Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10]1.Cl.[NH2:17][OH:18].C(N(CC)CC)C>CN(C=O)C>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][CH2:12][C:11](=[N:17][OH:18])[CH2:10]1
Reactant: O=C1CCCC(c2ccc(O)cc2O)C1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: ON=C1CCCC(c2ccc(O)cc2O)C1
Reaction time: 3 h
Yield: 86 %

Procedure:
(±)-3-(2,4-Dihydroxyphenyl)cyclohexanone (13 mg), hydroxylamine hydrochloride (0.0065 g), and triethylamine (16 μl) were heated at 80° C. in DMF (3 ml). After 3 hr, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, petroleum ether/ethyl acetate 3:2 v/v) to furnish the title compound as a white solid (12 mg, 86%). δH(CD3OD) 1.4-2.0 (6H, overlapping m), 2.10 (0.5H, m), 2.20 (0.5H, m), 2.35 (0.5H, m), 2.46 (0.5H, m), 2.94 (1H, m), 6.22-6.26 (2H, overlapping m), 6.92-6.95 (1H, overlapping m); m/z (ES+) 222 (M+H)−.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]1([S:13]([C:16]2[C:17]([CH2:33][CH3:34])=[N:18][N:19]3[C:24]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)=[CH:23][C:22](Cl)=[N:21][C:20]=23)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C>[C:7]1([S:13]([C:16]2[C:17]([CH2:33][CH3:34])=[N:18][N:19]3[C:24]([N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)=[CH:23][C:22]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[N:21][C:20]=23)(=[O:14])=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCc1nn2c(N3CCN(C)CC3)cc(Cl)nc2c1S(=O)(=O)c1ccccc1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: CCc1nn2c(N3CCN(C)CC3)cc(N3CCOCC3)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
0.26 ml (3 mmol) of morpholine in 5 ml of DMF was added to a solution of 0.50 g (1.2 mmol) of 3-benzenesulphonyl-5-chloro-2-ethyl-7-(4-methyl-piperazin-1-yl)-pyrazolo[1,5-a]pyrimidine in 15 ml of DMF and stirred at 100° for hr. After cooling to RT the reaction solution was evaporated and the residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH 15:1) and crystallization from EtOH yielded 0.45 g (80%) of 3-benzenesulphonyl-2-ethyl-7-(4-methyl-piperazin-1-yl)-5-morpholin-4-yl-pyrazolo[1,5-a]-pyrimidine as colorless crystals, m.p.>250°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[N:20]=[N:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:56][C:57]([CH3:61])([CH3:60])[CH2:58][OH:59]>CN(C=O)C.O>[OH:59][CH2:58][C:57]([NH:56][C:21]([C:18]1[N:19]=[N:20][C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:24])=[CH:16][CH:17]=1)=[O:23])([CH3:61])[CH3:60]
Reactant: CC(C)(N)CO
Reactant: Cc1onc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)nn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccc(F)cn2)c1COc1ccc(C(=O)NC(C)(C)CO)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To a solution of 6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid (69.4 mg, 0.21 mmol) in DMF (1.1 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (74.1 mg, 0.23 mmol), N,N-diisopropyl ethyl amine (179 μL, 1.05 mmol) and 2-amino-2-methyl-1-propanol (20.6 mg, 0.23 mmol). The resulting reaction mixture was stirred for 30 min at room temperature and diluted with water. The mixture was then extracted with ethyl acetate and the combined organic layers washed with aqueous sodium carbonate (saturated) and dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=1:0 to 3:7) afforded the title compound (74 mg, 88%) which was obtained as an off white solid. MS: m/e=402.4 [M+H]+.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Br.[NH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:34]=[CH:35][C:36](=[O:39])[NH:37][N:38]=2)=[CH:29][CH:28]=1.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:34]=[CH:35][C:36](=[O:39])[NH:37][N:38]=3)=[CH:29][CH:28]=2)=[O:9])[CH:3]=1
Reactant: O=C(O)c1cccnc1
Reactant: NCCCCOc1ccc(-c2ccc(=O)[nH]n2)cc1
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCCCCOc1ccc(-c2ccc(=O)[nH]n2)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.7 %

Procedure:
868 mg of nicotinic acid, 954 mg of N-hydroxybenzotriazole and triethylamine (1.23 ml) were added to a dimethylformamide solution (50 ml) containing 2.0 g of 6-[4-(4-aminobutoxy)phenyl]pyridazin-3(2H)-one hydrobromide. 1.35 g of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide was added to the mixture at 0° C., and the resulting mixture was stirred at room temperature for 6 hours and then poured into ice water, and precipitated crystal was collected by filtration. The crystal was recrystallized from ethanol to obtain 1.75 g of 6-[4-(4-(pyridin-3-ylcarbonylamino)butoxy)phenyl]pyridazin-3(2H)-one.
