Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:12])[CH3:11].[CH2:14]([S:18][C:19]([CH3:23])([CH3:22])[CH:20]=O)/[CH:15]=[CH:16]/[CH3:17]>>[CH2:14]([S:18][C:19]([CH3:23])([CH3:22])[CH2:20][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:11])[CH3:12])/[CH:15]=[CH:16]/[CH3:17]
Reactant: CC(C)(S)CNc1ccccc1N
Reactant: C/C=C/CSC(C)(C)C=O
Product: C/C=C/CSC(C)(C)CNc1ccccc1NCC(C)(C)S
Yield: 88.3 %

Procedure:
2-Amino-1-(2-mercapto-2-methylpropylamino)benzene (0.36 g, 1.84×10-3 mol) and 0.58 g (3.67×10-3 mol, 200 M %) 2-(trans-2-butenylthio)-2-methylpropanal were reacted by the procedures in Example 2 to give 0.55 g (88% yield) 1-[2-(trans-2-butenylthio)-2-methylpropylamino]-2-(2-mercapto-2-methylpropylamino)benzene as an oil after purification by radial chromatography on a 4 mm silica plate eluting with 100% hexane.
Reaction SMILES: C1(S([N:10]2[C:19]3[CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][NH:15][C:14](=[O:22])[C:13]=3[S:12][CH:11]2[C:23]2[CH:28]=[CH:27][N:26]=[C:25]3[NH:29][CH:30]=[CH:31][C:24]=23)(=O)=O)C=CC=CC=1.[OH-].[Na+]>CCO>[CH3:20][C:17]1([CH3:21])[CH2:16][NH:15][C:14](=[O:22])[C:13]2[S:12][C:11]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]4[NH:29][CH:30]=[CH:31][C:24]=34)=[N:10][C:19]=2[CH2:18]1
Reactant: CC1(C)CNC(=O)C2=C(C1)N(S(=O)(=O)c1ccccc1)C(c1ccnc3[nH]ccc13)S2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CNC(=O)c2sc(-c3ccnc4[nH]ccc34)nc2C1
Temperature: 25 °C

Procedure:
N-Benzene sulfonyl-5,6,7,8-tetrahydro-7,7-dimethyl-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)thiazolo[5,4-c]azepin-4-one (Made using methods D and E) (79 mg, 1.0 Eq.) was suspended/dissolved in EtOH (4.5 mL)and NaOH (15 wt %, 0.5 mL, ≈11 Eq.) was added. The reaction mixture was refluxed for 4 hours. The reaction mixture was then allowed to cool to RT, and the solvent removed in vacuo. The mixture was partitioned between EtOAc/sat. aq. NH4Cl, and extracted into EtOAc (3×20 mL). The combined organic layers were washed with 15 wt % NaOH (1×10 mL), brine (1×10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification was achieved using column chromatography (5% MeOH/95% DCM), followed by tritration in Et2O. The precipitate was then washed with pentane. The title compound was obtained as a tangerine solid (27.8 mg, 52% yield); 1H NMR (DMSO D6) 1.1(6H, s), 3.0(4H, m), 7.0(1H, m), 7.6(1H, m), 7.7(1H, m), 8.3(2H, m), 12.1(1H, br s); LC/MS M+1 (obs.) 313.20; LC/MS M−1 (obs.) 311.40.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])=[CH2:5].C(=O)([O-])[O-].[K+].[K+].[C:24]([O:28][C:29](=[O:34])[NH:30][CH2:31][CH2:32][NH2:33])([CH3:27])([CH3:26])[CH3:25].ClCCl>C(#N)C>[CH3:1][O:2][C:3](=[O:17])[CH:4]([N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])[CH2:5][NH:33][CH2:32][CH2:31][NH:30][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:34]
Reactant: C=C(C(=O)OC)N1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)C(CNCCNC(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.3 %

