Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:25])[C:5]2[C:11]([CH3:12])=[C:10]([CH2:13][C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=3[O:22][CH3:23])[C:9](=O)[NH:8][C:6]=2[N:7]=1.C[N+](C)=C[Cl:29].[Cl-].S(Cl)(Cl)=O.N1C2C=CC=NC=2C=NC=1.N>C(Cl)(Cl)Cl.CN(C)C=O>[NH2:1][C:2]1[N:3]=[C:4]([NH2:25])[C:5]2[C:11]([CH3:12])=[C:10]([CH2:13][C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=3[O:22][CH3:23])[C:9]([Cl:29])=[N:8][C:6]=2[N:7]=1
Reactant: C[N+](C)=CCl
Reactant: COc1ccc(OC)c(Cc2c(C)c3c(N)nc(N)nc3[nH]c2=O)c1
Agent: N
Agent: [Cl-]
Agent: c1cnc2cncnc2c1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(OC)c(Cc2c(Cl)nc3nc(N)nc(N)c3c2C)c1

Procedure:
2,4-Diamino-5-methyl-6-(2,5-dimethoxybenzyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine (8 g) was chlorinated by treatment with Vilsmeier reagent prepared by slowly adding thionyl chloride (28.6 ml) in dry chloroform (25 ml) to a solution of dimethylformamide (17.5 ml) in chloroform (100 ml) at 0°-5° C. The cold mixture of the pyridopyrimidine and Vilsmeier reagent was stirred, gradually allowed to reach ambient temperature and then heated at reflux for 3 hours. It was then treated with ethanolic base (80 ml) maintaining the temperature at 25°-30° C. with cooling. The brown product formed was isolated, treated further with aqueous ammonia and then recrystallized from ethanol to give 2,4-diamino-5-methyl-6-(2,5-dimethoxybenzyl)-7-chloro-pyrido[2,3-d]pyrimidine, m.p. 193°-196° (dec.).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][N:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N=C=NCCCN(C)C)C.[CH3:36][O:37][CH2:38][CH2:39][S:40]([NH2:43])(=[O:42])=[O:41]>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[C:1]12([CH2:11][O:12][C:13]3[C:21]([CH:22]4[CH2:23][CH2:24]4)=[CH:20][C:16]([C:17]([NH:43][S:40]([CH2:39][CH2:38][O:37][CH3:36])(=[O:42])=[O:41])=[O:19])=[CH:15][N:14]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: COCCS(N)(=O)=O
Reactant: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCCS(=O)(=O)NC(=O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.3 %

Procedure:
A mixture of 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid (0.24 g, 0.73 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.35 g, 1.83 mmol), 4-dimethylaminopyridine (0.22 g, 1.83 mmol), and 2-methoxyethanesulfonamide (0.13 g, 0.95 mmol) in dichloromethane (10 mL) was stirred at ambient temperature for 3 days. The reaction mixture was diluted with ethyl acetate (50 mL), washed with 1 M aqueous hydrochloric acid solution (2×30 mL), brine (30 mL); dried over anhydrous sodium sulfate; filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (3:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) to provide the title compound (0.25 g, 76%): 1H NMR (300 MHz, DMSO-d6) δ 11.97 (br s, 1H), 8.45 (d, J=2.3 Hz, 1H), 7.70 (d, J=2.3 Hz, 1H), 3.93 (s, 2H), 3.75-3.65 (m, 4H), 3.14 (s, 3H), 2.07-1.98 (m, 1H), 1.98-1.91 (m, 3H), 1.73-1.58 (m, 12H) 0.99-0.91 (m, 2H), 0.76-0.70 (m, 2H); MS (ES+) m/z 449.2 (M+1).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19][CH3:20])[CH2:13]2)[N:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]3[O:37][C:38]4[C:44]([CH:45]([CH3:47])[CH3:46])=[CH:43][CH:42]=[CH:41][C:39]=4[N:40]=3)=[CH:31][CH:30]=2)O1.NC1N=CN=C2N([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)N=C(C3C=CC(NC4OC5C=CC=CC=5N=4)=C(F)C=3)C=12>>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:12]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19][CH3:20])[CH2:13]3)[N:3]=[C:2]([C:29]3[CH:34]=[CH:33][C:32]([NH:35][C:36]4[O:37][C:38]5[C:44]([CH:45]([CH3:47])[CH3:46])=[CH:43][CH:42]=[CH:41][C:39]=5[N:40]=4)=[CH:31][CH:30]=3)[C:10]=12
Reactant: CC(C)c1cccc2nc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)oc12
Reactant: COCCN1CCC(n2nc(I)c3c(N)ncnc32)C1
Agent: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6ccccc6o5)c(F)c4)c4c(N)ncnc43)CC2)CC1
Product: COCCN1CCC(n2nc(-c3ccc(Nc4nc5cccc(C(C)C)c5o4)cc3)c3c(N)ncnc32)C1

