Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C@H:10]2[C@H:15]([OH:16])[C@@H:14]([OH:17])[C@H:13]([OH:18])[C@@H:12]([CH2:19][OH:20])[O:11]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=1.[H-].[Na+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>CN(C=O)C.C1COCC1>[CH2:33]([O:18][C@H:13]1[C@H:14]([O:17][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:15]([O:16][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:10]([C:5]2[CH:6]=[C:7]([O:8][CH3:9])[C:2]([Cl:1])=[C:3]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=3)[CH:4]=2)[O:11][C@@H:12]1[CH2:19][O:20][CH2:10][C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)cc(OC)c2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)cc(OC)c2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 182.2 %

Procedure:
To a solution of compound 75 (4.12 mmol) in DMF/THF (20 mL/60 mL) at 0° C. under an atmosphere of nitrogen were added NaH (60% oil, 825 mg, 20.6 mmol) and benzyl bromide (4.9 mL, 41.2 mmol) dropwise, and the mixture was stirred for 16 hours at the room temperature. To the mixture was added water (20 mL) to quench the reaction. After dilution with water, the mixture was stirred at room temperature for 30 min and extracted with EtOAc (200 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 76 (3.0 g, 93%) as colorless oil.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=O)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH2:31]([NH2:35])[CH:32]([CH3:34])[CH3:33]>>[ClH:1].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[C@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([NH:35][CH2:31][CH:32]([CH3:34])[CH3:33])=[O:27])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: CC(C)CN
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@@H]4CN5CCC4CC5)oc23)c1
Agent: Cl
Product: CC(C)CNC(=O)c1cccc(-c2cccc3cc(C(=O)N[C@@H]4CN5CCC4CC5)oc23)c1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 153) and 17.1 mg (0.23 mmol) of iso-butylamine are reacted together by general method E. 40.3 mg (71.4% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]1[CH:29]=[CH:28][C:6]([C:7]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:12]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:11][C@@H:10]2[CH3:27])=[O:8])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[C:40](Cl)(=[O:42])[CH3:41]>C(Cl)Cl>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([N:19]([C@H:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:9]([C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:30])=[CH:29][CH:28]=3)[C@@H:10]([CH3:27])[CH2:11]2)[C:40](=[O:42])[CH3:41])=[CH:25][CH:24]=1
Reactant: C[C@H]1C[C@@H](Nc2ccc(Cl)cc2)c2ccccc2N1C(=O)c1ccc(N(C)C)cc1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N(C)C)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 34 %

Procedure:
To a solution of (±)-cis-1-(4-dimethylamino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-4-(N-4-chlorophenyl)aminoquinoline (120 mg, 0.29 mmol) in methylene chloride (2 mL) was added diisopropylethylamine (37 mg, 0.051 mL, 0.29 mmol) followed by acetyl chloride (2 mL). The mixture was stirred at rt 4 h. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. aqueous sodium bicarbonate, brine and dried over sodium sulfate. The drying agent was removed by filtration under reduced pressure, concentrated and purified by silica gel chromatography (100% hexanes-25/75 hexanes/ethyl acetate gradient) to afford pure (±)-cis-N-(4-chloro-phenyl)-N-[1-(4-dimethylamino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (45 mg, 34%).
Reaction SMILES: [CH2:1]([N:3]([CH2:5][CH3:6])O)[CH3:2].[H-].[Na+].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[N:19]3[C:20]([CH2:23]Cl)=[N:21][N:22]=[C:18]3[CH2:17][N:16]=[C:15]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:14]=2[CH:31]=1.[Cl-].[Na+]>CN(C)C=O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[N:19]3[C:20]([CH2:23][N:3]([CH2:5][CH3:6])[CH2:1][CH3:2])=[N:21][N:22]=[C:18]3[CH2:17][N:16]=[C:15]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:14]=2[CH:31]=1
Reactant: CCN(O)CC
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 0 °C
Reaction time: 0.92 h

