Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K].[N+:2]([C:5]1[NH:6][CH:7]=[CH:8][N:9]=1)([O-:4])=[O:3].CS(O[CH2:15][CH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])(=O)=O.C1OCCOCCOCCOCCOCCOC1.C(OCC)(=O)C>C(#N)C.O>[CH2:16]([CH:17]([CH2:20][CH3:21])[CH2:18][CH2:19][N:6]1[CH:7]=[CH:8][N:9]=[C:5]1[N+:2]([O-:4])=[O:3])[CH3:15]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: CCC(CC)CCOS(C)(=O)=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCC(CC)CCn1ccnc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 87.6 %

Procedure:
A solution of 2-nitro-1H-imidazole potassium salt (300 mg, 2.0 mmol), 3-ethylpentyl methanesulfonate (463 mg, 2.4 mmol) and 18-crown-6 (1.1 g, 4.2 mmol) in acetonitrile (10 ml) was heated at 80° C. for 6 hours. After cooling to room temperature, ethyl acetate and water were added and the organic layer was separated off. After washing with water and brine, drying was performed with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (370 mg) as a colorless oil.
Reaction SMILES: [CH:1]([N:3]1[C:15]2[C:14]([O:16][CH3:17])=[CH:13][CH:12]=[C:11]([S:18](Cl)(=[O:20])=[O:19])[C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:2].C([N:24]([CH2:27][CH3:28])CC)C>C(Cl)(Cl)Cl>[CH:1]([N:3]1[C:15]2[C:14]([O:16][CH3:17])=[CH:13][CH:12]=[C:11]([S:18]([NH:24][C:27]3[CH:28]=[CH:4][C:9]([CH3:10])=[CH:8][CH:7]=3)(=[O:20])=[O:19])[C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:2]
Reactant: COc1ccc(S(=O)(=O)Cl)c2c3ccccc3n(C=O)c12
Reactant: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(=O)(=O)Nc2ccc(C)cc2)c2c3ccccc3n(C=O)c12
Yield: 75 %

Procedure:
Intermediate 63 (0.2 g, 0.62 mM) was dissolved in 50 ml of chloroform. To it was added p-toludine (0.165 g, 1.54 mM) and 0.16 g triethylamine. The reaction was refluxed for 15 hrs. Solvent was evaporated and the residue was taken up in ethyl acetate. The organic layer was washed with 10% HCl solution, brine and then dried over anh Na2SO4. It was then evaporated to obtain the crude residue which was then purified over silica gel column using ethylacetate-hexane system to obtain the desired compound as beige solid with a yield of 75% (0.18 g); mp 193-199° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[N:5]([CH3:13])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:30].[CH2:31]([O:33][C:34]([CH2:36][N:37]1[CH2:43][C:42]2[CH:44]=[C:45](/[CH:48]=[CH:49]/[C:50]([OH:52])=O)[CH:46]=[N:47][C:41]=2[NH:40][C:39](=[O:53])[CH2:38]1)=[O:35])[CH3:32].Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[ClH:30].[CH2:31]([O:33][C:34](=[O:35])[CH2:36][N:37]1[CH2:43][C:42]2[CH:44]=[C:45](/[CH:48]=[CH:49]/[C:50](=[O:52])[N:2]([CH3:1])[CH2:3][C:4]3[N:5]([CH3:13])[C:6]4[C:11]([CH:12]=3)=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:46]=[N:47][C:41]=2[NH:40][C:39](=[O:53])[CH2:38]1)[CH3:32]
Reactant: CCOC(=O)CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Reactant: CNCc1cc2ccccc2n1C
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: CCOC(=O)CN1CC(=O)Nc2ncc(/C=C/C(=O)N(C)Cc3cc4ccccc4n3C)cc2C1
Yield: 56 %