Procedure:
rac-N2-(4-{4-Amino-1-[1-(2-methoxyethyl)tetrahydro-1H-3-pyrrolyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-7-isopropyl-1,3-benzoxazol-2-amine was prepared from rac-3-iodo-1-[1-(2-methoxyethyl)tetrahydro-1H-3-pyrrolyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.200 g, 0.515 mmol) and N2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-7-isopropyl-1,3-benzoxazol-2-amine (0.244 g, 0.644 mmol) in a manner similar to that used for the preparation of cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-1,3-benzoxazol-2-amine. The compound was formed as an off-white solid (0.067 g, 25%). 1H NMR (DMSO-d6, 400 MHz) 1.361 (d, 6H), 2.30 (m, 2H), 2.66 (m, 2H), 2.76-2.83 (m, 3H), 3.17 (t, 1H), 3.24 (s, 3H), 3.38 (m, 1H), 3.45 (t, 2H), 5.37 (m, 1H), 7.04 (d, 1H), 7.18 (t, 1H), 7.32 (d, 2H), 7.67 (d, 2H), 7.95 (d, 2H), 8.24 (s, 1H), 10.88 (s, 1H); RP-HPLC Rt 12.337 min, 94% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 513 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]Br)=[CH:4][CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: BrCCCc1ccc(Br)cc1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Brc1ccc(CCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 51.6 %

Procedure:
To a solution of intermediate 50 (Example 100) (3.5 g, 13 mmol) in dioxane (40 mL) was added pyrrolidine (2.1 mL, 25 mmol), followed by cesium carbonate (8.2 g, 25 mmol). The mixture was stirred at room temperature for 15 h and poured into water. The mixture was extracted with ethyl acetate and the organic layer separated, washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (10% MeOH/DCM to 25% MeOH and 2% TEA/DCM) to afford the title compound (1.8 g, 53%) as a pale orange oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:7]=1[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:5])[CH3:2].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:34]3[CH:35]=[CH:36][C:31]([C:30]([F:41])([F:40])[F:29])=[CH:32][CH:33]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:7]=1[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1cccc(Cl)c1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1cccc(Cl)c1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 1-(3-chlorophenyl)-2-ethoxycarbonylmethyl-5-hydroxyindole-3-carboxylic acid ethyl ester (141 mg, 0.35 mmol, see step (b) Example 8) and 4-trifluoromethylphenylboronic acid (100 mg, 0.53 mmol). Yield 120 mg (63%).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][N:11]=2)[CH2:6][CH2:5]1.F[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1.[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>CN(C)C=O.CCOCC.O>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]([CH:7]3[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH2:8]3)=[N:11]2)=[CH:21][CH:22]=1
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Reactant: Fc1ccc(Cl)cc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CN1CCC(c2nn(-c3ccc(Cl)cc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 47.5 %

