Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([NH:32][CH2:33][C:34]1([C:49]([OH:51])=O)[CH2:39][CH2:38][N:37]([C:40]2[C:41]3[CH:48]=[CH:47][NH:46][C:42]=3[N:43]=[CH:44][N:45]=2)[CH2:36][CH2:35]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[Cl:52][C:53]1[CH:58]=[CH:57][C:56]([C@@H:59]([NH2:61])[CH3:60])=[CH:55][CH:54]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Cl:52][C:53]1[CH:58]=[CH:57][C:56]([C@@H:59]([NH:61][C:49]([C:34]2([CH2:33][NH:32][C:30](=[O:31])[O:29][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:35][CH2:36][N:37]([C:40]3[C:41]4[CH:48]=[CH:47][NH:46][C:42]=4[N:43]=[CH:44][N:45]=3)[CH2:38][CH2:39]2)=[O:51])[CH3:60])=[CH:55][CH:54]=1
Reactant: C[C@H](N)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)C1(CNC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 83.5 %

Procedure:
HATU (0.251 g, 0.66 mmol) was added in one portion to 4-((tert-butoxycarbonylamino)methyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 12) (0.225 g, 0.6 mmol), (S)-1-(4-chlorophenyl)ethanamine (0.093 g, 0.60 mmol) and DIPEA (0.314 mL, 1.80 mmol) in DMA (10 mL) at 25° C. under nitrogen. The resulting solution was stirred at 60° C. for 4 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using methanol. Residual HATU was removed by passing the methanol solution through a silica-supported carbonate column. The crude product thus obtained was evaporated to dryness to afford (S)-tert-butyl (4-(1-(4-chlorophenyl)ethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)methylcarbamate (0.257 g, 83%) as a colourless gum. This material was used directly in the next step without further purification.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH:5]=[CH:4][CH2:3]1.[NH2:11][C@@H:12]([CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[O:14]>>[CH2:32]([O:31][CH2:30][C@H:12]([NH:11][C:8](=[O:10])[CH2:7][N:2]1[CH2:3][CH:4]=[CH:5][CH2:6]1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[O:14])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)CN1CC=CC1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(CN1CC=CC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 65.6 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2,5-dihydro-1H-pyrrol-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 214, (S)-3-(benzyloxy)-2-(2-(2,5-dihydro-1H-pyrrol-1-yl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide (25.7 mg, 65.6%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.21 (s, 1H), 7.96 (d, 1H), 7.60 (d, 2H), 7.27-7.32 (m, 5H), 7.21 (m, 2H), 6.98-7.04 (m, 4H), 4.72 (m, 1H), 4.52 (s, 2H), 3.69-3.74 (m, 2H), 3.30 (s, 2H), 3.13 (d, 1H), 2.56 (d, 2H), 1.72 (s, 1H). MS (EI) for C28H28FN3O4. found 490.5 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][CH2:18][C:19](Cl)=[O:20])[CH2:12]1>>[CH2:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][CH2:18][C:19]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[O:20])[CH2:12]1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)CCC1CCCCC1
Product: O=C(CCC1CCCCC1)Nc1ccc(C(=O)O)cc1

Procedure:
βLactam content: 88.6%. B. 4-(3-cyclohexanepropionylamino)-benzoic acid was prepared as described in Example 3 from 10.0 g (0.073 mol) of p-aminobenzoic acid and 14.0 g (0.08 mol) of 3-cyclohexanepropionyl chloride.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH3:32])(=[O:28])=[O:27])=[CH:21][CH:20]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])C.C(O)C.[OH-].[Na+].Cl>O>[CH2:29]([S:26]([NH:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:4]([OH:33])=[O:3])=[CH:20][CH:21]=1)(=[O:28])=[O:27])[CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCC(Oc1ccc(NS(=O)(=O)CCCC)cc1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCC(Oc1ccc(NS(=O)(=O)CCCC)cc1)C(=O)O
Temperature: 25 °C

Procedure:
92 g (0.19 mol) of ethyl-α-[p-butylsulfonylaminophenoxy]tetradecanoate (Intermediate II) obtained in Step B, and 500 ml of ethyl alcohol were placed in a 3-necked flask. A solution of 20 g of sodium hydroxide (dissolved in a minimum amount of water) was added with good stirring. The reaction mixture was refluxed for 3 hours, allowed to cool to room temperature, poured into ice water and acidified with concentrated hydrochloric acid. The oil was extracted with ether, washed with water and saturated sodium chloride solution. The ether was removed under vacuo to give a gummy solid. After trituration with ligroine (boiling point: 35°-60° C.), the solid was collected. Yield was 50 g of Intermediate III, m.p. 80°-82° C. TLC analysis (benzene) showed one product.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[OH-].[Na+].[CH3:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br>CN(C=O)C.O>[CH3:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: Cc1cccc(CBr)c1
Reactant: c1ccc2[nH]nnc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2nnc3ccccc32)c1
Reaction time: 0.42 h

