Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([NH2:17])[N:7]=[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]3=2)[N:4]=1)=[CH2:2].[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[CH2:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([NH2:17])[N:7]=[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]3=2)[N:4]=1)[CH3:2]
Reactant: [H][H]
Reactant: C=Cc1ccc2c(n1)c(N)nc1ccccc12
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1ccc2c(n1)c(N)nc1ccccc12
Reaction time: 8 h

Procedure:
To a solution of 3-vinylbenzo[f][1,7]naphthyridin-5-amine (Example 23) in ethyl acetate/ethanol (1:1, 0.07 M) was added 10% wt palladium on carbon (0.2 eq.). Hydrogen gas was introduced via a balloon, and the reaction was stirred overnight. The mixture was filtered through a pad of celite, washing with dichloromethane. The filtrate was concentrated en vacuo giving 3-ethylbenzo[f][1,7]naphthyridin-5-amine as a white solid. 1H NMR (acetone d-6): δ 8.93 (d, 1H), 8.41 (d, 1H), 7.76 (d, 1H), 7.61 (d, 1H), 7.51-7.55 (dd, 1H), 7.30-7.34 (dd, 1H), 6.55 (br, 2H), 6.03 (q, 2H), 1.41 (t, 3H). LRMS [M+H]=224.1
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:4]=2[NH:3]1.O1CCC[CH2:21]1>>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[C:14]([C:17]([O:19][CH3:21])=[O:18])[CH:15]=[CH:16][C:4]=2[NH:3]1
Reactant: C1CCOC1
Reactant: O=C(O)c1ccc2c(c1)Sc1ccccc1C(=O)N2
Product: COC(=O)c1ccc2c(c1)Sc1ccccc1C(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dissolve 1 gm of the acid of Example 22 with heating in 100 ml of tetrahydrofuran. Filter and cool the filtrate to room temperature. Add 500 mg. of diazomethane and stir at room temperature for 30 minutes. Strip to dryness and triturate the residue in methanol. Recover the title product by filtration. (m.p. 240°-257° C.).
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:24]([O:25]C(=O)C)=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1.[NH2:31][CH2:32][C:33]([OH:35])=[O:34].C(=O)([O-])[O-].[K+].[K+]>CC#N.O>[OH:25][C:24]1[C:4]2[O:3][C:2]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[C:6]([C:7](=[O:20])[C:8]3[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=3)[C:5]=2[CH:21]=[CH:22][C:23]=1[O:29][CH3:30]
Reactant: NCC(=O)O
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc(C(=O)c2c(NCC(=O)O)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Reaction time: 0.33 h
Yield: 53.3 %

Procedure:
A mixture of 2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzofuran (50 mg, 0.10 mmol), glycine (18 mg, 0.29 mmol) and potassium carbonate (29 mg, 0.21 mmol) in a mixture of MeCN/water 80:20 (5 mL) was refluxed for six hours. Solvent was distilled and the residue was taken in water:dichloromethane 1:2 (30 mL) and stirred for 20 minutes. Aqueous layer was separated, washed with dichloromethane (20 mL) and acidified with 2 drops of concentrated HCl and was diluted with dichloromethane (50 mL) and was stirred for 30 minutes. The organic layer was separated and dried over magnesium sulfate and solvent was distilled to afford the title compound as yellow powder (23 mg, 51%); 1H NMR (300 MHz, Acetone d6) δ 9.09 (b, 1H, NH), 6.97 (s, 2H, benzoyl Hs), 6.74 (d, 1H, J=8.53 Hz), 6.45 (d, 1H, J=8.48 Hz), 4.48 (d, 2H, J=4.28 Hz), 3.82 (s, 6H, 2×OMe), 3.79 (s, 3H, OMe), 3.78 (s, 3H, OMe).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[CH3:7][O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.[O:16]1CCC[CH2:17]1>>[CH3:7][O:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:17]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])=[O:16])=[CH:11][CH:10]=1
Reactant: C1CCOC1
Reactant: O=C1CCCN1
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NC(=O)N2CCCC2=O)cc1
Yield: 85 %