Procedure:
To a stirred suspension of 1.1 g of sodium hydride (50% oil dispersion) in 40 ml of dimethylformamide was added, dropwise, under nitrogen, 4.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole dissolved in 25 ml of hot dimethylformamide. The reaction was stirred at ambient temperature for 45 min, and 2.9 ml of 4-fluorochlorobenzene was added. The temperature was increased to 120° and the reaction proceeded at this temperature for 24 hr. The reaction was poured into water and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was heated (steam bath) with 3N hydrochloric acid and the salt was collected. The salt was immediately recrystallized from water. The wet salt was treated with ammonium hydroxide and the base was extracted into dichloromethane. Evaporation of the dichloromethane in vacuo gave an oil. The oil solidified on standing. The solid was dissolved in ether and 1.4 g of fumaric acid was added. Recrystallization from 2-propanol gave 3.9 g (47.5%) of product, mp 176°-178° C.
Reaction SMILES: C(OC([NH:8][C:9]([CH3:19])([C:11]([O:13][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12])[CH3:10])=O)(C)(C)C.[ClH:20].O1CCOCC1>C1COCC1>[ClH:20].[CH3:19][C:9]([C:11]([O:13][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:12])([CH3:10])[NH2:8]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)OC1CCCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(C)(N)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
Cyclopentyl N-(tert-butoxycarbonyl)-2-methylalaninate (0.254 g, 0.93 mmol) was dissolved in THF (5 ml) and treated with 4M HCl/dioxane (2 ml) and the reaction mixture was stirred at RT for 24 hours. The crude mixture was concentrated under reduced pressure and triturated with Et2O to give a white precipitate. This was further washed with Et2O to give the desired product as a white powder (0.16 g, 82% yield).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[H-].[Na+].[Br:9][C:10]1[CH:11]=[C:12]([CH3:32])[C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[CH:25]=[N:26][C:27](F)=[CH:28][C:29]=3[CH3:30])=[O:23])[CH2:18][CH2:17]2)=[N:14][CH:15]=1.O>CN(C=O)C>[Br:9][C:10]1[CH:11]=[C:12]([CH3:32])[C:13]([N:16]2[CH2:17][CH2:18][N:19]([C:22]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([N:3]4[CH2:4][CH2:5][O:1][C:2]4=[O:6])=[N:26][CH:25]=3)=[O:23])[CH2:20][CH2:21]2)=[N:14][CH:15]=1
Reactant: O=C1NCCO1
Reactant: Cc1cc(F)ncc1C(=O)N1CCN(c2ncc(Br)cc2C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N2CCOC2=O)ncc1C(=O)N1CCN(c2ncc(Br)cc2C)CC1
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
To a solution of oxazolidin-2-one (174 mg) in DMF (4 mL) was added sodium hydride (80 mg) at 10° C., and the mixture was stirred for 30 min. Furthermore, [4-(5-bromo-3-methylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (590 mg) described in Preparation Example 113 was added, and the mixture was stirred at 80° C. for 5 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 3-{5-[4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carbonyl]-4-methylpyridin-2-yl}oxazolidin-2-one (423 mg).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH:27]1[CH2:30][CH:29]([OH:31])[CH2:28]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([N:27]3[CH2:30][CH:29]([OH:31])[CH2:28]3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: OC1CNC1
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Agent: Cl
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)N3CC(O)C3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and azetidin-3-ol monohydrochloride and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([OH:21])([C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)[C:10]([F:13])([F:12])[F:11].Br[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([O:36][CH3:37])=[O:35])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:37][O:36][C:34](=[O:35])[C:31]1[CH:32]=[CH:33][C:28]([O:27][CH2:26][CH2:25][O:23][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([OH:21])([C:14]3[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=3)[C:10]([F:13])([F:11])[F:12])=[C:2]([Cl:1])[CH:3]=2)=[CH:29][CH:30]=1
Reactant: Cc1cnc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn1
Reactant: COC(=O)c1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(OCCOc2ccc(C(C)C(O)(c3cnc(C)cn3)C(F)(F)F)c(Cl)c2)cc1

Procedure:
In analogy to Example 1, step 7, 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenol (Example 1, step 6) was reacted with methyl 4-(2-bromoethoxy)benzenecarboxylate and potassium carbonate to give the title compound as a colorless viscous oil. MS (m/e)=524.9 [M+H+].
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]2[C:8]([OH:12])=[CH:9][CH:10]=[CH:11][C:4]1=2.Cl[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[N:17]=[CH:16][N:15]=1>CN(C=O)C>[S:3]1[CH:7]=[CH:6][C:5]2[C:8]([O:12][C:14]3[CH:19]=[C:18]([C:20]4[CH:21]=[CH:22][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:25]=4)[N:17]=[CH:16][N:15]=3)=[CH:9][CH:10]=[CH:11][C:4]1=2
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Reactant: Oc1cccc2sccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2cc(Oc3cccc4sccc34)ncn2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium hydride (0.104 g, 2.6 mmol, 60% suspension in mineral oil, Aldrich) was added in small portions to a solution of benzo[b]thiophen-4-ol (0.3 g, 2 mmol, prepared according WO 01/68653) in DMF (4 mL) and the mixture was stirred at room temperature for 0.5 h. (4-Chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (0.776 g, 3 mmol) was then added and the mixture was stirred at room temperature for 18 h. The solvent was evaporated under vacuum, the residue was dissolved in EtOAc (50 mL), washed with 1 N NaOH and water, dried over MgSO4, and filtered. The filtrate was evaporated under vacuum and the residue purified by silica gel chromatography (10% EtOAc in hexanes) to give the title compound. Mp: 122.3–122.4° C. MS (ESI, pos. ion) m/z: 373.1 (M+1).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1.C(N(CC)CC)C.Cl>CN(C)C=O>[O:21]=[C:15]1[CH:14]([N:8]2[CH2:7][C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][C:24]([C:23]([F:22])([F:33])[F:34])=[CH:25][CH:26]=4)[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCC(N2Cc3cc(CNC(=O)c4ccc(C(F)(F)F)cc4)ccc3C2=O)C(=O)N1
Reaction time: 1 h
Yield: 49.1 %