Procedure:
To a solution of 12.60 g (51.38 mmol) of 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acrylic acid methyl ester (described in Synthetic Communications, 33(8), 1375-1382; 2003) dissolved in 170 mL of acetonitrile was added at room temperature 42.60 g (308.28 mmol) of potassium carbonate and 9.05 g (56.52 mmol) of (2-amino-ethyl)-carbamic acid tert-butyl ester. The resulting mixture was stirred at room temperature for 12 h. 300 mL of dichloromethane was added and the mixture was filtered and the solid obtained was triturated with dichloromethane, filtered, and the resulting filtrates were evaporated to dryness. The residue was dissolved in diethyl ether, washed with a saturated aqueous solution of sodium hydrogen carbonate, saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel eluting with a mixture of chloroform/methanol/aqueous ammonia solution (29%) in the proportions 98/2/0.2 led to afford 6.50 g (31%) of the desired compound.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[NH2:13][CH2:14][CH2:15][C:16]1[N:20]=[CH:19][NH:18][CH:17]=1>CO>[NH:18]1[CH:17]=[C:16]([CH2:15][CH2:14][NH:13][C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([S:11][CH3:12])[N:3]=2)[N:20]=[CH:19]1
Reactant: CSc1nc(Cl)n2nccc2n1
Reactant: NCCc1c[nH]cn1
Solvent: CO
Product: CSc1nc(NCCc2c[nH]cn2)n2nccc2n1

Procedure:
A solution of 30 mg 4-chloro-2-methylthiopyrazolo(1,5-a)-1,3,5-triazine and 33 mg free histamine in 3 ml of methanol is stirred at room temperature overnight. After evaporation of solvent, the residue is dissolved in ethylacetate, washed with water, and dried over MgSO4. After removal of solvent, the residue is subject to silica gel preparative thin layer chromatography using CHCl3 /methanol=9:1 as a developing solvent. Appropriate fractions are isolated, extracted with CHCl3 /CH3OH (3:1), and solvent removed in vacuo to dryness. 20 mg of a white solid are recovered. TLC (silica gel CHCl3 /CH3OH=3:1) Rf=0.15.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][OH:10])=[CH:7][CH:6]=[C:5]([O:11][CH3:12])[C:4]=1B(O)O.[CH2:16]([O:18][C:19](=[O:40])[C@H:20]([CH2:32][C:33]1[CH:38]=[CH:37][C:36](Br)=[CH:35][CH:34]=1)[NH:21][C:22](=[O:31])[C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:30])[CH3:17]>>[CH2:16]([O:18][C:19](=[O:40])[C@H:20]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:4]2[C:5]([O:11][CH3:12])=[CH:6][CH:7]=[C:8]([CH2:9][OH:10])[C:3]=2[O:2][CH3:1])=[CH:35][CH:34]=1)[NH:21][C:22](=[O:31])[C:23]1[C:24]([Cl:30])=[CH:25][CH:26]=[CH:27][C:28]=1[Cl:29])[CH3:17]
Reactant: COc1ccc(CO)c(OC)c1B(O)O
Reactant: CCOC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1c(Cl)cccc1Cl
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(OC)ccc(CO)c2OC)cc1)NC(=O)c1c(Cl)cccc1Cl

Procedure:
2,6-Dimethoxy-3-(hydroxymethyl)benzeneboronic acid was coupled with N-(2,6-dichlorobenzoyl)-4-bromo-L-phenylalanine ethyl ester in a similar method as described in Example 7-2) to give N-(2,6-dichlorobenzoyl)-4-[2,6-dimethoxy-3-(hydroxymethyl)phenyl]-L-phenylalanine ethyl ester.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]1[C:17](=[O:18])[C:16]2=[C:19]([N+]([O-])=O)[CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:26])([CH3:3])[CH3:2].[F-:27].[K+]>CS(C)=O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]1[C:17](=[O:18])[C:16]2=[C:19]([F:27])[CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:26])([CH3:3])[CH3:2]
Reactant: [F-]
Reactant: CC(C)c1cccc(C(C)C)c1N1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)c1cccc(C(C)C)c1N1C(=O)c2cccc(F)c2C1=O
Temperature: 100 °C
Yield: 34.8 %