Procedure:
N,N'-Carbonyldiimidazole (3.85 g) and 2 g of 2-pyrrolidinone were added to 20 ml of tetrahydrofuran, and the mixture was refluxed with heating for 8 hours. Next, 2.9 g of 4-methoxyaniline was added to the reaction mixture, and the mixture was further refluxed with heating for 8 hours. The solvent was then distilled off, and the resulting residue was subjected to silica gel column chromatography to obtain a chloroform eluate and crystals from, the eluate. The crystal were recrystallized from methanol, giving 4.7 g of 1-(4-methoxyphenylcarbamoyl)-2-pyrrolidinone (yield 85%) having a melting point of 113° to 114° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.[CH2:34]([NH2:36])[CH3:35]>O>[CH2:34]([NH:36][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH3:35]
Reactant: CCN
Reactant: Oc1ccc2ccccc2c1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: CCNc1ccc2ccccc2c1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
288 parts of β-naphthol, 6.6 parts of triphenyl phosphite and 115 parts of ethylamine gas are heated for 10 hours at 230° C in a pressure autoclave. The pressure is 35 atmospheres. The mixture is added to 2,000 parts of water and the batch is stirred for 30 minutes at 70° - 80° C. The lower oily phase is separated off and distilled. 328 parts of N-ethyl-β-naphthylamine of boiling point 119° - 120° C/0.1 mm Hg are obtained. This corresponds to a yield of 96% of theory.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].O.C(O)C.B(O)(O)[C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])=[CH:16][CH:15]=1>C1C=CC=CC=1>[CH:23]([S:20]([C:17]1[CH:18]=[CH:19][C:14]([C:2]2[C:3]([NH2:4])=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:15][CH:16]=1)(=[O:21])=[O:22])([CH3:25])[CH3:24]
Reactant: Nc1ccccc1Br
Reactant: CC(C)S(=O)(=O)c1ccc(B(O)O)cc1
Solvent: O
Solvent: CCO
Solvent: c1ccccc1
Product: CC(C)S(=O)(=O)c1ccc(-c2ccccc2N)cc1
Temperature: 85 °C
Reaction time: 48 h

Procedure:
To a solution of 2-bromoaniline (1.51 g, 8.78 mmol) in a mixture of benzene (58 mL), H2O (23 mL) and ethanol (3 mL) was added 4-(isopropylsulfonylphenyl)boronic acid (3.00 g, 13.2 mmol) followed by tetrakis(triphenylphoshine) palladium(0) (1.01 g, 0.88 mmol). After stirring 85° C. for 48 h the reaction mixture was poured into H2O (500 mL), extracted with chloroform (three times), dried over MgSO4 and concentrated under vacuum. Purification by silica gel chromatography (20% EtOAc/hexanes—40% EtOAc/hexanes) afforded the desired product.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1.CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]1([S:7]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CCN2
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
To a mixture of DMAP (1.5 g), benzenesulfonyl chloride (24 g, 136 mmol) and 2,3-dihydro-1H-indole (14.7 g, 124 mmol) in CH2Cl2 (200 mL) was added dropwise Et3N (19 g, 186 mmol) in an ice-water bath. After addition, the mixture was stirred at room temperature overnight, washed with water, dried over Na2SO4 and concentrated to dryness under reduced pressure to provide 1-benzenesulfonyl-2,3-dihydro-1H-indole (30.9 g, 96%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C[Mg+].[Br-].[C:13](OC(=O)C)(=[O:15])[CH3:14].[C:20](=O)(O)[O-].[Na+]>CCOCC.C(Cl)Cl>[F:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([NH:9][C:13](=[O:15])[CH3:14])=[CH2:20])=[N:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ncc(F)cn1
Reactant: O=C([O-])O
Agent: C[Mg+]
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: C=C(NC(C)=O)c1ncc(F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
5-Fluoropyrimidine-2-carbonitrile (Method 6, 1.0 g, 8.1 mmol) in TI-IF (10 ml) was added a solution of MeMgBr (3.3 ml, 9.75 mmol) in ether drop wise at 0° C. After addition, the reaction was warmed to room temperature, stirred at room temperature for 1 hour and then diluted with DCM (10 ml). Acetic anhydride (1.23 ml, 13.0 mmol) was added in one portion. The reaction was stirred at room temperature for 1 hour and 40° C. for 1 hour. Saturated sodium bicarbonate solution (10 ml) was added and extracted with EtOAc (2×20 ml). The combined organic was dried over sodium sulfate. After removal of solvent, the resulted residue was purified by column chromatography (hexane-EtOAc=2.5:1) to give the title compound as a white solid (0.38 g, 26%). 1H NMR (400 MHz) 9.34 (s, 1H), 8.95 (s, 2H), 6.25 (s, 1H), 6.03 (s, 1H), 2.11 (s, 3H). MS: Calcd.: 181. Found: [M+H]+ 182.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([F:15])([F:14])[F:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:16]Br.OS(O)(=O)=O>C(O)(=O)C>[Br:16][C:9]1[CH:10]=[CH:11][C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[C:7]([C:12]([F:13])([F:14])[F:15])[CH:8]=1
Reactant: FC(F)(F)c1ccccc1C1CCCC1
Reactant: BrBr
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(Br)ccc1C1CCCC1
Temperature: 0 °C
Yield: 36.5 %