Procedure:
To a stirred mixture of 3-(5-Aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (1.00 g, 3.20 mmol) and 4-(trifluoromethyl)benzoyl chloride (0.67 g, 3.20 mmol) in N,N-dimethylformamide (25 mL), was added triethylamine (0.90 mL, 6.40 mmol) at room temperature under nitrogen. After 1 h, 1N aq. HCl (50 mL) was added and the mixture was stirred for 10 min. The product was isolated by filtration, washed with 1N aq. HCl (50 mL), ethyl acetate (50 mL) and dried overnight in vacuo to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-4-trifluoromethyl-benzamide as a white solid (0.70 g, 49% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.75 min (95.6%); mp: 241-243° C.; 1H NMR (DMSO-d6) δ 1.92-2.14 (m, 1H), 2.29-2.48 (m, 1H), 2.54-2.67 (m, 1H), 2.80-3.04 (m, 1H), 4.31 (d, J=17.4 Hz, 1H), 4.45 (d, J=17.6 Hz, 1H), 4.62 (d, J=5.9 Hz, 2H), 5.11 (dd, J=5.1, 13.2 Hz, 1H), 7.49 (d, J=7.9 Hz, 1H), 7.56 (s, 1H), 7.71 (d, J=7.7 Hz, 1H), 7.88 (d, J=8.3 Hz, 2H), 8.11 (d, J=8.1 Hz, 2H), 9.39 (s, 1H), 10.99 (s, 1H); 13C NMR (DMSO-d6) δ 22.50, 31.19, 42.87, 47.13, 51.59, 122.15, 122.97, 123.90 (q, J=270 Hz), 125.38 (q, J=3.5 Hz), 127.13, 128.21, 130.47, 131.23 (q, J=31.6), 137.92, 142.42, 143.53, 165.14, 167.91, 170.98, 172.85; LCMS: MH=446; Anal Calcd for C22H18N3O4F3+0.35H2O: C, 58.50; H, 4.17; N, 9.30. Found: C, 58.55; H, 3.81; N, 9.18.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3]([NH:5][CH:6]([CH2:10][CH:11]=[CH2:12])[C:7]([OH:9])=O)=[O:4].[C:15](OC(=O)CC)(=O)[CH2:16]C.O>N1C=CC=CC=1>[CH3:13][C:2]([CH3:1])([CH3:14])[C:3]([NH:5][CH:6]([C:7](=[O:9])[CH2:15][CH3:16])[CH2:10][CH:11]=[CH2:12])=[O:4]
Reactant: C=CCC(NC(=O)C(C)(C)C)C(=O)O
Reactant: CCC(=O)OC(=O)CC
Solvent: c1ccncc1
Solvent: O
Product: C=CCC(NC(=O)C(C)(C)C)C(=O)CC

Procedure:
4.27 g of the above synthesized 2-(2,2-dimethyl-propionylamino)-pent-4-enoic acid (21.43 mmol) were dissolved in 13.5 ml of pyridine, treated with 132.81 ml of propionic anhydride (5 eq.), and heated to 100° for 15 h. After cooling, 10.04 ml of water were added and the mixture kept for 45 Min. at 90°. Careful pouring onto crashed ice/HCl, twofold extraction with AcOEt, washing twice with Na2CO3 and water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (silica gel, hexane/AcOEt=8/2) left finally 2.10 g of the title compound as yellowish oil.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH:4]1([C:10]2[S:14][C:13]([N:15]=[C:16]=[O:17])=[N:12][N:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.NN>C(Cl)Cl>[CH3:1][N:2]([C:16]([NH:15][C:13]1[S:14][C:10]([CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]2)=[N:11][N:12]=1)=[O:17])[NH2:3]
Reactant: O=C=Nc1nnc(C2CCCCC2)s1
Reactant: CNN
Agent: NN
Solvent: ClCCl
Product: CN(N)C(=O)Nc1nnc(C2CCCCC2)s1
Temperature: 25 °C

