Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([NH:23][CH2:24][C@H:25]4[CH2:29][CH2:28][CH2:27][O:26]4)[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[C:30](O)(=[O:32])[CH3:31].C([BH3-])#N.[Na+]>CO>[O:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([NH:12][C:13]3[N:14]=[C:15]([NH:23][CH2:24][C@H:25]4[CH2:29][CH2:28][CH2:27][O:26]4)[C:16]4[CH2:22][N:21]([CH2:31][CH2:30][OH:32])[CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:10][CH:11]=2)=[CH:4][N:3]=[CH:2]1
Reactant: CC(=O)O
Reactant: c1ncc(-c2ccc(Nc3nc4c(c(NC[C@H]5CCCO5)n3)CNCC4)cc2)o1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: OCCN1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(NC[C@H]3CCCO3)c2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 20.9 %

Procedure:
(R)-N2-(4-(Oxazol-5-yl)phenyl)-N4-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (135 mg, 0.34 mmol) was dissolved in methanol (3 mL). Acetic acid (0.020 mL, 0.34 mmol) was added followed by (R)-N2-(4-(oxazol-5-yl)phenyl)-N4-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (135 mg, 0.34 mmol). The reaction mixture was stirred at room temperature for 15 minutes and sodium cyanoborohydride (21.62 mg, 0.34 mmol) (MP—CNBH3) was added and the reaction was stirred overnight. The crude was filtered, concentrated under reduced pressure, dissolved in methanol, filtered and purified by preparative HPLC yielding (R)-2-(2-(4-(oxazol-5-yl)phenylamino)-4-((tetrahydrofuran-2-yl)methylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanol (31.0 mg, 18.15%) as acetate salt. MS (ES+) m/z 437.3 (M+H)+;
Reaction SMILES: [C:1](=[O:6])([O:4][CH3:5])OC.C[O-].[Na+].[CH3:10][O:11][C:12]1[C:13]([O:24][CH3:25])=[CH:14][C:15]2[S:21][CH2:20][CH2:19][CH2:18][C:17](=[O:22])[C:16]=2[CH:23]=1.Cl>>[CH3:10][O:11][C:12]1[C:13]([O:24][CH3:25])=[CH:14][C:15]2[S:21][CH2:20][CH2:19][CH:18]([C:1]([O:4][CH3:5])=[O:6])[C:17](=[O:22])[C:16]=2[CH:23]=1
Reactant: COC(=O)OC
Reactant: COc1cc2c(cc1OC)C(=O)CCCS2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: COC(=O)C1CCSc2cc(OC)c(OC)cc2C1=O
Temperature: 0 °C
Yield: 79 %

Procedure:
To dimethyl carbonate (87 g) is added sodium methoxide (10.5 g), to the mixture is added 7,8-dimethoxy-3,4-dihydro-1-benzothiepin-5(2H)-one(11.0 g) obtained in Reference Example 7. The mixture is heated for two hours under reflux. The reaction mixture is poured into ice-water and acidified (pH 3) with 2N hydrochloric acid, followed by extraction with ethyl acetate. The organic layer is washed with a saturated aqueous saline solution, dried, and concentrated under reduced pressure. The residue is recrystallized from hexane - methylene chloride to afford methyl 7,8-dimethoxy5-oxo-2,3,4,5-tetrahydro-1-benzothiepin-4-carboxylate as colorless needles (10.8 g), m.p. 132°-133° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23](Cl)=[N:24][C:17]=2[N:16]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])[C:15]1=[O:34])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:24][C:17]=2[N:16]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])[C:15]1=[O:34])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1CCNC1
Reactant: O=c1c2cc(F)c(Cl)nc2n(-c2ccccc2F)c(=O)n1OCc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=c1c2cc(F)c(N3CCCC3)nc2n(-c2ccccc2F)c(=O)n1OCc1ccccc1
Yield: 84.6 %