Procedure:
A stirred, ice cold solution of N,N-diethylhydroxylamine (50 ml.). in dimethylformamide (50 ml.) under nitrogen, was treated with a 57% suspension of sodium hydride in mineral oil (1.39 g., 0.033 mole). The mixture was kept at ambient temperature for 55 minutes, cooled in an ice bath and treated with 8-chloro-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine (10.3 g., 0.03 mole). This mixture was kept at ambient temperature for 18 hours and poured into ice water. The resulting mixture was saturated with sodium chloride and extracted with chloroform. The extract was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was mixed with xylene and concentrated in vacuo, the resulting material was crystallized from wet methanol-ethyl acetate to give 8-chloro-1-[(diethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, N1 -oxide dihydrate in two crops: 5.91 g., of melting point 137°-139.5° C. dec. and 1.16 g., of melting point 135°-137.5° C. The analytical sample had a melting point of 135°-137.5° C. dec.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:20](=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11]([CH:14]([CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cc1nsc(NC(=O)OC(C)(C)C)n1
Reactant: CCCCCC=O
Product: CCCCCC(O)C(C(=O)OCC)c1nsc(NC(=O)OC(C)(C)C)n1

Procedure:
1.0 g (3.5 mMol) of product from Example 28 were reacted with 1.26 ml (~10 mMol) of n-hexanal for 9 days in the manner described in Example 29. Yield of erythro/threo mixture of the title compound: 1.1 g (~80%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([Si:11]([CH3:37])([CH3:36])[O:12][CH:13]([CH2:17][NH:18][C:19]([O:21][CH2:22][CH:23]1[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])[C:14](O)=[O:15])([CH3:10])([CH3:9])[CH3:8].CCN(C(C)C)C(C)C.[NH2:47][C:48]1[S:49][CH:50]=[C:51]([CH3:53])[N:52]=1>C(Cl)Cl.CN(C=O)C.O.C1COCC1>[CH:34]1[C:35]2[CH:23]([CH2:22][O:21][C:19](=[O:20])[NH:18][CH2:17][CH:13]([O:12][Si:11]([C:7]([CH3:8])([CH3:9])[CH3:10])([CH3:37])[CH3:36])[C:14]([NH:47][C:48]3[S:49][CH:50]=[C:51]([CH3:53])[N:52]=3)=[O:15])[C:24]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:30]=2[CH:31]=[CH:32][CH:33]=1
Reactant: Cc1csc(N)n1
Reactant: CC(C)(C)[Si](C)(C)OC(CNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1csc(NC(=O)C(CNC(=O)OCC2c3ccccc3-c3ccccc32)O[Si](C)(C)C(C)(C)C)n1
Reaction time: 3 h
Yield: 6.3 %

Procedure:
Oxalyl chloride (1.12 g, 8.83 mmol) in DCM (5 mL) was added slowly to a stirred solution of 2-(tert-butyl-dimethyl-silanyloxy)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-propionic acid (Step 1) (1.30 g, 2.94 mmol) in DCM (25 ml) and DMF (50 μl ) at 0° C. After 3 hrs at ambient temperature, gas evolution had subsided and the reaction mixture was concentrated in vacuo. THF (20 mL) and DIPEA (0.57 g, 4.4 mmol) were added, followed by the addition of 2-amino-4-methylthiazole (0.403 g, 3.53 mmol) in DCM (5 mL). The reaction mixture was kept at ambient temperature for 3 hrs. Water (0.5 mL) was added and the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluting with a gradient consisting of 0-40% EtOAc in heptane) to give the title compound as a colorless oil (0.10 g). 1H NMR (500 MHz, CDCl3) δ 9.60 (br s, 1H), 7.75 (d, 2H), 7.57 (d, 2H), 7.39 (t, 2H), 7.30 (t, 2H), 6.56 (s, 1H), 5.19 (br s, 1H), 4.41 (t, 1H), 4.37 (d, 2H), 4.21 (t, 1H), 3.66 (m, 1H), 3.49 (m, 1H), 2.35 (s, 3H), 0.98 (s, 9H), 0.20 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[Cl:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>C1(C)C=CC=CC=1>[Cl:16][CH2:17][CH2:18][C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:20]
Reactant: O=C(Cl)CCCl
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Solvent: Cc1ccccc1
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)CCCl)cc1
Yield: 66.7 %