Procedure:
In 300 ml of dimethylsulfoxide was dissolved 14.0 g of N-(2',6'-diisopropylphenyl)-3-nitrophthalimide, and 10.0 g of potassium fluoride was added to the solution. The mixture was heated on an oil bath at 100° C. for 3 hours. The liquid reaction mixture was concentrated under reduced pressure below 80° C., and the residue was extracted with ethyl acetate. The ethyl acetate solution was washed with water, dried and concentrated. Then, 20 ml of methanol was added to the residue, and the mixture was cooled and allowed to stand still. The compound 3 was precipitated in the form of colorless crystals. The amount obtained of the crude product was 10.1 g, yield: 77.6%. The crude crystals were recrystallized from methanol two times to obtain 4.5 g of pure crystals.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:26])[C:6]=1[C:7](=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].Br[CH2:28][C:29]1[CH:41]=[CH:40][C:32](/[CH:33]=[CH:34]/[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][CH:30]=1>>[CH3:1][C:2]1[N:3]([CH2:28][C:29]2[CH:41]=[CH:40][C:32](/[CH:33]=[CH:34]/[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][CH:30]=2)[CH:4]=[C:5]([CH3:26])[C:6]=1[C:7](=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCOC(=O)/C=C/c1ccc(CBr)cc1
Reactant: CCCCCCCCCCCCCCCCCC(=O)c1c(C)c[nH]c1C
Product: CCCCCCCCCCCCCCCCCC(=O)c1c(C)cn(Cc2ccc(/C=C/C(=O)OCC)cc2)c1C

Procedure:
Preparation as in Example 2C with 362 mg (1 mmol) of 2,4-dimethyl-3-octadecanoylpyrrole (Lehr M., WO95/13266) in place of 3-dodecanoyl-2,4-dimethylpyrrole and with ethyl (E)-4-(bromomethyl)-cinnamate in place of ethyl (E)-3-(bromo-methyl)cinnamate.
Reaction SMILES: [Br:1]C1N=C(N)C([N+]([O-])=O)=CC=1.C[O:13][C:14]1[N:19]=[C:18]([NH2:20])[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][CH:15]=1>Br.C(O)(=O)C>[BrH:1].[NH2:20][C:18]1[N:19]=[C:14]([OH:13])[CH:15]=[CH:16][C:17]=1[N+:21]([O-:23])=[O:22]
Reactant: Nc1nc(Br)ccc1[N+](=O)[O-]
Reactant: COc1ccc([N+](=O)[O-])c(N)n1
Agent: Br
Solvent: CC(=O)O
Product: Nc1nc(O)ccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 95 %

Procedure:
6-Bromo-3-nitro-pyridin-2-ylamine. To a glass pressure vessel containing 6-methoxy-3-nitro-pyridin-2-ylamine (5.0 g, 29.5 mmol) was added 30% hydrogen bromide/acetic acid (60 mL). The vessel was sealed, and the contents were heated to 60° C. for 24 h. The reaction mixture was cooled, and the solvent was removed in vacuo giving 6.8 g (>95%) of crude 6-amino-5-nitro-pyridin-2-ol hydrobromide (HPLC: Rt=5.46). This material (2.0 g, 8.5 mmol) was taken up in toluene (30 mL), followed by phosphorus pentoxide (2.4 g, 17.0 mmol) and tetrabutyl ammonium bromide (3.2 g, 9.7 mmol). The mixture was heated to reflux for 4 h. The reaction mixture was cooled to 0° C., diluted with saturated NaHCO3, and extracted with ethyl acetate (3×100 mL). The combined organics were washed with water (100 mL) and dried (Na2SO4) to afford 1.18 g (64%) of 6-bromo-3-nitro-pyridin-2-ylamine.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[C:3]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([NH2:25])[N:16]3[CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:12][N:11]=2)[CH:2]=1.CCN(C(C)C)C(C)C.Br[CH2:36][CH2:37][CH2:38][C:39](Cl)=[O:40]>CN(C=O)C>[N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[C:3]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([N:25]4[CH2:36][CH2:37][CH2:38][C:39]4=[O:40])[N:16]3[CH:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[CH:12][N:11]=2)[CH:2]=1
Reactant: Nc1nc2cnc(-c3cnn4ccccc34)nc2n1C1CCOCC1
Reactant: O=C(Cl)CCCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCCN1c1nc2cnc(-c3cnn4ccccc34)nc2n1C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.6 %

Procedure:
To a suspension of example 33 (25 mg, 0.075 mmol) in DMF (1.5 mL), DIPEA (0.04 mL, 0.22 mmol) and 4-bromobutyryl chloride (0.01 mL, 0.082 mmol) ware added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated to dryness and 1.7 mg of the title compound were obtained (yield 6%) after HPLC preparative purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11]([OH:13])=O.[CH3:14][CH2:15][CH2:16][CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11]([NH:21][CH:17]([CH2:18][CH2:19][CH3:20])[CH2:16][CH2:15][CH3:14])=[O:13]
Reactant: CCCC(N)CCC
Reactant: COc1ccccc1C=CC(=O)O
Product: CCCC(CCC)NC(=O)C=Cc1ccccc1OC