Reaction SMILES: [O-]CC.[Na+].[Cl:5][C:6]1[CH:31]=[CH:30][C:9]([O:10][CH2:11][C:12]([N:14]2[CH2:19][C@H:18]([CH3:20])[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:16][C@H:15]2[CH3:29])=[O:13])=[C:8]([C:32]2[O:36][N:35]=[CH:34][CH:33]=2)[CH:7]=1.Cl.O>C(O)C>[Cl:5][C:6]1[CH:31]=[CH:30][C:9]([O:10][CH2:11][C:12]([N:14]2[CH2:19][C@H:18]([CH3:20])[N:17]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH2:16][C@H:15]2[CH3:29])=[O:13])=[C:8]([C:32](=[O:36])[CH2:33][C:34]#[N:35])[CH:7]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1-c1ccno1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C(=O)CC#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.2 %

Procedure:
To a stirred mixture of sodium ethoxide (0.14 g, 1.0 mmol) in ethanol (2 mL) was added 2-(4-chloro-2-isoxazol-5-yl-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.465 g, 1.0 mmol) in ethanol (3 mL). The resulting mixture was stirred at ambient temperature for 3 hours. To the reaction was then added 3M hydrochloric acid (2 mL) and the resulting solution was poured into water (30 mL). This was extracted with ethyl acetate and the organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography on silica gel gave the title compound (0.34 g).
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH2:14]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[F:28][C:29]([F:41])([F:40])[C:30]1[CH:31]=[C:32]([P:36](Cl)(Cl)=[O:37])[CH:33]=[CH:34][CH:35]=1>CCCCCC.C1CCCCC1>[F:41][C:29]([F:28])([F:40])[C:30]1[CH:31]=[C:32]([P:36]2(=[O:37])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: O=P(Cl)(Cl)c1cccc(C(F)(F)F)c1
Reactant: c1ccc(CNc2ccccc2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCCCC1
Product: O=P1(c2cccc(C(F)(F)F)c2)c2ccccc2CN1c1ccccc1
Temperature: 26 °C
Reaction time: 2 h
Yield: 29.5 %

Procedure:
Under a static nitrogen atmosphere at 0° C., a solution of n-butyllithium (8.06 g, 0.126 mol) in hexane was added to a solution of tetramethylethylenediamine (3.71 g, 0.032 mol) in 60 ml. of anhydrous cyclohexane with constant stirring. While maintaining the temperature of the reaction at 0° C., a solution of N-benzylaniline (11 g, 0.06 mol) in 60 ml. of anhydrous cyclohexane was added to the reaction mixture to produce a suspension containing a dilithio compound. This suspension was stirred for 2 hours at 26° C. and then cooled to 0° C. in an ice bath. A solution of 3-trifluoromethylphenylphosphonic dichloride (16.8 g, 0.064 mol) in 60 ml. of anhydrous cyclohexane was added dropwise to the suspension. The ice bath was removed and the resulting mixture was stirred for 3 hours at 26° C. The reaction was quenched with the rapid addition of 12 ml. of acetic acid. The cyclohexane was removed under vacuum and the resulting residue was partitioned in methylene chloride and water. The layers were separated and the methylene chloride layer was washed with 5% hydrochloric acid, then water, dried over sodium sulfate and concentrated in vacuo to yield a brown oil. The brown oil was separated on a silica gel column using a 3:1 mixture of methylene chloride:ethyl acetate as the eluant. Fractions containing the benzazaphosphole were combined and rechromatographed using methylene chloride as the eluant. Fractions containing the benzazaphosphole were combined and concentrated in vacuo and the residue was triturated in cyclohexane to yield a white solid. The white solid was evacuated under high vacuum to remove any cyclohexane and the resulting residue was recrystallized from diethyl ether and petroleum ether to yield 1-[3-(trifluoromethyl)phenyl]-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (6.6 g, 30% yield) as a beige solid having a melting point of 48°-51° C. and the following analysis:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][CH2:15][CH2:16][C:17](O)=[S:18])=[N:12][N:11]=[N:10]2)=[CH:5][CH:4]=1)[CH3:2].