Procedure:
6.0 g (29.6 millimoles) of 6-(p-aminophenyl)-5-methyl-4,5-dihydropyridaz-3-one and 4.1 g (32.3 millimoles) of 3-chloropropionyl chloride are stirred with 100 ml of absolute toluene for 4 hours at 80° C. The product is filtered off at 10° C., washed with water and dried under reduced pressure at 50° C. 5.8 g (67% of theory) of 6-[p-(3-chloropropionylamino)-phenyl]-5-methyl-4,5-dihydropyridaz-3-one are obtained as beige crystals which, after recrystallization from methanol, melt, with decomposition, at 221°-223° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13]3[C:19]4[C:20]([NH:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]6[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=6)=[C:27]([Cl:39])[CH:26]=5)=[N:21][CH:22]=[N:23][C:18]=4[S:17][C:14]=32)=[N:9]1)(=O)=O.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.C(N(C(C)C)CC)(C)C>CC#N>[CH2:32]([O:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:20]2[N:21]=[CH:22][N:23]=[C:18]3[S:17][C:14]4[C:15]5[C:10]([CH2:11][CH2:12][C:13]=4[C:19]=23)=[N:9][N:8]([CH2:7][CH2:6][N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[CH:16]=5)=[CH:26][C:27]=1[Cl:39])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)OCCn1cc2c(n1)CCc1c-2sc2ncnc(Nc3ccc(OCc4ccccc4)c(Cl)c3)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Clc1cc(Nc2ncnc3sc4c(c23)CCc2nn(CCN3CCOCC3)cc2-4)ccc1OCc1ccccc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 40.7 %

Procedure:
To CH3CN (4 mL) were sequentially added 2-(6-{[4-(benzyloxy)-3-chlorophenyl]amino}-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-2-yl)ethyl methanesulfonate (85 mg, 0.15 mmol), morpholine (0.04 mL, 0.44 mmol), and diisopropylethylamine (0.05 mL, 0.29 mmol). The mixture was stirred at 70° C. for 16 h after which time the mixture was removed from heating, and allowed to cool to rt. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure and purified by prep HPLC. The combined fractions were treated with saturated Na2CO3 and dried to afford free base product (35 mg, 42%) as a white solid. 1H-NMR (DMSO-d6) δ 8.42 (s, 1H), 8.25 (s, 1H), 7.93 (s, 1H), 7.72 (d, 1H), 7.33-7.49 (m, 6H), 7.18 (d, 1H), 5.19 (s, 2H), 4.18 (t, 2H), 3.55 (m, 4H), 3.39 (t, 2H), 2.89 (t, 2H), 2.71 (t, 2H), 2.42 (m, 4H); LCMS RT=1.98 min, [M+H]+=573.4.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[N:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)#[N:2].[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[C:1]([CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=3)[N:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)#[N:2]
Reactant: N#CCc1cccc(NC(=O)c2cccc(Br)n2)c1
Reactant: OB(O)c1ccc(Cl)cc1
Product: N#CCc1cccc(NC(=O)c2cccc(-c3ccc(Cl)cc3)n2)c1

Procedure:
The pyridyl bromide (91) (150 mg, 0.47 mmol) was coupled to 4-chloro-phenylboronic acid (81 mg, 0.52 mmol) using Method E. The crude residue was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:12]=[N:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[CH:15]=2)[N:6]=1)=[NH:4].[C:22](OCC)(=O)C.C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[Na+].[Cl-]>C1COCC1.C(OCC)(OCC)OCC>[O:1]1[CH:22]=[N:4][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]3[CH:12]=[N:13][N:14]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[CH:15]=3)[N:6]=2)=[N:2]1
Reactant: N=C(NO)c1cccc(-c2cnn(-c3cccnc3)c2)n1
Reactant: CCOC(C)=O
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(OCC)OCC
Product: c1cncc(-n2cc(-c3cccc(-c4ncon4)n3)cn2)c1
Reaction time: 2 h

Procedure:
0.24 g of N-hydroxy-6-(1-pyridin-3-yl-1H-pyrazol-4-yl)pyridine-2-carboxamidine (crude product from the previous step) was dissolved in THF/triethyl orthoformate, and 0.2 g of BF3-ET2O was added. After 2 h, ethyl acetate, aq. citrate buffer pH=6 and aq. NaCl were added and the aqueous phase was extracted 3 times with ethyl acetate. The combined organic phases were dried with MgSO4 and concentrated by evaporation, and the residue was purified by chromatography on silica gel (petroleum ether/acetone).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:22])([CH3:21])[C:14]2[O:15]CC(C)(C)N=2)=[CH:9][CH:8]=1)=[O:6].Cl.[O:24]1CCOCC1>>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([C:13]([CH3:22])([CH3:21])[C:14]([OH:15])=[O:24])=[CH:11][CH:12]=1)=[O:6]
Reactant: CC1(C)COC(C(C)(C)c2ccc(C(=O)CCCCl)cc2)=N1
Reactant: C1COCCO1
Agent: Cl
Product: CC(C)(C(=O)O)c1ccc(C(=O)CCCCl)cc1

