Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][CH:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([N:26]([CH3:35])[C:27]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:28])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1.[C:36](Cl)(=[O:39])[CH:37]=[CH2:38]>C(Cl)Cl>[C:36]([NH:10][CH:11]1[CH2:12][CH2:13][N:14]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([N:26]([CH3:35])[C:27]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:28])=[CH:24][CH:25]=2)(=[O:18])=[O:19])[CH2:15][CH2:16]1)(=[O:39])[CH:37]=[CH2:38]
Reactant: C=CC(=O)Cl
Reactant: CN(C(=O)C1CCOCC1)c1ccc(S(=O)(=O)N2CCC(N)CC2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)NC1CCN(S(=O)(=O)c2ccc(N(C)C(=O)C3CCOCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.4 %

Procedure:
Diisopropylethylamine (0.34 ml, 2.1 mmol) was added in one portion to a stirred solution of tetrahydro-pyran-4-carboxylic acid [4-(4-amino-piperidine-1-sulfonyl)-phenyl]-methyl-amide (0.17 g, 0.4 mmol) in DCM (10 ml), followed by the drop wise addition of acryloyl chloride (0.04 ml, 0.42 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the mixture was diluted with DCM (20 ml) and washed sequentially with HCl (1M solution, 10 ml), NaOH (1M solution, 10 ml) and brine (10 ml). The organic layer was separated, dried (MgSO4), filtered, concentrated and the resulting residue was purified by flash column chromatography (elution: 97% EtOAc, 3% Methanol) to give the title compound (0.032 g, 18% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([OH:26])=[CH:10][C:11]([CH2:17][C:18]3[C:19]([NH2:25])=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)=[CH:12][C:13]=2[O:14][CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1.[CH:27]([S:31](Cl)(=[O:33])=[O:32])([CH2:29][CH3:30])[CH3:28]>>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH2:15][CH3:16])=[CH:12][C:11]([CH2:17][C:18]3[C:19]([NH2:25])=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)=[CH:10][C:9]=2[O:26][S:31]([CH:27]([CH2:29][CH3:30])[CH3:28])(=[O:33])=[O:32])[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(C)S(=O)(=O)Cl
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(O)c1-c1cccc(N)c1
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)C(C)CC)c1-c1cccc(N)c1
Yield: 67.4 %

Procedure:
Starting from 3′-amino-4-(2,4-diamino-pyrimidin-5-ylmethyl)-6-ethoxy-biphenyl-2-ol (176 mg; 0.50 mmol) and sec-butyl-sulphonyl chloride (94 mg; 0.60 mmol), 159 mg of the title compound are isolated as a white solid.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:24])[CH:7]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:8][C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:2]([CH3:4])[CH3:3].C(O)(=O)C>C1(C)C=CC=CC=1>[F:20][C:19]([F:22])([F:21])[C:18]([NH:17][C:7]1[C:6](=[O:24])[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=1)=[O:23]
Reactant: CC(C)CNC(=O)C(CC(=O)c1ccccc1)NC(=O)C(F)(F)F
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)CN1C(=O)C(NC(=O)C(F)(F)F)=CC1c1ccccc1
Yield: 87.1 %

Procedure:
A solution of N-isobutyl-4-oxo-4-phenyl-2-[(trifluoroacetyl)amino]butanamide (0.500 g, 1.45 mmol) and acetic acid (0.831 mL, 14.5 mmol) in toluene (15 mL) was heated to reflux. After 48 hours the reaction was cooled and concentrated. The crude product was purified by chromatography (silica gel, 0 to 50% ethyl acetate in hexane gradient elution) to give the title compound as a solid (0.412 g). MS 327 (M+1) 1H NMR (500 MHz, CDCl3) □ 7.40-7.36 (m, 3H), 7.20 (d, J=2.0 Hz, 1H), 7.12-7.11 (m, 2H), 5.12 (d, J=2.0 Hz, 1H), 3.53 (dd, J=13.9, 9.4 Hz, 1H), 2.61 (dd, J=13.9, 5.9 Hz, 1H), 1.89-1.80 (m, 1H), 0.87 (d, J=6.6 Hz, 3H), 0.84 (d, J=6.6 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]2[O:10][C@@:9]([CH3:14])([C:11]([OH:13])=[O:12])[CH2:8][CH2:7][C:6]=2[C:15]=1[CH3:16].O.[C:20]1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]2[O:10][C@@:9]([CH3:14])([C:11]([O:13][CH3:20])=[O:12])[CH2:8][CH2:7][C:6]=2[C:15]=1[CH3:16]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1c(C)c2c(c(C)c1O)CC[C@](C)(C(=O)O)O2
Solvent: O
Solvent: CO
Product: COC(=O)[C@@]1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reaction time: 4 h

