Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:13]([N:15]1[CH2:20][CH2:19][C:18]([OH:27])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])(C)(C)C.FC(F)(F)CO>>[NH2:7][C@H:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:13]([N:15]1[CH2:20][CH2:19][C:18]([OH:27])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=[O:14]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC(O)(c2ccccc2)CC1)C(C)(C)C
Solvent: OCC(F)(F)F
Product: CC(C)(C)[C@@H](N)C(=O)N1CCC(O)(c2ccccc2)CC1
Temperature: 150 °C
Yield: 128.3 %

Procedure:
A 5 mL microwave vial was charged with [(R)-1-(4-hydroxy-4-phenyl-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-carbamic acid tert-butyl ester (0.20 g, 0.51 mmol) and 2,2,2-trifluoroethanol (2.6 mL). The vial was flushed with Argon then sealed and heated at 150° C. for 4 h under microwave irradiation. The reaction mixture was concentrated to afford 0.19 g of (R)-2-amino-1-(4-hydroxy-4-phenyl-piperidin-1-yl)-3,3-dimethyl-butan-1-one as light yellow oil which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:14][O:15][CH:16]=[O:17]>C(Cl)Cl.CO>[CH3:14][O:15][C:16](=[O:17])[NH:12][CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Reactant: O=COCCl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)NCCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a stirred solution of [2-(4-nitrophenyl)ethyl]amine (6.06 g, 30 mmol) in CH2Cl2 (75 ml), MeOH (5 ml), and TEA (9.5 ml) at 0° C. was added chloromethylformate (3.39 g, 36 mmol) dropwise. The reaction mixture was stirred at room temperature for 1 hour concentrated in vacuo, and partitioned between ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated under reduced pressure to afford a yellow solid (6.6 g, 98%). Mp: 38° C., MS (ES−): 223 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[C:15]([CH3:18])[CH:16]=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33](Cl)=[O:34])[C:28]2=[O:36])=[CH:23][CH:22]=1>ClCCl.N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:19][C:33]([C:29]2[C:28](=[O:36])[N:27]([C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=3)[CH:32]=[CH:31][CH:30]=2)=[O:34])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[C:15]([CH3:18])[CH:16]=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1
Reactant: O=C(Cl)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: Cc1ccn2ncnc(Oc3ccc(N)cc3F)c12
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccn2ncnc(Oc3ccc(NC(=O)c4cccn(-c5ccc(F)cc5)c4=O)cc3F)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
To a solution of 3-fluoro-4-(5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamine (62 mg, 0.24 mmol) in dichloromethane (2 mL) and pyridine (0.5 mL), was added dropwise a solution of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonyl chloride (30 mg, 0.12 mmol) in dichloromethane (0.5 mL). The reaction mixture was stirred at rt for 30 min, and then concentrated to dryness. The residue was washed with methanol. The solid that formed was collected by filtration and dried under vaccum to give the title compound (35 mg, 61%). 1H NMR (DMSO-d6) δ 12.10 (br s, 1H), 8.58 (dd, 1H, J=7.15, 2.20 Hz), 8.12 (dd, 1H, J=6.60, 1.65 Hz), 7.98 (s, 1H), 7.95 (d, 2H, J=2.75 Hz), 7.62-7.58 (m, 2H), 7.40-7.47 (m, 4H), 6.78 (d, 1H, J=2.75 Hz), 6.72 (t, 1H, J=7.15 Hz), 2.54 (s, 3H); MS(ESI+) m/z 474.23 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH2:5][C:4]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[N:3]1[CH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[CH:24][N:25]2[S:30]([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31]>CO.[Pd]>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][C:4]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:9][CH2:8]2)[N:3]1[CH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[CH:24][N:25]2[S:30]([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(CN4C(=O)C=CCC45CCN(C(=O)OC(C)(C)C)CC5)cccc32)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(CN4C(=O)CCCC45CCN(C(=O)OC(C)(C)C)CC5)cccc32)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.8 %