Procedure:
To a solution of 1-cyclopentyl-2-(trifluoromethyl)benzene (0.5 g, 2.334 mmol) in acetic acid (2.5 mL) was added bromine (1.202 mL, 23.34 mmol). The mixture was stirred well, concentrated H2SO4 (2.5 mL) was added, and stirred at 40° C. for 1.5 h. The reaction mixture was poured into ice-water and extracted with CH2Cl2. The CH2Cl2 layer was washed with water, followed by a solution of sodium thiosulfate, then with water. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (250 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.52-1.75 (m, 4H), 1.78-1.88 (m, 2H), 1.95-2.04 (m, 2H), 3.16-3.26 (m, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.76 (d, J=2 Hz, 1H), 7.81 (dd, J=8.4 Hz, 2 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH:13]=O.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[NH:16][NH2:17]>C(O)(=O)C.C(O)C>[CH2:20]([O:19][C:15](=[O:18])[NH:16][N:17]=[CH:13][C:3]1[N:4]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:6][C:2]=1[CH3:1])[CH3:21]
Reactant: Cc1[nH]c(-c2ccccc2)nc1C=O
Reactant: CCOC(=O)NN
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)NN=Cc1nc(-c2ccccc2)[nH]c1C
Temperature: 0 °C

Procedure:
A mixture of 5-methyl-2-phenyl-4imidazolecarboxaldehyde (10.25 g), ethyl carbazate (5.72 g) and ethanol (30 ml) containing 1 drop of acetic acid is heated at the boil for 30 minutes. The mixture is then concentrated under an air stream on a steam bath. Next, carbon tetrachloride (50 ml) is added and the mixture cooled at 0° C overnight. The solid is collected giving the title product, m.p. 209°-211° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=1)[C:10](O)=[O:11]>C1(C)C=CC=CC=1>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=1)[C:10]([Cl:3])=[O:11]
Reactant: COc1cc(C(=O)O)ccn1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)Cl)ccn1
Temperature: 80 °C
Yield: 45.8 %

