Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl.[N:32]1([CH2:39][CH2:40][O:41][C:42]2[CH:50]=[CH:49][C:45]([C:46](O)=O)=[CH:44][N:43]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[N:32]1([CH2:39][CH2:40][O:41][C:42]2[N:43]=[CH:44][C:45]([CH2:46][N:3]([CH2:1][CH3:2])[C:4]3[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=3[CH:14]3[CH2:23][CH2:22][C:21]4[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=4[CH2:15]3)=[CH:49][CH:50]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)nc1
Reactant: CCNc1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCCC2)nc1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 64.7 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 6-(2-azepan-1-ylethoxy)nicotinic acid hydrochloride (80 mg) according to an analogous synthetic method to Example 337 described below, the title compound (22 mg) was obtained.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][NH:8][C:7]2=[O:14].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[C:18]=1[CH2:19]Br>CN(C)C=O>[CH3:26][O:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:17]([O:16][CH3:15])[C:18]=1[CH2:19][N:8]1[C:7](=[O:14])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([OH:3])[CH:5]=2)[N:10]=[CH:9]1
Reactant: O=c1[nH]cnc2ccc(O)cc12
Reactant: COc1cccc(OC)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(OC)c1Cn1cnc2ccc(O)cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
76 mg of sodium hydride (80% in mineral oil) are added to a suspension of 400 mg of 6-hydroxy-3H-quinazolin-4-one in 20 ml of dry dimethylformamide. After stirring for 30 minutes at room temperature, 560 mg of 2,6-dimethoxybenzylbromide are added, and stirring is continued overnight. The solvent is distilled off in vacuo, and the residue partitioned between aqueous pH7-buffer solution and ethyl acetate. The organic phase is separated, dried over magnesium sulfate and evaporated in vacuo. Silica gel chromatography yields a minor amount of the N,O-bis-alkylated product followed by the pure title compound as colourless crystals. mp: 243-245°.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Cl:37][C:38]1[C:39]([C:48]([F:51])([F:50])[F:49])=[N:40][N:41]([CH2:44][C:45](O)=[O:46])[C:42]=1[CH3:43]>>[Cl:37][C:38]1[C:39]([C:48]([F:50])([F:49])[F:51])=[N:40][N:41]([CH2:44][C:45]([N:34]2[CH2:35][CH2:36][N:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:32][CH2:33]2)=[O:46])[C:42]=1[CH3:43]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccccc2)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-Phenylpiperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.32 (m 4H), 7.02 (m, 1H), 5.40 (s, 2H), 3.74 (m, 4H), 3.39 (m, 2H), 3.29 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) expect M+H=387.1, found 387.1.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4](S([O-])(=O)=O)=[CH:3][CH:2]=1.[Na+:17].[OH-:18].[Na+]>>[C:11]1([C:1]2[CH:6]=[CH:5][C:4]([O-:18])=[CH:3][CH:2]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+:17]
Reactant: O=S(=O)([O-])c1ccc(-c2ccccc2)cc1
Reactant: [OH-]
Agent: [Na+]
Product: [O-]c1ccc(-c2ccccc2)cc1

