Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:13]=[CH:14][C:15]([F:28])=[C:16]([NH:18][C:19]([C:21]4[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=4)=[O:20])[CH:17]=3)=[N:7][N:6]2[CH:29]=1.C(N(CC)CC)C.[CH:37]1([S:40](Cl)(=[O:42])=[O:41])[CH2:39][CH2:38]1.O>CN1CCCC1=O>[CH:37]1([S:40]([NH:2][C:3]2[N:4]=[C:5]3[CH:10]=[CH:9][C:8]([O:11][C:12]4[CH:13]=[CH:14][C:15]([F:28])=[C:16]([NH:18][C:19]([C:21]5[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=5)=[O:20])[CH:17]=4)=[N:7][N:6]3[CH:29]=2)(=[O:42])=[O:41])[CH2:39][CH2:38]1
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2F)n(C)n1
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NS(=O)(=O)C5CC5)cn4n3)ccc2F)n(C)n1
Temperature: 70 °C
Reaction time: 16 h
Yield: 15.7 %

Procedure:
To a solution of N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide.hydrochloride (400 mg, 0.97 mmol) in 1-methyl-2-pyrrolidone (4.0 mL) were added triethylamine (404 μL, 2.90 mmol) and cyclopropanesulfonyl chloride (204 mg, 1.45 mmol), and the mixture was stirred at 70° C. for 16 hr. After cooling the mixture to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate alone) and precipitated from hexane/ethyl acetate to give the title compound (74 mg, 16%) as a white powder.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([NH2:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(Cl)Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:1][C@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([NH2:9])=[O:8])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)C[C@@H](N)C(N)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(N)=O
Reaction time: 24 h

Procedure:
The above polymer-bound D-Leu-NH2 (20 g) was treated with CH2Cl2 (150 mL), pyridine (100 mL) and 4-chlorophenylsulfonyl chloride (20.0 g, 94.8 mmol). The mixture was shaken for 24 h, drained, washed with DMF (4×200 mL), CH2Cl2 (4×200 mL) and concentrated to give polymer-bound (R)-2-(4-chlorobenzenesulfonylamino)-4-methylpentanoic acid amide as a yellow resin (22 g). The completion of the reaction and the loading of the resin (0.57 mmol/g) were determined by the treatment of 50 mg of the resin with 10% (v/v) TFA/CH2Cl2 (2 mL) to give 8.7 mg of (R)-2-(4-chlorobenzenesulfonylamino)-4-methylpentanoic acid amide.
Reaction SMILES: B1(B2C3CCCC2CCC3)C2CCCC1CCC2.[NH2:19][C:20]1[C:21]2[C:28]([C:29]3[CH:30]=[N:31][C:32]4[C:37]([CH:38]=3)=[CH:36][CH:35]=[CH:34][CH:33]=4)=[C:27](Br)[N:26]([CH2:40][C@@H:41]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[CH:42]=[CH2:43])[C:22]=2[N:23]=[CH:24][N:25]=1.[OH-].[Na+]>COCCOC>[NH2:19][C:20]1[C:21]2[C:28]([C:29]3[CH:30]=[N:31][C:32]4[C:37]([CH:38]=3)=[CH:36][CH:35]=[CH:34][CH:33]=4)=[C:27]3[N:26]([C:22]=2[N:23]=[CH:24][N:25]=1)[CH2:40][C@@H:41]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:42][CH2:43]3
Reactant: C=C[C@@H](Cn1c(Br)c(-c2cnc3ccccc3c2)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Agent: C1CC2CCCC(C1)B2B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@H]1CCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2C1
Temperature: 48 °C
Reaction time: 0.67 h
Yield: 74.9 %

