Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:25][CH:26]=2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[F:33][C:34]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:35]=1[C:36](O)=[O:37].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(Cl)Cl>C(#N)C.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:36](=[O:37])[C:35]4[C:34]([F:33])=[CH:42][CH:41]=[CH:40][C:39]=4[F:43])[CH2:31][CH2:32]3)=[CH:25][CH:26]=2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1c(F)cccc1F
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(N3CCNCC3)nc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(N3CCN(C(=O)c4c(F)cccc4F)CC3)nc2)cc1
Temperature: 25 °C

Procedure:
Place 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(6-piperazin-1-yl-pyridin-3-yl)-urea (48 mg, 0.111 mmol), 2,6-difluorobenzoic acid (21 mg, 0.133 mmol), and 4-N,N-dimethylaminopyridine (3 mg, 0.022 mmol) in acetonitrile (5 mL). Add O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (50 mg, 0.133 mmol) and heat to 70° C. for 19 hours. Cool to room temperature and add CH2Cl2 and water. Separate organic layer and extract aqueous with CH2Cl2 (2×25 mL). Combine organics, dry over Mg2SO4, filter, and concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with 0-60% EtOAc:hexane to yield the title compound. LCMS(ES): m/z=574.2 [M+H].
Reaction SMILES: [CH3:1][Mg]Br.C([O:6][CH2:7][CH3:8])C.C(OC[CH2:14][CH2:15][NH:16][C:17]([C:19]1[N:20]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]([F:40])([F:39])[F:38])[CH:31]=2)[C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([Cl:28])=[CH:23][CH:22]=2)=[O:18])(C)C>C1COCC1>[OH:6][C:7]([CH3:8])([CH3:1])[CH2:14][CH2:15][NH:16][C:17]([C:19]1[N:20]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]([F:38])([F:40])[F:39])[CH:31]=2)[C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([Cl:28])=[CH:23][CH:22]=2)=[O:18]
Reactant: CCOCC
Reactant: C[Mg]Br
Reactant: CC(C)OCCCNC(=O)c1cc2cc(Cl)ccc2n1Cc1cccc(OC(F)(F)F)c1
Solvent: C1CCOC1
Product: CC(C)(O)CCNC(=O)c1cc2cc(Cl)ccc2n1Cc1cccc(OC(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 15 %

Procedure:
A solution of 3.0M methyl magnesium bromide in diethyl ether (0.5 ml, 1.50 mmol) was added dropwise to a solution of 3-{[5-chloro-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carbonyl]amino}propionic acid ethyl ester (Example 15) (200 mg, 0.42 mmol) in THF (4 ml) under nitrogen, maintaining temperature between 0 and 5° C. After stirring at 0° C. for 2 h, the reaction was quenched by slowly pouring the reaction mixture into water (2.0 ml). Volatile solvents were then removed under reduced pressure and the aqueous residue filtered. Purification was achieved by chromatography on silica using heptane:ethyl acetate (9:1 followed by 4:1) as eluent to afford 5-chloro-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid (3-hydroxy-3-methylbutyl)amide as an off-white solid (28 mg, 15%).
Reaction SMILES: [Cl:1]C1C2C(=CC(S(N(CC3C=CC=C(OC)C=3)CC(O)=O)(=O)=O)=CC=2)C([NH:29][C:30]([NH2:32])=[NH:31])=NC=1.[H-].[Na+].[C:35]([O:39][C:40](=[O:67])[CH2:41][N:42]([S:52]([C:55]1[CH:64]=[C:63]2[C:58]([C:59]([Cl:66])=[CH:60][N:61]=[C:62]2Cl)=[CH:57][CH:56]=1)(=[O:54])=[O:53])[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([O:50][CH3:51])[CH:45]=1)([CH3:38])([CH3:37])[CH3:36].O>COCCOC>[ClH:1].[C:35]([O:39][C:40](=[O:67])[CH2:41][N:42]([S:52]([C:55]1[CH:64]=[C:63]2[C:58]([C:59]([Cl:66])=[CH:60][N:61]=[C:62]2[NH:31][C:30]([NH2:32])=[NH:29])=[CH:57][CH:56]=1)(=[O:53])=[O:54])[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([O:50][CH3:51])[CH:45]=1)([CH3:36])([CH3:37])[CH3:38]
Reactant: COc1cccc(CN(CC(=O)OC(C)(C)C)S(=O)(=O)c2ccc3c(Cl)cnc(Cl)c3c2)c1
Reactant: COc1cccc(CN(CC(=O)O)S(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cccc(CN(CC(=O)OC(C)(C)C)S(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)c1
Product: Cl
Temperature: 60 °C
Yield: 53.8 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(3-methoxybenzyl)glycine ##STR22## Guanidine hydrochloride (149 mg, 1.55 mmol) was added in one portion to a suspension of NaH (35 mg, 80% dispersion by wt in mineral oil, 1.16 mmol) in DME (10 mL) and the mixture was heated at 60° C. under N2 for 30 min. N-[(1,4-Dichloro-7-isoquinolinyl)sulphonyl]-N-(3-methoxybenzyl)glycine t-butyl ester (200 mg, 0.39 mmol) was added and the mixture heated at 90° C. for 2 h. The cooled mixture was poured into water, extracted with EtOAc (×3), and the combined organic extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was dissolved in Et2O-EtOAc and a solution of HCl in Et2O (0.5 M) was added to give a precipitate. The solid was collected by filtration, triturated with EtOAc and then dried to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(3-methoxybenzyl)glycine t-butyl ester hydrochloride (124 mg, 0.21 mmol) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:13][C:14]([C:16]2[N:17]=[CH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[C:21]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=2)[CH:20]=3)=[O:15])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[Cl:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][C:43]=1[F:44].[C:48]1(C)C=CC=CC=1>CCCCCC.C(OCC)(=O)C>[CH3:48][O:12][C:10](=[O:11])[C@@H:9]([NH:13][C:14]([C:16]1[N:17]=[CH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[C:21]([O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=1)[CH:20]=2)=[O:15])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:40]2[CH:41]=[CH:42][C:43]([F:44])=[C:38]([Cl:37])[CH:39]=2)=[CH:3][CH:4]=1
Reactant: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)N[C@@H](Cc4ccc(Br)cc4)C(=O)O)ncc3c2)cc1
Reactant: Cc1ccccc1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)NC(=O)c1cc2ccc(Oc3ccc(C(C)(C)C)cc3)cc2cn1