Procedure:
Thionyl chloride (30.0 mL, 0.39 mol) was added to a suspension of 2-methoxy-isonicotinic acid (15.0 g, 97.9 mmol) in anhydrous toluene (150 mL). The mixture was heated at 80° C. under nitrogen for 3 hours, cooled to room temperature and filtered. The filtrate was concentrated in vacuo to afford the title compound 7.7 g (46% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH:6]=[CH:5]2.[C:18]([N:25]1[CH:29]=[CH:28]N=[CH:26]1)(N1C=CN=C1)=[O:19].[CH3:30][O:31][C:32]1[CH:33]=[C:34]2C(=[CH:39][C:40]=1[C:41]([F:44])([F:43])[F:42])NCC2.O>ClCCl.CN(C)C=O>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([NH:1][C:18]([N:25]4[C:26]5[C:34](=[CH:33][C:32]([O:31][CH3:30])=[C:40]([C:41]([F:43])([F:44])[F:42])[CH:39]=5)[CH2:28][CH2:29]4)=[O:19])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)[CH:13]=1
Reactant: COc1cc2c(cc1C(F)(F)F)NCC2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc2c(ccn2Cc2cccnc2)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1ccc3c(ccn3Cc3cccnc3)c1)CC2
Temperature: 110 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
A solution of aminoindole (D48, 0.40 g, 1.8 mmol) and 1,1′-carbonyldiimidazole (0.30 g, 1.8 mmol) in dichloromethane (40 mL) was stirred at room temperature for 1.75 h, then evaporated. To the residue was added dimethylformamide (DMF, 10 mL) and a solution of 5-methoxy-6-trifluoromethylindoline (D11, 0.39 g, 1.8 mmol) in DMF (5 mL). The mixture was stirred at 110° C. overnight, then poured into water and extracted with dichloromethane. The extract was washed with water, dried and evaporated. The residue was triturated with ether to give a grey solid, which was recrystallised from dichloromethane/methanol to give the title compound (0.15 g, 18%) m.p. 243-6° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[NH:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:9][N:8]=2)[C:4](=[O:21])[CH2:3]1.[C:23]([O-])([O-])=O.[K+].[K+].IC>C(#N)C>[CH3:23][N:6]1[C:2]([CH3:22])([CH3:1])[CH2:3][C:4](=[O:21])[N:5]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][N:8]=1
Reactant: CC1(C)CC(=O)N(c2ccc(C#Cc3ccccc3)cn2)N1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CN1N(c2ccc(C#Cc3ccccc3)cn2)C(=O)CC1(C)C
Temperature: 80 °C
Reaction time: 16 h
Yield: 49.1 %

Procedure:
(35 mg, 120 μmol) 5,5-Dimethyl-2-(5-phenylethynyl-pyridin-2-yl)-pyrazolidin-3-one (Example 1, step 4) was dissolved in ACN (2 ml). K2CO3 (33 mg, 240 μmol, 2 equiv.) and iodomethane (22 mg, 156 μmol, 1.3 equiv.) were added and the mixture was stirred for 16 hours at 80° C. The reaction mixture was evaporated and extracted with water and two times with ethyl acetate. The organic layers were extracted with brine, dried with sodium sulfate and evaporated to dryness. The crude product was purified by reverse phase column chromatography. The desired 1,5,5-trimethyl-2-(5-phenylethynyl-pyridin-2-yl)-pyrazolidin-3-one (18 mg, 49% yield) was obtained as a colorless oil, MS: m/e=306.2 (M+H+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][C:8](Cl)=[O:9].Cl.[CH2:12]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C(Cl)Cl>[Cl:5][CH2:6][CH2:7][C:8]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:14][CH:15]=1)=[O:9]
Reactant: O=C(Cl)CCCl
Reactant: c1ccc(Cc2cccnc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=C(CCCl)c1ccc(Cc2cccnc2)cc1
Yield: 86.6 %

Procedure:
In 15 ml of methylene chloride was suspended 8.1 g of anhydrous aluminum chloride, and 3.0 ml of 3-chloropropionyl chloride was added to the suspension with ice-cooling, after which 5.0 g of 3-benzylpyridine hydrochloride was added in small portions to the resulting mixture over 30 minutes. The resulting mixture was subjected to reaction at room temperature for one hour, and then the reaction mixture was added to 30 ml of iced water. The crystals thus precipitated were collected by filtration, and suspended in a mixture of 50 ml of ethyl acetate and 30 ml of water, after which the resulting suspension was neutralized with sodium hydrogen-carbonate with ice-cooling. Insolubles were removed by filtration, and the organic layer of the filtrate was separated, washed with 10 ml of a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure to obtain 5.5 g (yield 86.6%) of pale yellow, oily 3-[p-(3-chloropropionyl)benzyl]pyridine.
Reaction SMILES: [NH:1]1[CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]2[NH:3][C:2]1=[S:10].[Br:11][CH2:12][CH2:13][CH3:14]>C(O)C>[BrH:11].[CH2:12]([S:10][C:2]1[NH:3][CH:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]2[N:1]=1)[CH2:13][CH3:14]
Reactant: CCCBr
Reactant: S=C1NC2CCCCC2N1
Solvent: CCO
Product: Br
Product: CCCSC1=NC2CCCCC2N1
Yield: 95 %