Procedure:
According to the procedure of Example 1, except substituting methyl-(1-methyl-1H-indol-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-(4-ethoxycarbonylmethyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.22 g, 56%) was prepared as a yellow powder and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.53-10.54 (m, 1H), 8.56-8.59 (m, 1H), 8.09-8.16 (m, 1H), 7.28-7.61 (m, 4H), 7.10-7.15 (m, 1H), 6.99-7.04 (m, 1H), 6.19-6.42 (m, 1H), 4.86-5.06 (m, 2H), 4.00-4.14 (m, 5H), 3.62-3.72 (m, 7H), 2.99-3.12 (m, 3H), 1.12-1.20 (m, 3H); MS (ESI) m/e 476 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[CH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1)#[N:2].[NH:20]1[C:28]2[C:23](=[C:24]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH3:12][N:8]1[C:9]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[C:6]([CH:13]2[CH2:18][CH2:17][CH:16]([N:32]3[CH2:33][CH2:34][N:29]([C:24]4[C:23]5[CH:22]=[CH:21][NH:20][C:28]=5[CH:27]=[CH:26][CH:25]=4)[CH2:30][CH2:31]3)[CH2:15][CH2:14]2)=[CH:7]1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Reactant: Cn1cc(C2CCC(=O)CC2)c2cc(C#N)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cn1cc(C2CCC(N3CCN(c4cccc5[nH]ccc45)CC3)CC2)c2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
A solution of 4-(5-cyano-1-methyl-3-indolyl)-cyclohexanone (0.75 g, 3 mmol), 1-(indol-4-yl)piperazine (0.6 g, 3 mmol), sodium triacetoxyborohydride (0.95 g, 4.5 mmol) and acetic acid (0.34 ml, 6 mmol) in 1,2-dichloroethane (20 ml) was allowed to stir at room temperature overnight. The reaction was quenched with 1N sodium hydroxide (10 ml), extracted with methylene chloride (3×60 ml) and washed with brine (3×60 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (10% methanol-ethyl acetate) afforded 0.73 g (56%) of product as a white solid: mp 274-275° C.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)=[O:13].C(=O)([O-])O.[Na+].C1(C)C=CC=CC=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.O.O1CCCC1>[CH3:10][O:11][C:12]([C:14]1[CH:19]=[C:18]([C:2]2[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: COC(=O)c1cccc(B(O)O)c1
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: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(-c2ccc(C(=O)O)o2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To 5-bromofuran-2-carboxylic acid (0.50 g, 2.6 mmol), 3-methoxycarbonylphenylboronic acid (0.52 g, 2.9 mmol), tetrakis(triphenylphosphine)palladium (45 mg, 0.039 mmol), and sodium hydrogen carbonate (0.49 g, 5.9 mmol) were added toluene (3.5 mL), tetrahydrofuran (3.0 ml) and water (3.5 mL), and the mixture was stirred at 90° C. for 2 hours. Water was added to the reaction mixture, and the mixture was washed with ethyl acetate. The aqueous layer was acidified with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as a pale-yellow powder (0.58 g, 2.3 mmol, 91%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].C(N(CC)CC)C.[CH2:23]([OH:26])[CH2:24][OH:25].[Br:27][C:28]([CH3:33])([CH3:32])[C:29](Br)=[O:30]>C1COCC1>[Br:27][C:28]([CH3:33])([CH3:32])[C:29]([O:25][CH2:24][CH2:23][O:26][C:7](=[O:8])[C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=1)=[O:30]
Reactant: CC(C)(Br)C(=O)Br
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: OCCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(Br)C(=O)OCCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 58.5 %

