Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(Cl)Cl.C(O)C.[NH3:8].[CH3:9][C@H:10]([NH2:35])[CH:11]1[O:16][C@@H:15]([O:17][C@H:18]2[C@H:23]([OH:24])[C@H:22]([N:25](C(CN)=O)[CH3:26])[C@@H:21]([O:31][CH3:32])[C@@H:20]([OH:33])[C@@H:19]2[NH2:34])[CH2:14][CH2:13][CH2:12]1>CC(C)=O>[CH3:9][C@H:10]([NH2:35])[C:11]1[O:16][C@H:15]([O:17][C@H:18]2[C@H:23]([OH:24])[C@H:22]([NH:25][CH3:26])[C@@H:21]([O:31][CH3:32])[C@@H:20]([OH:33])[C@@H:19]2[NH2:34])[C@H:14]([NH2:8])[CH2:13][CH:12]=1
Reactant: CO[C@H]1[C@@H](O)[C@H](N)[C@@H](O[C@H]2CCCC([C@H](C)N)O2)[C@H](O)[C@@H]1N(C)C(=O)CN
Reactant: N
Solvent: CCO
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CN[C@H]1[C@@H](O)[C@H](O[C@H]2OC([C@H](C)N)=CC[C@H]2N)[C@@H](N)[C@H](O)[C@@H]1OC

Procedure:
The crude powders are then subjected to silica gel column chromatography using a mixed solvent of chloroform, ethanol, aqueous ammonia and acetone (2:2:1:2, by volume) as a developer. The crude powder containing Fortimicin factors B, KE and KG is suspended in the solvent and introduced into the column. Development is carried out with the same solvent at a flow rate of about 30 ml/hour. First, Fortimicin B and Fortimicin KE are eluted and then Fortimicin KG is eluted. The active fractions containing Fortimicin KG are collected and concentrated under reduced pressure. The concentrate is freeze-dried to obtain the free base of Fortimicin KG.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]/[C:10](=[C:18]2\[C:19](=[O:30])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)/[C:11]2[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[C:31]([O:35][CH3:36])(=[O:34])[CH:32]=[CH2:33].C(N(CC)CC)C>C(#N)C.CC(O)=O.CC(O)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]/[C:10](=[C:18]2\[C:19](=[O:30])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)/[C:11]2[CH:16]=[CH:15][C:14](/[CH:33]=[CH:32]/[C:31]([O:35][CH3:36])=[O:34])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccc(I)cc2)cc1
Reactant: C=CC(=O)OC
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CC#N
Product: COC(=O)/C=C/c1ccc(/C(Nc2ccc(OC)cc2)=C2/C(=O)Nc3ccc([N+](=O)[O-])cc32)cc1

Procedure:
257 mg (0.5 mmol) of (Z)-3-[1-(4-methoxyphenylamino)-1-(4-iodophenyl)-methylidene]-5-nitro-2-indolinone (Example 434), 0.06 ml (0.75 mmol) of methyl acrylate, 4.5 mg (0.02 mmol) of palladium-II-acetate and 1 ml of (7.2 mmol) of triethylamine are dissolved in 20 ml of acetonitrile under a nitrogen atmosphere. The solution is heated for 10 hours to 80° C. Then the reaction solution is filtered through Celite and the solvent is eliminated in vacuo. The residue is chromatographed on silica gel (dichloromethane/methanol=20:1).
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:10]Cl.Cl[C:13]([CH3:21])([CH2:15][C:16](Cl)(C)[CH2:17][CH3:18])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH3:8][C:1]1[C:6]([OH:7])=[CH:5][C:4]2[C:13]([CH3:14])([CH3:21])[CH2:15][CH2:16][C:17]([CH3:18])([CH3:10])[C:3]=2[CH:2]=1
Reactant: ClCCl
Reactant: CCC(C)(Cl)CC(C)(C)Cl
Reactant: Cc1ccccc1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: Cc1cc2c(cc1O)C(C)(C)CCC2(C)C
Temperature: 5 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
Into a round bottom flask there are introduced 10.8 g (100 mmoles) of ortho cresol, 100 ml of dichloromethane (CH2Cl2) and 18.3 g (100 mmoles) of 2,4-dichloro-2,4-dimethylhexane. The reaction mixture is cooled to 5° C. and there are added, in small quantities, 6.6 g (50 mmoles) of aluminum chloride. The temperature is permitted to rise to 20° C. The reaction mixture is stirred for 2 hours and it is then poured into 200 ml of water. The organic phase is decanted, dried on magnesium sulfate (MgSO4) and the solvents are evaporated. The residue is recrystallized in 100 ml of hexane, yielding 20.3 g (93%) of 3-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol which melts at 122°-123° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])/[C:12](=[CH:15]\[C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)/[N:11]([CH3:24])[C:10]2=[O:25])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:26]1N2CN3CN(C2)[CH2:28][N:27]1[CH2:34]3.C(NCC(O)=O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1(C)C=CC=CC=1>CN1CCCC1=O>[CH2:26]([N:27]1[CH2:34][C@@H:15]([C:16]2[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=2)[C@:12]2([N:11]([CH3:24])[C:10](=[O:25])[N:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:13]2=[O:14])[CH2:28]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(O)CNCc1ccccc1
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)/C1=C\c1ccc(C#N)cc1
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(Cc1ccccc1)C[C@H]2c1ccc(C#N)cc1
Temperature: 140 °C
Reaction time: 72 h