Procedure:
To a solution of tert-butyl 2-oxo-1-((1-tosyl-1H-indol-4-yl)methyl)-1,9-diazaspiro[5.5]undec-3-ene-9-carboxylate (0.12 g, 0.218 mmol) in methanol (6.0 mL) was added 10% Pd/C and the reaction mixture was stirred for 6 h under hydrogen (1 atm. pressure) at rt. The reaction mixture was filtered through a pad of celite and washed with methanol. The filtrate was concentrated and the product was isolated as a white solid (0.120 g, 99%). LCMS RtA=0.511, [M+H]+=551.9
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-])=O)[CH:4]=1.C(O)C>[Pd].C(OCC)(=O)C>[NH2:10][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[OH:9]
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(O)c(N)c1
Reaction time: 72 h
Yield: 83 %

Procedure:
A mixture of 4-methoxy-2-nitrophenol (30.2 g, 0.18 mol), 10% Pd/C, ethanol (200 mL), and ethyl acetate (200 mL) was hydrogenated at ambient pressure and temperature for three days before it was filtered and concentrated in vacuo to give the title compound as a dark brown solid (20.78 g): 1H NMR (CDCl3, 200 MHz): δ=6.64 (m, 1H), 6.32 (m, 1H), 6.21 (m, 1H), 3.71 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[N:14]([CH3:27])[C:15](=[O:26])[C:16]([CH3:25])=[C:17]([NH:18]C4C=CC=CC=4)[C:12]=3[C:11](=[O:28])[N:10]([CH:29]3[CH2:31][CH2:30]3)[C:9]2=[O:32])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:13]2[N:14]([CH3:27])[C:15](=[O:26])[C:16]([CH3:25])=[C:17]3[C:12]=2[C:11](=[O:28])[N:10]([CH:29]2[CH2:31][CH2:30]2)[C:9](=[O:32])[N:18]3[NH:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[CH:6][CH:7]=1
Reactant: Cc1c(Nc2ccccc2)c2c(=O)n(C3CC3)c(=O)n(-c3ccc(Br)cc3)c2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1c(=O)n(C)c(Nc2ccc(Br)cc2)c2c(=O)n(C3CC3)c(=O)n(Nc3ccccc3)c12
Temperature: 25 °C
Reaction time: 10 h
Yield: 26 %

Procedure:
To 1-(4-bromo-phenyl)-3-cyclopropyl-6,8-dimethyl-5-phenylamino-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione 41 (78 mg) obtained in Step 7 was added chloroform-methanol [1:1 (volume ratio), 2.0 ml], potassium carbonate (22 mg) was added, and the mixture was stirred at room temperature for 10 hrs. The mixture was further stirred under reflux for 3 hrs, and allowed to cool to room temperature. The mixture was concentrated under reduced pressure and purified by column chromatography (chloroform:acetone=50:1) to give 5-(4-bromo-phenylamino)-3-cyclopropyl-6,8-dimethyl-1-phenylamino-1H,6H-pyrido[4,3-d]pyrimidine-2,4,7-trione 42 (23′ mg, yield 26%) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O-])=O.N>C(O)C.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2]>[NH2:1][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: [Fe+2]
Agent: N
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCO
Product: Nc1ccccc1C=O
Temperature: 100 °C

Procedure:
A mixture of 2-nitrobenzaldehyde (10.0 g, 66.2 mmol) and iron(II) sulfate heptahydrate (129 g, 464 mmol) in ethanol (150 mL) and water (150 mL) was heated at 100° C. for 5 min, and then 28% aqueous ammonia (173 mL) was added dropwise carefully at same temperature. The reaction mixture was filtrated through Celite with diethyl ether. The organic layer was washed with water and saturated brine, dried over sodium sulfate, filtrated and concentrated in vacuo to give the crude 2-aminobenzaldehyde.
Reaction SMILES: [CH2:1]([N:3](CC)CC)C.CS(Cl)(=O)=O.[CH2:13]([N:17]1[C:21]([CH2:22]O)=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:19]=[C:18]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:14][CH2:15][CH3:16]>C(#N)C.[C-]#N.C([N+](CC)(CC)CC)C>[CH2:13]([N:17]1[C:21]([CH2:22][C:1]#[N:3])=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:19]=[C:18]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1CO
Reactant: CCN(CC)CC
Agent: CC[N+](CC)(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Solvent: CC#N
Product: CCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1CC#N
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Triethylamine (1.0 ml, 7.18 mmol) and methanesulfonyl chloride (0.37 ml, 4.89 mmol) are added to a stirred solution of (3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-methanol (1.0 g, 3.26 mmol)(185) in anhydrous acetonitrile (30 mL) at 0° C. After proceeding for 1 hour the reaction is concentrated at 60° C. to remove all solvent and excess MsCl. Cold acetonitrile is added to precipitate triethylammonium chloride, which is then removed by filtration. The remaining solution of mesylate product is reduced to a 30 ml volume; tetraethylammonium cyanide (1.53 g, 9.79 mmol) is added to the solution, and the reaction is heated at 60° C. overnight. Solvent is removed in vacuo and the crude product dissolved in ethyl acetate (100 mL). The organic layer is washed with saturated sodium bicarbonate (2×100 mL), brine (1×100 mL) and dried over magnesium sulfate. The sample is filtered, concentrated and purified by flash chromatography on SiO2 using an eluent of 2:3 acetate:hexane to afford (3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetonitrile (187) as a light orange oil.
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[OH:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6]([C:5]3[CH:28]=[CH:29][C:2]([N:34]4[CH2:35][CH2:36][CH:31]([OH:30])[CH2:32][CH2:33]4)=[N:3][CH:4]=3)=[O:7])=[CH:11][N:12]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:16]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Reactant: OC1CCNCC1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(N2CCC(O)CC2)nc1