Procedure:
To a solution of 3,5-dinitrobenzoyl chloride (10 g, 0.043 mol) in 80 ml anhydrous THF was added triethylamine (4.83 g, 0.048 mol) followed by anhydrous ethylene glycol (24 ml, 0.43 mol). After 1 h, the solution was quenched with 200 ml water and extracted into ethyl acetate (3×150 ml). The organics were washed with 100 ml each 10% KOH, water, 1M HCl, brine, dried over magnesium sulfate and concentrated to 8.8 g. To this material, dissolved in 50 ml anhydrous THF and cooled in an ice bath, was added triethylamine (3.83 g, 0.038 mol) and then bromoisobutyryl bromide (8.70 g, 0.038 mol). After 0.5 h, the solution was quenched with 100 ml water and extracted into ethyl acetate (3×100 ml). The organics were washed with 100 ml each 10% KOH, water, 1M HCl, brine, dried over magnesium sulfate and concentrated. Purification by column chromatography yielded 9 gm of product, 96% pure by HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([CH3:17])[NH:14][C:13](=O)[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:13]1[CH:12]=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:16]=[C:15]([CH3:17])[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2cc(=O)[nH]c(C)n2)cc1OC
Product: COc1ccc(-c2cc(Cl)nc(C)n2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 3,4-dihydro-6-(3,4-dimethoxyphenyl)-2-methylpyrimidin-4-one (2.4 g) in phosphorus oxychloride (20 ml) was refluxed for 2 hours, and evaporated. To the residue were added aqueous sodium bicarbonate solution and chloroform, and stirred at ambient temperature for 2 hours. The organic layer was obtained and washed with water. After evaporated, the residue was dissolved in ethyl acetate-diisopropyl ether mixture (1:6 v/v). The precipitates were filtered off, and the filtrate was evaporated to give 4-chloro-6-(3,4-dimethoxyphenyl)-2-methylpyrimidine (2.09 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[OH:14].[C:15]([O-])([O-])=O.[Cs+].[Cs+].[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1CBr.CCOCC>CC(C)=O>[O:21]1[CH:25]=[CH:24][C:23]([CH2:15][O:14][C:3]2[CH:4]=[C:5]([NH:8][C:9]3[S:10][CH:11]=[CH:12][N:13]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:22]1
Reactant: Cc1ccc(Nc2nccs2)cc1O
Reactant: O=C([O-])[O-]
Reactant: BrCc1ccco1
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: Cc1ccc(Nc2nccs2)cc1OCc1ccoc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54 %

Procedure:
Following the general procedure for O-alkylation, Method B, a mixture of 2-methyl-5-(thiazol-2-ylamino)phenol (100 mg, 0.48 mmol) and Cs2CO3 (0.48 mmol) in acetone (4.4 mL) was treated with a freshly prepeared solution of 2-furylbromomethane in ether (0.53 mmol) at 0°. After 30 min the reaction was heated to RT. After 4 h, another 2-furylbromomethane (35 mg) were added and stirred for another 1.5 h. Reaction control by TLC showed full conversion after 6 h 40 min. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 3/1) in 54% yield (75 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:10][C:11]([N:13]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:14])=[O:12])N)=[CH:4][CH:3]=1.CO[CH:22](OC)[CH2:23][CH2:24][CH2:25][NH:26][CH3:27]>>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:8]([CH2:10][C:11]([N:13]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:14])=[O:12])[CH:22]=[C:23]2[CH2:24][CH2:25][NH:26][CH3:27]
Reactant: CNCCCC(OC)OC
Reactant: CC(C)CCN(C)C(=O)CN(N)c1ccc(Cl)cc1
Product: CNCCc1cn(CC(=O)N(C)CCC(C)C)c2ccc(Cl)cc12