Procedure:
A mixture of (E)-4-((1-(3,5-dichlorophenyl)-3-methyl-2,5-dioxoimidazolidin-4-ylidene)methyl)benzonitrile (1.05 g, 2.82 mmol), hexamethylenetetramine (0.395 g, 2.82 mmol), N-benzylglycine (1.17 g, 7.05 mmol), toluene (5 ml), and 1-methyl-2-pyrrolidinone (NMP, 10 ml) was heated to 140° C. The extent of reaction was monitored by HPLC. After 72 hours, the reaction had stopped short of completion. The ratio of product to starting material ((E)-4-((1-(3,5-dichlorophenyl)-3-methyl-2,5-dioxoimidazolidin-4-ylidene)methyl)benzonitrile) was 1.36:1. Mass spectra of the mixture indicated the presence of the desired product. The mixture was washed with water and extracted into toluene. The impure product was obtained as an oil. Comparison of the product obtained to authentic material was made by HPLC. The ratio of the desired (5S, 9R) isomer to the undesired was 19:1.
Reaction SMILES: [N+:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([O-])=O.[C:11](O)(=O)C.[N:15]([O-:17])=[O:16].[Na+]>O>[N+:15]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]2[C:6]=1[CH:11]=[N:1][NH:4]2)([O-:17])=[O:16]
Reactant: CC(=O)O
Reactant: O=N[O-]
Reactant: O=[N+]([O-])Nc1ccccc1
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cccc2[nH]ncc12
Temperature: 14 °C
Reaction time: 0.08 h

Procedure:
Alternatively, to a 4-necked 5-L jacketed round bottom flask fitted with a mechanical stirrer and a thermocouple was charged the nitroaniline (100 g, 1.0 equiv.) and acetic acid (2000 mL). The solution was cooled to 14° C. A chilled to about 1° C. (ice-water bath) solution of sodium nitrite (100 g, 2.2 equiv.) in water (250 mL) was added quickly in one portion. The internal temperature rose from 14° C. to 27.6° C. over 5 min., stayed at this temperature for 5 min. before gradually cooling to 15° C. The mixture was stirred for 24 h after which it was concentrated in vacuo to an approximate volume of 500 mL. The residue was re-slurried in water (1800 mL) at ambient temperature for 21 hours. The orange solid was filtered, washed with water (3×250 mL), and dried in a vacuum oven at 70° C. to afford 97.0 g of the title compound as a bright orange solid.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=1>>[Cl:1][S:2]([C:13]1[CH:12]=[C:11]([CH2:14][C:15](=[O:17])[CH3:16])[CH:10]=[CH:9][C:8]=1[O:7][CH3:6])(=[O:5])=[O:3]
Reactant: COc1ccc(CC(C)=O)cc1
Reactant: O=S(=O)(O)Cl
Product: COc1ccc(CC(C)=O)cc1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
To 250 g of chlorosulfonic acid was added dropwise 50 g of 4-methoxyphenylacetone at 0°-5° C. After stirring the mixture for 4 hours at room temperature, the reaction mixture was poured into 2,500 ml of ice water and extracted thrice with 500 ml of ethyl acetate. The extract was washed with water and after drying the extract with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The crude crystals obtained were recrystallized from benzeneether to provide 32 g of 3-chlorosulfonyl-4-methoxyphenylacetone.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[N:11]3[C:12](=[N:17][C:18]([CH3:19])=[C:10]3[C:9]1=[O:20])[CH:13]=[CH:14][CH:15]=2.C(N(CC)CC)C.[F:28][C:29]([F:36])([F:35])[CH2:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:19][C:18]1[N:17]=[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[N:11]2[C:10]=1[C:9](=[O:20])[N:8]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:31]([CH2:30][C:29]([F:36])([F:35])[F:28])(=[O:33])=[O:32]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: Cc1nc2cccc3n(CCCCCCN)c(=O)c1n23
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2cccc3n(CCCCCCNS(=O)(=O)CC(F)(F)F)c(=O)c1n23
Yield: 77.3 %