Procedure:
Prepared in a similar manner as described in example 4 from 3-(2-methoxyphenyl)-acrylic acid and 4-heptylamine. MS (M+H, 276.2).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:13][C:14]1[CH:29]=[CH:28][C:17]([C:18]([N:20]2[CH2:24][CH2:23][CH2:22][CH:21]2C(O)=O)=O)=[CH:16][CH:15]=1.C(OC(C)C)(C)C>C(OC(=O)C)(=O)C>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]2[N:20]3[C:21]([CH2:22][CH2:23][CH2:24]3)=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:28][CH:29]=1
Reactant: COC(=O)C#Cc1ccccc1
Reactant: O=C(O)C1CCCN1C(=O)c1ccc(F)cc1
Solvent: CC(C)OC(C)C
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1c(-c2ccccc2)c(-c2ccc(F)cc2)n2c1CCC2
Temperature: 28 °C
Reaction time: 4 h

Procedure:
Methyl phenylpropiolate (methyl dehydrocinnamate (0.96 g, 6 mmol)) is dissolved in acetic anhydride (14 ml) and brought to the boiling temperature of acetic anhydride in a hot oil bath (140° C.). The total amount of 1-(4-fluorobenzoyl)pyrrolidine-2-carboxylic acid (1.42 g, 6 mmol) is added, and the thoroughly mixed solution is refluxed (1 28° C.) for 20 h with stirring. After standing for 4 hours and cooling to RT, a pure crystalline solid deposits (TLC: Al2O3, diisopropyl ether, Rf 0.7). The crystals are filtered off with suction, washed with water (20 ml) and finally with isopropyl ether (10 ml). The dried crystals weigh 650 mg (32.5% of theory)
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1.CN(C)C=O.[H-].[Na+].[Cl:16][C:17]1[N:22]=[C:21](Cl)[CH:20]=[CH:19][N:18]=1>O1CCCC1>[Cl:16][C:17]1[N:22]=[C:21]([O:1][CH2:2][C:3]2([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]2)[CH:20]=[CH:19][N:18]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: OCC1(CO)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: OCC1(COc2ccnc(Cl)n2)CCC1
Reaction time: 0.25 h
Yield: 45.7 %

Procedure:
To a solution of 1.00 g (8.62 mmol) of [1-(hydroxymethyl)cyclobutyl]methanol in 20 ml of (1:1) tetrahydrofuran:dimethylforamide was added a 60% dispersion of 0.413 g (8.62 mmol) of sodium hydride in oil. The reaction was stirred for 15 min and 1.28 g (8.62 mmol) of 2,4-dichloropyrimidine was added. After stirring for 2 h, the reaction was concentrated under vacuum and the residue was purified using silica gel chromatography eluting with ethyl acetate:hexane (4:6) to afford 0.9 g (51%) of (1-{[(2-chloro-4-pyrimidinyl)oxy]methyl}cyclobutyl)methanol as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 8.32 (d, J=6 Hz, 1H), 6.69 (d, J=7 Hz, 1H), 4.51 (s, 2H), 3.67 (s, 2H), 2.35 (br s, 1H), 2.05-1.87 (m, 6H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6]1)#[N:2].[N+:14]([O-])([O-:16])=[O:15].[Na+]>FC(F)(F)C(O)=O>[C:1]([CH2:3][CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:7]=2[O:6]1)#[N:2]
Reactant: N#CCCC1Cc2ccccc2O1
Reactant: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: N#CCCC1Cc2cc([N+](=O)[O-])ccc2O1
Yield: 36.2 %