Procedure:
50 mg (0.089 mmol) of 3-(4-bromo-phenyl)-(2S)-{[7-(4-tert-butyl-phenoxy)-isoquinoline-3-carbonyl]-amino}-propionic acid was reacted with 31 mg (0.17 mmol) of 3-chloro-4-fluorophenylboronic acid in toluene as described in procedure D. Column chromatography using 8:2 hexane and ethyl acetate as an eluent gave 46 mg of title compound as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([NH2:21])=[O:20])[C:12]=3[N:11]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].[CH:22]1([NH2:25])[CH2:24][CH2:23]1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH:22]1([NH:25][CH:1]([C:4]2[CH:9]=[CH:8][C:7]([C:10]3[NH:14][C:13]4[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([NH2:21])=[O:20])[C:12]=4[N:11]=3)=[CH:6][CH:5]=2)[CH3:2])[CH2:24][CH2:23]1
Reactant: CC(=O)c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)cc1
Reactant: NC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(NC1CC1)c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of EXAMPLE 1A (0.07 g, 0.3 mmol) and cyclopropylamine (0.33 mL, 4.8 mmol) in methanol (1 mL) was treated with sodium cyanoborohydride (0.016 g, 0.3 mmol) and acetic acid (0.2 mL). The mixture was stirred at ambient temperature for 48 hours and concentrated. The residue was purified by chromatography on silica gel column with 0-10% dichloromethane/methanol/0.1% ammonium hydroxide to provide the title compound. 1H NMR (DMSO-d6) δ 9.12 (s, 2H), 8.33 (d, J=8.3 Hz, 2H), 7.88 (d, J=7.4 Hz, 1H), 7.71-7.78 (m, 4H), 7.37 (t, J=7.8 Hz, 1H), 4.59 (m, 1H), 2.57 (s, 1 Hz), 1.64 (d, J=6.6 Hz, 3H), 0.81-0.87 (m, 1H), 0.75-0.79 (m, 1H), 0.66-0.72 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[N:17]=[CH:16][C:15]([CH2:18][C:19]#N)=[CH:14][CH:13]=1.C([O:26][C:27](=O)[C@H:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[OH:29])(=O)C>>[OH:29][C@@H:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:27]([N:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:19][CH2:18][C:15]1[CH:16]=[N:17][C:12]([C:11]([F:22])([F:21])[F:10])=[CH:13][CH:14]=1)=[O:26]
Reactant: CC(=O)OC(=O)[C@@H](O)c1ccccc1
Reactant: COc1cccc(N)c1
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Product: COc1cccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)[C@@H](O)c2ccccc2)c1

