Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[F:15].C[O:17][B:18](OC)[O:19]C.Cl>C1COCC1>[F:15][C:8]1[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=1[B:18]([OH:19])[OH:17]
Reactant: COc1ccc(Br)c(F)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)c(F)c1
Temperature: 25 °C

Procedure:
n-Butyllithium (1.6 M solution in hexanes, 29.1 mmol, 18.2 mL) was added to 1-bromo-2-fluoro-4-methoxybenzene (24.4 mmol, 5.0 g) in THF (150 mL) at −78° C. under an atmosphere of nitrogen. After stirring for thirty minutes the trimethylborate (95.1 mmol, 10.8 mL) was added over twenty minutes. The reaction was allowed to warm to room temperature overnight while stirring. The solution was then acidified with HCl (3 M, 200 mL), and extracted into EtOAc. The EtOAc was then extracted with NaOH (1 N, 4×100 mL), which was subsequently acidified with concentrated HCl forming (2-fluoro-4-methoxyphenyl) boronic acid as a white precipitate. The white precipitate (2.04 g, 49%) was filtered and dried. 1H NMR (CD3OD, 300 MHz): 7.29 (1H, t, J 8.0 Hz), 6.73 (1H, dd, J 8.5 and 2.2 Hz), 6.62 (1H, dd, J 11.4 and 2.2 Hz), 3.78 (3H, s.)
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][CH2:7][C@@H:8]([F:27])[CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH2:17][C@H:18]([O:23][CH:24]([CH3:26])[CH3:25])[C:19]([O:21]C)=[O:20])[CH:14]=[CH:15][CH:16]=2)=[C:4]([C:30]#[N:31])[CH:3]=1.C(OC)(C)(C)C.Cl>O1CCCC1.O.[OH-].[Na+]>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][CH2:7][C@@H:8]([F:27])[CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH2:17][C@H:18]([O:23][CH:24]([CH3:26])[CH3:25])[C:19]([OH:21])=[O:20])[CH:14]=[CH:15][CH:16]=2)=[C:4]([C:30]#[N:31])[CH:3]=1
Reactant: COC(=O)[C@H](Cc1cccc(OC[C@H](F)COc2ccc(Cl)cc2C#N)c1)OC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC(C)O[C@@H](Cc1cccc(OC[C@H](F)COc2ccc(Cl)cc2C#N)c1)C(=O)O
Reaction time: 3.5 h
Yield: 103.5 %

Procedure:
Methyl (2S)-3-[3-[(2S)-3-(4-chloro-2-cyanophenoxy)-2-fluoropropoxy]phenyl]-2-isopropoxypropionate (186 g, 0.41 mol) was suspended in tetrahydrofuran (928 mL) and water (928 mL), followed by adding dropwise a 2N NaOH aqueous solution (309 mL, 0.62 mmol) to the reaction mixture at room temperature and the mixture was stirred for 3.5 hours. Tert-butylmethyl ether (1,856 mL) and water (928 mL) were added to the reaction mixture to separate an aqueous layer. Tert-butylmetyl ether (1,856 mL) was added to the aqueous layer, followed by adding dropwise a 2N hydrochloric acid aqueous solution (371 mL, 0.74 mol) at room temperature to separate an organic layer. The organic layer was washed with water (928 mL) and then subjected to vacuum concentration to obtain 185 g of the title compound (yield: 90%).
Reaction SMILES: [NH2:1][C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.Br[C:24]1[CH:25]=[C:26]([CH:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1.Cl.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:21][N:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:1][C:28]3[CH:29]=[CH:24][CH:25]=[C:26]([CH:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH:27]=3)[N:22]=2)[CH:9]=[CH:8][CH:7]=1)[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: CN(c1ccccc1-c1cccn2nc(N)nc12)S(C)(=O)=O
Reactant: CN1CCC(c2cccc(Br)c2)CC1
Agent: Cl
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCC(c2cccc(Nc3nc4c(-c5ccccc5N(C)S(C)(=O)=O)cccn4n3)c2)CC1

