Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:25]=[CH:24][C:11]3[CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][CH2:16][C:10]=3[CH:9]=2)[C:5]([O:26][CH2:27][C:28]2[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][N:29]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:25]=[CH:24][C:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:10]=3[CH:9]=2)[C:5]([O:26][CH2:27][C:28]2[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][N:29]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccnc(COc2ccc(Cl)nc2-c2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccnc(COc2ccc(Cl)nc2-c2ccc3c(c2)CCNCC3)c1
Temperature: 25 °C

Procedure:
To an ice cooled solution of 1,1-dimethylethyl 7-(6-chloro-3-{[(4-methyl-2-pyridinyl)methyl]oxy}-2-pyridinyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate in DCM (1 ml) was added dropwise TFA (1 ml) and the reaction mixture stirred at room temperature until the starting material had been consumed. The reaction mixture was concentrated in vacuo, dissolved in water and backwashed with ethyl acetate. The aqueous layer was neutralised with aqueous sodium bicarbonate then extracted with ethyl acetate, dried over sodium sulphate and concentrated in vacuo to yield the title compound, 27 mg.
Reaction SMILES: [NH2:1][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1)([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(#N)C>[Br:12][C:8]1[CH:7]=[C:6]([C:2]([NH:1][C:22](=[O:23])[CH2:21][Cl:20])([CH3:5])[CH2:3][OH:4])[CH:11]=[CH:10][CH:9]=1
Reactant: CC(N)(CO)c1cccc(Br)c1
Reactant: O=C(Cl)CCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(CO)(NC(=O)CCl)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
A solution of crude (RS)-2-amino-2-(3-bromo-phenyl)-propan-1-ol (8.38 g, 36 mmol) and triethylamine (6.08 ml, 44 mmol) in acetonitrile (140 ml) was treated dropwise at −2° C. with chloro-acetyl chloride (3.25 ml, 40 mmol). After complete addition, the orange colored solution was left to warm to room temperature and stirring was continued for 2 h. For the workup, to the reaction was added silica gel (10 g) and it was evaporated at reduced pressure, thereafter, it was purified by chromatography on silica gel using a gradient of dichloromethane/methanol=100/0 to 90/10 as the eluent. There were obtained 9.62 g (86% of theory) of (RS)—N-[1-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide as a light brown oil. MS (ISP): m/z=304.1 [M+H]+, 306.1 [M+2+H]+, 308.2 [M+4+H]+.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[CH2:9](Br)[CH:10]=[CH2:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:8][C:2]1[CH:1]=[C:6]([O:7][CH2:11][CH:10]=[CH2:9])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cccc(C)c1
Reaction time: 18 h
Yield: 94.5 %

Procedure:
m-Cresol 10.4 ml (100 mmole), 10.8 ml (125 mmole) allyl bromide, and 16.56 g (120 mmole) of potassium carbonate were stirred in 50 ml of acetone and refluxed, with stirring, under nitrogen, for 18 hours. The reaction was cooled, the insoluble inorganics were filtered off and the filtrate was stripped to give 14.0 g (95%) of subtitled product, which was used without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[OH:10])=[CH2:2].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[CH:1]([C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[O:10][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH2:2]
Reactant: BrCc1ccccc1
Reactant: C=Cc1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=Cc1cc(F)ccc1OCc1ccccc1