Procedure:
To a solution of benzotriazole (3 g) in DMF (38 mL) at r.t. was added a solution of 10N NaOH (2.75 mL). After stirring for 25 min., 3-methylbenzyl bromide (3.9 mL) was added. The mixture was further stirred for 30 min, diluted with H2O, and extracted with EtOAc. The EtOAc extract was washed with brine (2×), water, brine, and was then dried (MgSO4) and concentrated. The residue was stirred in diethyl ether/hexane to give the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:30])=[C:24]([C:27]([OH:29])=O)[CH:25]=2)[NH:20][C:19](=[O:31])[C:18]=1[C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[CH:33]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)[CH2:43][CH2:44][CH2:45][N:46]=[C:47]=NCC.ON1C2C=CC=CC=2N=N1.N1CCCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:30])=[C:24]([C:27]([N:46]3[CH2:47][CH2:43][CH2:44][CH2:45]3)=[O:29])[CH:25]=2)[NH:20][C:19](=[O:31])[C:18]=1[C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[CH:33]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(C(=O)O)c(Cl)cc3[nH]c2=O)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCNC1
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(C(=O)N4CCCC4)c(Cl)cc3[nH]c2=O)c1
Reaction time: 0.17 h
Yield: 48.7 %

Procedure:
To a solution of 4-[2-(1-tert-butoxycarbonyl-piperidin-2-yl)-ethoxy]-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydro-quinoline-6-carboxylic acid (15 mg in 0.6 mL of dry methylene chloride) was added 8.0 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) followed by 6.0 mg 1-hydroxybenzotriazole (HOBt) and the mixture stirred for 10 minutes. At this time, 9.4 mg of pyrrolidine and the reaction allowed to proceed at room temperature. After 4 hours, the mixture was concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride:10% ammonium hydroxide in methanol, 95:5) to give the tilte compound (8 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:33]([NH2:36])([CH3:35])[CH3:34]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:36][CH:33]([CH3:35])[CH3:34])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CC(C)N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)NC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine3-acetic acid (5.0 g, 0.017 mole) and 1,1'-carbonyldiimidazole (2.82 g, 0.017 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 2 hours with a stream of nitrogen bubbling through it. A solution of isopropylamine (2.06 g, 0.035 mole) in tetrahydrofuran was added dropwise and the reaction mixture was allowed to stir at room temperature overnight. The tetrahydrofuran was evaporated and the solid residue was triturated with water. The solid was collected and dried under high vacuum overnight. The solid was crystallized from isopropyl alcohol with cooling in the freezer, collected by filtration, washed with water, and dried under high vacuum at 50° C. overnight to give 4.0 g (70%), mp 248°-9° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11](OCC)(=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:1][C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Nc1nc2ccccc2s1
Reactant: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(=O)Nc1nc2ccccc2s1
Yield: 44 %

Procedure:
A mixture of 2-aminobenzothiazole (5.0 g., 0.033 mol) and diethyl oxalate (50 ml.) is heated at reflux for 2.5 hours. A white solid precipitates from the cooled reaction mixture. The solid is recrystallized from ethanol (with a hot filtration) to give the desired product (3.72 g., m.p. 185°-186°, 44%).
Reaction SMILES: Cl.[F:2][C:3]1([F:8])[CH2:7][CH2:6][NH:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[Cl:15][C:16]1[C:22](Cl)=[CH:21][C:19]([NH2:20])=[C:18]([N+:24]([O-:26])=[O:25])[CH:17]=1>CN(C=O)C>[Cl:15][C:16]1[C:22]([N:5]2[CH2:6][CH2:7][C:3]([F:8])([F:2])[CH2:4]2)=[CH:21][C:19]([NH2:20])=[C:18]([N+:24]([O-:26])=[O:25])[CH:17]=1
Reactant: FC1(F)CCNC1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(N2CCC(F)(F)C2)c(Cl)cc1[N+](=O)[O-]
Temperature: 130 °C