Procedure:
A solution of 2 g (8 mmol) of optically pure (R)-(+)-3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl2 H-1-benzopyran-2-carboxylic acid (1) and 0.1 g of p-toluenesulphonic acid monohydrate in 40 ml methanol were stirred and re-fluxed for 4 hours. After cooling, the solution was diluted with water, extracted three times into ether that was subsequently washed with brine and aqueous sodium bicarbonate solution. The ether solution was washed, dried with MgSO4 and evaporated to give (R)-(+)-methyl 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2 H- 1-benzopyran-2 carboxylate (2).
Reaction SMILES: OC1C=C([NH:8][C:9]2[N:14]=[C:13]([NH:15]C3C=CC=C(O)C=3)[C:12]([F:23])=[CH:11][N:10]=2)C=CC=1.ClC1N=C(Cl)C(F)=CN=1>>[F:23][C:12]1[C:13]([NH2:15])=[N:14][C:9]([NH2:8])=[N:10][CH:11]=1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Agent: Fc1cnc(Cl)nc1Cl
Product: Nc1ncc(F)c(N)n1

Procedure:
In a manner similar to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-isoptopoxyaniline were reacted to yield N2,N4-bis(4-isopropoxy)phenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.89 (bs, 1H), 7.47 (d, 2H, J=8.7 Hz), 7.38 (d, 2H, J=9.0 Hz), 6.87 (d, 2H, J=9.0 Hz), 6.83 (d, 2H, J=8.7 Hz); LCMS: ret. time: 27.51 min.; purity: 98%; MS (m/e): 397 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:27][C:28]1[CH:29]=[C:30]([C:34]2[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([O:44][CH3:45])[CH:35]=2)[CH:31]=[N:32][CH:33]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=2)[CH2:27][C:28]2[CH:29]=[C:30]([C:34]3[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([O:44][CH3:45])[CH:35]=3)[CH:31]=[N:32][CH:33]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(-c2cncc(CCl)c2)cc(OC)c1OC
Reactant: CCCCOc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: CCCCOc1ccc(N(Cc2cncc(-c3cc(OC)c(OC)c(OC)c3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
1-(tert-Butoxycarbonyl)-4-[(4-butoxyphenyl)amino]piperidine (697 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[CH:4][N:3]=1.[NH2:11][C:12]([CH3:22])([CH3:21])[C:13]([NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[O:14].CCN(C(C)C)C(C)C>C1COCC1>[Cl:8][C:6]1[C:5]([C:9]#[N:10])=[CH:4][N:3]=[C:2]([NH:11][C:12]([CH3:22])([CH3:21])[C:13]([NH:15][CH2:16][C:17]([F:18])([F:19])[F:20])=[O:14])[N:7]=1
Reactant: N#Cc1cnc(Cl)nc1Cl
Reactant: CC(C)(N)C(=O)NCC(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(Nc1ncc(C#N)c(Cl)n1)C(=O)NCC(F)(F)F
Temperature: 90 °C

Procedure:
2,4-dichloropyrimidine-5-carbonitrile (E. F. Godefroi, J. Org. Chem., 1962, 27(6), 2264-6) (0.10 g, 0.57 mmol), 2-amino-2-methyl-N-(2,2,2-trifluoroethyl)propanamide.1TFA (Meinke, Peter T.; Shih, Thomas L.; Fisher, Michael H., U.S. Pat. No. 6,221,894 B1) (0.171 g, 1.14 mmol) and DIPEA (0.39 mL, 2.29 mmol) were combined in anhydrous THF (5 mL) in a sealed tube and heated to 90° C. for 18 hours, before cooling to room temperature. The solvent was evaporated in vacuo and the residue purified by flash chromatography (40 g SiO2, pentane/ethyl acetate, 30-70% over 14 column volumes) to afford the title compound as a colorless waxy solid (0.036 g, 19.7%).
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[C:17]3[CH2:23][CH2:22][NH:21][CH2:20][C:18]=3[N:19]=2)=[CH:10][CH:9]=1)=[O:6])[CH3:3].CC1C=CC(S(O[CH2:42][C@@H:43]2[CH2:47][O:46][C:45]([CH3:49])([CH3:48])[O:44]2)(=O)=O)=CC=1.[I-].[Na+].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:48][C:45]1([CH3:49])[O:44][C@H:43]([CH2:42][N:21]2[CH2:22][CH2:23][C:17]3[C:16]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])=[N:15][C:14]([C:11]4[CH:10]=[CH:9][C:8]([NH:7][C:5]([NH:4][CH2:2][CH3:3])=[O:6])=[CH:13][CH:12]=4)=[N:19][C:18]=3[CH2:20]2)[CH2:47][O:46]1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C[C@@H]2COC(C)(C)O2)C3)cc1
Yield: 64.7 %