Procedure:
A mixture of 4-(4-chloro-1-oxobutyl)-α,α-dimethyl-α-(4,4-dimethyloxazolin-2-yl) toluene, prepared according to Example 3, (47.8 g, 0.15 mole), 150 mL concentrated hydrochloric acid, and 150 mL 1,4-dioxane is brought to reflux for 18 hours. The mixture is extracted three times with ethyl acetate. The organics are washed with saturated NaCl solution, dried over MgSO4, and concentrated. Crude product is purified by column chromatography using silica gel, and eluting with hexane/ethyl acetate/acetic acid. Cleaner fractions are combined and recrystallized from methylene chloride/hexanes to afford 4-(4-chloro-1-oxobutyl)-α, α-dimethylphenylacetic acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[CH:4][N:3]=1.[F:11][C:12]([F:25])([F:24])[C:13]1[NH:23][C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH2:22])[CH:20]=[C:15]2[CH:14]=1.CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[CH:8]1([C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH:22][CH2:21][C:19]3[CH:20]=[C:15]4[CH:14]=[C:13]([C:12]([F:25])([F:24])[F:11])[NH:23][C:16]4=[N:17][CH:18]=3)[CH:7]=2)[CH2:10][CH2:9]1
Reactant: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Reactant: Clc1cc(C2CC2)ncn1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1cc2cc(CNc3cc(C4CC4)ncn3)cnc2[nH]1
Temperature: 120 °C
Yield: 24.7 %

Procedure:
To a stirred solution of 4-chloro-6-cyclopropylpyrimidine (Intermediate 30, 75 mg, 0.485 mmol) in NMP (2 mL) in a 2 mL microwave vial was added and 1-[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 104 mg, 0.485 mmol), DIPEA (0.169 mL, 0.970 mmol), vial de-gassed with argon and heated in a microwave at 120° C. for 2 hrs. The reaction mixture was poured into water (25 mL) and extracted with ethyl acetate (2×20 mL). The organic layers were combined, dried (MgSO4) and evaporated to dryness in vacuo to afford the crude residues. Resulting residues were then purified via MDAP. The appropriate fractions were collected, residue washed with methanol and evaporated to dryness in vacuo to give the title compound as a brown solid (40 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2].[CH2:32](Br)[CH:33]=[CH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:32][CH:33]=[CH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2]
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1
Reactant: BrCC=Cc1ccccc1
Product: COc1ccc2ccc(S(=O)(=O)N(CC=Cc3ccccc3)[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1

Procedure:
The title compound is prepared as described in EXAMPLE 25, Part A using 7-methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide, prepared as described in EXAMPLE 43, part A, and cinnamyl bromide. The crude product is purified by column chromatography eluting with gradient of 20% EtOAc/hexanes to 30% EtOAc/hexanes to afford the title compound as a white foam.
Reaction SMILES: CO[C:3]1[CH:14]=[CH:13][C:6]2N[C:8](=O)[NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]2[NH:26][C:25](=[O:27])[N:24]([CH:28]3[CH2:33][CH2:32][N:31]([C:34]4[N:39]=[CH:38][N:37]=[C:36]([C:40](O)=[O:41])[CH:35]=4)[CH2:30][CH2:29]3)[CH2:23][CH2:22][C:21]=2[CH:43]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:8]1[C@@H:6]2[C@H:5]([CH2:4][CH2:3][CH2:14][CH2:13]2)[CH2:11][CH2:10][N:9]1[C:40]([C:36]1[N:37]=[CH:38][N:39]=[C:34]([N:31]2[CH2:32][CH2:33][CH:28]([N:24]3[CH2:23][CH2:22][C:21]4[CH:43]=[C:17]([O:16][CH3:15])[CH:18]=[CH:19][C:20]=4[NH:26][C:25]3=[O:27])[CH2:29][CH2:30]2)[CH:35]=1)=[O:41]
Reactant: COc1ccc2c(c1)CCNC(=O)N2
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CC[C@H]5CCCC[C@@H]5C4)ncn3)CC1)C(=O)N2

