Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH2:13][OH:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[C:19]([C:21]1[CH:22]=[C:23]([CH:59]([CH3:61])[CH3:60])[C:24]2[O:28][C:27]([C:29]3[CH:57]=[CH:56][C:32]([C:33]([NH:35][CH2:36][CH:37]4[CH2:42][CH2:41][N:40]([C:43](OCC5C=CC([N+]([O-])=O)=CC=5)=[O:44])[CH2:39][CH2:38]4)=[O:34])=[CH:31][CH:30]=3)=[N:26][C:25]=2[CH:58]=1)#[N:20]>O1CCCC1>[C:19]([C:21]1[CH:22]=[C:23]([CH:59]([CH3:61])[CH3:60])[C:24]2[O:28][C:27]([C:29]3[CH:30]=[CH:31][C:32]([C:33]([NH:35][CH2:36][CH:37]4[CH2:38][CH2:39][N:40]([C:43]([O:14][CH2:13][C:5]5[CH:4]=[C:3]([C:2]([F:15])([F:16])[F:1])[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=5)=[O:44])[CH2:41][CH2:42]4)=[O:34])=[CH:56][CH:57]=3)=[N:26][C:25]=2[CH:58]=1)#[N:20]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)CC4)cc3)oc12
Reactant: OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(C(=O)OCc5cc(C(F)(F)F)cc(C(F)(F)F)c5)CC4)cc3)oc12
Reaction time: 0.08 h
Yield: 21.6 %

Procedure:
To a solution of [3,5-bis(trifluoromethyl)phenyl]methanol (17 mg) in tetrahydrofuran (5 ml) was added sodium hydride (5 mg, 60% dispersion in mineral oil). The mixture was allowed to stir for 5 min, and then 4-nitrobenzyl 4-({[4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoyl]amino}methyl)piperidine-1-carboxylate (20 mg) was added. The reaction mixture was stirred overnight at room temperature, and then was concentrated. The residue was purified by reverse-phase HPLC on a Biotage Parallex Flex, Kromasil C18 21×100 mm column, eluting at 15 mL/min with 90% water (0.1% TFA) to 95% acetonitrile (0.1% TFA) over 10 min, hold for 2 min, then back to 90% water over 0.5 min, hold for 0.5 min, to provide the title compound (5 mg, 21%). Mass spectrum (ESI) 673.1 (M+1). NMR signals are doubled and broadened because of restricted rotation about the amide C—N bond. 1H NMR (500 MHz, CDCl3): δ 8.34 (d, J=8 Hz, 2H), 7.95 (m, 2H), 7.93 (s, 1H), 7.83 (s, 1H), 7.80 (s, 2H), 7.52 (s, 1H), 6.316 (app t, 1H), 5.23 (s, 2H), 4.23 (m, 2H), 2.82-2.90 (m, 2H), 1.89-1.93 (m, 1H), 1.83 (m, 3H), 1.73 (m, 3H), 1.46 (d, J=7 Hz, 6H), 1.21-1.31 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1.[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: O=C(O)Cc1ccc2ccn(Cc3ccc(Cl)cc3Cl)c2c1

Procedure:
The titled compound (29 mg) as a white solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 2,4-dichlorobenzyl chloride according to the method of the process (7) of Example 4.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)(=O)=O.[CH2:26]([NH:29][CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28]>ClCCl>[CH2:26]([N:29]([CH2:30][CH2:31][CH3:32])[C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)[CH2:27][CH3:28]
Reactant: CCCNCCC
Reactant: CCCOc1ccccc1-c1nc2nc(S(C)(=O)=O)ncc2c(=O)[nH]1
Solvent: ClCCl
Product: CCCOc1ccccc1-c1nc2nc(N(CCC)CCC)ncc2c(=O)[nH]1