Procedure:
Using the method of Example N-4, pyrrolidine (0.04 mL, 0.52 mmol), 3-benzyloxy-7-chloro-6-fluoro-1-(2-fluorophenyl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example R-2, 0.15 g, 0.42 mmol) and triethylamine (0.36 mL, 2.6 mmol) were combined in 20 mL of acetonitrile to give 0.16 g of the title compound as a solid, mp 221-222° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.O1CCOCC1.Cl[CH2:27][CH2:28][S:29]([F:32])(=[O:31])=[O:30]>O>[F:32][S:29]([CH2:28][CH2:27][NH:4][C:3]1[CH:5]=[C:6]([NH:9][C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][C:2]=1[CH3:1])(=[O:31])=[O:30]
Reactant: CC(=O)Nc1ccc(C)c(N)c1
Reactant: O=S(=O)(F)CCCl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(C)c(NCCS(=O)(=O)F)c1

Procedure:
2-Methyl-5-acetamido aniline (49.2 g, 0.3 m), triethyl amine (32.7 g, 0.3 m) and p-dioxane (350 ml) are stirred together at room temperature. 2-Chloroethane sulfonylfluoride (43.0 g, 0.3 m) is added dropwise allowing temperature to rise to 45° C. The reaction mixture is then heated at reflux for 3 hrs. When thin-layer chromatography shows reaction to be complete, the reaction is allowed to cool and then drowned into water (2000 ml). The product is collected by filtration, washed with water and melts at 154°-155° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].II.[CH2:11]([N:18]1[CH2:24][CH2:23][C:22]([Cl:25])=[C:21]([CH:26]=[O:27])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)C>[CH2:11]([N:18]1[CH2:24][CH2:23][C:22]([Cl:25])=[C:21]([CH:26]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[OH:27])[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=CC1=C(Cl)CCN(Cc2ccccc2)CC1
Reactant: Brc1ccccc1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: OC(C1=C(Cl)CCN(Cc2ccccc2)CC1)c1ccccc1
Reaction time: 0.25 h
Yield: 323 %

Procedure:
136.6 g brombenzol in 300 mL diethylether was added to 21.2 g magnesium in 100 mL diethylether. The Grignard reaction is initiated with a small amount of iodine, kept at reflux by adding the bromebenzole and stirred additional 15 min for completion. Then, 21.2 g 1-benzyl-5-chloro-2,3,6,7-tetrahydro-1H-azepine-4-carbaldehyde in 300 mL diethylether was added. The mixture was stirred 2 h at 50° C. and quenched with 200 ml 6 M HCl solution at 0° C. The reaction was filtered and the filtrate was washed with diethylether and water. The filtrate was dissolved in sodium carbonate solution and chloroform. The layers were separated and the organic layer was washed with water and evaporated to give 89.9 g of the desired product. Fp:124° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([CH2:10][OH:11])[C:7]([O:12][CH2:13][CH3:14])=[CH:6][C:5]=2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH2:3][CH2:2]1>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[CH:1]1([C:4]2[CH:9]=[C:8]([CH:10]=[O:11])[C:7]([O:12][CH2:13][CH3:14])=[CH:6][C:5]=2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH2:3][CH2:2]1
Reactant: CCOc1cc(-c2cccc(F)c2)c(C2CC2)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCOc1cc(-c2cccc(F)c2)c(C2CC2)cc1C=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
Manganese dioxide (5.47 g) was added to a toluene (80 mL) solution of (2-cyclopropyl-5-ethoxy-3′-fluorobiphenyl-4-yl)methanol (1.80 g), and the mixture was stirred at 60° C. for 1 hour in a nitrogen atmosphere. The reaction mixture was filtered, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.14 g).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4](I)[N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)[N:3]=1
Reactant: Oc1ccc(I)nc1Br
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Oc1ccc(-c2ccc(Cl)cc2)nc1Br
Temperature: 80 °C
Yield: 51.7 %