Procedure:
9-Borabicyclo[3.3.1]nonane dimer (431 mg) was added to a solution of (S)-tert-butyl (1-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate (300 mg) obtained in Reference Example 1 in 1,2-dimethoxyethane (4.5 ml) under a nitrogen atmosphere at room temperature, and the mixture was stirred at 48° C. for 40 minutes. After the mixture was allowed to cool to room temperature, a 4 N sodium hydroxide aqueous solution (2.1 ml) was slowly added to the reaction mixture at room temperature, and degassed under reduced pressure. Under a nitrogen atmosphere, (tetrakistriphenylphosphine)palladium(0) (136 mg) was added thereto, and stirred at 79° C. for 5 hours. After the reaction mixture was cooled, and diluted with ethyl acetate, a saturated ammonium chloride aqueous solution was added. The insoluble matter resulting in this stage was removed by filtration, and the organic layer was separated. The resulting organic layer was dried over anhydrous sodium sulfate and filtered, and then concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (developing solvent: ethyl acetate/methanol) to obtain (S)-tert-butyl (4-amino-5-(quinolin-3-yl)-6,7,8,9-tetrahydropyrimido[5,4-b]indolizin-8-yl)carbamate (0.190 g) (yield: 75%) as a light-yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.Br[C:37]#[C:38][Si:39]([CH:46]([CH3:48])[CH3:47])([CH:43]([CH3:45])[CH3:44])[CH:40]([CH3:42])[CH3:41]>C1(C)C=CC=CC=1.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([C:37]#[C:38][Si:39]([CH:40]([CH3:42])[CH3:41])([CH:46]([CH3:48])[CH3:47])[CH:43]([CH3:45])[CH3:44])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CC(C)[Si](C#CBr)(C(C)C)C(C)C
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C#C[Si](C(C)C)(C(C)C)C(C)C)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 49.9 %

Procedure:
To a stirred solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (10 g, 0.05 mol) and copper sulfate (1.24 g, 0.005 mol) in toluene (200 mL) was added potassium carbonate (13.8 g, 0.1 mol) and 1,10 phenanthroline (1.8 g, 0.01 mol). The reaction mixture was stirred for 5 min at RT. (Bromoethynyl) triisopropylsilane (14.4 g, 0.055 mol) was added to the reaction mixture at the same temperature. After completion of addition, the reaction mixture was stirred overnight at 80° C. The reaction was monitored by TLC. After completion of reaction, the mixture was cooled to RT, diluted with water (500 mL), and extracted with EtOAc (3×500 mL). The organic layer was dried over anhydrous sodium sulfate and solvent was removed under reduced pressure. The crude product was purified by column chromatography (1% MeOH:DCM in silica 100-200 mesh, diameter of column—5 cm, height of silica—approx. 5 inch) to provide the desired compound as a dark brown colored oil (9.5 g, 50% yield).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])[C:4](=[O:9])[C:5]([Cl:8])=[CH:6][N:7]=1.[CH3:19][C@@:20]1([NH2:26])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1>>[NH2:26][C@:20]1([CH3:19])[CH2:25][CH2:24][CH2:23][N:22]([C:2]2[N:3]([CH2:10][C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])[C:4](=[O:9])[C:5]([Cl:8])=[CH:6][N:7]=2)[CH2:21]1
Reactant: N#Cc1ccccc1Cn1c(Cl)ncc(Cl)c1=O
Reactant: C[C@@]1(N)CCCNC1
Product: C[C@@]1(N)CCCN(c2ncc(Cl)c(=O)n2Cc2ccccc2C#N)C1
Yield: 65 %