Procedure:
N-Methyl-N-(2-{2-[3-(1-methyl-piperidin-4-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-phenyl)-methanesulfonamide was prepared from N-[2-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide (75.0 mg, 0.236 mmol) and 4-(3-bromo-phenyl)-1-methyl-piperidine; hydrochloride (76.0 mg, 0.262 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a pale yellow foam (0.099 g, 85%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.48 (dd, J=6.8, 0.9 Hz, 1H), 7.59-7.36 (m, 7H), 7.28-7.23 (m, 1H), 6.98 (t, J=7.1 Hz, 1H), 6.86 (d, J=7.6 Hz, 1H), 6.76 (s, 1H), 3.17 (s, 3H), 3.02-2.95 (m, 2H), 2.74 (s, 3H), 2.53-2.43 (m, 1H), 2.34 (s, 3H), 2.10-2.00 (m, 2H), 1.89-1.78 (m, 4H). MS=491 (MH)+.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: C[O-]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc([N+](=O)[O-])cc1C=O
Temperature: 25 °C

Procedure:
A mixture of 2.5 grams (13.5 mmol) of 2-chloro-5-nitrobenzaldehyde (Aldrich Chem. Co.) in 250 mL of CH3OH was treated with 2.92 grams (54.1 mmol) of sodium methoxide, refluxed for 16 hours and allowed to cool to room temperature. After removal of the solvent in vacuo, the residue was suspended in water, treated with 2N HCl (adjusting to pH<5) and extracted into methylene chloride. After drying over MgSO4, the solvent was removed in vacuo to give a yellow solid, 2.02 grams (83%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C:13](=[S:15])[NH2:14])=[N:8][CH:9]=1)([O-:3])=[O:2].Br[CH2:17][CH:18](OC)OC.C([O-])(O)=O.[Na+]>COCCOC.Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C:13]2[S:15][CH:17]=[CH:18][N:14]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NC(=S)CCCc1ccc([N+](=O)[O-])cn1
Reactant: COC(CBr)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(CCCc2nccs2)nc1
Temperature: 90 °C
Reaction time: 5 h
Yield: 77.6 %

Procedure:
To a solution of the compound 137 (2.1 g, 9.3 mmol) and 2-bromo-1,1-dimethoxyethane (6.31 g, 37.3 mmol) in DME (100 mL) was added dropwise 10 drops of the concentrated HCl at room temperature. The reaction mixture was stirred at 90° C. for 5 h, treated aq. NaHCO3 and extracted with DCM. The combined organic layers was washed with brine (30 mL), dried over Na2SO4, concentrated and purified with silica gel column chromatography (PE:EtOAc=3:1) to give compound 138 (1.8 g, 76%) as a white solid. 1H NMR (400 MHz, CDCl3) δ9.33-9.38 (m, 1H), 8.34-8.40 (m, 1H), 7.65-7.70 (m, 1H), 7.32-7.36 (m, 1H), 7.18-7.23 (m, 1H), 3.12 (t, 2H, J=7.6 Hz), 3.03 (d, 2H, J=7.2 Hz), 2.25-2.35 (m, 2H).
Reaction SMILES: [H-].[Na+].[C:3]([O:6][CH2:7][CH3:8])(=[O:5])[CH3:4].[H][H].C[O:12][CH2:13][CH2:14]OC>>[C:3]([O:6][CH2:7][CH3:8])(=[O:5])[CH2:4][C:13]([CH3:14])=[O:12]
Reactant: CCOC(C)=O
Reactant: COCCOC
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(C)=O
Yield: 62 %