Procedure:
The title compound is prepared by General Method 10 using 2-(1-(4-chlorophenyl)hydrazinyl)-N-isopentyl-N-methylacetamide (Example 7) and 4,4-dimethoxy-N-methylbutan-1-amine.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[CH2:7][NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][NH:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+].O(OC(C(C)(C)C)=O)[O:28][C:29](C(C)(C)C)=O.[C:42]([OH:46])([CH3:45])([CH3:44])[CH3:43]>>[C:42]([O:46][C:29]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:9]([NH:8][CH2:7][C:6]2[CH:21]=[CH:22][CH:23]=[CH:24][C:5]=2[O:4][CH3:3])[C@@H:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:28])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)O
Reactant: COc1ccccc1CN[C@H]1CCCN[C@H]1c1ccccc1
Reactant: CC(C)(C)C(=O)OOOC(=O)C(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccccc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
To a stirred and ice-cooled mixture of Compound 3 (10.0 g, 27.1 mmol), 3.0 M NaOH aq. (36.1 ml, 108.4 mmol) and tert-BuOH (15.0 ml) was added (tert-BuOCO)2O (Boc2O, 7.39 g, 33.8 mmol). After stirring at room temperature overnight, the mixture was extracted with AcOEt (×3). The combined AcOEt extracts were washed with sat. NaHCO3 and brine, dried over Na2SO4, and concentrated to give Compound 4 (11.3 g, quant.) as a pale yellow syrup.
Reaction SMILES: [Na].[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:22])[NH:20][OH:21])[CH:9]=[CH:10]2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl[CH2:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31]>>[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:22])[NH:20][O:21][CH2:29][C:30](=[O:31])[N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[CH:9]=[CH:10]2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: O=C(CCl)N1CCCC1
Reactant: CCOC(=O)c1c2ccc(CC(=O)NO)ccc-2c(C(=O)OCC)c1N
Agent: [Na]
Product: CCOC(=O)c1c2ccc(CC(=O)NOCC(=O)N3CCCC3)ccc-2c(C(=O)OCC)c1N
Yield: 24 %

Procedure:
In an analogous manner to that described in Example 1, from diethyl 2-amino-6-[(hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate sodium and N-chloroacetyl-pyrrolidine the title compound of m.p. 168-170° C. is obtained in 24% yield.
Reaction SMILES: [CH3:1][C:2]([CH3:10])=[CH:3][CH2:4][CH2:5][C:6]([CH:8]=[CH2:9])=[CH2:7].[C:11]1([SiH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1([SiH](CC(=CC)CCC=C(C)C)C2C=CC=CC=2)C=CC=CC=1>>[C:18]1([SiH:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:9][CH:8]=[C:6]([CH3:7])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:10])[CH3:1])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C=CC(=C)CCC=C(C)C
Reactant: c1ccc([SiH2]c2ccccc2)cc1
Agent: CC=C(CCC=C(C)C)C[SiH](c1ccccc1)c1ccccc1
Product: CC(C)=CCCC(C)=CC[SiH](c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 95 %

Procedure:
A mixture of 0.170 ml (1.0 mmol) of myrcene, 0.186 ml (1.2 mmol) of diphenylsilane, and 6.0 mg (0.01 mmol) of tetraethylammonium μ-hydridebis(pentacarbonylmolybdenum) was heated in a sealed tube at 100° C. for 24 hours while being stirred. GLC analysis of the reaction mixture revealed that 6-(diphenylsilyl)methyl-2-methyl-2,6-octadiene and 8-diphenylsilyl-2,6-dimethyl-2,6-octadiene were produced at a ratio of about 75:25 in a total yield of 95%. 6-(Diphenylsilyl)methyl-2-methyl-2,6-octadiene:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:2]1.C(N(CC)CC)C.Cl[C:22](OC1C=CC=CC=1)=[O:23].[Br:31][C:32]1[CH:37]=[C:36]([NH2:38])[N:35]=[C:34]([NH2:39])[CH:33]=1>C(#N)C>[NH2:38][C:36]1[N:35]=[C:34]([NH:39][C:22]([NH:13][S:10]([C:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[O:1][CH:2]=2)(=[O:12])=[O:11])=[O:23])[CH:33]=[C:32]([Br:31])[CH:37]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NS(=O)(=O)c1coc2ccccc12
Reactant: Nc1cc(Br)cc(N)n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1cc(Br)cc(NC(=O)NS(=O)(=O)c2coc3ccccc23)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 14.1 %