Procedure:
A mixture of 2-bromo-6-iodopyridin-3-ol (0.65 g, 2.167 mmol), 4-chlorobenzeneboronic acid (339 mg, 2.167 mmol) and potassium carbonate (749 mg, 5.419 mmol) in dimethoxyethane (15 mL) and water (5 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (125.2 mg, 0.108 mmol) was added and the reaction mixture heated to 80° C. in a sealed vial for 15 hours. The cooled reaction mixture was partitioned between ethyl acetate (50 mL) and saturated aqueous ammonium chloride solution (50 mL), the organic phase separated, washed with water (50 mL) and saturated brine (50 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give a yellow syrup. The crude product was purified by chromatography on silica eluting with a solvent gradient of 0 to 40% ethyl acetate in hexanes to give 2-bromo-6-(4-chlorophenyl)pyridin-3-ol (0.319 g, 52% yield) as a yellow crystalline solid.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[C:11]([OH:26])[CH:12]=[CH:13][C:14]=3[NH:18]C(=O)OC(C)(C)C)[C:9]2=[O:27])[CH2:6][CH2:5][C:4](=[O:28])[NH:3]1.FC(F)(F)C(O)=O>>[NH2:18][C:14]1[CH:13]=[CH:12][C:11]([OH:26])=[C:10]2[C:15]=1[C:16](=[O:17])[N:8]([CH:7]1[CH2:6][CH2:5][C:4](=[O:28])[NH:3][C:2]1=[O:1])[C:9]2=[O:27]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(O)c2c1C(=O)N(C1CCC(=O)NC1=O)C2=O

Procedure:
deprotecting tert-butyl 2-(2,6-dioxopiperidin-3-yl)-7-hydroxy-1,3-dioxoisoindolin-4-ylcarbamate with trifluoroacetic acid to form 4-amino-2-(2,6-dioxopiperidin-3-yl)-7-hydroxyisoindoline-1,3-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[N+:17]([O-])=O)=[CH:4][CH:3]=1>O1CCCC1.[Ni]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[NH2:17])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1NCc1ccc(Cl)cc1
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cc(F)ccc1NCc1ccc(Cl)cc1
Yield: 91.6 %

Procedure:
41.7 g of 2-(4-chlorophenylmethylamino)-5-fluoronitrobenzene, prepared in Example 1, are dissolved in 1 l of tetrahydrofuran and hydrogenated at ordinary temperature and pressure in the presence of 5 g of Raney nickel. When the theoretical amount of hydrogen has been absorbed, the catalyst is filtered off and the solvent is evaporated off under vacuum to give 34.1 g of 2-(4-chlorophenylmethylamino)-5-fluoroaniline in the form of crystals melting at 99° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:18]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[C:3]=12.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34]([N:38]=[C:39]=[O:40])[CH:35]=[CH:36][CH:37]=1>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:18]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:39]([NH:38][C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:30])([F:41])[F:42])[CH:33]=4)=[O:40])=[CH:13][CH:12]=3)[C:3]=12
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](n2nc(-c3ccc(N)cc3)c3c(N)ncnc32)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](n2nc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of (S)-tert-butyl 3-(4-amino-3-(4-aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate (0.035 g, 0.09 mmol) in CH2Cl2 (10 mL) was cooled in an ice-water bath. To this, 3-(trifluoromethyl)phenyl isocyanate (0.012 mL, 0.09 mmol) diluted in CH2Cl2 (5 mL) was added dropwise. The reaction was allowed to warm to room temperature and left stirring for 6 hours. The reaction proceeded until completion as judged by TLC and LC-MS, was concentrated in vacuo, resuspended in 50:50 H2O—CH3CN, and purified on a C18 column in CH3CN/H2O/0.1% TFA (1-100% gradient) to afford AD78. ESI-MS m/z [M+H]+ found 583.5, calculated 583.2.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH2:28]([O:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)[CH2:29][CH2:30][CH3:31]>C1COCC1>[CH2:28]([O:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[CH:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:35][CH:34]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCOc1ccc(C=O)cc1
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCCOc1ccc(C=CCCCC(=O)O)cc1
Yield: 72.8 %