Procedure:
A solution of methylhydrazine (0.3 mole) in methylene chloride (150 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 5-Cyclohexyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.1 mole) is then added, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 4 hours. After this time the reaction mixture is stripped of solvent and excess hydrazine to yield the desired product 2-methyl-4-(5-cyclohexyl-1,3,4-thiadiazol-2-yl)semicarbazide as the residue.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([N:25]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:12][CH:13]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:15]=1.Br[C:41]1[C:42]([CH2:59][O:60][CH3:61])=[N:43][N:44]([CH:46]2[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH2:47]2)[CH:45]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[C:14]([C:41]2[C:42]([CH2:59][O:60][CH3:61])=[N:43][N:44]([CH:46]3[CH2:47][CH2:48][N:49]([C:52]([O:54][C:55]([CH3:57])([CH3:58])[CH3:56])=[O:53])[CH2:50][CH2:51]3)[CH:45]=2)[CH:13]=[N:12][C:11]=1[N:25]([C:26]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:32])[C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34]
Reactant: COCc1nn(C2CCN(C(=O)OC(C)(C)C)CC2)cc1Br
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(B2OC(C)(C)C(C)(C)O2)cc1-c1nc2ccccc2o1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COCc1nn(C2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c2nc3ccccc3o2)c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 74.5 %

Procedure:
A mixture of tert-butyl N-[3-(1,3-benzoxazol-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (808 mg), tert-butyl 4-(4-bromo-3-(methoxymethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (439 mg), trisdibenzylideneacetone dipalladium (53.7 mg), dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphane (48.2 mgl) and potassium phosphate (0.233 g) in a mixture of dioxane (14 ml) and water (350 μl) was degassed. The resulting suspension was stirred at 120° C. for 3 hours under argon. After the mixture was cooled to room temperature the solvent was concentrated, ethyl acetate (80 ml) and water (20 ml) were added. The organic layer was washed with brine, dried over magnesium sulphate, filtered and evaporated under reduce pressure. The crude product was purified by flash chromatography on silica gel eluting with 30 to 80% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford tert-butyl 4-[4-[5-(1,3-benzoxazol-2-yl)-6-(bis(tert-butoxycarbonyl)amino)-3-pyridyl]-3-(methoxymethyl)pyrazol-1-yl]piperidine-1-carboxylate (616 mg). The N-tert-butoxycarbonyl groups on the resultant product were removed by conventional treatment with hydrogen chloride in isopropanol to afford 3-(1,3-benzoxazol-2-yl)-5-[3-(methoxymethyl)-1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (300 mg).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][C:2]21[CH2:10][CH2:9][C:8]1[C:11]3[C:16](=O)[NH:15][CH:14]=[N:13][C:12]=3[S:18][C:7]=1[CH2:6]2.C(N(CC)CC)C.O=P(Cl)(Cl)[Cl:28]>>[Cl:28][C:16]1[C:11]2[C:8]3[CH2:9][CH2:10][C:2]4([CH2:6][C:7]=3[S:18][C:12]=2[N:13]=[CH:14][N:15]=1)[O:3][CH2:4][CH2:5][O:1]4
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2sc3c(c12)CCC1(C3)OCCO1
Solvent: CCN(CC)CC
Product: Clc1ncnc2sc3c(c12)CCC1(C3)OCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a stirring solution of 3,5,6,8-tetrahydro-4H-spiro[1-benzothieno[2,3-d]pyrimidine-7,2′-[1,3]dioxolan]-4-one (20.0 g, 0.076 mol) in POCl3 (200 mL) at 0° C. was added triethylamine (200 mL) over a 15 min. period. The resulting mixtures were allowed to warm to rt, and then heated to 80° C. After 3 h, the contents were removed from heating, and allowed to cool to rt. The heterogeneous mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL), and concentrated again to further remove the volatile materials. The residue was then diluted with EtOAc (100 mL) and the heterogeneous mixture poured onto a stirring mixture of ice-water/aq NaHCO3 (800 mL). After 5 min. stirring, the contents (pH 7) were filtered and the solid filter cake washed with water. The product was dried in vacuum oven overnight to afford the desired product (20.7 g, 97%) as an off-white solid. 1H-NMR (DMSO-d6) δ 8.82 (s, 1H), 3.97 (s, 4H), 3.10 (t, 2H), 3.07 (s, 2H), 1.95 (t, 2H); LCMS RT=2.45 min, [M+H]+=283.1.