Procedure:
1 g of octahydro 2H-benzimidazol-2-thione and 1.3 ml of bromopropane in 20 ml of ethanol are heated under reflux until complete dissolution is obtained. The solvent is evaporated off under reduced pressure, the residue is taken up in a minimum amount of dichloromethane, isopropyl ether is added, the solvents are evaporated off under reduced pressure, the residue is recrystallized from isopropyl ether, the expected product is separated off and dried with a yield of 95%.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[CH:6]1([N:12]=[C:13]=[N:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>>[CH2:1]([NH:5][C:13]([NH:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[N:12][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:2][CH2:3][CH3:4]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CCCCN
Product: CCCCNC(=NC1CCCCC1)NC1CCCCC1
Yield: 99 %

Procedure:
A mixture of 15.69 g of N-butylamine (0.214 mol) and 22.13 g of dicyclohexylcarbodiimide (0.107 mol) is heated at reflux for 2 h. GC analysis then shows a conversion of the dicyclohexylcarbodiimide of greater than 99.6%. The final colorless mixture is concentrated at 60° C. under 1 mbar for 2 h to give 29.7 g of a colorless, virtually odorless and moderately viscous liquid corresponding to the expected guanidine 2 (99% yield).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:14]=[C:15]([C:19](=[O:21])[CH3:20])[CH:16]=[CH:17][CH:18]=1)#[CH:12].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]([C:19](=[O:21])[CH3:20])[CH:16]=[CH:17][CH:18]=3)[O:1][N:2]=2)[CH:5]=1
Reactant: C#Cc1cccc(C(C)=O)c1
Reactant: ON=C(Cl)c1cccnc1
Agent: N
Product: CC(=O)c1cccc(-c2cc(-c3cccnc3)no2)c1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 1-(3-ethynylphenyl)ethanone (GFS Chemicals, 72 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 2.70 (s, 3H), 7.67-7.85 (m, 2H), 7.94 (s, 1H), 8.13 (dt, J=5.1, 1.5 Hz, 1H), 8.18 (dt, J=7.6, 1.5 Hz, 1H), 8.40-8.54 (m, 2H), 8.80 (dd, J=5.2, 1.6 Hz, 1H), 9.20 (d, J=1.5 Hz, 1H) ppm; MS (DCI/NH3) m/z 265 (M+H)+.
Reaction SMILES: [O:1]=O.[C:3]([NH:6][CH:7]([C:20]1[CH:24]=[CH:23][O:22][C:21]=1[Si](CC)(CC)CC)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:5])[CH3:4].[BH4-].[Na+]>>[C:3]([NH:6][CH:7]([C:20]1[C:21](=[O:1])[O:22][CH2:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:5])[CH3:4]
Reactant: CCCCCCCCCCCCC(NC(C)=O)c1ccoc1[Si](CC)(CC)CC
Reactant: O=O
Agent: [BH4-]
Agent: [Na+]
Product: CCCCCCCCCCCCC(NC(C)=O)C1=CCOC1=O

Procedure:
Reacting 3-(I-hydroxytridecyl)-2-triethylsilylfuran with diphenylphosphoryl azide and diethyl azidocarboxylate gives 3-(1-azidotridecyl)-2-triethylsilylfuran. Reducing this intermediate with lithium aluminum hydride, followed by acetylation with acetic anhydide gives 3-(1-acetamido tridecyl)-2-triethylsilylfuran. Singlet oxygen oxidation of this amide, followed by reduction with sodium borohydride gives 3-(1-acetamidotridecyl)-2(5H)-furanone.
Reaction SMILES: [C:1]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:9]=2[CH:10]=1)(=O)[CH2:2][CH2:3][CH3:4].NN.C(O)COCCO.[OH-].[K+]>O>[CH2:1]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:9]=2[CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cc2cc(Cl)ccc2o1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CCCCc1cc2cc(Cl)ccc2o1