Procedure:
The title compound was prepared in 65% yield from 2-(2,5-dichloro-6-oxo-6H-pyrimidin-1-ylmethyl)-benzonitrile (Example 15B) and (R)-3-methyl-piperidin-3-ylamine according to the general procedure outlined for Example 1 and was isolated as the HCl salt. 1H NMR (400 MHz, DMSO-d6): δ 8.43 (br s, 3H), 8.09 (s, 1H), 7.80 (d, 1H, J=7.6 Hz), 7.64 (t, 1H, J=7.6 Hz), 7.45 (t, 1H, J=7.6 Hz), 7.22 (d, 1H, J=7.6 Hz), 5.39 (AB q, 2H, J=98.0, 14.8 Hz), 3.39-3.47 (m, 1H), 3.01-3.15 (m, 2H), 2.80-2.90 (m, 1H), 1.81-2.00 (m, 2H), 1.56-1.66 (m, 2H), 1.30 (m, 3H). MS (ES) [m+H] calc'd for C18H20N5OCl, 358, 360; found 358, 360.
Reaction SMILES: [CH2:1]([C:3]1[NH:7][N:6]=[C:5]([NH2:8])[CH:4]=1)[CH3:2].[Cl:9][C:10]1[N:15]=[C:14](Cl)[C:13]([Cl:17])=[CH:12][N:11]=1.C([O-])([O-])=O.[Na+].[Na+].O>C(O)(C)C>[Cl:9][C:10]1[N:15]=[C:14]([NH:8][C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[NH:7][N:6]=2)[C:13]([Cl:17])=[CH:12][N:11]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CCc1cc(N)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CCc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-ethyl-1H-pyrazol-3-amine (1.00 g, 6.77 mmol), 2,4,5-trichloropyrimidine (1.24 g, 6.77 mmol) and Na2CO3 (1.79 g, 16.9 mmol) in iso-propanol (15 mL) was stirred in a sealed vial at rt for two days. Water (10 mL) was added. The solid was collected by filtration, washed with water (10 mL) and dried to give 2,5-Dichloro-N-(5-ethyl-1H-pyrazol-3-yl)pyrimidin-4-amine as a light yellow solid; ESMS m/z 258.0 (M+H+).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[CH:9]=[CH:10][N:11]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12](=[O:16])[C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28].C[O-].[Na+]>>[CH2:17]([N:11]1[CH:10]=[CH:9][C:8]2[CH:7]=[N:6][C:5]([C:3]([NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:4])=[C:14]([OH:15])[C:13]=2[C:12]1=[O:16])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1ncc2ccn(Cc3ccccc3)c(=O)c2c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2ccn(Cc3ccccc3)c(=O)c2c1O
Yield: 67.2 %

Procedure:
A mixture of 6-benzyl-4-hydroxy-5-oxo-5,6-dihydro-[2,6]naphthyridine-3-carboxylic acid methyl ester (25 mg, 0.081 mmol), β-alanine (956 mg, 10.7 mmol) and NaOMe solution (16 mL, 8.06 mmol, 0.5 M in MeOH) was refluxed for 16 h. Solvent was evaporated in vacuo, and the residue was partitioned between water and EtOAc. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The crude solid was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH about 2 with 4 M HCl, and then extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 20 mg of the title compound. MS: (+) m/z 368.00 (M+1).
Reaction SMILES: S(Cl)([Cl:3])=O.[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][CH2:11][CH2:12]O>C1COCC1>[Cl:3][CH2:12][CH2:11][CH2:10][C:6]1[S:5][CH:9]=[CH:8][CH:7]=1
Reactant: OCCCc1cccs1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Product: ClCCCc1cccs1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (420 μL, 5.7 mmol) was added to a solution of 3-(2-thienyl)propanol (682.0 mg, 4.8 mmol) in THF (3 mL) at room temperature. The reaction mixture was stirred at 50° C. for 2 hours and then concentrated to dryness to afford the title compound as a brown oil. The product was used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[C:5]([O:40][C:41]([F:44])([F:43])[F:42])[CH:4]=1)#[N:2].[OH:45]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[C:5]([O:40][C:41]([F:42])([F:43])[F:44])[CH:4]=1)(=[O:45])[NH2:2]
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2OC(F)(F)F)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(N)=O)cc2OC(F)(F)F)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 10 °C
Reaction time: 1 h
Yield: 22.5 %

Procedure:
To the solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-trifluoromethoxy-phenyl)-amide (40 mg, 0.06 mmol) prepared in Example 145 in DMSO (1 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.1 g, 0.9 mmol), then aqueous solution (1N) of NaOH (0.3 mL, 0.3 mmol) was added dropwise. The reaction mixture was stirred at 10° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (0-100% EtOAc in dichlormethane) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-2-trifluoromethoxy-phenyl)-amide as a white solid (Yield 9 mg, 22%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[CH:20]=[CH:19][N:18]=[C:17]3[C:12]=2[C:13]2[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=2[C:15](=[O:21])[NH:16]3)[CH:6]=[CH:7][CH:8]=1.C([O-])=O.[NH4+]>O1CCOCC1.[Pd].[C]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][N:18]=[C:17]3[C:12]=2[C:13]2[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=2[C:15](=[O:21])[NH:16]3)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C#Cc2ccnc3[nH]c(=O)c4ccccc4c23)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: COc1cccc(CCc2ccnc3[nH]c(=O)c4ccccc4c23)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 30.3 %