Procedure:
The below prepared benzofuran-3-sulfonic acid amide (0.051 g, 0.259 mmol) was dissolved in 1.5 mL of abs. acetonitrile and treated successively with triethylamine (0.090 mL, 2.5 eq.) and phenyl chloroformate (0.0405 g, 1.0 eq.), and the mixture was then kept at ambient temperature for 1 h. 4-Bromo-pyridine-2,6-diamine (0.0486 g, 1.0 eq.), dissolved in a tiny amount of acetonitrile, was added, and the mixture heated to 60° C. for 18 h. Cooling, pouring onto crashed ice, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=3/7) and crystallization from AcOEt/heptane, yielded finally 0.015 g of the title compound as off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[CH:3]=1.[CH3:9][C:10](C)([O-:12])[CH3:11].[K+]>CC(O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:12][CH:10]([CH3:11])[CH3:9])[CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: Fc1cc(Br)ccn1
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)Oc1cc(Br)ccn1
Temperature: 80 °C

Procedure:
To the stirred solution of 4-bromo-2-fluoro-pyridine 17BV (4.12 g, 23.41 mmole) in 50 mL anhydrous IPA in a 150 mL pressure vessel was added 2.627 g (23.41 mmole) of solid potassium tert-butoxide under dry N2 gas. The pressure vessel was tightly sealed and heated at 80° C. for 3 hours. The pressure vessel was cooled to 0° C. in ice-bath before opening. The contents of the pressure vessel were transferred to 250 mL RBF and concentrated to a small volume. The resulting mixture was partitioned between EtOAc and H2O. The organic phase was separated, washed with saturated NaCl solution and dried over MgSO4. The solvent was evaporated and resulting clear oil was purified on RediSep 80 g cartridge eluting with 20:1 Hexanes/EtOAc to give clear oil 18BV (4.2 g, 83%).
Reaction SMILES: [N:1]1C=CC=N[CH:2]=1.Cl[C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=1>CN(C=O)C.CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N>[CH3:14][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([C:2]#[N:1])[N:13]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: c1cncnc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccnc(C#N)n1
Temperature: 110 °C
Yield: 67 %

Procedure:
2-chloro-4-methylpyrimidine pyrimidine (725 mg, 5.62 mmol) was combined with zinc cyanide (396 mg, 3.37 mmol) and tetrakis (triphenylphosphne)palladium (0) (716 mg, 0.562 mmol) in DMF (10 mL) and the slurry was heated at 110° C. under nitrogen for 0.5 h. The mixture was cooled to rt, diluted with EtOAc (70 mL) and washed twice with 2N ammonium hydroxide (50 mL). The EtOAc solution was washed with brine (20 mL) and concentrated in vacuo to provide the crude mixture. The crude was then purified by column chromatography (30% EtOAc in hexanes) to afford 4-methylpyrimidine-2-carbonitrile in 67% yield.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:14])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=[CH:25][C:24]=1[N+:33]([O-:35])=[O:34]>ClCCl>[OH:14][C:3]1([CH2:2][NH:1][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=[CH:25][C:24]=2[N+:33]([O-:35])=[O:34])[CH2:4][CH2:5][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:8]1
Reactant: CCOC(=O)N1CCC(O)(CN)CC1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(O)(CNc2c([N+](=O)[O-])cnc3ccccc23)CC1
Reaction time: 18 h
Yield: 68 %