Procedure:
To a refluxing slurry of 2.5 g (52 mmol) of 50% sodium hydride in 150 ml of DME was added 1.14 g (13 mmol) of ethyl acetate in 20 ml of DME. After a reaction period of 1.5 hours, hydrogen evolution ceased (285 ml at STP, 12.7 mmol) and the reaction mixture was worked up as described above to give a 0.47 g (62%) of crude ethyl acetoacetate, which was identified by VPC.
Reaction SMILES: [N:1]1([CH2:6][C:7]2N3C=C(C)C=CC3=[N:9][C:8]=2C2C=CC(C)=CC=2)C=CN=C1.Cl.[Cl:25][C:26]1[CH:27]=[C:28]([Cl:44])[C:29]2[N:30]([C:32]([CH2:42]Cl)=[C:33]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)[N:34]=2)[CH:31]=1.N1C=CC=N1>>[N:9]1([CH2:42][C:32]2[N:30]3[CH:31]=[C:26]([Cl:25])[CH:27]=[C:28]([Cl:44])[C:29]3=[N:34][C:33]=2[C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)[CH:8]=[CH:7][CH:6]=[N:1]1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2ccnc2)cc1
Reactant: Cc1ccc(-c2nc3c(Cl)cc(Cl)cn3c2CCl)cc1
Agent: Cl
Agent: c1cn[nH]c1
Product: Cc1ccc(-c2nc3c(Cl)cc(Cl)cn3c2Cn2cccn2)cc1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 1 from 6,8-dichloro-3-(chloromethyl)-2-p-tolylimidazo[1,2-a]pyridine hydrochloride and 1H-pyrazole. m/e+ 357 for C18H15Cl2N4 [M+H]+; 1H-NMR (300 MHz, CDCl3) δ 8.28 (d, J=2.1 Hz, 1H), 7.67 (d, J=7.8 Hz, 2H), 7.60 (d, J=1.5 Hz, 1H), 7.35 (d, J=7.8 Hz, 2H), 7.30 (m, 2H), 6.31 (t, J=2.7 Hz, 1H), 5.71 (s, 2H), 2.44 (s, 3H) ppm.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([Cl:15])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:22]1(C)C=CC=C[CH:23]=1>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>[Cl:15][C:4]1[CH:3]=[C:2]([CH:22]=[CH2:23])[CH:14]=[CH:13][C:5]=1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: Cc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Cl
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: C=Cc1ccc(C(=O)OC(C)(C)C)c(Cl)c1
Yield: 46 %

Procedure:
To a stirred solution of tert-butyl 4-bromo-2-chlorobenzoate (1.6 g, 5.50 mmol) in toluene (20 mL) was added tetrakis(triphenylphospine)palladium(0) (Pd(PPh3)4; (0.31 mg, 0.27 mmol), K2CO3 (2.27 g, 16.5 mmol) and vinylboronic anhydride pyridine complex (2.0 g, 8.3 mmol) and the reaction mixture was heated to reflux for 16 h. The reaction mixture was filtered, and the filtrate was washed with H2O and brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 5-6% EtOAc in n-hexane) afforded the title compound as a liquid (0.6 g, 46%): 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J=8.1 Hz, 1H), 7.44 (m, 1H), 7.31 (d, J=8.0 Hz, 1H), 6.69 (dd, J=17.6, 10.8 Hz, 1H), 5.85 (d, J=17.6 Hz, 1H), 5.40 (d, J=10.8 Hz, 1H), 1.60 (s, 9H); ESIMS m/z 238.95 ([M+H]+); IR (thin film) 2931, 1725, 1134 cm−1.
Reaction SMILES: S(=O)(=O)(O)O.Cl.[CH:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH:8]1[NH2:17])[CH2:14]2.[OH-:18].[Na+]>[N+]([O-])(O)=O>[OH:18][C:13]12[CH2:15][CH:9]3[CH2:10][CH:11]([CH2:16][CH:7]([CH:8]3[NH2:17])[CH2:14]1)[CH2:12]2
Reactant: [OH-]
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=[N+]([O-])O
Product: NC1C2CC3CC1CC(O)(C3)C2
Temperature: 10 °C
Reaction time: 2 h

Procedure:
To a mixture of concentrated sulfuric acid (300 ml) and concentrated nitric acid (30 ml) cooled in an ice bath to 10° C. is added tricyclo[3.3.1.13,7 ]decan-2-amine hydrochloride (20 g; 0.107 mole) in 5 g portions over 10 minutes. This mixture is then stirred for 2 hours with cooling. The reaction mixture is poured over ice and the pH raised to pH 10-11 using 40% NaOH. This mixture is extracted with chloroform, dried over MgSO4 and evaporated to dryness to give 5-hydroxytricyclo[3.3.1.13,7 ]decan-2-amine as a solid residue (m.p. 267°-270° C.) which is used directly in step B.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][C@H:7]1[CH2:11][CH2:10][C@@H:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:8]1[S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:18][C:15]1[CH:14]=[CH:13][C:12]([C@H:9]2[N:8]([S:19]([C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)(=[O:21])=[O:20])[C@@H:7]([CH2:6][CH2:5][CH2:4][CH2:3][OH:2])[CH2:11][CH2:10]2)=[CH:17][CH:16]=1
Reactant: COC(=O)CCC[C@H]1CC[C@@H](c2ccc(F)cc2)N1S(=O)(=O)c1ccc(C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2[C@@H](CCCCO)CC[C@H]2c2ccc(F)cc2)cc1