Procedure:
Analogously to decahydroisoquinoline-2-carbonyl)pyrimidin-4-yl)piperidin-4-yl)-7-methoxy-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one the following compounds were prepared from 4.0 mg (10 μmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 3.6 mg (11 μmol) TBTU, 12 μmol of the corresponding amine and 3.9 μL DIPEA in 350 μL DMF:
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].[C:5]([N:9]=[N:10][C:11](Cl)([CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:12])([CH3:8])([CH3:7])[CH3:6].O>C(O)(C)C>[C:5]([N:9]=[N:10][C:11]([N:3]=[C:2]=[S:1])([CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:12])([CH3:8])([CH3:7])[CH3:6]
Reactant: N#C[S-]
Reactant: CC(C)CC(C)(Cl)N=NC(C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)CC(C)(N=C=S)N=NC(C)(C)C
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 26.1 grams (0.3 moles) of sodium thiocyanate in 150 ml of 75% aqueous isopropanol in a 500 ml erlenmeyer flask, cooled to 5° C., was added 61.2 grams (0.3 moles) of 2-t-butylazo- 2-chloro-4-methylpentane holding the reaction temperature at 10°-20° C. After the addition was complete, the reaction mixture was stirred an additional two hours at 30° C., poured into 300 ml water and the product extracted with 200 ml pentane. The pentane extract was washed with water, 10% NaHCO3 solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure to leave 55.7 grams (80% crude yield) of a yellow liquid. The product had a strong broad band at 1980- 2080 cm-1 in its infrared spectrum which is indicative of the isothiocyano band.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[CH:30][CH:29]=4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:42]C1C=CC(COC2C=CC(COC(=O)OC(Cl)C)=CC=2)=CC=1.C(N1CCNCC1)(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>>[F:42][C:39]1[CH:38]=[CH:37][C:36]([CH2:35][O:34][C:31]2[CH:30]=[CH:29][C:28]([CH2:27][O:26][C:24]([N:21]3[CH2:20][CH2:19][N:18]([C:16]([O:15][CH2:14][CH:12]4[C:11]5[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=5[C:5]5[C:13]4=[CH:1][CH:2]=[CH:3][CH:4]=5)=[O:17])[CH2:23][CH2:22]3)=[O:25])=[CH:33][CH:32]=2)=[CH:41][CH:40]=1
Reactant: O=C(OCc1ccc(OCc2ccccc2)cc1)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Reactant: CC(Cl)OC(=O)OCc1ccc(OCc2ccc(F)cc2)cc1
Agent: O=C(OCC1c2ccccc2-c2ccccc21)N1CCNCC1
Product: O=C(OCc1ccc(OCc2ccc(F)cc2)cc1)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1

Procedure:
Prepared in analogy to piperazine-1,4-dicarboxylic acid 4-benzyloxy-benzyl ester 9H-fluoren-9-ylmethyl ester (Example 41) from (RS)-carbonic acid 1-chloro-ethyl ester 4-(4-fluoro-benzyloxy)-benzyl ester) and N-Fmoc-piperazine: yellow solid. 1H-NMR (CDCl3): 3.3–3.6 m, 8H; 4.23 t, J=6 Hz, 1H; 4.48 d, J=6 Hz, 2H; 5.03 s, 2H; 5.08 s, 2H; 6.95 d, J=8.5 Hz, 2H, 7.08 t, J=8.5 Hz, 2H, 7.25–7.46 m, 8H, 7.55 d, J=7 Hz, 2H and 7.77 d, J=7 Hz, 2H.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[O:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[CH:38][C:39]([NH2:42])=[N:40][CH:41]=2)O1>>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[O:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:36]3[CH:37]=[CH:38][C:39]([NH2:42])=[N:40][CH:41]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3o2)CC1
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4ccc(N)nc4)nc(N4CCOCC4)c3o2)CC1

Procedure:
2-Chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinofuro[3,2-d]pyrimidine was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine via General Procedure E to give, after purification by reverse HPLC, 22 mg of 236. MS (Q1) 474 (M+).
Reaction SMILES: O=[C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:5]=[C:4]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)O1.[H-].[Na+].[CH2:23]1[CH2:27]O[CH2:25][CH2:24]1>>[N:10]1([C:6]2[CH:5]=[C:4]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[C:25]3[CH2:24][C:23]4[C:27]([C:2]=3[C:7]=2[C:8]#[N:9])=[CH:6][CH:5]=[CH:4][CH:16]=4)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCOC1
Reactant: N#Cc1c(N2CCCCC2)cc(-c2cccs2)oc1=O
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)cc(-c2cccs2)c2c1-c1ccccc1C2

Procedure:
A mixture of 2-oxo-4-(piperidin-1-yl)-6-(thiophen-2-yl)-2H-pyran-3-carbonitrile (286 mg), indanone-1 (132 mg) and NaH (37 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent Yellowish solid; mp 152-154° C.; ESMS 357 (M++1); IR (KBr). 2217 cm−1 (CN); HRMS calcd. for C23H20N2S 356.1347 found 356.1139.