Procedure:
In a similar manner to Example 56 reaction of 7-methylsulphonyl-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.40 g) and dipropylamine (0.74 g) in dichloromethane (10 ml) yielded the title compound, 83 mg, m.p. 123-4° C. (recrystallized from cyclohexane).
Reaction SMILES: [NH2:1][C:2]1[C:16]([CH2:17][NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Cl)=[O:7])=[CH:4][C:3]=1[Br:23].[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][C:40]([O-:42])=[O:41].[Na+]>>[NH2:1][C:2]1[C:16]([CH2:17][NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:42][C:40](=[O:41])[CH2:39][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[NH:32][C:26]2[C:25]([Cl:24])=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:31])=[O:7])=[CH:4][C:3]=1[Br:23]
Reactant: CC(C)(C)NCc1cc(C(=O)OCCCCCCl)cc(Br)c1N
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: [Na+]
Product: CC(C)(C)NCc1cc(C(=O)OCCCCCOC(=O)Cc2ccccc2Nc2c(Cl)cccc2Cl)cc(Br)c1N

Procedure:
This compound was prepared from 5-(4-Amino-3-bromo-5-tert. butylaminomethyl-benzoyloxy)-n-pentyl chloride and sodium 2-[(2,6-dichlorophenyl)-amino]-phenylacetate analogous to Example 8.
Reaction SMILES: [P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26](CC=CN)[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][C@@H:16]1[OH:32])([O:4][P:5]([O:8][P:9]([OH:12])([OH:11])=[O:10])([OH:7])=[O:6])(=[O:3])[OH:2].C(N(CC)CC)C>O.CN(C=O)C>[P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[CH:26][C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][C@@H:16]1[OH:32])([O:4][P:5]([O:8][P:9]([OH:11])([OH:12])=[O:10])([OH:7])=[O:6])(=[O:2])[OH:3]
Reactant: NC=CCc1cn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]c1=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2 mg of 5-(3-aminoallyl)-2′-deoxyuridine-5′-triphosphate, ammonium salt (Sigma Chemical) in 100 μL of water is added a solution of 3 mg of Compound 72 (Example 73) in 100 μL of DMF, followed by addition of 5 μL of triethylamine. After the mixture is stirred at room temperature for 3 hours, the solution is evaporated to dryness under vacuum and the residue is purified by chromatography over lipophilic SEPHADEX resin using water for elution. The first green fluorescent fractions are combined and lyophilized to give the fluorescent nucleotide conjugate as an orange solid (Compound 107) Alternatively a fluorescent conjugate (Compound 108) of deoxyuridine-5′-triphosphate is prepared using 5-(3-amino-1-propynyl)-2′-deoxyuridine-5′-triphosphate in place of 5-(3-aminoally)-2′-deoxyuridine-5′-triphosphate (as described in Hobbs, Jr. et al, supra).
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[C:13]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:25][S:26]([C:29]1[CH:30]=[C:31]([NH2:35])[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27].Cl.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:25][S:26]([C:29]1[CH:30]=[C:31]([NH:35][C:2]2[N:24]=[C:5]3[C:6]([NH:10][CH2:11][C:12]4[C:13]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[N:14][CH:15]=[CH:16][CH:17]=4)=[CH:7][CH:8]=[CH:9][N:4]3[N:3]=2)[CH:32]=[CH:33][CH:34]=1)(=[O:27])=[O:28]
Reactant: CN(c1ncccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Reactant: CS(=O)(=O)c1cccc(N)c1
Agent: Cl
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN(c1ncccc1CNc1cccn2nc(Nc3cccc(S(C)(=O)=O)c3)nc12)S(C)(=O)=O