Procedure:
Starting from 7.5 g (43 mmol) of 2-cyanoethyl-2,3-dihydrobenzofuran in 120 ml of trifluoroacetic acid and 11 g (130 mmol) of sodium nitrate treated under the conditions described in step 6 of Example 7, 3.4 g of product were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH3:11])[C:3]=1[CH2:12][CH:13](Cl)[CH3:14].[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[Na+].[Na+].Cl.C(O)C>C(O)C>[ClH:1].[C:16]([N:20]1[C:2]2[N:7]3[N:8]=[CH:9][N:10]=[C:6]3[N:5]=[C:4]([CH3:11])[C:3]=2[CH2:12][CH:13]1[CH3:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)N
Reactant: Cc1nc2ncnn2c(Cl)c1CC(C)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nc2ncnn2c2c1CC(C)N2C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2.4g of 7-chloro-6-(2-chloropropyl)-5-methyl-s-triazolo[1,5-a]pyrimidine, 0.9g of tert-butylamine, 1.8g of sodium carbonate and 20 ml of ethanol was stirred for 3 hours at room temperature and then refluxed for 5 hours. The hot reaction mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was purified by a column chromatography of alumina. To an oily substance thus obtained was added a solution of hydrogen chloride-ethanol and the crystals precipitated thereby were collected by filtration.
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]2=[N:6][C:7]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[N:4]2[N:3]=1.[CH3:15][N:16]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:15][N:16]1[CH2:22][CH2:21][CH2:20][N:19]([C:2]2[CH:14]=[CH:13][C:5]3=[N:6][C:7]4[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=4[N:4]3[N:3]=2)[CH2:18][CH2:17]1
Reactant: CN1CCCNCC1
Reactant: Clc1ccc2nc3c(n2n1)CCCC3
Product: CN1CCCN(c2ccc3nc4c(n3n2)CCCC4)CC1

Procedure:
A mixture was prepared from 5.0 g of 2-chloro-6,7,8,9-tetrahydropyridazino[1,6-a]benzimidazole and 30 ml of 1-methylhomopiperazine and this was stirred and heated at reflux for 18 hours. The reaction mixture was then cooled and excess amine was removed by distillation to leave a tan solid residue. This solid was partitioned between methylene chloride and an aqueous 1% solution of sodium hydroxide. The methylene chloride layer was separated and the solvent was evaporated under reduced pressure to leave a residual solid. This solid was recrystallized from a mixture of ethanol and water to give 2-(4-methyl-1-homopiperazinyl)-6,7,8,9-tetrahydropyridazino[1,6-a]benzimidazole melting at about 106°-107° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.[N:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[CH2:27]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[N:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[CH2:27][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:9])=[CH:4][CH:3]=1
Reactant: OCc1cnccn1
Reactant: O=C(c1ccc(O)cc1)N1CCC[C@H]1CN1CCCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(c1ccc(OCc2cnccn2)cc1)N1CCC[C@H]1CN1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 1.6 %

Procedure:
To a mixture of (4-Hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone (0.57 g, 2.0 mmol), pyrazin-2-yl-methanol [CAS 6705-33-5] (0.25 g, 2.3 mmol), and triphenylphosphine (0.57 g, 2.2 mmol) in THF (20 mL) is added DEAD (0.36 mL, 2.3 mmol). The mixture is stirred at room temperature overnight and partitioned between ethyl acetate and water. The aqueous phase is extracted with ethyl acetate (2×), and the combined organic phase is dried (Na2SO4) and concentrated. The crude material is purified by SCX chromatography followed by silica gel chromatography eluting with 20% (10% 2M MeOH/CH2Cl2)/80% CH2Cl2 to 70% (10% 2M MeOH/CH2Cl2)/30% CH2Cl2 to yield 12 mg of the title compound. MS (ES+) 367.3
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:19]2[N:23]=[C:22]([C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=3)=[O:25])[O:21][N:20]=2)[CH:5]=[C:6]([Cl:18])[C:7]=1[O:8]CC1C=CC(OC)=CC=1.[F:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][C:37]=1[C:45]([F:48])([F:47])[F:46].N1C=CC=CC=1>ClCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Cl:1][C:2]1[CH:3]=[C:4]([C:19]2[N:23]=[C:22]([C:24]([NH:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:34][C:39]4[CH:40]=[CH:41][C:36]([F:35])=[C:37]([C:45]([F:48])([F:47])[F:46])[CH:38]=4)=[CH:32][CH:33]=3)=[O:25])[O:21][N:20]=2)[CH:5]=[C:6]([Cl:18])[C:7]=1[OH:8]
Reactant: OB(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: COc1ccc(COc2c(Cl)cc(-c3noc(C(=O)NCc4ccc(O)cc4)n3)cc2Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NCc1ccc(Oc2ccc(F)c(C(F)(F)F)c2)cc1)c1nc(-c2cc(Cl)c(O)c(Cl)c2)no1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.8 %