Procedure:
A mixture of 31.5 g. (0.14 mol.) of 2-butyryl-5-chlorobenzofuran and 35 ml. of 98% hydrazine in 70 ml. of diethylene glycol was warmed for a few minutes on a steam bath. Then 23.3 g. of potassium hydroxide was added and the reaction mixture was refluxed for two hours. After cooling, water was added to the mixture and the resulting aqueous solution was extracted with benzene. The extract was washed with water, 10% aqueous hydrochloric acid and water, dried (MgSO4) and concentrated in vacuo to yield 2-n-butyl-5-chlorobenzofuran, b.p. 70°-75° (10-15 mm.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][CH:10]([NH2:12])[CH3:11].Cl[C:14]1[CH:19]=[CH:18][NH:17][C:16](=[O:20])[C:15]=1[C:21]1[NH:37][C:24]2=[CH:25][C:26]3[C:27](=[O:36])[N:28]([CH:33]([CH3:35])[CH3:34])[C:29](=[O:32])[C:30]=3[CH:31]=[C:23]2[N:22]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][CH:10]([NH:12][C:14]1[CH:19]=[CH:18][NH:17][C:16](=[O:20])[C:15]=1[C:21]1[NH:22][C:23]2=[CH:31][C:30]3[C:29](=[O:32])[N:28]([CH:33]([CH3:35])[CH3:34])[C:27](=[O:36])[C:26]=3[CH:25]=[C:24]2[N:37]=1)[CH3:11]
Reactant: CC(C)N1C(=O)c2cc3nc(-c4c(Cl)cc[nH]c4=O)[nH]c3cc2C1=O
Reactant: CC(N)Cc1cc(F)ccc1F
Product: CC(Cc1cc(F)ccc1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C(C)C)C3=O
Yield: 98.8 %

Procedure:
Racemic 1-(2,5-difluorophenyl)propan-2-amine (0.051 g) and 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-isopropylimidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.2965 mmol) were submitted to general procedure A to give 0.144 g the title compound. 1H NMR (500 MHz, DMSO-d6) δ 13.04 (s, 1H), 11.20 (d, 1H), 11.10 (d, 1H), 8.13 (s, 1H), 7.82 (t, 2H), 7.36-7.31 (m, 2H), 7.22-7.14 (m, 1H), 7.09-7.03 (m, 1H), 6.17 (d, 1H), 4.51-4.42 (m, 3H), 4.18-4.10 (m, 1H), 3.09-2.93 (m, 2H), 1.32 (d, 3H), 1.25 (d, 6H). APCI MS: m/z 489.9 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][C@@H:5]([OH:29])[C@@H:6]2[N:12]1[C:20]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]=2[C:14]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])=[N:13]1.C(N(CC)CC)C.[C:37](Cl)(=[O:40])[CH2:38][CH3:39].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][C@@H:5]([OH:29])[C@@H:6]2[N:12]1[C:20]2[CH2:19][CH2:18][N:17]([C:37](=[O:40])[CH2:38][CH3:39])[CH2:16][C:15]=2[C:14]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])=[N:13]1
Reactant: CCC(=O)Cl
Reactant: N#Cc1cccc(-c2nn([C@@H]3c4cc(F)cc(F)c4C[C@H]3O)c3c2CNCC3)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2[C@@H]2c3cc(F)cc(F)c3C[C@H]2O)C1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 26.3 %

Procedure:
According to Scheme 9: To a solution of 3-[1-((1R,2R)-4,6-difluoro-2-hydroxy-indan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (13c) (0.05 g, 0.127 mmol) in CH2Cl2 (2 ml) at 0° C. triethylamine (19 mg, 0.191 mmol) and propionyl chloride (13 mg, 0.140 mmol) was added and the mixture was stirred for 30 min at 0-5° C. After addition of aqueous saturated NaHCO3 (2 ml), the mixture was extracted with CH2Cl2 (10 ml), the organic layer was dried over Na2SO4, solvents were evaporated in vacuo and the crude product was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 15 mg of 3-[1-((1R,2R)-4,6-difluoro-2-hydroxy-indan-1-yl)-5-propionyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (14a).