]([CH:20]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:21]1[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[NH:23][CH:22]=1)[C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14]
Reactant: Br[Mg]c1ccccc1
Reactant: COC(=O)C(=Cc1c[nH]c2cccnc12)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC(C)(C)C)C(c1ccccc1)c1c[nH]c2cccnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a RT solution of PhMgBr (1 M in THF, 6.5 mL) in THF (10 mL) was added a solution of 2-(1H-pyrrolo[3,2-b]pyridin-3-yl-methylene)-malonic acid tert-butyl ester methyl ester in THF (15 mL) dropwise. After stirring the mixture for 1 hour at RT, the reaction was quenched by addition of water. The diluted mixture was neutralized by addition of HCl (I M) to pH 7 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc) affording 2-[Phenyl-(1H-pyrrolo[3,2-b]pyridin-3-yl)-methyl]-malonic acid tert-butyl ester methyl ester (680 mg, 69% yield).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]([CH:10]([CH3:21])[CH2:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)([OH:9])=[O:8].Cl[C:23]1[C:28]([S:29]([N:32]([C:42]([O:44][CH2:45][CH:46]([CH3:48])[CH3:47])=[O:43])[C:33]2[C:38]([O:39][CH3:40])=[N:37][C:36]([CH3:41])=[CH:35][N:34]=2)(=[O:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=1.C(O)C>O.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.C1(C)C=CC=CC=1>[CH2:45]([O:44][C:42]([N:32]([C:33]1[C:38]([O:39][CH3:40])=[N:37][C:36]([CH3:41])=[CH:35][N:34]=1)[S:29]([C:28]1[C:23]([C:15]2[CH:16]=[CH:17][C:12]([CH2:11][CH:10]([C:7]([OH:9])=[O:8])[CH3:21])=[CH:13][CH:14]=2)=[N:24][CH:25]=[CH:26][CH:27]=1)(=[O:31])=[O:30])=[O:43])[CH:46]([CH3:48])[CH3:47]
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1Cl
Reactant: CC(Cc1ccc(B(O)O)cc1)C(=O)O
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(CC(C)C(=O)O)cc1
Temperature: 80 °C
Yield: 39 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (500 mg) was added to a deoxygenated solution of sodium carbonate (3.74 g), 4-(2-carboxypropyl)phenyl boronic acid (3.67 g) and 2-chloro-N-(isobutoxycarbonyl)-N-(3-methoxy-5-methyl-pyrazin-2-yl)pyridine-3-sulphonamide (6.1 g) in a mixture of water (30 ml), ethanol (75 ml) and toluene (75 ml). The mixture was stirred and heated under argon at 80° C. for 17 hours and then allowed to cool to ambient temperature. Ice water (5 g) was added and the reaction extracted with ethyl acetate (75 ml). The combined organic layers were extracted with saturated aqueous sodium carbonate solution (2×15 ml) and combined aqueous extracts were acidified to pH 2 with 2M hydrochloric-acid and extracted with ethyl acetate (3×100 ml). The combined organic extracts were dried (MgSO4) and evaporated to low volume affording crystalline material which was filtered and washed with diethyl ether to give N-(isobutoxycarbonyl)-2-(4-(2-carboxypropyl)phenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (3.11 g); NMR 1H (d6 -DMSO): 0.61 (d, 6 H), 1.09 (d, 3 H), 1.50-1.73 (m, 1 H), 2.55 (partly obscured by DMSO, 3 H), 2.6-2.77 (m, 2 H), 2.72-3.09 (m, 1 H), 2.83 (d, 2 H), 3.96 (s, 3 H), 7.25 (d, 2 H), 7.43 (d, 2 H), 7.78 (dd, 1 H), 8.15 (s, 1 H), 8.83-8.96 (m, 2 H), 12.14 (br s, 1 H); mass spectrum (-ve ESP) 541.1 (M-H )-.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9].ClC1C=C[N:15]=[C:14](C#N)C=1>>[Cl:1][C:2]1[C:3]([C:14]#[N:15])=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9]
Reactant: N#Cc1cc(Cl)ccn1
Reactant: CCc1cc[n+]([O-])cc1Cl
Product: CCc1ccnc(C#N)c1Cl

Procedure:
The title compound was prepared from 3-chloro-4-ethylpyridine-N-oxide according to the procedure for preparing 4-chloro-2-pyridinecarbonitrile described in Example 33.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.C(O[K])(C)(C)C.[CH3:16][N:17]([CH3:22])[CH2:18][CH2:19][NH:20]C>C1(C)C=CC=CC=1>[Br:9][C:4]1[CH:3]=[C:2]([NH:20][CH2:19][CH2:18][N:17]([CH3:22])[CH3:16])[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: CNCCN(C)C
Reactant: Fc1cc(Br)cc(Br)c1
Agent: CC(C)(C)O[K]
Solvent: Cc1ccccc1
Product: CN(C)CCNc1cc(F)cc(Br)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
To a solution of 1,3-dibromo-5-fluorobenzene (LXXIV) (4 g, 15.75 mmol) in toluene (50 mL) was added tBuOK (5.3 g, 47.25 mmol) and N1,N1,N2-trimethylethane-1,2-diamine (2.778 mL, 31.5 mmol). The reaction was stirred at 110° C. overnight. The solvent was removed under vacuum and the residue was partitioned between EtOAc and water. The organic layer was separated, washed with water, brine, dried over MgSO4 and evaporated under vacuum. The crude product was purified on a silica gel column (100% CHCl3→5:95 MeOH:CHCl3) to produce N1-(3-bromo-5-fluorophenyl)-N2,N2-dimethylethane-1,2-diamine (LXXV) as a brown viscous oil (1.02 g, 3.91 mmol, 24.8% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.17 (s, 6H), 2.40 (t, J=3.5 Hz, 2H), 3.01-3.09 (m, 2H), 6.10 (t, J=5 Hz, 1H), 6.38 (dt, J=12 Hz, J=2 Hz, 1H), 6.51 (dt, J=8.5 Hz, J=2 Hz, 1H), 6.60 (s, 1H); ESIMS found C12H16BrFN2 m/z 261 (M+H).