[CH2:20]1[CH2:30][CH2:29][N:28]2[C:23](=NC[CH2:26][CH2:27]2)[CH2:22][CH2:21]1.ClC(OCC(C)C)=O.C(NC1CCCCC1)C>O1CCCC1>[CH2:27]([N:28]([CH:23]1[CH2:22][CH2:21][CH2:20][CH2:30][CH2:29]1)[C:17](=[S:18])[CH2:16][CH2:15][CH2:14][C:13]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[N:10]=[N:11][N:12]=1)[CH3:26]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCc1ccc(-n2nnnc2CCCC(O)=S)cc1
Agent: CC(C)COC(=O)Cl
Agent: CCNC1CCCCC1
Solvent: C1CCOC1
Product: CCc1ccc(-n2nnnc2CCCC(=S)N(CC)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
4-[1-(4-Ethylphenyl)-1,2,3,4-tetrazol-5-yl]-thio-butyric acid (45 mmole) is dissolved in tetrahydrofuran (50 ml), and thereto is added DBU (50 mmole). To the mixture is added dropwise with stirring isobutyl chloroformate (50 mmol) under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise N-ethyl-cyclohexylamine (54 mmole), and the mixture is further stirred at room temperature for 2 hours. The solvent is distilled off under reduced pressure and the resulting residue is extracted with chloroform. The chloroform layer is washed with 5% aqueous hydrochloric acid, an aqueous saturated sodium hydrogen carbonate solution and an aqueous saturated sodium chloride solution and then dried over anhydrous sodium sulfate. Chloroform is distilled off and the resulting residue is subjected to column chromatography (Wakogel C-200, eluting solvent, benzene:chloroform=4:1, V/V) to isolate N-ethyl-N-cyclohexyl-4-[1-(4-ethylphenyl)-1,2,3,4-tetrazol-5-yl]thio-butyramide (yield: 43%), colorless liquid, nD19 =1.5533.
Reaction SMILES: IC1C(O)=NC2CCN(C(=O)C(F)(F)F)CC(C)C=2C=1.C([O-])([O-])=O.[K+].[K+].CI.[I:29][C:30]1[C:47]([O:48][CH3:49])=[N:46][C:33]2[CH2:34][CH2:35][N:36](C(=O)C(F)(F)F)[CH2:37][CH:38]([CH3:39])[C:32]=2[CH:31]=1>CO.CC(C)=O>[I:29][C:30]1[C:47]([O:48][CH3:49])=[N:46][C:33]2[CH2:34][CH2:35][NH:36][CH2:37][CH:38]([CH3:39])[C:32]=2[CH:31]=1
Reactant: COc1nc2c(cc1I)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: CC1CN(C(=O)C(F)(F)F)CCc2nc(O)c(I)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Solvent: CO
Product: COc1nc2c(cc1I)C(C)CNCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.9 %

Procedure:
A mixture of 3-iodo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol (100 mg, 250 μmol), K2CO3 (200 mg), MeI (2 ml) and acetone (4 ml) was stirred for 16 h at ambient temperature. The reaction mixture was concentrated in vacuo and purified by column chromatography rendering 25.5 mg (25%) of 3-iodo-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine and 41.9 mg (41%) of 3-iodo-1,5-dimethyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one. 1H-NMR of O-methylated product (CDCl3) δ 7.79 (2× s, 1H), 3.95 (2× s, 3H), 3.94-3.78 (br m, 2H), 3.59 (br m, 1H), 3.56-3.36 (br m, 1H), 3.22 (m, 1H), 3.08 (br m, 2H), 1.30 (2× d, 3H) ppm. 1H-NMR N-methylated product (CDCl3) δ 7.80 (s, 1H), 3.97-3.65 (br m, 3H), 3.68 (2× s, 3H), 3.44-3.01 (m, 4H), 1.30 (2× d, 3H) ppm. A mixture of 3-iodo-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (25.5 mg, 62.0 μmol), K2CO3 (17.0 mg, 124 μmol) and MeOH (7 ml) was heated for 5 h at 60° C. The reaction mixture was concentrated in vacuo and purified by column chromatography to furnish 5.90 mg (30%) of 3-iodo-2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (DMSO-d6) δ 7.84 (s, 1H), 3.83 (s, 3H), 3.00-2.90 (m, 3H), 2.86-2.77 (m, 3H), 2.65 (dd, 1H), 1.21 (d, 3H) ppm.