Procedure:
A solution of (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride (jk) (270 mg, 0.69 mmol), (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (377 mg, 132 mmol), sodium iodide (104 mg, 0.69 mmol), DIPEA (0.48 mL, 2.8 mmol), and DMF (1.0 mL) was heated at 110° C. for 22 h. The mixture was partitioned between ethyl acetate and sat. NaHCO3. The phases were separated, and the aqueous layer extracted with ethyl acetate (2×). The combined organic phases were dried over Na2SO4, filtered and concentrated onto Celite, and the residue chromatographed: ISCO 12 g column 0-20% IPA in DCM to afford 228 mg (64%) of the title compound jz as an off-white solid: LC-MS: m/z=+511 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][NH:5][C:4](=[O:9])[N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][CH2:19][CH2:20][Cl:21].O>CS(C)=O>[Cl:21][CH2:20][CH2:19][CH2:18][CH2:17][N:5]1[CH:6]=[C:7]([CH3:8])[C:2](=[O:1])[NH:3][C:4]1=[O:9]
Reactant: Cc1c[nH]c(=O)nc1O
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cn(CCCCCl)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 41 %

Procedure:
10.1 g (80.0 mmol) of 4-hydroxy-5-methylpyrimidin-2(1H)-one (thymine) in 300 ml of dimethyl sulfoxide (DMSO) and 11.1 g (80.0 mmol) of K2CO3 were stirred at room temperature for 1 hour. Then 13.7 g (80.0 mmol) of 1-bromo-4-chlorobutane were added dropwise to the mixture, and the reaction mixture was then stirred at room temperature for 5 hours. Water was added to the reaction mixture, and it was then extracted with ethyl acetate. The aqueous phase was then neutralized and extracted with methylene chloride. Drying of the organic phase, removal of the desiccant by filtration and evaporation of the solvent to dryness in vacuo resulted in 7.1 g of the title compound
Reaction SMILES: C(OC([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:24]([C:33]([NH:35][C:36]2[CH:44]=[CH:43][C:39]([C:40]([OH:42])=[O:41])=[CH:38][C:37]=2[O:45][CH3:46])=[O:34])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.[ClH:47].O1CCOCC1>O1CCOCC1>[ClH:47].[CH3:46][O:45][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][C:36]=1[NH:35][C:33]([N:24]1[CH2:25][C@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:22]([CH2:21][NH:8][C@@H:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH2:23]1)=[O:34])[C:40]([OH:42])=[O:41]
Reactant: COc1cc(C(=O)O)ccc1NC(=O)N1C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c2cccc3ccccc23)[C@@H](c2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(C(=O)O)ccc1NC(=O)N1C[C@H](CN[C@H](C)c2cccc3ccccc23)[C@@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An 8.0 ml 1,4-dioxane solution of 226 mg of 4-({[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin 1-yl]carbonyl}amino)-3-methoxybenzoic acid was mixed with 2.0 ml of 4 M hydrogen chloride/1,4-dioxane at room temperature and stirred overnight at room temperature. The solvent was evaporated under a reduced pressure, and the residue was crystallized with 1,4-dioxane-diisopropyl ether to obtain 180 mg of 3-methoxy-4-({[(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}amino)benzoic acid hydrochloride as a beige solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].[La:24]>CC(O)=O.CN(C=O)C>[La:24].[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:22][CH3:23])[N:13]=[CH:12][CH:11]=[C:10]2[O:9][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[CH:3][CH:2]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: [La]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reaction time: 19 h