Procedure:
N-(3-{[2-(3-Methanesulfonyl-phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino]-methyl}-pyridin-2-yl)-N-methyl-methanesulfonamide was prepared from N-{3-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-pyridin-2-yl}-N-methyl-methanesulfonamide (75.0 mg, 0.204 mmol) and 3-methanesulfonyl-phenylamine; hydrochloride (39.0 mg, 0.188 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.010 g, 11%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.42 (dd, J=4.8, 1.5 Hz, 1H), 8.24 (s, 1H), 7.88-7.83 (m, 3H), 7.53 (d, J=4.9 Hz0, 1H), 7.29 (dd, J=7.7, 4.7 Hz, 1H), 6.96 (s, 1H), 6.72 (t, J=7.5 Hz, 1H), 6.36 (d, J=7.7 HZ, 1H), 5.36 (t, J=6.3 Hz, 1H), 4.78 (d, J=6.1 Hz, 1H), 3.33 (s, 3H), 3.10 (s, 6H). MS=502 (MH)+.
Reaction SMILES: FC1C=CC=CC=1C(Cl)=O.[CH3:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.[NH2:22][C:23]1[CH:24]=[C:25]([CH:36]=[CH:37][N:38]=1)[C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>>[CH2:29]([NH:28][C:26](=[O:27])[C:25]1[CH:36]=[CH:37][N:38]=[C:23]([NH:22][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[CH:24]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: O=C(Cl)c1ccccc1F
Product: COc1ccc(C(=O)Nc2cc(C(=O)NCc3ccccc3)ccn2)cc1
Yield: 28 %

Procedure:
Following the procedure as describe in Example 6, making variations as required to replace 2-fluorobenzoyl chloride with 4-methoxybenzoyl chloride to react with 2-amino-N-benzylisonicotinamide, N-benzyl-2-(4-methoxybenzamido)isonicotinamide was obtained as a colorless solid in 28% yield: mp 165-166° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.91 (s, 1H), 8.65 (s, 1H), 8.38 (d, J=5.2 Hz, 1H), 7.91-7.86 (m, 2H), 7.58 (dd, J=5.2, 1.5 Hz, 1H), 7.34-7.25 (m, 5H), 6.99-6.94 (m, 2H), 6.77 (s, 1H), 4.64 (d, J=5.8 Hz, 2H), 3.86 (s, 3H); MS (ES+) m/z 362.5 (M+1).
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.O>C1COCC1>[N:14]1([S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: C1COCCN1
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
To a solution of 4-(chlorosulfonyl)-benzoic acid (0.5 g, 2.2 mmol) in THF (20 ml) was added morpholine (0.434 ml, 5 mmol) dropwise over 5 min, and this mixture stirred at r.t. for 1 h. Water (50 ml) was then addedand the mixture agitated, the phases were separated and the aqueous phase extracted with EtOAc (2×50 ml). The combined organic phases were washed with satd. aq. NaCl solution, dried, filtered and evaporated. The residue was chromatographed over SiO2 (Merck 230-400 mesh) eluting with a CHCl3/(acetone+10% HCO2H) (9:1), the product fractions were pooled, evaporated and dried in vacuo (0.05 mmHg, 50° C.) to afford the title compound as a beige solid (270 mg, 20% yield), MS: m/e=271 (M+).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][OH:21])[O:17][N:16]=1.Cl[C:23]1[C:28]([C:29]#[N:30])=[CH:27][CH:26]=[CH:25][N:24]=1.[H-].[Na+].Cl>O.CN(C)C=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][O:21][C:23]2[N:24]=[CH:25][CH:26]=[CH:27][C:28]=2[C:29]#[N:30])[O:17][N:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cc(CO)on1
Reactant: N#Cc1cccnc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1cc(COc2ncccc2C#N)on1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.2 %