Reaction SMILES: [CH:1]1[C:13]2NC3[C:6](=CC=CC=3)[C:5]=2[CH:4]=[CH:3][N:2]=1.[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][C:25]([OH:27])=O)[C:19]1[CH2:28][N:29]([CH3:32])[CH2:30][CH2:31][C:18]2=1>>[CH3:3][NH:2][CH2:1][CH2:13][CH:5]([CH3:6])[CH3:4].[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][C:25]([N:2]([CH2:1][CH2:13][CH:5]([CH3:6])[CH3:4])[CH3:3])=[O:27])[C:19]1[CH2:28][N:29]([CH3:32])[CH2:30][CH2:31][C:18]2=1
Reactant: c1ccc2c(c1)[nH]c1cnccc12
Reactant: CN1CCc2c(n(CC(=O)O)c3ccc(Cl)cc23)C1
Product: CC(C)CCN(C)C(=O)Cn1c2c(c3cc(Cl)ccc31)CCN(C)C2
Product: CNCCC(C)C

Procedure:
Method for the preparation of compound 14[2-(6-chloro-2-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-N-isopentyl-N-methylacetamide]: (4-chlorophenyl)hydrazine is alkylated with ethyl 2-bromoacetate to give the substituted phenylhydrazine ethyl 2-(1-(4-chlorophenyl)hydrazinyl)acetate (III). The reaction of III with 4,4-dimethoxy-N-methylbutan-1-amine gives the indole derivative ethyl 2-(5-chloro-3-(2-(methylamino)ethyl)-1H-indol-1-yl)acetate (V). Effecting the indole to standard Pictet Spingler conditions with formaldehyde gives the β-carboline intermediate (VI) ethyl 2-(6-chloro-2-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)acetate. Following treatment of VI with base the acid (VIII) 2-(6-chloro-2-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)acetic acid is obtained. The treatment of this acid under standard peptide coupling conditions with N,3-dimethylbutan-1-amine gives compound 15 2-(6-chloro-2-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-N-isopentyl-N-methylacetamide. After the successful synthesis of the compound, purification can be achieved using standard normal phase or reverse phase methods.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[CH:15]1([NH2:18])[CH2:17][CH2:16]1>C(O)C>[CH:15]1([NH:18][C:2]2[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[C:7]3[C:3]=2[NH:4][CH:5]=[N:6]3)[CH2:17][CH2:16]1
Reactant: FC(F)(F)c1nc(Cl)c2[nH]cnc2n1
Reactant: NC1CC1
Solvent: CCO
Product: FC(F)(F)c1nc(NC2CC2)c2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 108 h
Yield: 62 %

Procedure:
A mixture of 12 g (54 mmol) of 6-chloro-2-trifluoromethylpurine, 30 g (540 mmol) of cyclopropylamine and 250 mL of ethanol was stirred at room temperature for 4.5 days leaving a white solid. The mixture was concentrated in vacuo to dryness, 215 mL of H2O was added and the mixture was stirred for 1 hour. The product was collected by filtration and after drying (vacuum oven, 50° C., 5 hours) 8.1 g of product was obtained, 62% yield. M.P. 260° C. (dec.); 1H NMR (CD3OD) δ 8.18 (s, 1H), 3.30 (bs, 1H), 0.904 (m, 2H), 0.67 (m, 2H).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[C:26]([C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1)#[N:27].C(N(CC)CC)C.Cl>C(#N)C>[C:26]([C:28]1[CH:29]=[CH:30][C:31]([NH:34][C:35]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[O:36])=[CH:32][CH:33]=1)#[N:27]
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: N#Cc1ccc(N=C=O)cc1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1
Reaction time: 18 h