Procedure:
Sodium biphenyl-4-sulfonate is reacted with about 70% strength by weight NaOH to give sodium 4-phenylphenolate (about 320° C.; 16-26 bar), with the molar ratio of NaOH to biphenyl-4-sulfonate having to be about 10:1. The reaction mixture is diluted to a content of about 12% by weight of 4-hydroxybiphenyl by direct expansion at 320° C. to a water reservoir or by pumping water into the reaction mixture after prior cooling to 200° C. The resulting alkaline 4-hydroxybiphenyl sodium salt suspension is metered into a water reservoir simultaneously with roughly 50% strength by weight H2SO4 at 90° C. and a pH of 5.5. The resulting aqueous Na2SO3 /NaHSO3 -containing 4-hydroxybiphenyl suspension having a content of about 4.3% by weight of 4-hydroxybiphenyl is then heated at 130°-135° C. and about 2 bar for about 2 h, stirred cold at 10 K/h to 100° C. and then further to 60° C. The highly readily filtering coarsely crystalline product is isolated at 60° C. via a glass sinter vacuum filter and washed with water. A virtually colorless flowable non-thixotropic substantially Na2SO4 -free product having a drastically decreased water content of 10-20% by weight is obtained, in comparison with the highly thixotropic product containing 65-70% by weight of H2O obtained without the heating according to the invention.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][S:15][CH3:16])[C:8]([C:17]([N:19]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@@H:20]2[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23][C@H:22]([C:33]([O:35][CH3:36])=[O:34])[CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:49])C=1>ClCCCl.C(=O)([O-])O.[Na+]>[C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][S:15]([CH3:16])=[O:49])[C:8]([C:17]([N:19]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@@H:20]2[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:23][C@H:22]([C:33]([O:35][CH3:36])=[O:34])[CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2cnc(C(C)(C)C)nc2NCCCSC)CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2cnc(C(C)(C)C)nc2NCCCS(C)=O)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
1-tert-Butyl 3-methyl (3R,5S)-5-{[(2-tert-butyl-4-{[3-(methylsulfanyl)propyl]amino}pyrimidin-5-yl)carbonyl](2-methylpropyl)amino}piperidine-1,3-dicarboxylate (150 mg) was dissolved in 1,2-dichloroethane (3 ml), 3-chloroperbenzoic acid (65% contained, 70 mg) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate-hexane (10:90-85:15) and concentrated under reduced pressure to give the object compound (113 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(N(CC)CC)C.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[S:26](Cl)(=[O:28])=[O:27]>CC(C)=O>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:26]([C:17]1[CH:18]=[CH:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=1)(=[O:28])=[O:27]
Reactant: Nc1ccccc1O
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=S(=O)(Nc1ccccc1O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
A flask with a stirrer was charged with 10.9 g of 2-aminophenol, 10.1 g of triethylamine and 100 ml of acetone, and a solution of 22.7 g of 2-naphthalenesulfonyl chloride in 50 ml of acetone was dropwise added with cooling with ice over 30 minutes. After completion of the addition, the reaction mixture was stirred at room temperature for 2 hours and then poured into 500 ml of ice water. A precipitated crystal was recovered by filtration and washed with water. The obtained crystal was recrystallized from ethyl acetate/n-hexane mixed solvents, to give 15.0 g of an end product. Melting point 136.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([N+:16]([O-:18])=[O:17])=[N:11][CH:12]=[C:13](Br)[N:14]=1.[NH2:19][CH2:20][CH2:21][NH:22][C:23]1[N:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:19][CH2:20][CH2:21][NH:22][C:23]2[N:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[CH:12]=[N:11][C:10]=1[N+:16]([O-:18])=[O:17]
Reactant: N#Cc1ccc(NCCN)nc1
Reactant: O=[N+]([O-])c1ncc(Br)nc1-c1ccc(Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1ccc(NCCNc2cnc([N+](=O)[O-])c(-c3ccc(Cl)cc3Cl)n2)nc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of 3-(2,4-dichlorophenyl)-5-bromo-2-nitropyrazine (20 mg, 0.057 mmol) in DMF (1 ml), 6-[(2-aminoethyl)amino]pyridine-3-carbonitrile (10.0 mg, 0.06 mmol) and diisopropylethyl amine (40 μl, 0.228 mmol) were added. The reaction mixture was stirred for 12 hours at 80° C. The crude mixture was concentrated in vacuo and subjected to column chromatography (5% methanol in methylene chloride) to afford the title compound as bright yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([CH3:21])=[N:19][N:20]=3)[N:17]=2)[CH:7]=1)=[O:4].[H-].[Na+].CI.[C:27](=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:1][N:2]([CH3:22])[C:3]([N:5]([CH3:27])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([CH3:21])=[N:19][N:20]=3)[N:17]=2)[CH:7]=1)=[O:4]
Reactant: O=C([O-])O
Reactant: Cc1nnc2ccc(-c3cccc(NC(=O)N(C)C)c3)nn12
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1nnc2ccc(-c3cccc(N(C)C(=O)N(C)C)c3)nn12
Reaction time: 0.5 h

Procedure:
A suspension of 1.0 g of N,N-dimethyl-N'-[3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]urea and 0.09 g of sodium hydride in 100 ml of dry dimethylformamide was stirred for 30 minutes, then 0.23 ml of methyl iodide was added. This solution was stirred overnight, then poured into saturated aqueous sodium bicarbonate and extracted with four 100 ml portions of dichloromethane. The extracts were combined and treated as described in Example 19, giving 0.8 g of the desired product as off-white crystals mp 159°-161° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:16][CH2:15][CH2:14][NH:13]2)=[CH:8][CH:7]=1.[C:18]1(C)[CH:23]=CC(S(OCCC#C)(=O)=O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:17])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:20][CH2:19][C:18]#[CH:23])=[CH:8][CH:7]=1
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)/C=C/c1ccc(C2CCCN2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCCN1CCCC1c1ccc(/C=C/C(=O)OC)cc1
Temperature: 65 °C
Yield: 63 %