Procedure:
3,3-Difluoropyrrolidine hydrochloride (3.12 g, 21.7 mmol) followed by potassium carbonate (4.00 g, 29.0 mmol) were added to 4,5-dichloro-2-nitroaniline (3.00 g, 14.5 mmol) in DMF (60 mL). The reaction mixture was stirred at 130° C. over the weekend. After cooling the reaction mixture was poured into ice-water and extracted with EtOAc. The combined organic layers were washed with water, dried, concentrated and the crude was purified by chromatography to give the sub-title compound.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[C:9]2[CH3:13].C[N:15](C=O)C>>[F:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([NH2:15])[CH:10]=[C:9]2[CH3:13]
Reactant: Cc1c[nH]c2c(F)cccc12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: Cc1cn(N)c2c(F)cccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of NaH (805 mg, 20.1 mmol, 60% in mineral oil) in DMF (5 mL) at 0° C. is treated with 7-fluoro-3-methylindole (200 mg, 1.34 mmol) and stirred at 0° C. for 1 h. The mixture is treated with HOSA (757 mg, 6.7 mmol) portion wise and warmed to rt over 2 h. The mixture is then poured over ice, and extracted with EtOAc (3×100 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo to afford 7-fluoro-3-methyl-indol-1-ylamine, which is used in the next step without further purification.
Reaction SMILES: [Na].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:11].[O:12]1[CH:16]=[CH:15][C:14]([C:17](OCC)=[O:18])=[CH:13]1>C(O)C>[O:12]1[CH:16]=[CH:15][C:14]([C:17]([CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[NH:2][C:3]2=[O:11])=[O:18])=[CH:13]1
Reactant: O=C1Cc2ccccc2N1
Reactant: CCOC(=O)c1ccoc1
Agent: [Na]
Solvent: CCO
Product: O=C1Nc2ccccc2C1C(=O)c1ccoc1
Yield: 3.1 %

Procedure:
To a stirred solution of 2.8 g (0.12 mole) of sodium in 200 ml of ethanol was added 13.3 g (0.10 mole) of 2-oxindole, followed by 16.8 g of ethyl 3-furoate. The mixture was heated under reflux for 47 hours, cooled and then the solvent was removed by evaporation in vacuo. The residue was triturated under 200 ml of ether, and the solid was collected by filtration and discarded. The filtrate was evaporated in vacuo, and the residue triturated under isopropyl alcohol and recovered by filtration. The solid was suspended in 250 ml of water, which was then acidified with concentrated hydrochloric acid. This mixture was stirred to give a solid, which was recovered by filtration. This latter solid was recrystallized from acetic acid followed by acetonitrile to give 705 mg of the title compound, m.p. 185°-186° C.
Reaction SMILES: O.[NH2:2][NH2:3].[O:4]=[C:5]([C:15]([F:18])([F:17])[F:16])[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=O>C(OCC)C>[OH:4][C:5]1([C:15]([F:18])([F:17])[F:16])[NH:3][N:2]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:6]1
Reactant: NN
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccn1
Solvent: O
Solvent: CCOCC
Product: OC1(C(F)(F)F)CC(c2ccccn2)=NN1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 104.9 %