Procedure:
Reduction of (2S,5S)-4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyric acid methyl ester with lithium aluminum hydride (1.5 eq.) in THF at RT, aqueous work-up and purification by column chromatography yielded the title compound as a colorless oil, MS: m/e=392.3 (M+H+) and [α]D20=−80.1° (c=1.0870 in chloroform).
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:19][C:20]([C:22]12[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2)=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[C:22]12([C:20](=[O:21])[CH2:19][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=4)[CH2:6][CH2:5]3)[CH2:29][CH:28]3[CH2:27][CH:26]([CH2:25][CH:24]([CH2:30]3)[CH2:23]1)[CH2:31]2
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=C(CBr)C12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1ccc(N2CCN(CC(=O)C34CC5CC(CC(C5)C3)C4)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 4-(piperazin-1-yl)benzoate (100 mg), 1-admantyl bromomethyl ketone (110 mg) and sodium carbonate (46 mg) were suspended in anhydrous acetonitrile (2 mL). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with saturated NaHCO3 aqueous solution, and extracted with ethyl acetate. The organic phase was washed with water, brine, dried over Na2SO4, filtered and concentrated to afford the title compound
Reaction SMILES: Cl.[CH3:2][C@@:3]([S:31]([CH3:34])(=[O:33])=[O:32])([CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][C:17]1=[O:30])[C:4]([NH:6][O:7]C1CCCCO1)=[O:5]>ClCCl.CO>[OH:7][NH:6][C:4](=[O:5])[C:3]([CH3:2])([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:18][C:17]1=[O:30]
Reactant: C[C@@](CCn1ccc(/C=C/c2ccccc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC(CCn1ccc(/C=C/c2ccccc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 4 h
Yield: 100.6 %

Procedure:
A solution of hydrochloric acid (2.5 mL, 4.0 M in 1,4-dioxane) was added to a solution of (2R)-2-methyl-2-(methylsulfonyl)-4-{2-oxo-4-[(E)-2-phenylvinyl]pyridin-1(2H)-yl}-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (40 mg, 0.084 mmol) in 5:1 dichloromethane-methanol (2.5 mL) at 0° C. After 4 h, the reaction was concentrated under reduced pressure. The resulting residue was triturated with 1:1 pentane-diethyl ether, filtered, washed with pentane and dried under reduced pressure to provide a light yellow solid (33 mg, 76%). MS (LCMS) m/z 391.4 (M+1). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.69 (s, 3H) 2.30-2.42 (m, 1H) 2.56-2.69 (m, 1H) 3.08 (s, 3H) 3.93-4.06 (m, 1H) 4.32 (td, J=11.76, 4.98 Hz, 1H) 6.75 (s, 1H) 7.00 (d, J=6.24 Hz, 1H) 7.11 (d, J=16.39 Hz, 1H) 7.30-7.42 (m, 3H) 7.47 (d, J=16.39 Hz, 1H) 7.62 (d, J=7.02 Hz, 2H) 7.75 (s, 1H)
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7](OCC)=[O:8].[CH:18]([NH2:20])=O>CN(C=O)C.C(O)=O>[C:12]1([C:4]2[NH:3][C:2]3[N:1]=[CH:18][N:20]=[C:7]([OH:8])[C:6]=3[CH:5]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)[nH]c1N
Reactant: NC=O
Solvent: CN(C)C=O
Solvent: O=CO
Product: Oc1ncnc2[nH]c(-c3ccccc3)cc12

Procedure:
Under a protective gas, 2.30 g (10 mmol) of 2-amino-3-ethoxycarbonyl-5-phenyl-1H-pyrrole [for preparation see: Synthesis, 272 (1987)] in 20 ml of formamide, 10 ml of DMF and 5 ml of formic acid are heated at 150° C. for 24 hours. The reaction mixture is cooled and filtered and the residue is washed with isopropanol/hexane. Stirring in hot isopropanol yields the title compound; m.p.>300° C.; FAB-MS: (M+H)+ =212.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:3]=[CH:2]1.Cl.CCN([CH:19]([CH3:21])[CH3:20])C(C)C.[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29](Cl)(=[O:31])=[O:30]>C(#N)C>[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29]([N:9]1[CH2:10][CH2:11][CH:6]([C:4]2[N:3]=[CH:2][N:1]([S:29]([C:20]3[CH:19]=[CH:21][CH:25]=[CH:24][C:23]=3[Br:22])(=[O:31])=[O:30])[CH:5]=2)[CH2:7][CH2:8]1)(=[O:31])=[O:30]
Reactant: c1nc(C2CCNCC2)c[nH]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=S(=O)(Cl)c1ccccc1Br
Agent: Cl
Solvent: CC#N
Product: O=S(=O)(c1ccccc1Br)N1CCC(c2cn(S(=O)(=O)c3ccccc3Br)cn2)CC1
Reaction time: 15.5 h
Yield: 92 %