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline [starting compound A] (415 mg) was dissolved in 10 ml of a 1% AcOH/DMF solution to prepare a solution. Further, aldehyde linker lanthanum (D-series; 28 μmol/unit) (10 units) was added to the solution. The reaction mixture was slowly shaken for 19 hr. Sodium boron triacetoxyhydride (475 mg) was added thereto, and the mixture was further slowly shaken for 24 hr. Lanthanum was taken out of the reaction solution and was washed with alternate N,N-dimethylformamide and dichloromethane each three times, followed by drying under the reduced pressure to give lanthanum with 4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline supported thereon. This lanthanum (3 units) was added to 1 ml of dichloromethane, and a solution of N-(chlorocarbonyl)isocyanate [starting compound B] (55 μl) in dichloromethane (0.2 ml) was added to the mixture at 0° C. The mixture was slowly shaken overnight at room temperature. Further, a mixed solution composed of aniline [starting compound C] (68 μl), diisopropylamine (0.2 ml), and dichloromethane (0.3 ml) was then added thereto at 0° C. The mixture was shaken at room temperature for 7 hr and was then washed with alternate N,N-dimethylformamide and dichloromethane each five times. Drying under the reduced pressure was carried out, a 50% TFA/dichloromethane solution (1 ml) was added thereto, and the mixture was shaken at room temperature for 50 min to take off the product from lanthanum, followed by purification by thin layer chromatography on silica gel to give 6.8 mg of the title compound.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC[C:45]1[CH:50]=[CH:49][CH:48]=C[C:46]=1[C:51]([F:54])([F:53])[F:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:48]=[CH:49][CH:50]=[CH:45][C:46]=3[C:51]([F:54])([F:53])[F:52])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3ccccc3C(F)(F)F)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2-(trifluoromethyl)benzene and isolated as colorless gum (8.5 mg, 47%). MS (m/e): 441.4 (MH+).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=[O:2].[CH2:24](Br)[CH:25]([CH3:27])[CH3:26]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([O:3][CH2:24][CH:25]([CH3:27])[CH3:26])=[O:2])([CH2:9][CH2:8]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: CC(C)CBr
Product: CC(C)COC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Yield: 60.5 %

Procedure:
In a similar manner to Example 8, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (20.0 mg) and isobutyl bromide (9.3 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-(2-methylpropyl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (14.2 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[C:4]([CH3:11])[CH:3]=1.[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:25]=[N:26][CH:27]=[C:28]([NH2:30])[CH:29]=3)=[O:23])=[CH:20][N:19]([CH:31]([CH3:33])[CH3:32])[C:15]=2[N:16]=[CH:17][N:18]=1>N1C=CC=CC=1>[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:29]=[C:28]([NH:30][C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=4[CH3:11])=[O:10])[CH:27]=[N:26][CH:25]=3)=[O:23])=[CH:20][N:19]([CH:31]([CH3:33])[CH3:32])[C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: Cc1cc(Cl)ccc1N=C=O
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2c(N)ncnc21
Solvent: c1ccncc1
Product: Cc1cc(Cl)ccc1NC(=O)Nc1cncc(C(=O)c2cn(C(C)C)c3ncnc(N)c23)c1
Temperature: 45 °C
Yield: 83.3 %

Procedure:
4-Chloro-1-isocyanato-2-methyl-benzene (93.3 mg, 0.56 mmol) was added to a solution of (4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(5-amino-pyridin-3-yl)-methanone (150 mg, 0.51 mmol) in pyridine (5 mL). The mixture was heated to 45° C. for 12 h. The reaction mixture was concentrated in vacuo and the resulting yellow solid was triturated with CH2Cl2, filtered, and washed with CH2Cl2. Purification by flash column chromatography [(10% NH4OH/MeOH)/ethyl acetate 2:98] afforded the title compound as a white solid (197 mg, 83%). MS: 464.1 (MH+); HPLC Rf: 5.55 min. (HPLC method 4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:22])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([O:16]CC)=[O:15])=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20].S(=O)(=O)(O)O>O>[Cl:22][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=[O:15])=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 78.1 %