Procedure:
This compound was synthesized from 4-carboxybutyltriphenylphosphonium bromide (8.86 g, 20 mmol) and p-butoxybenzaldehyde (3.56 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Crystallization (petroleum ether) afforded the product (3.82 g, 73%) as white crystals (mp: 56-57° C.). IR: 3350-2500, 1700 cm-1 ; 1H-NMR: 1.00 (t, 3H), 1.50 (m, 2H), 1.80 (m, 4H), 2.40 (m, 4H), 3.90 (t, 2H), 5.50+6.00 (m, 1H), 6.38 (q, 1H), 7.05 (q, 4H), 11.00 (bs, 1H). Anal. Calcd. for C16H22O3 : C, 73.25, H, 8.45%; Found: C, 73.32, H, 8.46%. Z:E=37:63.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([O-:16])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.O1CCCC1.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: CC(C)n1ncc2c(C(=O)[O-])cc(Br)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)n1ncc2c(C(=O)O)cc(Br)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To a solution of 6-bromo-1-(1-methylethyl)-1H-indazole-4-carboxylate (0.58 g, 1.952 mmol in methanol (12 mL) and tetrahydrofuran (3 mL) was added 3 N NaOH (3.25 mL, 9.76 mmol) via syringe and stirred for 3 h at RT. The volatiles were removed in vacuo then diluted with water and slowly acidified with 1 N HCl to pH 4-5. The contents were extracted with 20% THF/EtOAc (3×). The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated to give 6-bromo-1-(1-methylethyl)-1H-indazole-4-carboxylic acid (0.52 g, 94% yield). 1H NMR (400 MHz, DMSO-d6) d ppm 13.54 (s, 1H) 8.36-8.43 (m, 2H) 7.82 (d, J=1.52 Hz, 1H) 5.11 (quin, J=6.57 Hz, 1H) 1.48 (s, 3H) 1.47 (s, 3H); LC-MS (ES) [M+H]+ 283.4/285.2
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:25])[CH2:12][CH2:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][C:16]=2[CH3:24])[CH2:7][CH2:6]1.[C:28]([O:32][C:33]([N:35]1[CH2:41][C:40]2[CH:42]=[CH:43][CH:44]=[CH:45][C:39]=2[NH:38][CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.ClCCl>[C:28]([O:32][C:33]([N:35]1[CH2:41][C:40]2[CH:42]=[CH:43][CH:44]=[CH:45][C:39]=2[N:38]([C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:15]([CH2:14][CH2:13][CH2:12][C:11]([N:8]3[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C:2]([CH3:1])([CH3:27])[CH3:26])[CH2:6][CH2:7]3)=[O:25])=[C:16]([CH3:24])[CH:17]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCNc2ccccc2C1
Reactant: Cc1cc(C(=O)O)ccc1CCCC(=O)N1CCN(CCC(C)(C)C)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)Cc3ccccc32)ccc1CCCC(=O)N1CCN(CCC(C)(C)C)CC1
Yield: 28 %

Procedure:
WSCD (58 mg, 0.30 mmol) and DMAP (18 mg, 0.15 mmol) were added to a solution of 4-{4-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-4-oxo-butyl}-3-methyl-benzoic acid from Example E43 (55 mg, 0.15 mmol) and 1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester (73 mg, 0.30 mmol) in dichloromethane (3 ml) and DIEA (0.052 ml, 0.30 mmol). The mixture was heated at reflux for 5 days, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to yield the title compound (25 mg, 28%).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][C:6]([CH3:8])=[N:5][CH2:4][NH:3]1>[Ni]>[CH3:1][C:2]1([CH3:9])[CH2:7][CH:6]([CH3:8])[N:5]=[CH:4][NH:3]1
Reactant: CC1=NCNC(C)(C)C1
Agent: [Ni]
Product: CC1CC(C)(C)NC=N1