Procedure:
A mixture of (E)-3-(4-pyrrolidin-2-yl-phenyl)-acrylic acid methyl ester (5.52 g, 20.6 mmol), 3-butynyl p-toluenesulfonate (4.55 mL, 24.7 mmol) and potassium carbonate (5.98 g, 43.3 mmol) in acetonitrile (15 mL) was heated at 65° C. for 9 h. After cooled to room temperature, the reaction mixture was filtered, concentrated, and purified via silica gel column chromatography, and the residue was recrystallized from heptane to provide (E)-3-[4-(1-but-3-ynyl-pyrrolidin-2-yl)-phenyl]-acrylic acid methyl ester (3.68 g, 63% yield). LCMS (m/z): 284.2 (M+1).
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[OH-].[K+].Cl[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14]>CN(C)C=O>[CH2:1]([S:3][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14])[CH3:2]
Reactant: NS(=O)(=O)c1ccccc1Cl
Reactant: CCS
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCSc1ccccc1S(N)(=O)=O
Reaction time: 0.25 h

Procedure:
62 g (1.0 mol) of ethanethiol were added to a mixture of 65.9 g (1.0 mol) of 85% strength potassium hydroxide powder and 500 ml of dimethylformamide at 25° C. while stirring, and stirring was continued for 15 minutes. Thereafter, a solution of 95.8 g (0.5 mol) of 2-chlorobenzenesulfonamide was added at 90° C. while stirring in the course of 30 minutes, and stirring was continued for 8 hours at 110° C. The mixture was cooled and was evaporated down under reduced pressure, after which the residue was partitioned between methylene chloride and water, and the organic phase was washed with dilute sodium chloride solution. Evaporating down under reduced pressure gave 88.4 g (81.5% of theory) of the title compound as a semicrystalline mass.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([CH2:12][C:13](=[O:35])[NH:14][O:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9](O)=[O:10])([CH3:4])([CH3:3])[CH3:2].[NH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][OH:43]>>[C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([C:9](=[O:10])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][OH:43])[CH2:12][C:13](=[O:35])[NH:14][O:15][C:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: NCCCCCO
Reactant: CC(C)(C)OC(=O)CC(CC(=O)NOC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Product: CC(C)(C)OC(=O)CC(CC(=O)NOC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCCCCCO

Procedure:
This compound was prepared by reacting the compound of Example 63 with 5-amino-pentan-1-ol.
Reaction SMILES: [F:1][C:2]1[C:3]([CH:22](C#N)[C:23]([O:25]CC)=[O:24])=[C:4]2[C:9]3=[C:10]([C:12](=[O:20])[C:13]([C:15]([O:17]CC)=[O:16])=[CH:14][N:8]3[N:7]([CH3:21])[CH2:6][CH2:5]2)[CH:11]=1.Cl>C(O)(=O)C>[C:15]([C:13]1[C:12](=[O:20])[C:10]2[C:9]3[N:8]([CH:14]=1)[N:7]([CH3:21])[CH2:6][CH2:5][C:4]=3[C:3]([CH2:22][C:23]([OH:25])=[O:24])=[C:2]([F:1])[CH:11]=2)([OH:17])=[O:16]
Reactant: CCOC(=O)c1cn2c3c(c(C(C#N)C(=O)OCC)c(F)cc3c1=O)CCN2C
Agent: Cl
Solvent: CC(=O)O
Product: CN1CCc2c(CC(=O)O)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 34.5 %

Procedure:
To 450 mg of the compound (161) obtained in Example 39, 4 ml of concentrated hydrochloric acid and 16 ml of acetic acid were added, and the solution was heated at reflux for 7.5 hours. The solvent was removed by distillation, and crystals were filtered off and washed with ethanol and ether in this order to obtain 124 mg of the subject compound (163).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([Br:15])[CH:12]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[C:7]=3[NH:8][C:9]=2[CH:10]=1.Cl.Cl[CH2:22][CH2:23][N:24]([CH2:26][CH2:27]Cl)[CH3:25].C(=O)([O-])[O-].[Na+].[Na+]>CC(O)(C)C>[Br:15][C:13]1[CH:12]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[C:7]2[NH:8][C:9]3[CH:10]=[C:2]([N:1]4[CH2:27][CH2:26][N:24]([CH3:25])[CH2:23][CH2:22]4)[CH:3]=[CH:4][C:5]=3[C:6]=2[N:14]=1
Reactant: CN(CCCl)CCCl
Reactant: COC(=O)c1cc(Br)nc2c1[nH]c1cc(N)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: COC(=O)c1cc(Br)nc2c1[nH]c1cc(N3CCN(C)CC3)ccc12
Yield: 69 %