Procedure:
Ethyl 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylate (1.8 g, 4.74 mmol) was added to a solution of concentrated sulfuric acid (10 mL) diluted with water (20 mL), and the resulting mixture was heated at 100° C. for 5 hours. After this time, the mixture was poured into ice (4.5 mL) and stirred at room temperature for 20 minutes, then the resulting solid was collected by filtration, washed with water and dried in vacuo at 40° C. overnight to afford the title product as a white solid (1.3 g, 78% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.0 (2H, s), 8.1 (1H, s). MS m/z: 350.85, 352.90 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:22]=[C:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[C:14]5[CH:21]=[CH:20][CH:19]=[C:16]([C:17](=[O:18])[N:8]3[C:6]=2[CH:7]=1)[C:15]=45.O1CCCC1.[CH3:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][N:46]=[C:47]=[O:48].[N-]=C=O>CCOCC>[CH2:45]([NH:46][C:47](=[O:48])[NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:22]=[C:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[C:14]5[CH:21]=[CH:20][CH:19]=[C:16]([C:17](=[O:18])[N:8]3[C:6]=2[CH:7]=1)[C:15]=45)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH3:28]
Reactant: Nc1ccc2nc3c4cccc5cccc(c(=O)n3c2c1)c54
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Agent: [N-]=C=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCNC(=O)Nc1ccc2nc3c4cccc5cccc(c(=O)n3c2c1)c54

Procedure:
A 5.7 g portion of the 10-amino-benzimidazo[2,1-a]benz[de]isoquinoline-7-one was added to 200 ml of distilled tetrahydrofuran in a 500 ml flask. To this mixture was added 5.9 g of Mondur O (octodecyl isocyanate) and 0.3 g of 1,4-diazobicyclo-octane. The mixture was stirred with a magnetic stirring bar and brought to reflux. The mixture was refluxed until no isocyanate peak was visible at 2240 cm-1 on infrared spectraphotometric analysis (~48-72 hours). It was then cooled and the solvent removed on the rotary evaporator. The solid thus obtained was ground to a fine powder, stirred in ether, filtered and dried in the vacuum oven. The yield was 10.7 g of 10 octadecylureido benzimidazo [2,1-a]benz[de]isoquinoline-7-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=O)[NH:7][C:6]=2[CH:17]=1.P(Cl)(Cl)([Cl:20])=O.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([Cl:20])=[N:7][C:6]=2[CH:17]=1
Reactant: O=C1Nc2cc(Cl)ccc2Nc2ccccc21
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: ClC1=Nc2cc(Cl)ccc2Nc2ccccc21
Temperature: 25 °C
Yield: 57.9 %

Procedure:
A mixture of amide 9 (1.39 g, 5.70 mmol), phosphorus oxychloride (1.6 mL, 17.1 mmol) and N-dimethylaniline (2.9 mL, 22.8 mmol) in benzene (10 mL) was heated at reflux for 2 hours. The reaction mixture was then cooled to room temperature and excess of phosphorus oxychloride, N-dimethylaniline and benzene were removed at reduced pressure. The resulting residue was dissolved in dioxane (20 mL) and 2 M Na2CO3 (30 mL 0.06 mol) and then heated at 80° C. for 1 hour. The reaction mixture was cooled to room temperature and dioxane was removed at reduced pressure and the resulting aqueous solution was extracted with EtOAc (30 mL). The organic phase was washed with water, brine, dried (Na2SO4), filtered and solvent evaporated. The resulting crude residue was purified by column chromatography (10% ethyl acetate in hexanes) to afford title compound 10 (869 mg, 58%) as an orange solid. LRMS (ESI): (calc) 262.01. (found) 263.1 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[C:38]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)(=[O:40])[CH3:39]>>[C:38]([N:41]1[CH2:46][CH2:45][N:44]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:43][CH2:42]1)(=[O:40])[CH3:39]
Reactant: CC(=O)N1CCNCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: CC(=O)N1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCCCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and N-acetylpiperazine according to conditions described in general procedure C. Mp: 102-104° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.58-1.61 (m, 6 H), 1.96 (s, 3 H), 3.28-3.30 (m, 4 H), 3.36 (s, 4 H), 3.47-3.51 (m, 4 H), 6.25 (d, J=5.5 Hz, 1 H), 6.94-6.98 (m, 1 H), 7.15 (d, J=8.8 Hz, 1 H), 7.42 (d, J=8.0 Hz, 1 H), 7.46 (s, 1 H), 7.54-7.62 (m, 3 H), 7.82-7.84 (m, 1 H), 7.98-8.00 (m, 1 H), 8.28 (d, J=5.5 Hz, 1 H), 10.44 (s, 1 H).