Procedure:
In analogy to example 55, 3-Methoxy-phenylamine, (6-Trifluoromethyl-pyridin-3-yl)-acetonitrile & (S)-(+)-O-acetyl-L-mandelic acid were successively coupled then hydrolysed to give the target compound. MS(m/e): 431.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Mg].[CH:10]1[C:23]2[C:22](=[O:24])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:25])[C:14]=2[CH:13]=[CH:12][CH:11]=1.Cl>C1(C)C=CC=CC=1.O1CCCC1>[OH:25][C:15]1([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=2[C:22](=[O:24])[C:23]2[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Reactant: Cc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(C2(O)c3ccccc3C(=O)c3ccccc32)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 21.6 %

Procedure:
A Grignard solution, consisting of 85.5 g (0.5 mol) of 4-bromotoluene and 11.5 g of magnesium filings, is added dropwise to 104 g (0.5 mol) of anthraquinone in 2,000 ml of absolute toluene and 500 ml of absolute tetrahydrofurane at 80° C. After the dropwise addition has ended, the mixture is subsequently stirred for 6 hours at 80° C. The reaction mixture is then hydrolysed in 2,000 ml of ice water, containing hydrochloric acid. The organic phase is separated off, washed with water, dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. The solid residue is recrystallised from acetonitrile. 32.5 g (21% of theory) of 9,10-dihydro-9-hydroxy-9-(4-methylphenyl)-10-oxoanthracene of melting point 203°-209° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.C([Li])CCC.[S:14](=[O:16])=[O:15].S(Cl)(Cl)(=O)=O.[CH3:22][NH:23][CH3:24]>C(OCC)C.ClCCl>[Br:1][C:2]1[N:3]=[C:4]([S:14]([N:23]([CH3:24])[CH3:22])(=[O:16])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S=O
Reactant: CNC
Reactant: Brc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CN(C)S(=O)(=O)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38 %

Procedure:
2,6-Dibromopyridine (12 g, 50 mmol) was dissolved in diethyl ether (150 mL) and the solution was cooled to −70° C. n-Butyl lithium (1.6M in hexane, 35 mL, 55 mmol) was added slowly and the solution was stirred for 15 minutes. Sulfur dioxide gas was then passed through the mixture until a pale yellow precipitate was produced. The reaction mixture was then warmed to room temperature and the solvent was evaporated under reduced pressure. The resulting residue was triturated with petroleum ether to afford the intermediate. The salt was then suspended in dichloromethane, cooled to −70° C. and sulfuryl chloride (75 mL, 93 mmol) was added slowly. The reaction mixture was stirred for 75 minutes and dimethylamine was then added until a basic pH was achieved. The mixture was washed with water and the organic solution was dried over magnesium sulfate and concentrated in vacuo. Trituration of the residue with dichloromethane and petroleum ether afforded the title compound as a white solid in 38% yield, 5.1 g
Reaction SMILES: [CH2:1]([NH:4][CH2:5][C:6]([Cl:8])=[CH2:7])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[C:20](Cl)=[O:21]>C1C=CC=CC=1>[Cl:8][C:6](=[CH2:7])[CH2:5][N:4]([CH2:1][CH:2]=[CH2:3])[C:20](=[O:21])[C:19]1[CH:18]=[C:17]([CH3:16])[CH:25]=[C:24]([CH3:26])[CH:23]=1
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: C=CCNCC(=C)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CCN(CC(=C)Cl)C(=O)c1cc(C)cc(C)c1
Temperature: 10 °C

Procedure:
A solution was formed by dissolving N-allyl-2-chloroallylamine (0.032 moles) in 40 ml. of benzene. Then, triethylamine (0.032 moles) was added thereto. This solution was then cooled to 10°C. in an ice bath. Then, 3,5-dimethylbenzoylchloride was diluted with 40 ml. of benzene and added to the amine solution. The temperature rose to about 35°C. with triethylamine hydrogen chloride separation. The next day the reaction mixture was washed two times with diluted HCl and then two times with dilute (5% solution) sodium carbonate and dried. The solvent was removed to yield 7.0 grams of product ND30 1.5367.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][NH:7][CH:8]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[H-].[Na+].[Cl:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>CN(C=O)C>[ClH:30].[F:27][C:2]([F:1])([F:26])[C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][NH:7][CH:8]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:15]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)C(NCc1cccc(C(F)(F)F)c1)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(NCc1cccc(C(F)(F)F)c1)c1cn(C(=O)OCC)c2ccccc12
Product: Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.4 %