Procedure:
A mixture of methyl 7-amino-2-bromo-5H-pyrido[3,2-b]indole-4-carboxylate (1.0 g, 3.1 mmol), 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride (1.20 g, 6.25 mmol) and sodium carbonate (1.66 g, 15 6 mmol) in t-BuOH (40 mL) was heated at reflux overnight. The reaction was partitioned between EtOAc and water and the organic phase was washed with sat. aq. NaHCO3 solution, water, and brine. After drying with sodium sulfate, the solvents were removed and silica gel chromatography (elution with 5% MeOH in DCM) afforded methyl 2-bromo-7-(4-methylpiperazin-1-yl)-5H-pyrido[3,2-b]indole-4-carboxylate (900 mg, 2.14 mmol, 69% yield). MS (ESI) m/z 405.14 (M+H); LCMS Ret Time: 1.995 min; Xbridge S10 4.6×50 mm column, 3 min gradient, 0-100% B, 4 mL/min. Solvent A: 95% MeOH—5% H2O—0.1% TFA; Solvent B: 5% MeOH—95% H2O—0.1% TFA.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]1([C:19]2[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:23][NH:22][C:21](=[O:31])[CH:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O[CH2:33][CH2:34][C:35]1[CH:36]=[C:37]([CH:44]=[CH:45][CH:46]=1)[O:38][CH2:39][C:40]([O:42][CH3:43])=[O:41].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[O:31]=[C:21]1[N:22]([CH2:33][CH2:34][C:35]2[CH:36]=[C:37]([CH:44]=[CH:45][CH:46]=2)[O:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])[N:23]=[C:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:20]1
Reactant: O=c1cc(-c2ccccc2)c(-c2ccccc2)n[nH]1
Reactant: COC(=O)COc1cccc(CCO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)COc1cccc(CCn2nc(-c3ccccc3)c(-c3ccccc3)cc2=O)c1
Temperature: 0 °C
Reaction time: 1.75 h
Yield: 96.9 %

Procedure:
Diethyl azodicarboxylate (2.73 g, 2.50 mL, 16 mmol) was added to a stirred solution of 5,6-diphenyl-3(2H)-pyridazinone (3.00 g, 12 mmol), methyl [3-(2-hydroxyethyl)-phenoxy]acetate (2.80 g, 13 mmol) and triphenylphosphine (4.12 g, 16 mmol) in dry THF (75 mL) maintained at 0° C. The ice bath was removed and the mixture stirred at room temperature for 1.75 hours before removal of the solvent. The residue was chromatographed twice on columns of silica gel using mixtures of diethyl ether and hexanes (7:3) and then (3:2) as eluent to give methyl [3-[2-(1,6-dihydro-6-oxo-3,4-diphenyl-1-pyridazinyl)ethyl]phenoxyacetate] (5.12 g, 98%), contaminated with 0.6 equivalents of 1,2-dicarbethoxy hydrazine, as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][O:14][C:15]1[CH:32]=[CH:31][C:18]([CH2:19][N:20]2[C:24]3[N:25]=[CH:26][CH:27]=[C:28]([OH:29])[C:23]=3[C:22]([I:30])=[N:21]2)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]2[C:24]3=[N:25][CH:26]=[CH:27][C:28]([O:29][C:6]4[CH:7]=[C:2]([Cl:1])[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][C:5]=4[F:9])=[C:23]3[C:22]([I:30])=[N:21]2)=[CH:31][CH:32]=1
Reactant: COc1ccc(Cn2nc(I)c3c(O)ccnc32)cc1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(I)c3c(Oc4cc(Cl)c([N+](=O)[O-])cc4F)ccnc32)cc1
Temperature: 50 °C
Yield: 40.3 %