Procedure:
4-Hydroxy-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-5′-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate E and 4-hydroxypiperidine. MS calcd. for C27H25ClN4O3 [(M+H)+] 489.2, obsd. 489.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+].[Cl:32][C:33]1[C:38](B(O)O)=[CH:37][CH:36]=[CH:35][N:34]=1>O>[Cl:32][C:33]1[C:38]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=2)=[CH:37][CH:36]=[CH:35][N:34]=1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Reactant: OB(O)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccc(COc2ccc(-c3cccnc3Cl)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A first stock solution was prepared consisting of 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of Intermediate 1; 1.77 g, 4.8 mmol), bis(tri-cyclohexyl-phosphine)palladium (available from Strem Chemicals, Inc., Newburyport, Mass.; 168 mg, 0.25 mmol), and dioxane (approximately 100 mL). A second stock solution was prepared consisting of potassium carbonate (1.99 g, 14.4 mmol) and water (approximately 10 mL). The solutions were sonicated and degassed by bubbling nitrogen gas through them. 4 mL of the first stock solution and 0.4 mL of the second stock solution were added to a reaction vial containing 2-chloropyridine-3-boronic acid (ASDI Incorporated, Newark, Del.; 94 mg, 0.6 mmol). The mixture was heated in a microwave oven at 170 degrees for 25 min and then passed through a silica gel column (1 g of silica), and washed with dioxane (1 mL) and dimethylacetamide (1 mL). 2 M potassium hydroxide solution (0.4 mL) was added. The mixture was stirred at room temperature overnight, and then 1 M HCl (0.8 mL) was added and the solvents were removed in the Genevac. Aqueous methanol (50%; approximately 2 mL) was added, then the vial was centrifuged and the solvent was removed. This process was repeated and then the sample was dried overnight in the oven to give 3-[4-(2-chloro-pyridin-3-yl)-phenoxymethyl]-benzoic acid. Mass spectrum MH+=340.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:24][CH2:25][N:26]3[C:30](=[O:31])[CH2:29][S:28][C:27]3=[O:32])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.[CH:33](=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1CCCCC1>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:24][CH2:25][N:26]3[C:30](=[O:31])[C:29](=[CH:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[S:28][C:27]3=[O:32])[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: O=Cc1ccccc1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2CCN1C(=O)CSC1=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2CCN1C(=O)SC(=Cc2ccccc2)C1=O
Temperature: 70 °C
Reaction time: 12 h
Yield: 26.4 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 3-[2-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-1,3-thiazolidine-2,4-dione (100 mg, 0.22 mmol, 1.00 equiv) in ethanol (20 mL) and benzaldehyde (47 mg, 0.44 mmol, 1.98 equiv) and piperidine (479.5 mg, 5.63 mmol, 25.14 equiv) were added. The resulting solution was stirred for 12 h at 70° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (100/1) to give 31 mg (24%) of 3-[2-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-5-(phenylmethylidene)-1,3-thiazolidine-2,4-dione as a light yellow solid. LC-MS: (ES, m/z): 535 (M+H)
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:20]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:33][C:34]1[CH:49]=[CH:48][C:37]([C:38]([NH:40][CH:41]2[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]2)=[O:39])=[CH:36][CH:35]=1>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([C:38]([NH:40][CH:41]5[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]5)=[O:39])=[CH:48][CH:49]=4)=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Cl)ncc21
Reactant: CN1CCC(NC(=O)c2ccc(N)cc2)CC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: CC(C)O
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCC3)CC(F)(F)C(=O)N4C)cc2)CC1
Yield: 63.8 %