Procedure:
Compound 160 (45 mg, 0.14 mmol), ammonium formate (100 mg, 1.60 mmol), and Pd/carbon (100 mg, 10% by weight, wet) were suspended in dioxane (2 mL), and stirred for 4 h at 70° C. The reaction mixture was filtered, and purified via Biotage eluting with a gradient of 25 to 75 EtOAc in hexanes to provide 162 (14 mg, 31% yield) as a white solid. LC-MS (M+H=331, obsd.=331).
Reaction SMILES: CN(CCN(C)C)C.[C:9]([O:13][C:14](=[O:22])[NH:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)([CH3:12])([CH3:11])[CH3:10].[C:23](=[O:25])=[O:24].[OH-].[Na+]>C1COCC1>[C:9]([O:13][C:14]([NH:15][C:16]1[C:21]([C:23]([OH:25])=[O:24])=[CH:20][N:19]=[CH:18][CH:17]=1)=[O:22])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)Nc1ccncc1
Reactant: O=C=O
Agent: CN(C)CCN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccncc1C(=O)O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 30 %

Procedure:
n-Buli (1.6 M soln, 155 mL, 249 mmol) was added to a stirred solution of TMEDA (37.36 mL, 249 mmol) in THF at −40° C. The solution was allowed to come at room temperature over 10 min and stirred for another 10 min. The solution was cooled to −78° C. A solution of pyridine-4-yl-carbamic acid-tert-butyl ester (117) (22 g, 113.26 mmol) in THF was added slowly. The solution was allowed to come at room temperature within 3 h. After stirring at room temperature for 15 min the solution was again cooled to −78° C. and a freshly crushed dry ice was added. The solution was allowed to come at room temperature, stirred for 30 min and poured into ice cold 10% NH4Cl solution. The solution was basified by 1N NaOH solution and washed by dichloromethane. The pH of aqueous phase was adjusted to 4 by cold 10% HCl solution. The solids formed were filtered, washed by water and dried under vacuum at room temperature to yield 16.3 g (30%) 4-tert-butoxycarbonylamino-nicotinic acid (118) as white solids. MP: 260° C.; 1H-NMR (DMSO-d6): δ 1.49 (s, 9H), 8.23 (d, J=6.0 Hz, 1H), 8.55 (d, J=6.0 Hz, 1H), 8.96 (s, 1H); EIMS m/z 238 (M+1).
Reaction SMILES: [CH:1]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]1[CH2:15][S:12](=[O:14])(=[O:13])[O:11][CH2:10]1.[K+].[Br-]>C1COCC1>[CH:1]1([NH:8][CH2:10][CH2:9][CH2:15][S:12]([OH:14])(=[O:13])=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S1(=O)CCCO1
Reactant: NC1CCCCCC1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=S(=O)(O)CCCNC1CCCCCC1
Temperature: 25 °C
Yield: 72 %

Procedure:
Cycloheptylamine (3.9 mL, 30 mmol) was added to a solution of 1,3-propane sultone (4.1 g, 33 mmol) in THF (65 mL). The mixture was heated at reflux for 5 hours with a heating mantle. The mixture was cooled to room temperature and the solid was collected by filtration, and then dried in a vacuum oven for 1 hour at 60° C. (6.21 g). The solid material was dissolved in methanol/water (30 mL/3 mL, v/v). The solution was cooled slowly to room temperature, and further cooled with an ice-bath. The solid product was collected by filtration, rinsed with methanol, air-dried for 15 minutes, and further dried in a vacuum oven at 60° C. Compound CK was obtained as small white flakes (5.08 g, 72% yield). m.p. 341-43° C. 1H NMR (500 MHz, D2O) δ 1.21-1.42 (m, 8H), 1.45-1.51 (m, 2H), 1.79-1.89 (m, 4H), 2.76 (7, J=7.3 Hz, 2H), 2.96 (t, J=7.8 Hz, 2H), 3.35 (m, J=4.6 Hz, 1H). 13C NMR (125 MHz, D2O) δ 21.6, 23.3, 27.3, 30.5, 43.6, 48.0, 59.6. FT-IR (KBr) vmax 2924, 1615, 1464, 1243.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][C:17]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>>[C:11]([C:9]1[CH:8]=[N:7][N:6]2[C:2]([C:19]3[CH:20]=[CH:21][C:16]([F:15])=[C:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH:18]=3)=[CH:3][N:4]=[C:5]2[N:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: OB(O)c1ccc(F)c(-c2ccccn2)c1
Reactant: CC(C)(C)c1cnn2c(Br)cnc2n1
Product: CC(C)(C)c1cnn2c(-c3ccc(F)c(-c4ccccn4)c3)cnc2n1
Yield: 29 %