Procedure:
A mixture of 1-chloro-4,5-difluoro-2-nitrobenzene (2.23 g, 11.5 mmol), 1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-ol (4.00 g, 10.5 mmol), K2CO3 (1.60 g, 11.5 mmol) and DMF (100 mL) was heated to 50° C. for 18 hours. The reaction was cooled to ambient temperature, diluted with water (500 mL), extracted with EtOAc, dry over sodium sulfate, filter and concentrate. The residue was purified by flash column chromatography (5% MeOH in CH2Cl2) to provide a light pink solid. The solid was triturated with hot MeOH to afford the product (2.35 g, 40% yield) as a white solid. LRMS (APCI pos) m/e 554.8 (M+H).
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[CH2:7]([O:9][CH2:10][C:11]1[N:12]([CH2:24][C:25]2([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:13]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:23]=1)[CH3:8]>>[CH2:7]([O:9][CH2:10][C:11]1[N:12]([CH2:24][C:25]2([NH:31][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:13]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:23]=1)[CH3:8]
Reactant: CC(C)N=C=O
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(N)CCCCC1
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(NC(=O)NC(C)C)CCCCC1
Reaction time: 4 h

Procedure:
Isopropyl isocyanate (0.15 mL, 1.45 mmol) was added to a solution of 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanamine (0.50 g, 1.45 mmol) dichloromethane (5 mL) at rt. After 4 h, the reaction was set up on a larger scale with 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanamine (1.50 g, 4.43 mmol). Both reactions were allowed to stir overnight and additional isopropyl isocyanate (0.5 equivalent) was added to each reaction. After stirring another day, the reactions were combined and concentrated under reduced pressure to yield an oil. The oil was triturated with hexane and N-(1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexyl)-N′-isopropylurea was isolated as a white solid (2.23 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][N:20]([CH3:27])[CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:24]3[CH2:25][CH2:26][CH:21]([N:20]([CH3:27])[CH3:19])[CH2:22][CH2:23]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CN(C)C1CCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Yield: 20 %

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carboxaldehyde 10 was reacted with dimethyl-piperidin-4-yl-amine using standard reductive amination conditions. The resulting crude solid was triturated with diethyl ether to give [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-dimethyl-amine as an off white solid (45% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was purified by mass directed chromatography (20% yield) to give 337. NMR (CDCl3, 400 MHz), 1.60-1.65 (2H, m), 1.83-1.86 (2H, d, J 12.2), 2.11-2.17 (3H, m), 2.32 (6H, s), 3.04 (2H, d, J 11.4), 3.83 (2H, s), 3.88-3.91 (4H, m), 4.03-4.06 (4H, m), 5.24 (2H, br s), 7.27 (1H, br s), 7.27 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=455
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:44])[CH2:15][C@H:16]([C:39]1[CH:43]=[CH:42][O:41][N:40]=1)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[CH2:26][CH3:27])=[CH:19][CH:18]=1)C1C=CC=CC=1.[OH:45]O.[OH-].[Li+].Cl>C1COCC1.O>[O:41]1[CH:42]=[CH:43][C:39]([C@H:16]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:34]=3)[CH2:26][CH3:27])=[CH:21][CH:22]=2)[CH2:15][C:14]([OH:44])=[O:45])=[N:40]1
Reactant: OO
Reactant: CCC(COc1ccc([C@H](CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)c2ccon2)cc1)Oc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(COc1ccc([C@H](CC(=O)O)c2ccon2)cc1)Oc1ccc(C(F)(F)F)cc1
Reaction time: 1 h
Yield: 32.2 %

Procedure:
To a solution of the oxazolidinone (49.2) (23.0 mg, 0.038 mmol) dissolved in THF (2 mL), was added a 30% hydrogen peroxide solution (43 μL, 0.38 mmol) followed by a 2 M lithium hydroxide solution (94 μL, 0.19 mmol). The resulting slurry was stirred for one hour. The reaction mixture was then diluted with water and acidified with hydrochloric acid to pH ˜3. The mixture was then extracted with EtOAc (1×20 mL), and the organic layer was washed with an acidic sodium sulfite solution (2×15 mL) and brine (1×15 mL), and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase HPLC to give 49 (5.5 mg). MS ESI (pos.) m/e: 450.1 (M+H). 1H NMR (400 MHz, CD3CN) δ ppm 8.33 (1H, d, J=1.6 Hz), 7.51 (2H, d, J=8.6 Hz), 7.12 (2H, d), 6.95 (2H, d, J=8.6 Hz), 6.78 (2H, d, J=8.6 Hz), 6.16 (1H, d, J=1.6 Hz), 4.44 (1H, t, J=7.8 Hz), 4.02 (2H, t, J=6.1 Hz), 3.94 (2H, t, J=6.1 Hz), 3.09 (1H, dd, J=16.6, 8.4 Hz), 2.84 (1H, dd, J=16.4, 7.4 Hz), 1.81-1.84 (4H, m).