Procedure:
A sample of 12 g. of 4,4,6-trimethyl-2,3,4,5-tetrahydropyrimidine and 1.0 g. of W-2 Raney nickel were heated under a hydrogen atmosphere at 178° C. for 18 hrs. to yield 4,4,6-trimethyl-3,4,5,6-tetrahydropyrimidine identical to the product described in example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)=O.[CH2:18]([CH:20]([CH2:26][CH3:27])[C:21](=O)[CH2:22][C:23]#[N:24])[CH3:19]>>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:21]([CH:20]([CH2:26][CH3:27])[CH2:18][CH3:19])[C:22]([C:23]#[N:24])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1
Reactant: CCC(CC)C(=O)CC#N
Reactant: Nc1ccc(Cl)cc1C(=O)c1cccc(Cl)c1
Product: CCC(CC)c1nc2ccc(Cl)cc2c(-c2cccc(Cl)c2)c1C#N

Procedure:
The title compound was prepared in analogy to example 101 step B from (2-amino-5-chloro-phenyl)-(3-chloro-phenyl)-methanone (prepared as described in example 91 step A) and 4-ethyl-3-oxo-hexanenitrile (prepared as described in example 101 step A). Light yellow oil. MS (ESI): 369.3 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].C(OC([N:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:35]([C:37]2[CH:38]=[N:39][C:40]([NH2:43])=[CH:41][CH:42]=2)=[O:36])[CH2:30][CH2:29]1)=O)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10]([NH:43][C:40]3[CH:41]=[CH:42][C:37]([C:35](=[O:36])[NH:34][CH:31]4[CH2:32][CH2:33][NH:28][CH2:29][CH2:30]4)=[CH:38][N:39]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc(N)nc2)CC1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)NC4CCNCC4)cn3)nc2n1C1CCCC1
Yield: 40.2 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (25 mg, 0.85 mmol) and 4-[(6-amino-pyridine-3-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (27 mg, 0.094 mmol), followed by deprotection using 0.6 mL of TBAF in 2 mL of THF to give 7-cyclopentyl-2-[5-(piperidin-4-ylcarbamoyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (18 mg, 72%). MS(ESI) m/z 424.2 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24](Br)[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([F:35])[CH:29]=1.C(N(CC)CC)C.[H][H]>CO.CN(C)C=O.[Pd]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[CH:24][CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([F:35])[CH:29]=1
Reactant: [H][H]
Reactant: C[C@H](Nc1ncnc(N)c1-c1ccc(O)c(F)c1)c1nn2ccc(Br)c2c(=O)n1-c1ccccc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CN(C)C=O
Product: C[C@H](Nc1ncnc(N)c1-c1ccc(O)c(F)c1)c1nn2cccc2c(=O)n1-c1ccccc1
Reaction time: 48 h
Yield: 0 %

Procedure:
(S)-2-(1-((6-Amino-5-(3-fluoro-4-hydroxyphenyl)pyrimidin-4-yl)amino)ethyl)-5-bromo-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (150 mg, 0.28 mol) was dissolved in 10 mL methanol and 2 mL dimethylformamide. Triethylamine and palladium on carbon were added under nitrogen atmosphere and the mixture was submitted at 30 psi of hydrogen conditions for 4 h. Further catalyst was added and the mixture was hydrogenated at 30 psi for 48 h. The reaction mixture was filtered off and evaporated to dryness. The residue was purified by reverse phase using SP1® Purification System and then was purified by normal phase (0% to 100%, hexane-ethyl acetate) to give 5 mg (4%) of the title compound as a solid. Purity 99%.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11](Cl)=[O:12].Cl.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>C(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:25]1[CH2:26][CH2:27][CH2:28][C@@H:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([O:16][CH3:15])[CH:18]=2)[CH2:24]1)=[O:12]
Reactant: COc1cccc(C2CCCNC2)c1
Reactant: O=C(Cl)[C@H]1COc2ccccc2O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc([C@@H]2CCCN(C(=O)[C@H]3COc4ccccc4O3)C2)c1
Reaction time: 1 h