Procedure:
This compound was prepared in 29% yield as described in the final paragraph of Example 2, step d, but using 7-bromo-3-tert-butylimidazo[1,2-b][1,2,4]triazine instead of 7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine, and using 4-fluoro-3-(pyridin-2-yl)phenylboronic acid instead of 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile: 1H NMR (400 MHz, CDCl3) δ 1.50 (9H, s), 7.29-7.33 (2H, m), 7.80 (1H, m), 7.86 (1H, m), 8.07 (1H, m), 8.25 (1H, s), 8.59 (1H, s), 8.66 (1H, dd, J 2.3, 7.4 Hz), 8.77 (1H, m); MS (ES+) m/z 348 M+H]+. Anal. Found: C, 66.95; H, 5.15; N, 19.00%. Required for C20H18FN5.0.75H2O: C, 66.56; H, 5.45; N, 19.41%.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:13]=[CH:12][C:6]2[O:7][C:8]([F:11])([F:10])[O:9][C:5]=2[CH:4]=1.[C-:14]#[N:15].[Na+]>CS(C)=O>[F:10][C:8]1([F:11])[O:7][C:6]2[CH:12]=[CH:13][C:3]([CH2:2][C:14]#[N:15])=[CH:4][C:5]=2[O:9]1
Reactant: FC1(F)Oc2ccc(CCl)cc2O1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ccc2c(c1)OC(F)(F)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
A mixture of crude 5-chloromethyl-2,2-difluoro-benzo[1,3]dioxole (4.4 g) and sodium cyanide (1.36 g, 27.8 mmol) in dimethylsulfoxide (50 mL) was stirred at room temperature overnight. The reaction mixture was poured into ice and extracted with ethyl acetate (300 mL). The organic layer was dried over sodium sulfate and evaporated to dryness to give crude (2,2-difluoro-benzo[1,3]dioxol-5-yl)-acetonitrile (3.3 g) which was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([OH:12])[N:3]=1.[CH3:13][CH:14]([CH3:18])[CH2:15][CH2:16][NH2:17].C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:17][CH2:16][CH2:15][CH:14]([CH3:18])[CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([OH:12])[N:3]=1
Reactant: CC(C)CCN
Reactant: Nc1nc(O)c([N+](=O)[O-])c(Cl)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)CCNc1nc(N)nc(O)c1[N+](=O)[O-]