Procedure:
To a magnetically stirred solution of ethyl α-[3(trifluoromethyl)-benzylamino]-indole-3-acetate (1.00 g, 2.66 mmol) in 15 mL of DMF was added under nitrogen 0.112 g (2.79 mmol) of sodium hydride (60% oil dispersion). After stirring at room temperature for 10 minutes, 0.26 ml (2.79 mmol) of ethyl chloroformate was added. Stirring was continued for two hours at room temperature. At the end of this time, the reaction contents were poured into ice water, the aqueous solution extracted with ether and the ether solution washed with saturated brine and dried over anhydrous Na2SO4. Removal of the solvent in vacuo gave the crude product which was chromatographed with 80 g of silica gel using hexane-ethyl acetate (4:1) to yield 0.857 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][N:10]=2)=[CH:5][C:3]=1[NH2:4].[C:17]([O:21][C:22]([NH:24][C:25]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=S)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl>[C:31]([O:30][C:28]([NH:27][C:25]([NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])=[N:4][C:3]1[CH:5]=[C:6]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=[CH:8][C:2]=1[F:1])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: COc1ccnc(-c2ccc(F)c(N)c2)c1
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccnc(-c2ccc(F)c(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Reaction time: 18 h
Yield: 67.5 %

Procedure:
To a suspension of 2-fluoro-5-(4-methoxypyridin-2-yl)aniline (174 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (265 mg) and diisopropylethylamine (0.417 ml) in dichloromethane (10 ml) was added 1-methyl-2-chloropyridinium iodide (266 mg), and the mixture was stirred for 18 hours. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 30 g, n-hexane:ethyl acetate=3:1) to give N,N′-bis(tert-butoxycarbonyl)-N″-(2-fluoro-5-(4-methoxypyridin-2-yl)phenyl)guanidine (248 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH2:22])=[CH:18][CH:17]=1.[CH:23]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)=O>>[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH:22][C:8]2[CH:7]=[CH:6][C:5]3[C:4]([NH:1][CH2:23][C:25]4[S:26][CH:27]=[CH:28][N:29]=4)=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=2)=[CH:18][CH:17]=1
Reactant: O=Cc1nccs1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: Cc1ccc(CN)o1
Product: Cc1ccc(CNc2ccc3c(NCc4nccs4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=351.4 (M+H+), was prepared from 5-nitro-2-chloroquinoline, 5-methyl-2-furanmethanamine and 2-formylthiazole as described in example 26.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N:9]2[CH2:14][CH2:13][CH:12]([NH:15][CH3:16])[CH2:11][CH2:10]2)[N:5]=[N:4][C:3]=1[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1.C(N(CC)CC)C.[C:32]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([Cl:40])=[O:39])=[CH:36][CH:35]=1)#[N:33].Cl>C(Cl)Cl.CO>[ClH:40].[C:32]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([N:15]([CH:12]2[CH2:13][CH2:14][N:9]([C:6]3[N:5]=[N:4][C:3]([C:17]4[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=4)=[C:2]([CH3:1])[C:7]=3[CH3:8])[CH2:10][CH2:11]2)[CH3:16])=[O:39])=[CH:36][CH:35]=1)#[N:33]
Reactant: CNC1CCN(c2nnc(-c3ccc(C#N)cc3)c(C)c2C)CC1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(-c2ccc(C#N)cc2)nnc(N2CCC(N(C)C(=O)c3ccc(C#N)cc3)CC2)c1C
Yield: 95.3 %

Procedure:
Treat a solution of 4-(4,5-dimethyl-6-(4-(methylamino)piperidin-1-yl)pyridazin-3-yl)benzonitrile (90 mg, 0.28 mmol) and triethylamine (0.12 mL, 0.84 mmol) in CH2Cl2 (2.8 mL) with 4-cyanobenzoyl chloride (56 mg, 0.34 mmol). Stir the reaction at ambient temperature overnight. Wash with H2O and separate the layers. Directly purify the organic layer by flash silica gel chromatography (gradient of 0 to 2% 2 M NH3/MeOH in CH2Cl2). Concentrate to afford a white solid. Dissolve the material in MeOH and add 1.1 eq of methanolic HCl (preform by dripping acetyl chloride into MeOH). Concentrate the mixture under a stream of N2 gas and dry the residue in a vacuum oven at 45° C. to obtain the title compound as yellow solid (130 mg, 95%). ES/MS m/z 451.2 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[CH2:9]([O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1)[CH3:10]>>[CH2:9]([O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[NH:2])=[CH:14][CH:13]=1)[CH3:10]
Reactant: N#Cc1ccncc1
Reactant: CCOc1ccc(N)cc1
Product: CCOc1ccc(NC(=N)c2ccncc2)cc1
Yield: 89.3 %