Procedure:
To a 20 mL vial were added a stirbar, 4-(1H-imidazol-4-yl)piperidine.HCl (696 mg, 3.71 mmol), ACN (5 mL), and DIPEA (2.0 mL, 12 mmol). The mixture was then treated with 2-bromobenzene-1-sulfonyl chloride (900 mg, 3.52 mmol) and the mixture was stirred for 15.5 hours before concentrating to dryness and subjecting the residue to FCC to give the title compound (950 mg, 92%). MS (ESI): mass calcd. for C20H19Br2N3O4S2 586.92 m/z found 587.9 [M+H]+; 1H NMR (600 MHz, CDCl3) δ 8.20 (dd, J=7.9, 1.8, 1H), 8.08 (dd, J=7.8, 1.7, 1H), 8.06 (d, J=1.3, 1H), 7.75 (dd, J=7.7, 1.3, 1H), 7.72 (dd, J=7.9, 1.2, 1H), 7.58-7.53 (m, 1H), 7.53-7.49 (m, 1H), 7.45-7.40 (m, 1H), 7.39-7.34 (m, 1H), 6.93-6.91 (m, 1H), 3.90-3.82 (m, 2H), 2.93-2.83 (m, 2H), 2.68-2.59 (m, 1H), 2.02 (dd, J=13.9, 3.0, 2H), 1.70-1.59 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(CC)CC)C.O>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(F)c1
Temperature: 27.5 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
3,4-difluoro nitrobenzene (100 gr) is slowly added to a mixture of morpholine (76.6 gr), triethylamine (23 ml) and in presence of acetonitrile solvent (115 ml) at 40-50° C. Reaction mass is heated for 6 hrs at reflux temperature, cooled to 25-30° C. Then water (600 ml) is added slowly to the reaction mass and then cooled to 0-5° C. The reaction mixture is stirred for 1 hr. The solid is filtered to give 134 gr of 3-fluoro-4-morpholinyl nitrobenzene.
Reaction SMILES: [C:1]([O:4][C:5](=O)C)(=[O:3])C.[CH2:8]([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])C.O.C(=O)([O-])[OH:17].[Na+]>C(Cl)(Cl)Cl>[CH3:5][O:4][C:1](=[O:3])[C@H:13]([CH3:14])[N:10]([C:11](=[O:17])[CH3:12])[CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: O=C([O-])O
Reactant: CCN(CC)CC
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](C)N(C)C(C)=O
Reaction time: 24 h

Procedure:
In 300 ml of chloroform is dissolved 33.7 g (0.22 mole) of N-methyl-L-analine methyl ester.hydrochloride, followed by the addition of 65 ml of acetic anhydride and 110 ml of triethylamine. The mixture is allowed to stand at a room temperature for 24 hours and, after the excess of acetic anhydride is decomposed with water, is neutralized with sodium hydrogen carbonate. The chloroform layer is separated and, the water layer is extracted with ethyl acetate (120 ml×5), followed by combining the chloroform and ethyl acetate layers to concentrate under reduced pressure. The brown, oily substance obtained is dissolved in chloroform, washed with aqueous sodium hydrogen carbonate and concentrated under reduced pressure. By the above procedure, there is obtained 31.8 g of N-acetyl-N-methyl-L-alanine methyl ester as brown oil.
Reaction SMILES: C(N(CC)CC)C.CN(C)S([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)(=O)=O.Cl[C:21]1[N:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1>C1COCC1>[N+:27]([C:24]1[CH:23]=[N:22][C:21]([CH:15]2[CH2:14][NH:13][CH2:18][CH2:17][NH:16]2)=[N:26][CH:25]=1)([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Reactant: CN(C)S(=O)(=O)N1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc(C2CNCCN2)nc1