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxine-2-carbonyl chloride (54 mg, 0.27 mmol) was dissolved in DCM (4 ml). 3-(3-Methoxyphenyl)piperidine HCl (72 mg, 0.26 mmol) and triethylamine (59 mg, 0.58 mmol) were added. After stirring for 1 h, acidic work-up as above gave the crude product, which was purified by flash chromatography using heptane/EtOAc as eluent. The second eluting diastereomer was collected to give 19 mg of A14.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[O:23][CH3:24].[CH2:25]([N:27]1[CH:32]=[C:31]([C:33](O)=[O:34])[C:30](=[O:36])[N:29]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[C:28]1=[O:44])[CH3:26]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:33]([C:31]2[C:30](=[O:36])[N:29]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[C:28](=[O:44])[N:27]([CH2:25][CH3:26])[CH:32]=2)=[O:34])=[CH:18][C:17]=1[O:23][CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3OC)c2cc1OC
Reactant: CCn1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Product: CCn1cc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(OC)c2)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
This compound was synthesized using 4-(6,7-dimethoxy-quinolin-4-yloxy)-3-methoxy-phenylamine and 1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid using the procedure for example 1. mp=245-247° C.; LCMS m/z=587 (M+1); 1H NMR (DMSO-d6) δ: 10.98 (s, 1H), 8.89 (s, 1H), 8.46 (d, 1H, J=6 Hz), 7.56 (d, 1H, J=2 Hz), 7.53 (s, 1H), 7.49 (dd, 1H, J=3, 9 Hz), 7.45-7.41 (m, 2H), 7.39-7.34 (m, 3H), 7.25 (d, 1H, J=9 Hz), 6.36 (d, 1H, J=6 Hz), 4.01 (q, 2H, J=8 Hz), 3.95 (d, 6H), 3.71 (s, 3H), 1.3 (t, 3H, J=8 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH:17]([C:22]3[CH:27]=[C:26]([Cl:28])[C:25]([Cl:29])=[C:24]([Cl:30])[CH:23]=3)[C:18]([F:21])([F:20])[F:19])=[CH:11][C:8]=2[C:9]#[N:10])[N:3]=1.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>C(Cl)Cl>[C:9]([C:8]1[CH:11]=[C:12](/[CH:15]=[CH:16]/[CH:17]([C:22]2[CH:23]=[C:24]([Cl:30])[C:25]([Cl:29])=[C:26]([Cl:28])[CH:27]=2)[C:18]([F:19])([F:20])[F:21])[CH:13]=[CH:14][C:7]=1[N:4]1[CH:5]=[N:6][C:2]([NH:1][C:34]([CH:31]2[CH2:33][CH2:32]2)=[O:35])=[N:3]1)#[N:10]
Reactant: O=C(Cl)C1CC1
Reactant: N#Cc1cc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1-n1cnc(N)n1
Solvent: ClCCl
Product: N#Cc1cc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1-n1cnc(NC(=O)C2CC2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.4 %

Procedure:
To a stirred solution of (E)-2-(3-amino-1H-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzonitrile (0.15 g, 0.31 mmol) in CH2Cl2 at 0° C., were added TEA (0.1 g, 1 mmol) and cyclopropylcarbonyl chloride (0.04 g, 0.38 mmol) and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2 and washed with water and brine and dried over Na2SO4. Concentration under reduced pressure and purification by column chromatography (SiO2, 100-200 mesh) afforded the title compound as a solid (66 mg, 34%): mp 109-112° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.94 (br s, 1H), 8.36 (s, 1H), 8.08 (m, J=8.4 Hz, 1H), 7.91 (s, 2H), 7.84 (d, J=8.4 Hz, 1H), 7.13 (dd, J=15.6, 9.2 Hz, 1H), 6.87 (d, J=15.6 Hz, 1H), 4.92 (m, 1H), 1.99 (br s, 1H), 0.82 (s, 4H); ESIMS m/z 540.04 ([M+H]+); IR (thin film) 3233, 2233, 1699, 1114, 807 cm−1.