Procedure:
2-(2′,4′-difluorophenyl)pyrazole (3.6 g, 20 mmol) and K3IrBr6 (6.3 g, 8 mmol) were added to a flask containing 90 ml 2-ethoxyethanol and 30 ml water. The reaction mixture was heated to reflux and stirred under a nitrogen atmosphere for 24 h. After cooling, the pale yellow precipitate was vacuum filtered and washed first with ethanol followed by heptanes. The product [2-(4′,6′-diflouorophenyl)pyrazole]2Ir2(μ-Br)2[2-(4′,6′-diflouorophenyl)pyrazole]2 was dried in vacuum oven (4.2 g, 81%). Step 2 To a 60 ml THF suspension of potassium t-butoxide (7.9 g, 59 mmol) and 2-acetylpyridine(7.1 g, 59 mmol) was added dropwise ethyl trifluoroacetate (10 g, 70 mmol) at 10° C., and the mixture was stirred at room temperature for 15 h. After the PH value of the mixture had been adjusted to 6-7 with 10% H2SO4, the solution was extracted with Et2O. The organic layer was dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel with CH2Cl2 followed by recrystallization from ethanol to give 2-(3-oxo-4,4,4-trifluorobutanoyl)pyridine (10.2 g, 81%). Step 3 Hydrazine hydrate (1.44 g, 27.7 mmol) was added dropwise to 2-(3-oxo-4,4,4-trifluorobutanoyl)pyridine (5 g, 23 mmol) in 250 ml diethyl ether, and the mixture was stirred at ambient temperature for 3.5 h. Most of the solvent was evaporated and the mixture was extracted with water. The organic layer was dried (MgSO4) and evaporated to give 5-hydroxy-3-(pyridine-2-yl)-5-trifluoromethyl-4,5-dihydropyrazole (5.58 g, 78%). Step 4 Compound 5-hydroxy-3-(pyridine-2-yl)-5-trifluoromethyl-4,5-dihydropyrazole (5.58 g, 24 mmol) was boiled under reflux in 300 ml ethanol in the presence of conc. sulfuric acid (1.85 ml) for 30 min. The reaction mixture was then extracted with water. Evaporation and chromatography (ethyl acetate/heptanes 1:5) gave 3-(pyridine-2-yl)-5-trifluoromethylpyrazole (4.2 g, 85%). Step 5 [2-(4′,6′-difluorophenyl)pyrazole]2Ir2(μ-Br)2[2-(4′,6′-difluorophenyl)pyrazole]2 (0.15 g, 0.12 mmol), 3-(pyridine-2-yl)-5-trifluoromethylpyrazole (70 mg, 0.3 mmol) and 0.2 g of K2CO3 were refluxed under an nitrogen atmosphere in 2-ethoxyethanol for 18 h. After cooling to room temperature, water was added and a white precipitate was filtered and washed with water. The crude product was chromatographed on a silicon column with dichloromethane/methanol (9:1 v/v) as the mobile phase (110 mg, 60%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[Br:6][C:7]1[CH:8]=[C:9]([CH:13]([NH2:15])[CH3:14])[CH:10]=[N:11][CH:12]=1.CCN(CC)CC>C(Cl)Cl>[Br:6][C:7]1[CH:8]=[C:9]([CH:13]([NH:15][C:1](=[O:4])[CH2:2][CH3:3])[CH3:14])[CH:10]=[N:11][CH:12]=1
Reactant: CC(N)c1cncc(Br)c1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NC(C)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
At 0° C., propionyl chloride (138 mg, 1.5 mmol) was added dropwise to a solution of (rac)-1-(5-bromo-pyridin-3-yl)-ethylamine (201 mg, 1 mmol) and Et3N (153 mg, 1.5 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 1 hour before it was concentrated to dryness. The residue was redissolved in EtOAc and washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography to give the title compound (200 mg, 78%).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[O:24][C:25]([F:28])([F:27])[F:26])(=[O:15])=[O:14])[C:8](=[O:29])[C:7]2([N:46]1[CH2:55][C@H:54]([OH:56])[CH2:53][C@H:47]1[C:48]([N:50]([CH3:52])[CH3:51])=[O:49])[C:30]1[CH:35]=[C:34]([CH:36](O)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=[CH:32][C:31]=1[O:44][CH3:45].[OH-].[Na+]>C(O)(C(F)(F)F)=O.O>[CH2:36]([C:34]1[CH:33]=[CH:32][C:31]([O:44][CH3:45])=[C:30]([C:7]2([N:46]3[CH2:55][C@H:54]([OH:56])[CH2:53][C@H:47]3[C:48]([N:50]([CH3:52])[CH3:51])=[O:49])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([Cl:3])[CH:5]=3)[N:9]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[O:24][C:25]([F:26])([F:27])[F:28])(=[O:15])=[O:14])[C:8]2=[O:29])[CH:35]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(C(O)c4ccccc4)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(Cc4ccccc4)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 91.9 %