Procedure:
To a mixture of [3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolyl]methanol (2.00 g), 2-chloro-3-cyanopyridine (1.16 g) and N,N-dimethylformamide (60 mL) was gradually added sodium hydride (60%, oil, 335 mg) under ice-cooling. After stirring the reaction mixture at room temperature for 90 min., water was added to the reaction mixture. The mixture was neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (2.61 g, 96%) of 2-[[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-5-isoxazolyl]methoxy]nicotinonitrile from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 139-140° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([N:11]2[CH2:15][CH2:14][CH2:13][S:12]2(=[O:17])=[O:16])[CH:3]=1.[CH:18]1([C:21]2[CH:22]=[C:23]([CH3:33])[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH2:20][CH2:19]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:30]2[CH2:31][CH2:32][N:27]([C:24]3[C:23]([CH3:33])=[CH:22][C:21]([CH:18]4[CH2:19][CH2:20]4)=[CH:26][N:25]=3)[CH2:28][CH2:29]2)=[O:8])=[C:4]([N:11]2[CH2:15][CH2:14][CH2:13][S:12]2(=[O:17])=[O:16])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1N1CCCS1(=O)=O
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2N2CCCS2(=O)=O)CC1
Yield: 88.8 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 90 and using 4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)benzoic acid (6.72 g) described in Preparation Example 178 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (4.56 g) described in Preparation Example 96, the title compound (9.68 g) was obtained.
Reaction SMILES: C(=O)(O)O.Cl[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH2:15])=[NH:14])=[CH:8][CH:7]=1.CC1(C)C(C)(C)OB([C:24]2[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[OH-].[Na+]>O.O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:30][C:26]1[CH:25]=[C:24]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH2:15])=[NH:14])=[CH:8][CH:7]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Reactant: N=C(N)Nc1ccc(Cl)cc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1COCCO1
Product: N=C(N)Nc1ccc(-c2cccc(O)c2)cc1
Temperature: 25 °C
Reaction time: 3.33 h

Procedure:
A mixture of 4-chlorophenylguanidine carbonate (644 mg), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (373 mg), sodium carbonate (495 mg), palladium (II) acetate (14 mg) and tricyclohexylphosphine (19 mg) in water (1.2 ml) and dioxane (5.7 ml) is kept at 100° C. under micro wave conditions for 200 min. The mixture is cooled down to rt, basified with 1 N NaOH to pH 10.5 and extracted 4 times with EtOAc. The combined organic phases are washed with brine and dried over sodium sulfate. The solvent is evaporated to afford crude N-(3′-hydroxy-biphenyl-4-yl)guanidine.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:11](=[O:13])[CH3:12])[CH:7]1[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)=[O:5])[CH3:2]>[Pd].C(O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:11](=[O:13])[CH3:12])[CH:7]1[C:14]1[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(C(C)=O)C1c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CCN(C(C)=O)C1c1ccc(N)cc1
Reaction time: 4 h
Yield: 63.2 %

Procedure:
A stirred mixture of 1-acetyl-2-(4-nitro-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (3 g, Reference Example 20) and 10% palladium on charcoal in ethanol (150 mL) was hydrogenated under atmospheric pressure for 4 hours at room temperature and then filtered through a celite pad. The filter pad was washed with ethanol (50 mL) and the combined filtrate plus washings were evaporated. The residue was subjected to flash chromatography on silica (330 g, 20-451 μm, 0.6 bar) eluting with a mixture of dichloromethane and methanol (95:5, v/v). The fractions containing the compound of RF 16/63 (thin layer chromatography plate ref. #05719, Merck KGaA, 64271 Darmstatd, Germany, dichloromethane:methanol, 95:5, v/v) were pooled and evaporated under reduced pressure (2.7 kPa) to give the title compound (1.71 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[C:11]1[CH2:24][CH2:25][O:26][CH3:27].[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[NH2:23][C:14]1[C:13]2[N:12]=[C:11]([CH2:24][CH2:25][O:26][CH3:27])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:35]([NH:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:36])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: O=C=Nc1ccccc1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCN
Solvent: ClCCl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCNC(=O)Nc1ccccc1
Temperature: 0 °C