Procedure:
To a solution of ethyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate (22.4 mmol, prepared as described above) in dichloromethane (90 mL) was added triethylamine (3.12 mL, 22.4 mmol) and 4-chloro-3-nitroquinoline (3.71 g, 17.8 mmol). The mixture was sonicated and more dichloromethane (10 mL) was added in order to dissolve the 4-chloro-3-nitroquinoline. The solution was allowed to stand at rt for 18 h, then was poured into a separatory funnel and washed with 1 M NaOH (25 mL), water (2×30 mL), and brine (30 mL). The organic layer was dried over MgSO4, filtered, and concentrated to yield a yellow foam that was crystallized from isopropanol. The solid was isolated by filtration and dried to afford ethyl 4-hydroxy-4-{[(3-nitroquinolin-4-yl)amino]methyl}piperidine-1-carboxylate as yellow crystals (4.53 g, 54%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18]C(CC#N)=C[C:15]=2[O:23][CH3:24])=[C:4]([CH3:25])[N:3]=1.[OH-:26].[K+].[CH2:28]([OH:32])[CH2:29][CH2:30][CH3:31]>>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:30]([CH2:29][C:28]([OH:26])=[O:32])=[CH:31][C:15]=2[O:23][CH3:24])=[C:4]([CH3:25])[N:3]=1
Reactant: [OH-]
Reactant: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1OC
Reactant: CCCCO
Agent: [K+]
Product: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1OC
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
The product from step (v) (2.1 g) was dissolved in butan-1-ol (20 mL) and aq. 5M KOH (3.71 ml) was added and the mixture was heated at 100° C. for 36 h. The mixture was allowed to cool and the solvent was evaporated under reduced pressure. The residue was diluted with water (5 mL) and the pH adjusted to ˜7 using conc HCl. The resulting precipitate was collected by filtration and the solid was then suspended in MeCN (10 mL) for 10 min. The suspension was filtered and the solid dried under vacuum overnight to give the subtitle compound as a white solid, 2.60 g.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:41][CH2:42][CH2:43][O:44][C:45]([CH3:66])([CH3:65])[CH2:46][N:47]1[C:59]2[C:58]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=3[N:52]=[C:51]([NH2:60])[C:50]=2[N:49]=[C:48]1[CH2:61][O:62][CH2:63][CH3:64]>CN(C=O)C>[NH2:60][C:51]1[C:50]2[N:49]=[C:48]([CH2:61][O:62][CH2:63][CH3:64])[N:47]([CH2:46][C:45]([CH3:66])([O:44][CH2:43][CH2:42][NH:41][C:1](=[O:9])[C:2]3[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=3)[CH3:65])[C:59]=2[C:58]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[N:52]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCN
Reactant: O=C(O)c1cccnc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCNC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Nicotinic acid (11.4 mg, 92.3 μmol) was combined with DMF (1.0 mL) to give a colorless solution. To this solution was added TBTU (29.6 mg, 92.3 μmol), and DIEA (54.2 mg, 71.8 μl) were added. Finally 1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (30 mg, 83.9 μmol) was added and the reaction mixture was stirred for 1 hour at room temperature. Volatiles were removed in high vacuum at 40° C. The residue was dissolve in a mixture of ethyl acetate (5 mL) and methanol (0.5 mL). 1N sodium hydroxide solution (1.5 mL) was added and after a few minutes stirring the layers were separated. The aqueous layer was extracted with ethyl acetate. The organic phases were combined dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel-NH2, 0% to 10% methanol in DCM) to give the title product (33 mg, 85%) as white foam; LC-MS (UV peak area, ESI) 88%, 463.2459 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]=2)=[CH:8][C:7]=1[CH3:25])=[O:4].[C-:26]#[N:27].[Na+]>CS(C)=O>[C:26]([CH2:2][C:3]([O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]=2)=[CH:8][C:7]=1[CH3:25])=[O:4])#[N:27]
Reactant: [C-]#N
Reactant: Cc1cc(Nc2ccn(-c3ccccc3)n2)cc(C)c1OC(=O)CCl
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(Nc2ccn(-c3ccccc3)n2)cc(C)c1OC(=O)CC#N

Procedure:
2,6-Dimethyl-4-(1-phenyl-1H-pyrazol-3-yl)aminophenyl chloroacetate, Example 4k, (1 g) and sodium cyanide (0.5 g) stirred in dimethyl sulfoxide for 16 hours gave, after dilution with brine, extraction with ethyl acetate and subsequent evaporation, the title compound (0.3 g), mp 116°-117° (from ethyl acetate/hexane).