Yield: 38.3 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.37 g, 1.0 mmol) and 4-cyanophenylisocyanate (0.14 g, 1.0 mmol) in acetonitrile (10 mL), was added triethylamine (0.28 mL, 2.0 mmol) at room temperature under nitrogen. After 18 h, 1 N aq. HCl (15 mL) was added and the solids were isolated by filtration, washed with water (40 mL). The crude product was purified by prep-HPLC (MeCN/H2O, 10/90 to 90/10 gradient over 15 min). The product fractions were combined, triturated in Et2O then filtered and dried in vacuo to give 1-(4-cyano-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.16 g, 38% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 to 90/10 CH3CN/0.1% H3PO4 gradient over 15 mins, 7.31 min (97.64%); mp: 258-260° C.; 1H NMR (DMSO-d6) δ 1.86-2.06 (m, 1H, CHH), 2.27-2.47 (m, 1H, CHH), 2.60 (d, J=17.0 Hz, 1H, CHH), 2.78-3.03 (m, 1H, CHH), 4.31 (d, J=17.2 Hz, 1H, CHH), 4.38-4.59 (m, 3H, CHH, CH2), 5.11 (dd, J=4.9, 13.2 Hz, 1H, CH), 7.00 (t, J=5.7 Hz, 1H, NH), 7.45 (d, J=7.9 Hz, 1H, Ar), 7.52 (s, 1H, Ar), 7.56-7.63 (m, 2H, Ar), 7.64-7.82 (m, 3H, Ar), 9.23 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 31.20, 42.79, 47.12, 51.56, 102.50, 117.56, 119.40, 121.89, 122.96, 126.91, 130.36, 133.15, 142.39, 144.39, 144.84, 154.68, 167.92, 170.98, 172.85; LCMS: MH=418; Anal Calcd for C22H19N5O4: C, 62.76; H, 4.64; N, 16.63. Found: C, 62.65; H, 4.55; N, 16.69.
Reaction SMILES: C1(C(C2C=CC=CC=2)[O:8][C:9]([C:11]([C:13]2[C:22]([F:23])=[C:21]([F:24])[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([F:25])[C:14]=2[F:26])=[CH2:12])=[O:10])C=CC=CC=1.FC(F)(F)C(O)=O.CCCCCC.C(=O)([O-])O.[Na+]>C1(OC)C=CC=CC=1>[C:9]([C:11]([C:13]1[C:14]([F:26])=[C:15]([F:25])[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:21]([F:24])[C:22]=1[F:23])=[CH2:12])([OH:10])=[O:8]
Reactant: C=C(C(=O)OC(c1ccccc1)c1ccccc1)c1c(F)c(F)c(C(=O)OC)c(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Solvent: COc1ccccc1
Product: C=C(C(=O)O)c1c(F)c(F)c(C(=O)OC)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
In 15 ml of anisole was dissolved 3.2 g of methyl 4-(1-diphenylmethoxycarbonylvinyl)-2,3,5,6-tetrafluorobenzoate. To the resulting solution was added 15 ml of trifluoroacetic acid. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue obtained was mixed with 20 ml of n-hexane. The resulting mixture was adjusted to pH 7.5 with a saturated aqueous sodium hydrogencarbonate solution. The aqueous layer was separated and mixed with 50 ml of ethyl acetate. The resulting mixture was adjusted to pH 1 with 6N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 1.9 g (yield: 95.0%) of methyl 4-(1-carboxyvinyl)-2,3,5,6-tetrafluorobenzoate.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:9][CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH2:5])=[O:4].[ClH:17]>C(OCC)(=O)C.CCOCC>[NH:1]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH2:5])=[O:4].[ClH:17]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(N)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: NC(=O)[C@@H]1CCCCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