Procedure:
Under a nitrogen atmosphere a mixture of 1-(8-aminooctyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.5 g, 4.06 mmol) and dichloromethane (50 mL) was cooled to 0° C. Phenyl isocyanate was added dropwise. The reaction mixture was allowed to slowly warm to ambient temperature overnight. The reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (110 g silica gel eluting with 9:1 dichloromethane:methanol). The resulting orange solid was triturated with hexanes, isolated by filtration and then dried. This material was recrystallized from propyl acetate with a small amount of methanol, isolated by filtration, washed with hexanes, and then dried in a vacuum oven at 60° C. for 2 days to provide 0.6 g of N-{8-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]octyl}-N′-phenylurea as an off white powder, m.p. 136-142° C. Analysis: Calculated for C28H36N6O2: %C, 68.83; %H, 7.43; %N, 17.20; Found: %C, 68.27; %H, 7.44; %N, 16.85. 1H NMR (300 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.61 (dd, J=8.3-1.0 Hz, 1H), 7.44-7.35 (m, 3H), 7.29-7.17 (m, 3H), 6.87 (t, J=7.3 Hz, 1H), 6.52 (s, 2H), 6.08 (m, 1H), 4.51 (t, J=7.8 Hz, 2H), 3.82 (m, 2H), 3.29 (s, 3H), 3.18 (t, J=6.8 Hz, 2H), 3.05 (m, 2H), 1.81 (m, 2H), 1.42-1.29 (m, 10H); 13C NMR (75 MHz, DMSO-d6) 155.5, 152.0, 151.0, 145.0, 141.0, 132.6, 128.9, 126.8, 126.7, 126.6, 121.5, 121.2, 120.7, 117.9, 115.1, 70.5, 58.5, 45.3, 30.1, 29.0, 27.5, 26.6, 26.2. MS m/z 489 (M+H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[C:28]1[C:29]([NH2:40])=[N:30][CH:31]=[C:32]([C:34]#[C:35][Si](C)(C)C)[CH:33]=1>C1COCC1>[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[C:28]1[C:29]([NH2:40])=[N:30][CH:31]=[C:32]([C:34]#[CH:35])[CH:33]=1
Reactant: C[Si](C)(C)C#Cc1cnc(N)c(-c2nc3ccccc3o2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cnc(N)c(-c2nc3ccccc3o2)c1
Reaction time: 1 h
Yield: 79.5 %

Procedure:
Tetrabutylammonium fluoride 1.0M in THF (0.629 ml) was added to a stirred solution of 3-(1,3-benzoxazol-2-yl)-5-(2-trimethylsilylethynyl)pyridin-2-amine (0.370 g) in THF (10 ml) at room temperature. The resulting solution was stirred for 1 hour. A yellow precipitate appeared during the reaction. After concentration, the crude product was purified by flash chromatography on silica gel eluting with 0 to 15% ethyl acetate in dichloromethane to afford 3-(1,3-benzoxazol-2-yl)-5-ethynyl-pyridin-2-amine (225 mg) as a solid; NMR Spectrum: (DMSOd6) 4.20 (s, 1H), 7.42-7.51 (m, 2H), 7.80 (dd, 1H), 7.85 (dd, 1H), 8.04 (bs, 2H), 8.31 (d, 1H), 8.36 (d, 1H); Mass spectrum: M+H+: 236
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:18])=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[NH:9][C:8]1([CH2:16][CH2:15][CH2:14]1)[CH2:7][C:6]2=[O:17].[BH4-].[Na+]>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:18])=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[NH:9][C:8]1([CH2:14][CH2:15][CH2:16]1)[CH2:7][CH:6]2[OH:17]
Reactant: COc1c(C)cc2c(c1C)C(=O)CC1(CCC1)N2
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1c(C)cc2c(c1C)C(O)CC1(CCC1)N2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6′-methoxy-5′,7′-dimethyl-1′H-spiro[cyclobutane-1,2′-quinolin]-4′(3′H)-one (1 g) in a mixture of 35 mL methanol and 15 mL CH2Cl2, was added NaBH4 (2 g) slowly at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes and then at room temperature for three days. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried with Na2SO4 and evaporated, to yield 6′-methoxy-5′,7′-dimethyl-3′,4′-dihydro-1′H-spiro[cyclobutane-1,2′-quinolin]-4′-ol was used in the next step without further purification.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:10]2[CH:26]=[CH:27][CH:28]=[CH:29][C:9]=2[N:8]=1)[CH2:2][CH2:3][CH3:4].[F:30][C:31]1[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](Cl)=[O:34]>C1(C)C=CC=CC=1.ClC(Cl)C>[CH2:1]([N:5]([CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:10]2[CH:26]=[CH:27][CH:28]=[CH:29][C:9]=2[N:8]=1)[C:33](=[O:34])[C:32]1[CH:36]=[CH:37][CH:38]=[C:39]([F:40])[C:31]=1[F:30])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)c1cccc(F)c1F
Reactant: CCCCNCc1nc2ccccc2n1Cc1ccccc1CN1CCCCC1
Solvent: Cc1ccccc1
Solvent: CC(Cl)Cl
Product: CCCCN(Cc1nc2ccccc2n1Cc1ccccc1CN1CCCCC1)C(=O)c1cccc(F)c1F