Procedure:
To a solution of 676 mg (2.48 mmol) of 1-[6-(amino)hexyl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one and 0.52 ml (3.73 mmol) of triethylamine in 30 ml of methylene chloride was added, while stirring under ice-cooling, 0.55 g (3.01 mmol) of 2,2,2-trifluoroethanesulfonylchloride, and the mixture was stirred for 30 minutes at the same temperature range. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to give 802 mg of the desired compound (77.2%, pale brown solid).
Reaction SMILES: [C:1](=[O:21])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[CH:5]=1.C(N(C(C)C)C(C)C)C.Cl.[NH2:32][CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>C(Cl)Cl>[Br:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[CH2:3][O:2][C:1]([NH:32][CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:21]
Reactant: O=C(OCc1cccc(Br)c1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)CCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCNC(=O)OCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To a solution of 3-bromobenzyl 4-nitrophenyl carbonate (8 g, 21.58 mmol) in DCM (50 mL) was added N-ethyl-N-isopropylpropan-2-amine (7.47 mL, 43.2 mmol) and tert-butyl 3-aminopropanoate hydrochloride (3.92 g, 21.58 mmol). Upon the completion of addition, the reaction mixture was stirred at room temperature for 1 h and then quenched with water. The resulting mixture was extracted with CH2Cl2 and the combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was purified by flash chromatography (0-50% ethyl acetate:hexanes) to afford the title compound (7.10 g, 89% yield) as a light brown oil. LCMS, [M-tBu+2H]+=302.1. 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.44 (d, J=7.7 Hz, 1H), 7.29-7.19 (m, 2H), 5.31 (br. s, 1H), 5.06 (s, 2H), 3.43 (dd, J=12.1, 6.1 Hz, 2H), 2.46 (t, J=6.0 Hz, 2H), 1.45 (s, 9H).
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:23][C:24]#[C:25][C:26]1[N:30]=[CH:29][N:28]([C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:27]=1.C(N(CC)CC)C>ClCCl>[Br:1][CH2:23][C:24]#[C:25][C:26]1[N:30]=[CH:29][N:28]([C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:27]=1
Reactant: OCC#Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: BrCC#Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C

Procedure:
A solution of bromine (1.72 ml) in dry dichloromethane (10 ml) was added dropwise to a stirred, cooled (-5° C.), solution of triphenylphosphine (8.74 g) in dry dichloromethane (140 ml) whilst maintaining the temperature below 0° C. The solution was stirred for a further ten minutes at 0° C., then treated dropwise over one hour with a solution of the above alcohol (12.17 g) and triethylamine (4.64 ml) in dry dichloromethane (200 ml). After ten minutes, the mixture was evaporated under reduced pressure and the residue chromatographed on silica, using dichloromethane-ether (25:2) as eluant, to give 1-bromo-3(1-trityl-1,2,4-triazol-3-yl)prop-2-yne (8.10 g, m.p. 181-183° C. dec). NMR (CDCl3): δ 4.1(2H,s), 7.05-7.35(15H,m), 7.95(1H,s). M/S: M+ 427,429.
Reaction SMILES: [P:1]([O-:8])([O:5]CC)[O:2]CC.O.[CH2:10]([NH2:28])[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][CH2:24][CH2:25][CH2:26][CH3:27]>C(O)C>[CH2:10]([P:1](=[O:2])([O-:5])[O-:8])[CH3:11].[CH2:10]([NH3+:28])[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][CH2:24][CH2:25][CH2:26][CH3:27].[CH2:10]([NH3+:28])[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][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCOP([O-])OCC
Reactant: CCCCCCCCCCCCCCCCCCN
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCC[NH3+]
Product: CCP(=O)([O-])[O-]
Yield: 93.2 %