Procedure:
The title compound was prepared from 4-cyanopyridine (7.58 g, 72 mmol) and 4-ethoxyaniline (10 g, 72 mmol) by following the procedure described in preparation 10 (15.70 g, yield 89.3%, purity 99.4% by HPLC). MS m/z:242.3 (M+).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.Br[CH:19]1[CH2:22][CH2:21][CH2:20]1>>[CH:19]1([N:15]2[C:13]3=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]3[N:17]=[CH:16]2)[CH2:22][CH2:21][CH2:20]1
Reactant: BrC1CCC1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Product: Oc1ccc2ncn(C3CCC3)c2n1

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and bromocyclobutane, prepared in a similar manner as the one described in Example 1.2, the title compound was obtained. LCMS m/z=190.0 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 2.07 (m, 2H), 2.67 (m, 2H), 2.78 (m, 2H), 5.24 (m, 1H), 6.95 (d, J=8.9 Hz, 1H), 8.08 (d, J=8.9 Hz, 1H), 9.33 (s, 1H).
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].[CH2:8]([Li])CCC.[C:13]([OH:18])(=[O:17])[CH:14]([CH3:16])[CH3:15].ICCCC>C1COCC1.CCCCCC>[CH3:15][C:14]([CH3:8])([CH2:16][CH2:2][CH2:1][CH3:3])[C:13]([OH:18])=[O:17]
Reactant: [Li]CCCC
Reactant: CC(C)C(=O)O
Reactant: CC(C)NC(C)C
Solvent: CCCCI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCC(C)(C)C(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 102 g (1.02 mol) of diisopropylamine (distilled from calcium hydride) in 730 ml of dry THF was stirred under argon in an ice-bath as a full bottle (1.0 mol) of solution of n-butyllithium in hexane (Alpha, 2.4 M, ca. 417 ml) was added dropwise at a rate such that the temperature held below 8°. About halfway through the addition, the ice-bath was replaced by an ice-methanol bath to better control the temperature at 0° C. throughout the rest of the addition. The resultant mixture was kept in the cold bath and stirred for 15 minutes before a 41.6 g (0.427 mol) portion of isobutyric acid was added dropwise, again keeping the temperature below 0°. Final portions of the acid were rinsed into the reaction mixture with several ml of dry THF. After another 15 minutes a 57 ml (0.499 mol) portion of 1-iodo-butane was added dropwise. After the addition was completed, the ice-bath was removed and the resultant mixture was stirred for 2 hours. The ice-bath was used again as the resultant mixture was quenched by the dropwise addition of a solution of 200 ml of concentrated hydrochloric acid in 640 ml of water. The phases were separated and the aqueous phase was back-extracted with ether. The combined extract was washed with aqueous sodium bisulfite, dried (MgSO4) and evaporated in vacuo. The residue was distilled at 20 mm to yield 56.8 g of XXIX as an oil, bp 110°-113°; nmr 0.90 (3, broad t, J=5.7 Hz), 1.18 (6, s) and 1.0-2.0 (6, m).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:21]([O:25][CH2:26][C:27]([F:44])([F:43])[C:28]([F:42])([F:41])[C:29]([F:40])([F:39])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)[CH2:22][CH2:23][CH3:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][C:35]2[CH:34]=[CH:33][C:32]([O:31][CH2:30][C:29]([F:39])([F:40])[C:28]([F:42])([F:41])[C:27]([F:43])([F:44])[CH2:26][O:25][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:37][CH:36]=2)=[O:17])=[CH:19][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCOCC(F)(F)C(F)(F)C(F)(F)COc1ccc(O)cc1
Reactant: CCCCCCCCCCOc1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCOc1ccc(C(=O)Oc2ccc(OCC(F)(F)C(F)(F)C(F)(F)COCCCC)cc2)cc1
Yield: 12.1 %

Procedure:
0.45 g (0.0016 moles) of 4-decyloxybenzoic acid and 0.58 g (0.0016 moles) of 4-(5-butoxy-2,2,3,3,4,4-hexafluoropentoxy)phenol (prepared essentially as in Example 5) were dissolved in 25 ml of methylene chloride. N,N-dicyclohexylcarbodiimide (0.35 g, 0.0017 moles) was added to the reaction mixture, followed by 0.05 g of 4-(N,N-dimethylamino)pyridine. The resultant mixture was stirred at room temperature under nitrogen for 18 hours. The resulting urea precipitate was removed from the product solution by filtration, and the filtrate was concentrated on a rotary evaporator at reduced pressure. The crude product was purified by flash chromatography on silica gel (chloroform) to yield 0.12 g of 4-(5-butoxy-2,2,3,3,4,4-hexafluoropentoxy)phenyl 4-decyloxybenzoate.