Procedure:
A solution of 0.9 g (1.7 mmole) of compound D was treated with 10 mL of butyl amine in 50 mL of acetonitrile at room temperature for 2 hr. The resulting solution was concentrated and partitioned between ethyl acetate and 1N NaOH. The organic layer was dried over anhydrous Na2SO4 and concentrated to yield 0.55 g of Butyl-[1-(2-piperidin-1-ylmethyl-benzyl)-1H-benzoimidazol-2-ylmethyl]-amine. 1H NMR (300 MHz, CDCl3) 7.8 (d, 1H), 7.2 (m, 5H), 7.05 (d, 1H), 6.4 (d, 1H), 5.8 (s, 2H), 4.0 (s, 2H), 3.6 (s, 2H), 2.6 (t, 2H), 1.2-1.6 (m, 14H), 0.8 (t, 3H). A quantity of 0.1 mL of a 0.2 M solution of Butyl-[1-(2-piperidin-1-ylmethyl-benzyl)-1H-benzoimidazol-2-ylmethyl]-amine in toluene is treated with 0.15 mL of a 0.2 M solution of 2,3-Difluoro-benzoyl chloride in dichloroethane at room temperature for 1 hr. The resulting mixture was chromatographed on SiO2 with ethyl acetate to yield 9 mg of N-Butyl-2,3-difluoro-N-[1-(2-piperidin-1-ylmethyl-benzyl)-1H-benzoimidazol-2-ylmethyl]-benzamide. LCMS MF=C32H36F2N4O MW=530.6 found 531. B. N-Butyl-2,3-difluoro-N-[1-(4-piperidin-1-yl-but-2-Enyl)-1H-benzoimidazol-2-ylmethyl]-benzamide
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][CH2:6][C:7](Cl)=[O:8].[CH2:10]([OH:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[Cl:5][CH2:6][C:7]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][OH:18])=[CH:13][CH:14]=1)=[O:8]
Reactant: O=C(Cl)CCl
Reactant: OCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCl)c1ccc(CCO)cc1
Temperature: -10 °C
Yield: 81.9 %

Procedure:
Finely ground AlCl3 (92.0 g, 0.69 mol) was mixed with dichloromethane (120 ml) in a flask and cooled to -10° C. Chloracetyl chloride (37.3 g, 0.33 mol) was added to the mixture as it was kept cool. Phenethyl alcohol (36.6 g, 0.30 mol) was dissolved in dichloromethane (20 ml) and charged to a dropping funnel. The phenethyl alcohol solution was added slowly dropwise to the mixture over 2 hours while stirring and keeping the temperature at about 10° C. At the end of the addition, the mixture was allowed to warm to room temperature and stirred overnight. The red color solution was poured into a large quantity of ice (about 300 g). The organic layer was separated and the aqueous layer was extracted with dichloromethane (200 ml), and the dichloromethane portions were washed with water until neutral. The organic phase was then dried (magnesium sulfate), concentrated, recrystallized (ether), and dried to give 48.8 g (81.9%) of compound 5. Analysis of the products gave the following results: mp 41°-45° C.; NIR (KBr) 3477, 3355, 2947, 1702, 1693, 1606, 1218, 1044, 818 cm-1 ; 1H NMR (60 MHz) δ 1.96 (s, 1H), 2.92 (t, 2H, J=6.5 Hz), 3.90 (t, 2H, J=6.5 Hz), 4.67 (s,2H), 7.2-7.4 (m, 2H), 7.8-8.0 (m, 2H).