Procedure:
2-Amino-4-chloro-6-hydroxy-5-nitropyrimidine (4 g), 3-methylbutylamine (1.8 g) and triethylamine (6 ml) were heated at reflux for 5 h then left stirring overnight at room temperature in ethanol. The precipitate was filtered and washed with water and air dried to yield the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[N:16]([CH2:18][CH3:19])[C:15](=[O:20])[C:14]([C:21]3[CH:22]=[C:23]([CH:27]=[C:28]([F:31])[C:29]=3[CH3:30])[C:24]([OH:26])=O)=[N:13][C:12]=2[CH:11]=[N:10]1.C(Cl)(=O)C(Cl)=O.[NH2:38][C:39]1[CH:43]=[CH:42][O:41][N:40]=1.CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[N:16]([CH2:18][CH3:19])[C:15](=[O:20])[C:14]([C:21]3[CH:22]=[C:23]([CH:27]=[C:28]([F:31])[C:29]=3[CH3:30])[C:24]([NH:38][C:39]3[CH:43]=[CH:42][O:41][N:40]=3)=[O:26])=[N:13][C:12]=2[CH:11]=[N:10]1
Reactant: CCn1c(=O)c(-c2cc(C(=O)O)cc(F)c2C)nc2cnn(-c3ccc(F)cc3F)c21
Reactant: Nc1ccon1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1c(=O)c(-c2cc(C(=O)Nc3ccon3)cc(F)c2C)nc2cnn(-c3ccc(F)cc3F)c21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-(1-(2,4-difluorophenyl)-7-ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[4,3-b]pyrazin-5-yl)-5-fluoro-4-methylbenzoic acid (360 mg, 0.84 mmol) in 5.0 mL of DCM was treated with oxalyl chloride (0.84 mL of 2.0 M in DCM solution, 1.68 mmol) followed by two drops of DMF while cooling in an ice bath at 0° C. It was stirred at this temperature for 15 min then allowed to stir at RT for 45 min. The reaction mixture was then concentrated under reduce pressure to remove the excess oxalyl chloride. The residue was dissolved in 5.0 mL of DCM, treated with 3-aminoisoxazole (212 mg, 2.52 mmol) followed by Et3N (0.18 mL, 1.26 mmol) and stirred for 18 h. The reaction mixture was treated with 15 mL saturated NaHCO3 and extracted with DCM (2×15 mL). The combined DCM layers were dried over MgSO4. Purification on the ISCO (12 g column, 20-70% EtOAc in hexanes) afforded 3-(1-(2,4-difluorophenyl)-7-ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[4,3-b]pyrazin-5-yl)-5-fluoro-N-(isoxazol-3-yl)-4-methylbenzamide as a light yellow amorphous solid. MS (ES+): 495.1 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.O[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=1>>[N:12]1[CH:13]=[CH:14][C:9]([N:6]2[CH2:5][CH2:4][CH:3]([CH2:2][O:1][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=3)[CH2:8][CH2:7]2)=[CH:10][CH:11]=1
Reactant: OCC1CCN(c2ccncc2)CC1
Reactant: COC(=O)CCc1ccc(O)cc1
Product: COC(=O)CCc1ccc(OCC2CCN(c3ccncc3)CC2)cc1
Yield: 14 %

Procedure:
Following the method of Example 96, but starting from 4-(4-hydroxymethylpiperidin-1-yl)pyridine and methyl 3-(4-hydroxyphenyl)propionate, the title compound was prepared in 14% yield:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][CH2:18][CH2:17]3)=[O:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:23](I)[CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH2:23][CH3:24])[CH2:18][CH2:17]3)=[O:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(CCC(=O)c2ccc3c(c2)CCN3)CC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCN1CCc2cc(C(=O)CCC3CCN(C(C)=O)CC3)ccc21
Yield: 97.2 %

Procedure:
In 10 ml of ethanol were dissolved 0.8 g of 5-[3-(1-acetylpiperidin-4-yl)-1-oxopropyl]-2,3-dihydro-1H-indole, 2.1 g of ethyl iodide and 0.5 g of potassium carbonate and the solution was refluxed for 24 hours. The solid matter and the solvent were removed and the residue was purified by column chromatography (eluent: ethyl acetate: methanol=20:1) to give 0.85 g of the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[C:5]([CH2:7][C:8]#[N:9])=O.Cl.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C@@H:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[CH:28]=2)[C@@H:24]([NH2:26])[CH3:25])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][C@@H:23]([C:27]2[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=2)[C:33]#[N:34])[C@@H:24]([NH:26][CH:5]([C:4]2[CH:3]=[C:2]([F:1])[CH:12]=[C:11]([F:13])[CH:10]=2)[CH2:7][C:8]#[N:9])[CH3:25])=[CH:20][CH:21]=1
Reactant: N#CCC(=O)c1cc(F)cc(F)c1
Reactant: C[C@H](N)[C@@H](Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Agent: Cl
Product: C[C@H](NC(CC#N)c1cc(F)cc(F)c1)[C@@H](Cc1ccc(Cl)cc1)c1cccc(C#N)c1

Procedure:
This compound was synthesized according to the procedure of Example 33 from 205 mg (1.13 mmol) of 3,5-difluorobenzoyl-acetonitrile and 300 mg (0.93 mmol) of 3-(4-chlorophenyl)-2(S)(3-cyanophenyl)-1(S)-methyl-propylamine hydrochloride. LC-MS: m/e=450 (M+1), 452 (M+3) (3.55 min).