Procedure:
Triethylamine (7.2 mL, 51.8 mmol) was added to a solution of piperazine-1-sulfonic acid dimethyl amide (10 g, 51.8 mmol) dissolved in 400 mL of THF. 2-chloro-5-nitropyrimidine (7.7 g, 48.3 mmol) dissolved in 20 mL of THF was added to the stirred mixture. After 24 hours stirring at room temperature (RT), THF was removed under vacuum and 600 mL of CHCl3 was added to the residue. The CHCl3 layer was washed with 0.5 N HCl and brine, dried over Na2SO4, and filtered. Solvent evaporation gave 14.1 g (92%) of straw yellow solid 1-N,N′-dimethylsulfamoyl-4-(2-(5-nitropyrimidyl)piperazine. The structure was confirmed by 1H-NMR. 1H NMR (CDCl3) δ9.08 (s, 2H), 4.09 (appt, J=5.13 Hz, 4H), 3.35 (appt, J=5.13 Hz, 4H), 2.87 (s, 6H). Step 2: NH4Cl (1.43 g, 26.76 mmol) was added to a suspension of 1-N,N′-dimethylsulfamoyl-4-(2-(5-nitropyrimidyl)piperazine (14.1 g, 44.6 mmol) in a mixture of EtOH (175 mL) and H2O (48 mL), followed by iron powder (7.5 g, 133.9 mmol). After refluxing 1 hour, the reaction mixture was filtered and concentrated to give a brown solid which was dissolved in 800 mL of CHCl3, washed with NaHCO3 and brine, dried over Na2SO4, and filtered. Solvent evaporation gave a yellow solid which after CC with 100:1 CHCl3:MeOH gave 11.5 g (90%) of solid yellow 1-N,N′-dimethylsulfamoyl-4-(2-(5-nitro-pyrimidyl)-piperazine. The structure was confirmed by 1H-NMR and EI-MS. 1H NMR (CDCl3) δ7.98 (s, 2H), 3.76 (t, J=4.88 Hz, 4H), 3.30 (t, J=4.88 Hz, 4H), 2.86 (s, 6H); EI-MS (m/z) 286 (M+). Step 3: A suspension of 1-N,N′-dimethylsulfamoyl-4-(2-(5-nitro-pyrimidyl)-piperazine (5.76 g, 20.2 mmol) in 100 mL of 2 M H2SO4 was refluxed for 1.5 hours until the suspension became clear. After cooling to RT, the solution pH was adjusted to 6-7 with 10 N NaOH, and the cloudy mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and filtered. Solvent evaporation gave a yellow solid, which was purified by CC using 1:1 EtOAc:hexane to yield 3.23 g (56%) of white solid JHX-2, mp 134-135° C. The structure was confirmed by 1H-NMR, 13C-NMR, ESI-MS and elemental analysis. 1H NMR (CDCl3) δ8.08 (s, 2H), 3.78 (appt, J=5.13 Hz, 4H), 3.29 (appt, J=5.13 Hz, 4H), 2.86 (s, 6H); 13C NMR (CDCl3) 156.9, 145.8, 143.5, 46.0, 44.3, 38.1; EI-MS (m/z) 287 (M+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[Cl:10].Cl[C:12]1[N:17]=[C:16]2[NH:18][N:19]=[CH:20][C:15]2=[CH:14][N:13]=1.[CH3:21][N:22]1[CH:26]=[C:25]([NH2:27])[CH:24]=[N:23]1>>[Cl:10][C:4]1[C:5]([Cl:9])=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:18]1[C:16]2=[N:17][C:12]([NH:27][C:25]3[CH:24]=[N:23][N:22]([CH3:21])[CH:26]=3)=[N:13][CH:14]=[C:15]2[CH:20]=[N:19]1
Reactant: Clc1cccc(CBr)c1Cl
Reactant: Clc1ncc2cn[nH]c2n1
Reactant: Cn1cc(N)cn1
Product: Cn1cc(Nc2ncc3cnn(Cc4cccc(Cl)c4Cl)c3n2)cn1

Procedure:
The following compound was made according to the procedures in Example 1 (Step ii) using 1-(bromomethyl)-2,3-dichlorobenzene and 6-chloro-1H-pyrazolo[3,4-d]pyrimidine, followed by Example 1 (Step i) using 1-methyl-1H-pyrazol-4-amine.