Procedure:
A solution of 5 mg of NaBH4 in TFA (1 ml) was stirred for 15 minutes at room temperature, then, a solution of 28.1 mg of the compound obtained in Example 249 in TFA (3 ml) was added dropwise over 10 minutes. Two hours later, the solution was diluted with water, neutralized with NaOH, and the resulting mixture was extracted with CHCl3. The organic layer was washed with water and with saturated brine and dried over MgSO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: MeOH/CHCl3=2/98; v/v) to obtain 25.3 mg of the title compound (colorless amorphous).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:64]1([CH2:67][N:68]2[CH2:74][CH2:73][CH2:72][N:71]([CH:75]3[CH2:80][CH2:79][CH:78]([NH2:81])[CH2:77][CH2:76]3)[CH2:70][CH2:69]2)[CH2:66][CH2:65]1>CN(C=O)C>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:81][CH:78]5[CH2:77][CH2:76][CH:75]([N:71]6[CH2:72][CH2:73][CH2:74][N:68]([CH2:67][CH:64]7[CH2:65][CH2:66]7)[CH2:69][CH2:70]6)[CH2:80][CH2:79]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Reactant: NC1CCC(N2CCCN(CC3CC3)CC2)CC1
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: COc1cc(C(=O)NC2CCC(N3CCCN(CC4CC4)CC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 5) (88 mg, 0.2 mmol, 1 eq), DIPEA (70 μl, 0.4 mmol, 2 eq) and TBTU (72 mg, 0.24 mmol, 1.2 eq) were added to 2 mL DMF and the resulting solution was stirred at rt for 20 min before the addition of 4-(4-(cyclopropylmethyl)-1,4-diazepan-1-yl)cyclohexanamine (Intermediate 14) (60 mg, 0.24 mmol, 1.2 eq). The RM was then stirred at rt for 2 hours before purifying by preparative RP-HPLC-MS (Preparative—2) to provide 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-N-(4-(4-(cyclopropylmethyl)-1,4-diazepan-1-yl)cyclohexyl)-3-methoxybenzamide as a mixture cis and trans isomers (off-white solid, 67 mg, 50%).
Reaction SMILES: [Br:1][CH2:2][C:3]([NH:5][C:6]1[CH:10]=[CH:9][O:8][N:7]=1)=[O:4].[N:11]12[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]1)[C@@H:13]([OH:19])[CH2:12]2>C(Cl)(Cl)Cl.C(#N)C>[Br-:1].[OH:19][C@@H:13]1[CH:14]2[CH2:17][CH2:18][N+:11]([CH2:2][C:3](=[O:4])[NH:5][C:6]3[CH:10]=[CH:9][O:8][N:7]=3)([CH2:16][CH2:15]2)[CH2:12]1
Reactant: O=C(CBr)Nc1ccon1
Reactant: O[C@H]1CN2CCC1CC2
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1ccon1
Product: [Br-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution comprising 2-bromo-N-isoxazol-3-yl-acetamide (0.975 g, 4.72 mmol), (R)-1-aza-bicyclo[2.2.2]octan-3-ol (0.549 g, 4.32 mmol) in chloroform/acetonitrile (1:1) (10 ml) is stirred at room temperature for 30 minutes. The resultant precipitate is filtered, washed with chloroform/acetonitrile (1:1) and dried under vacuum to yield the titled compound as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:35]=[CH:34][C:15]([C:16]([NH:18][CH2:19][C:20]2[S:21][C:22]([S:25]([N:28]3[CH2:32][CH2:31][C@@H:30]([OH:33])[CH2:29]3)(=[O:27])=[O:26])=[CH:23][CH:24]=2)=[O:17])=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:18][CH2:19][C:20]2[S:21][C:22]([S:25]([N:28]3[CH2:32][CH2:31][C:30](=[O:33])[CH2:29]3)(=[O:26])=[O:27])=[CH:23][CH:24]=2)=[O:17])=[CH:34][CH:35]=1
Reactant: O=C(NCc1ccc(S(=O)(=O)N2CC[C@@H](O)C2)s1)c1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCN(S(=O)(=O)c2ccc(CNC(=O)c3ccc(Cl)cc3)s2)C1
Yield: 80.2 %

Procedure:
At −80° C. oxalylchloride (36 mg, 0.28 mmol) was dissolved in dry CH2Cl2, while DMSO (50 ul, 0.6 mmol) were added slowly. The solution was stirred under Ar. For 15′. 351a (100 mg, 0.25 mmol) was dissolved in 2 ml CH2Cl2, and this solution was added dropwise to the above reaction mixture at −80° C. The reaction was stirred for 15′ at low temperature, before DIEA (0.21 ml, 1.25 mmol) was added. The reaction was stirred at −80° C. for 30′ and allowed to warm to it during 2 h. A white solid was formed, the reaction was quenched with water and extracted with CH2Cl2 several times. The combined organic layers were dried over MgSO4 and evaporated to dryness. The crude was purified by flash chromatography on silica gel using EtOAc/cyclohexane 2:1 as eluent. 351b (80 mg, 80%) was obtained as a colourless solid.: H′ NMR (CDCl3) δ 7.72 (d, J=8.7 Hz, 2H), 7.46 (d, J=3.8 Hz, 1H), 7.42 (d, J=8.7 Hz, 2H), 7.08 (d, J=3.8 Hz, 1H), 6.59 (t, J=5.8, 1H), 4.80 (d, J=6.0 Hz, 2H), 3.58 (t, J=7.5 Hz, 2H), 3.50 (s, 3H), 2.54 (t, J=7.5, 2H), 3.35-3.23 (m, 3H), 2.95 (m, 2H), 1.94 (m, 2H), 1.86 (m, 2H), 1.70-1.50 (m, 5H), 130-1.20 (m, 8H), 0.87 (t, J=6.8, 3H), M/Z APCI-399.0 (M+1), 397.2 (M−1)