Procedure:
To a mixture of 34.6 g. (0.25 moles) of diethyl phosphite, 50 ml. of water and 50 ml. of ethanol a mixture of 67.4 g. (0.25 moles) of octadecyl amine and 70 ml. of ethanol is added. The reaction mixture is refluxed for 4 hours, whereupon the solvent is distilled off in vacuo. 88.5 g. (93.2%) of octadecyl-ammoniumethyl phosphonate are obtained, melting at 54° to 56° C.
Reaction SMILES: [OH:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]=1[C:17]([NH:19][CH2:20][C:21]([O:23]CC)=[O:22])=[O:18].CI.[C:28](=O)([O-])[O-].[Na+].[Na+].Cl>CN(C)C=O>[OH:1][C:2]1[N:7]([CH3:28])[C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]=1[C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CNC(=O)c1c(O)[nH]c(=O)n(Cc2ccccc2)c1=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(O)c(C(=O)NCC(=O)O)c(=O)n(Cc2ccccc2)c1=O
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 28.2 %

Procedure:
A mixture of ethyl N-{[6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycinate (295 mg, 0.85 mmoles), methyl iodide (62 uL, 1.0 mmoles) and sodium carbonate (320 mg, 3.0 mmoles) in dimethylformamide (5.0 mL) was stirred under argon at 100° C. for 2.5 hours. The mixture was cooled, poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The ester was hydrolysed by stirring in a mixture of ethanol (5 mL) and 1 molar sodium hydroxide solution (4 mL) for 4 hours. The mixture was acidified and extracted with ethyl acetate. Purification by preparative HPLC (acetonitrile-water—0.1% TFA, 20-100%) and crystallization from ether-hexane gave the title compound (80 mg, 28%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.11 (br. s., 1 H), 10.09 (br. s., 1 H), 7.28-7.36 (m, 4 H), 7.19-7.29 (m, 1 H), 5.01 (s, 2 H), 4.14 (d, J=5.81 Hz, 2 H), 3.21 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11]Br.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N:24]1[C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]2[C:20]1=[O:30]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCBr)c(Cl)c1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
A reaction vessel was charged with 4.09 g of 3,5-dichloro-4-(3-bromopropyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene, 2.41 of potassium phthalimide and 30 ml of N,N-dimethylformamide. After stirring at room temperature for 24 hours, the reaction mixture was poured into water and extracted twice with 150 ml of chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and diluted aqueous sodium hydroxide, dried over anhydrous magnesium sulfate, and then concentrated, which afforded 4.67 g of crude 3,5-dichloro-4-(3-phthalimidopropyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (98% yield).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:30]1[C:33]2([CH2:36][NH:35][CH2:34]2)[CH2:32][N:31]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([N:35]5[CH2:34][C:33]6([CH2:30][N:31]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH2:32]6)[CH2:36]5)=[O:22])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CC2(CNC2)C1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5(CN(C(=O)OC(C)(C)C)C5)C4)cn3)nc2n1C1CCCC1
Yield: 74 %

Procedure:
Following amide formation method 1, 6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (199 mg, 0.5 mmol, 1.0 eq) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (100 mg, 0.5 mmol, 1.0 eq) were combined and gave tert-butyl 6-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate as a white solid (214 mg, 0.37 mmol) in 74% yield. 1H NMR (400 MHz, chloroform-d) δ ppm 8.79 (s, 1H) 8.53-8.66 (m, 2H) 8.08 (dd, J=8.84, 2.27 Hz, 1H) 6.53 (s, 1H) 4.74-4.92 (m, 1H) 4.20-4.61 (m, 4H) 4.07-4.16 (m, 4H) 3.18 (br s, 6H) 2.47-2.65 (m, 2H) 2.03-2.20 (m, 4H) 1.68-1.85 (m, 3H) 1.46 (s, 9H). MS (m/z, MH+): 575.6
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:2].C(=O)(O)[O-].[Na+].[CH2:21](I)[CH3:22].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[C:11]([C:12]([O:14][CH2:21][CH3:22])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)Cc1ncccc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ncccc1C(=O)OCC
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a mixture of 54 g (0.26 mole) of 3-carboxy-2-pyridineacetic acid ethyl ester* and 24.4 g (0.29 mole) of sodium bicarbonate in 300 ml of dimethylformamide was added 60.8 g (0.39 mole) of ethyliodide. The mixture was stirred at 50° C. for 24 hr; cooled to 25° C. and treated with 300 ml of water. The aqueous solution was extracted 3 times with isopropyl ether. The isopropyl ether solution was extracted with dilute hydrochloric acid. The acid layer was made basic with sodium hydroxide and extracted with isopropyl ether. The ether layer was dried over anhydrous sodium sulfate, concentrated and the residue was distilled to give 47 g (76%), b.p. 128°-130° C./0.5 mm.
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[N:4]=1.Cl.Cl.[NH2:29][CH2:30][CH2:31][NH:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][N:34]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[C:5]1[N:4]=[C:3]([NH:29][CH2:30][CH2:31][NH:32][C:33]2[N:34]=[CH:35][C:36]([C:37]#[N:38])=[CH:39][CH:40]=2)[N:8]2[N:9]=[C:10]([CH:12]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]3)[N:11]=[C:7]2[CH:6]=1
Reactant: N#Cc1ccc(NCCN)nc1
Reactant: CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(Cl)n3n2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(NCCNc4ccc(C#N)cn4)n3n2)CC1
Temperature: 130 °C