1.6 g (7 mmoles) of BOC-HPro-NH2 are dissolved in 10 ml of ethyl acetate under heating. The solution is cooled to room temperature, and 10 ml of a 6 n hydrochloric acid solution in ethyl acetate are added. After one hour of standing the mixture is diluted with ether, the separated precipitate is triturated and then filtered off. 1.05 g (91%) of H-HPro-NH2.HCl are obtained; m.p.: 178°-180° C., Rf6 =0.32, [α]D25 =+26.2° (c=1%, in methanol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:34](=[CH:35][CH:36]=3)[CH2:33][C@:23]3([C:31]5[C:26](=[N:27][CH:28]=[CH:29][CH:30]=5)[NH:25][C:24]3=[O:32])[CH2:22]4)=[O:17])[C:13](=[O:37])[C:12]([CH3:39])([CH3:38])[C:11](=O)[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[BH3-]C#[N:43].[Na+]>CO.O.C([O-])(O)=O.[Na+]>[NH2:43][C@@H:11]1[CH2:10][C@@H:9]([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)[N:14]([CH2:15][C:16]([NH:18][C:19]2[CH:20]=[C:21]3[C:34](=[CH:35][CH:36]=2)[CH2:33][C@:23]2([C:31]4[C:26](=[N:27][CH:28]=[CH:29][CH:30]=4)[NH:25][C:24]2=[O:32])[CH2:22]3)=[O:17])[C:13](=[O:37])[C:12]1([CH3:38])[CH3:39]
Reactant: CC1(C)C(=O)C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)Nc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)C1=O
Reactant: [BH3-]C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(C)C(=O)N(CC(=O)Nc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)[C@H](c2cc(F)cc(F)c2)C[C@H]1N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2-[(6S)-6-(3,5-difluorophenyl)-3,3-dimethyl-2,4-dioxopiperidin-1-yl]-N-[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamide (380 mg, 0.698 mmol, described in Example 7) and NH4OAc (571 mg, 7.41 mmol) in CH3OH (2 mL) was stirred at ambient temperature for 20 min. NaCNBH3 (498 mg, 7.92 mmol) was added and stirring was continued at ambient temperature for 12 h. The reaction mixture was diluted with H2O (40 mL) and aqueous NaHCO3 (70 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:CH3OH—100:0 to 80:20, to give 2-[(4R,6S)-4-amino-6-(3,5-difluorophenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]-N-[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamide, which eluted first, and 2-[(4S,6S)-4-amino-6-(3,5-difluorophenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]-N-[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamide, which eluted second, the title compound. MS: m/z=546 (M+1). HRMS: m/z=546.2287; calculated m/z=546.2311 for C30H30F2N5O3.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[O:26][C:25](=O)[C:24]3[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=3[N:22]=2)[CH2:13][CH2:12]1.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([N:39]1[C:25](=[O:26])[C:24]2[C:23](=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:22]=[C:21]1[CH2:20][CH2:19][CH2:18][CH2:17][N:14]1[CH2:13][CH2:12][N:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH2:16][CH2:15]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=c1oc(CCCCN2CCN(c3ccc4ccccc4n3)CC2)nc2ccccc12
Reactant: NCc1ccccc1
Product: O=c1c2ccccc2nc(CCCCN2CCN(c3ccc4ccccc4n3)CC2)n1Cc1ccccc1
Temperature: 250 °C
Yield: 64.8 %

Procedure:
A mixture of 207 mg of 2-[4-(4-quinolin-2-ylpiperazin-1-yl)-butyl]-3,1-benzoxazin-4-one as synthesized in above Step 7-15-B and 150 mg of benzylamine was stirred at 250° C. for an hour. Cooling the solution, the residue was purified on silica gel column chromatography (dichloromethane:methanol=15:1) to provide 163 mg (65%) of 3-benzyl-2-[4-(4-quinolin-2-ylpiperazin-1-yl)butyl]-3H-quinazolin-4-one.