Procedure:
A mixture of 0.0605 g (0.20 mmole) 2-chloro-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-1), 0.0571 g (0.30 mmole) of toluenesulfonic acid monohydrate, 0.0467 g (0.20 mmole) of 4-amino-N-(1-methyl-piperidin-4-yl)-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 19.5 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from acetonitrile-methanol to give 0.0637 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-benzamide (I-16) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:15]([NH2:18])(=[O:17])=[O:16])=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=2)[N:7]=1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:15]([N:18]=[CH:21][N:22]([CH3:24])[CH3:23])(=[O:17])=[O:16])=[C:9]([C:11]([F:12])([F:14])[F:13])[N:10]=2)[N:7]=1
Reactant: COC(OC)N(C)C
Reactant: NS(=O)(=O)c1c(C(F)(F)F)nc2ccc(Cl)nn12
Solvent: Cc1ccccc1
Product: CN(C)C=NS(=O)(=O)c1c(C(F)(F)F)nc2ccc(Cl)nn12
Reaction time: 3.5 h

Procedure:
6-Chloro-2-trifluoromethylimidazo[1,2-b]pyridazin-3-ylsulfonamide (1.70 g, 5.65 mmol) was suspended in toluene (10.0 ml), and N,N-dimethylformamide dimethyl acetal (90%, 1.84 ml, 12.4 mmol) was added thereto and stirred for 3.5 hours under reflux. The reaction mixture was concentrated under reduced pressure. To the residue concentrated was added diisopropyl ether, and the crystals were collected by filtration to give the title compound as brown crystals. The yield was 1.96 g (97.4%).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([Cl:15])[CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](OB(O)O)=[CH:19][CH:18]=1>>[Cl:15][C:4]1[CH:3]=[C:2]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: OB(O)Oc1ccc(Cl)cc1
Reactant: CCOC(=O)COc1ccc(Br)cc1Cl
Product: CCOC(=O)COc1ccc(-c2ccc(Cl)cc2)cc1Cl

Procedure:
Prepared analogously to Example 130a from ethyl (4-bromo-2-chloro-phenoxy)-acetate (Z26) and 4-chlorophenylboric acid.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC[N:16]=C=NCCCN(C)C.ON1C(=O)CCC1=O.[OH-].[NH4+]>O1CCCC1.CN(C)C=O>[NH2:16][C:11](=[O:13])[C@@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH3:10]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: O=C1CCC(=O)N1O
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.5 %

Procedure:
To a solution containing Boc-L-alanine (1.0 g, 5.29 mmol) in a mixture of tetrahydrofuran (25 mL) and N,N-dimethylformamide (5 mL) were added EDAC (1.5 g, 7.82 mmol) and N-hydroxysuccinimide (0.91 g, 7.91 mmol) and the mixture was stirred at room temperature for 16 hours. Aqueous ammonium hydroxide solution (15 mL, 28%) was added and the mixture was stirred for 0.5 hours at room temperature. The reaction was partitioned between ethyl acetate and water, and the organic was washed with brine and dried over MgSO4, filtered and evaporated to give the product (0.483 g, 49% yield), which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:2].[H-].[Na+].[CH3:17][O:18][C:19](=[O:35])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29]Br)=[C:22]([CH2:31][CH2:32][CH3:33])[C:21]=1[OH:34]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:29][CH2:28][CH2:27][O:26][C:23]2[CH:24]=[CH:25][C:20]([C:19]([O:18][CH3:17])=[O:35])=[C:21]([OH:34])[C:22]=2[CH2:31][CH2:32][CH3:33])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Reactant: CCCc1c(OCCCBr)ccc(C(=O)OC)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2ccc(C(=O)C(=O)OCC)cc2)ccc(C(=O)OC)c1O
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 55.9 %