Procedure:
50 mg (0.13 mmol) of 5-chloro-7-(2,4-dichlorophenyl)-2-(1-methylpiperidin-4-yl)[1,2,4]triazolo-[1,5-c]pyrimidine hydrochloride (Example 49A), 30 mg (0.15 mmol) of 6-[(2-aminoethyl)amino]pyridin-3-carbonitrile hydrochloride (Example 2A) and 0.13 ml (0.76 mmol) of N,N-diisopropylethylamine were initially charged in 1.5 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 25 mg (37% of theory) of the product as a solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:12]2[NH:11][CH2:10][C@@H:9]3[CH2:15][C@H:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:17][C:7]=1[C:8]=23>C(Cl)Cl.O=[Mn]=O>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:12]2[NH:11][CH:10]=[C:9]3[CH2:15][C@H:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:17][C:7]=1[C:8]=23
Reactant: CCCN(CCC)[C@@H]1Cc2c(-c3ncco3)ccc3c2[C@H](CN3)C1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCCN(CCC)[C@H]1Cc2c[nH]c3ccc(-c4ncco4)c(c23)C1
Yield: 37.1 %

Procedure:
A solution of 0.65 g (2.0 mmol) of (-)(2aR,4S)-6-(2-oxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole in 30 ml of CH2Cl2 was sonicated (50-55 KHz) in the presence of 2.5 g of MnO2 for 5 hours. The oxidant was removed by filtration through celite. The crude product obtained after filtering and removing the solvent was chromatographed over 15 g of silica gel using 1:9 EtOAc/toluene, then crystallized from isooctane to provide 0.24 g of title compound. mp 73°-74° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH:22]1([O:28][CH2:29][CH2:30]O)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(OCC)(=O)C>ClCCl>[CH:22]1([O:28][CH2:29][CH2:30][O:20][C:19](=[O:21])[CH2:18][O:17][C:14]2[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][N:15]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: OCCOC1CCCCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)OCCOC1CCCCC1
Yield: 51 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 2-cyclohexyloxy-ethanol (37 mg, 0.26 mmol) as the coupling partner. Chromatography (1:1 ethyl acetate:dichloromethane) through SiO2 yielded 36 mg (51%) of the titled compound. ESI-MS m/z 418 (MH30 ), 416 (M−H−).
Reaction SMILES: [NH:1]1[CH:7]([CH2:8][C:9]([OH:11])=O)[C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH:12]([C:15]1[N:19]([CH2:20][C:21]2[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=2)[C:18]2[CH:28]=[CH:29][CH:30]=[CH:31][C:17]=2[N:16]=1)([CH3:14])[CH3:13]>CS(C)=O>[O:3]=[C:2]1[NH:1][CH:7]([CH2:8][C:9]([NH:25][C:24]2[CH:23]=[CH:22][C:21]([CH2:20][N:19]3[C:18]4[CH:28]=[CH:29][CH:30]=[CH:31][C:17]=4[N:16]=[C:15]3[CH:12]([CH3:14])[CH3:13])=[CH:27][CH:26]=2)=[O:11])[C:5](=[O:6])[NH:4]1
Reactant: O=C(O)CC1NC(=O)NC1=O
Reactant: CC(C)c1nc2ccccc2n1Cc1ccc(N)cc1
Solvent: CS(C)=O
Product: CC(C)c1nc2ccccc2n1Cc1ccc(NC(=O)CC2NC(=O)NC2=O)cc1
Yield: 90.4 %

Procedure:
Commercially available (+/−) hydantoin-5-acetic acid (11 mg, 0.07 mmol) and 4-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]aniline (30 mg, 0.06 mmol) were warmed in 1 mL dry DMSO until dissolved and coupled using GENERAL COUPLING METHOD A. Purified on silica gel using 5% MeOH in EtOAc to give 22 mg (89%) of a white solid. MS found: (M+H)+=406.