Procedure:
3-(3,5-Dichloro-4-(4-methoxybenzyloxy)phenyl)-N-(4-hydroxybenzyl)-1,2,4-oxadiazole-5-carboxamide (compound G, 60 mg, 0.12 mmol), 4-fluoro-3-(trifluoromethyl)phenylboronic acid (50 mg, 0.24 mmol), Cu(OAc)2 (44 mg, 0.24 mmol) and 3A powdered molecular sieves (70 mg) were stirred in an open tube in dichloromethane (3 mL). Pyridine (57 mg, 0.72 mmol) was added and the dark green suspension stirred vigorously at room temperature in an open tube for 1 d. The molecular sieves were filtered, washed with dichloromethane and the filtrate concentrated in vacuo. The residue was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (0.3 mL) was added. The dark solution was stirred at room temperature for 5 h, then methanol (1 mL) was added and the solution concentrated in vacuo. The residue was purified by preparative HPLC providing the title compound (46 mg, 0.085 mmol, 71%). 1H NMR δ (ppm) (DMSO-d6): 4.53 (2 H, d, J=6.20 Hz), 7.06-7.13 (2 H, m), 7.36-7.48 (4 H, m), 7.53-7.60 (1 H, m), 8.01 (2 H, s), 10.03 (1 H, t, J=6.20 Hz), 11.20 (1 H, s). LCMS (10 cm_esci_Bicarb_MeCN) tR 3.48 min; m/z 540/542/544 [M−H]−.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1I)([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]([F:29])([F:28])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O>>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][C:17]([F:16])([F:29])[F:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cnccc1I
Reactant: OB(O)c1ccccc1OC(F)(F)F
Product: CC(C)(C)OC(=O)Nc1cnccc1-c1ccccc1OC(F)(F)F

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester and 2-trifluoromethoxyphenylboronic acid after a reaction time of 16 hours at reflux. The crude product was purified by column chromatography eluting with a gradient of n-hexane:EtOAc (80:20 to 70:30). Light yellow sticky liquid (80%). MS (ESI): m/z=355.2 [M+H]+.
Reaction SMILES: C(C[C:4]1[N:5]([CH3:23])[C:6](=[O:22])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:10]([CH3:20])=[C:9]([CH3:21])[CH:8]=2)#N.Cl.[C:25]([OH:28])(=[O:27])[CH3:26]>>[CH3:23][N:5]1[C:4]([CH2:26][C:25]([OH:28])=[O:27])=[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:12]2[C:7](=[CH:8][C:9]([CH3:21])=[C:10]([CH3:20])[CH:11]=2)[C:6]1=[O:22]
Reactant: CC(=O)O
Reactant: Cc1cc2c(-c3ccccc3)c(CC#N)n(C)c(=O)c2cc1C
Agent: Cl
Product: Cc1cc2c(-c3ccccc3)c(CC(=O)O)n(C)c(=O)c2cc1C
Temperature: 110 °C

Procedure:
A mixture of the compound (4.7 g) obtained in Step 1, acetic acid (150 ml) and hydrochloric acid (150 ml) was heated for 7 hours at 110° C. The solvent was distilled off. To the residue was added ethyl acetate, which was washed with water and dried (MgSO4), then the solvent was distilled off to leave the title compound as colorless crystals (3.7 g).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[OH:14])(=O)[CH3:2].CCO.Cl.[NH2:19][OH:20]>[OH-].[Na+]>[OH:14][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:4]=1[C:1](=[N:19][OH:20])[CH3:2])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(C(C)=O)c(O)c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)c1ccc(C(C)=NO)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
Methyl 4-acetyl-3-hydroxybenzoate (350 mg, 1.8 mmole) is combined with 5 ml absolute EtOH. The solution is treated with hydroxylamine hydrochloride (125 mg, 1.8 mmole) dissolved in 0.9 ml 2N aqueous NaOH, and the reaction is stirred overnight at rt. The volatiles are removed in vacuo and the residue is washed with H2O, collected, and dried to give 294 mg (78%) of methyl 3-hydroxy-4-[N-hydroxyethanimidoyl]benzoate as a tan solid. MS (EI) m/z: 209 (M+).