Procedure:
A mixture of 4-hydroxy-alpha-oxobenzeneacetic acid ethyl ester (0.47 g) and 55% sodium hydride (0.116 g) in dimethylformamide (10 mL) was stirred for 15 minutes and then treated with 4-(3-bromopropoxy)-2-hydroxy-3-propylbenzoic acid methyl ester (0.8 g) in dimethylforrnamide (5 mL). The mixture was heated at 50° C. for 20 hours and worked up as in Example 20. The residual oil was purified by flash chromatography over silica gel (ethyl acetate-hexane; 3:17) and then was crystallized from hexane to give 0.6 g of 4-[3-[3-hydroxy-4-(methoxycarbonyl)-2-propylphenoxy) propoxy]-alpha-oxobenzeneacetic acid ethyl ester, mp 62°-64° C.
Reaction SMILES: C(OC(C1C([O:24][C:25](=O)[C:26]([CH3:29])([CH3:28])[CH3:27])=C2C(C)=C(C)N(CC3C=CC=CC=3)C2=CN=1)=O)C.[CH2:31]([O:33][C:34]([C:36]1[C:37]([OH:48])=[C:38]2[C:44]([Br:45])=[C:43]([Br:46])[N:42]([CH3:47])[C:39]2=[CH:40][N:41]=1)=[O:35])[CH3:32]>>[CH2:31]([O:33][C:34]([C:36]1[C:37]([O:48][C:25](=[O:24])[C:26]([CH3:29])([CH3:28])[CH3:27])=[C:38]2[C:44]([Br:45])=[C:43]([Br:46])[N:42]([CH3:47])[C:39]2=[CH:40][N:41]=1)=[O:35])[CH3:32]
Reactant: CCOC(=O)c1ncc2c(c(C)c(C)n2Cc2ccccc2)c1OC(=O)C(C)(C)C
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2C
Product: CCOC(=O)c1ncc2c(c(Br)c(Br)n2C)c1OC(=O)C(C)(C)C

Procedure:
Prepared in analogy to that of 1-benzyl-4-(2,2-dimethyl-propionyloxy)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester from 2,3-Dibromo-4-hydroxy-1-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester. The title product, 1H NMR (200 MHz, CDCl3): δ (ppm)=8.62 (s, 1H), 4.42 (q, 2H, J=7.0 Hz), 3.94 (s, 3H), 1.49 (s, 9H), 1.42 (t, 3H, J=7.0 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:13]=[CH:12][NH:11][N:10]=1.Cl[CH2:15][C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:16]([CH2:15][N:11]1[CH:12]=[CH:13][C:9]([C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[N:10]1)#[N:17]
Reactant: N#CCCl
Reactant: Fc1cccc(F)c1-c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCn1ccc(-c2c(F)cccc2F)n1
Temperature: 25 °C
Yield: 47.7 %

Procedure:
3.0 g of 3-(2,6-difluorophenyl)pyrazole was dissolved in 20 ml of acetonitrile, and 2.52 g of chloroacetonitrile and 4.61 g of potassium carbonate were added thereto at room temperature, and heated under reflux for 5 hours. After acetonitrile was distilled off under reduced pressure, ethyl acetate was added to the residue, which was then washed with a small amount of water. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residual product was recrystallized from a mixed solvent of isopropylether and diethyl ether to obtain 1.74 g of 1-cyanomethyl-3-(2,6-difluorophenyl)pyrazole.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:15])[CH:12](Cl)[F:13])=[CH:8][S:7][CH:6]=1)=[O:4].[Cl:16][C:17]1[CH:18]=[C:19]([OH:24])[CH:20]=[CH:21][C:22]=1[Cl:23]>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][C:22]=1[Cl:23])[O:24][CH:12]([F:13])[C:11]([NH:10][C:9]1[C:5]([C:3]([OH:2])=[O:4])=[CH:6][S:7][CH:8]=1)=[O:15]
Reactant: COC(=O)c1cscc1NC(=O)C(F)Cl
Reactant: Oc1ccc(Cl)c(Cl)c1
Product: O=C(O)c1cscc1NC(=O)C(F)Oc1ccc(Cl)c(Cl)c1

Procedure:
In analogy to Example 58, the title compound was prepared using 4-(2-chloro-2-fluoro-acetylamino)-thiophene-3-carboxylic acid methyl ester and 3,4-dichlorophenol. MS (m/e): 362.0 (M−H).