Procedure:
A mixture of 2-ethenyl-4-fluorophenol (C16) (1.03 g, 7.46 mmol) and potassium carbonate (3.12 g, 22.4 mmol) in acetone (35 mL) was treated with benzyl bromide (1.78 mL, 14.9 mmol) and stirred at reflux for 3 hours. The mixture was concentrated in vacuo, ethyl acetate (100 mL) was added and the mixture was washed with water (2×50 mL) and saturated aqueous sodium chloride solution (50 mL). The organic layer was dried over magnesium sulfate, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 15% ethyl acetate in heptane) afforded the title compound as a colorless oil. Yield: 1.64 g, 7.23 mmol, 97%. GCMS m/z 228 (M+). 1H NMR (400 MHz, CDCl3) δ 5.08 (s, 2H), 5.33 (dd, J=11.1, 1.0 Hz, 1H), 5.76 (dd, J=17.8, 1.0 Hz, 1H), 6.85-6.95 (m, 2H), 7.11 (ddd, J=17.8, 11.1, 1.5 Hz, 1H), 7.23 (dd, J=9.4, 2.9 Hz, 1H), 7.33-7.48 (m, 5H).
Reaction SMILES: C[O:2][C:3](=O)[N:4]=[C:5](SC)[C:6]([C:20]1[CH:21]=[C:22]([CH2:30][CH3:31])[C:23]2[O:28][CH2:27][O:26][CH2:25][C:24]=2[CH:29]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.[NH:35]([C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1)[NH2:36].C(N(CC)CC)C>CN(C=O)C>[CH2:30]([C:22]1[C:23]2[O:28][CH2:27][O:26][CH2:25][C:24]=2[CH:29]=[C:20]([CH:6]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:18]=[C:17]([CH3:19])[O:16][N:15]=3)=[CH:12][CH:13]=2)[C:5]2[NH:4][C:3](=[O:2])[N:35]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:36]=2)[CH:21]=1)[CH3:31]
Reactant: NNc1ncccn1
Reactant: CCc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)cc2c1OCOC2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc2c1OCOC2
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a solution of 101 mg of [2-(8-ethyl-4H-benzo[1,3]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in 2 ml of DMF there were added 21 mg of 2-hydrazinopyrimidine and 50 μl of triethylamine, and the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 200 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{(8-ethyl-4H-benzo[1,3]dioxin-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[N:28][NH:29]2)=[CH:25][CH:24]=1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:35]4[CH2:36][CH2:37][N:32]([C:27]5[C:26]6[C:30](=[CH:31][C:23]([F:22])=[CH:24][CH:25]=6)[NH:29][N:28]=5)[CH2:33][CH2:34]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Reactant: Fc1ccc2c(N3CCNCC3)n[nH]c2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCN(c2n[nH]c3cc(F)ccc23)CC1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 6-fluoro-3-piperazin-1-yl-1H-indazole (Table No.1, SM 4) in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=506.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH3:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:4]([CH2:9][CH3:10])[CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CCc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(Br)ccc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a DMF solution of 4-bromo-2-ethylphenol were added potassium carbonate and benzyl bromide, and the whole was stirred at an oil bath temperature of 60° C. for 30 minutes to obtain benzyl (4-bromo-2-ethylphenyl) ether, which was then treated in a similar manner to the first half of Reference Example 2 to obtain methyl 6-(4-benzyloxy-3-ethylphenyl)pyridine-2-carboxylate. The obtained compound was stirred in a mixed solution of methanol and THF in the presence of 10% palladium/carbon under a hydrogen atmosphere of normal pressure at room temperature for 24 hours and then thus obtained product was dissolved in trifluoroacetic acid. Pentamethylbenzene was added thereto under ice cooling and the whole was stirred at an oil bath temperature of 50° C. for 1 hour and further at room temperature for 4.5 days to obtain methyl 6-(3-ethyl-4-hydroxyphenyl)pyridine-2-carboxylate. The obtained compound was treated with trifluoromethanesulfonic anhydride in pyridine to obtain methyl 6-(3-ethyl-4-trifluoromethanesulfonyloxyphenyl)pyridine-2-carboxylate. Further, to a 1,4-dioxane solution of the ester compound obtained above were added tributylvinyltin, lithium chloride, tetrakis(triphenylphosphine)palladium(0), and 2,6-di-t-butyl-4-methylphenol, and the whole was heated to reflux for 18 hours. Thereafter, tetrakis(triphenylphosphine)palladium(0) was further added thereto, followed by 2 days of heating under reflux. Then, potassium fluoride was added thereto at room temperature and the whole was stirred at room temperature for 2 days to obtain methyl 6-(3-ethyl-4-vinylphenyl)pyridine-2-carboxylate. The compound was treated with a 1M aqueous sodium hydroxide solution in methanol to obtain an objective compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14]2=[O:19])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N:20]1([C:24]([C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][N:27]=2)=[O:25])[CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[N:20]1([C:24]([C:26]2[N:27]=[CH:28][C:29]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]4[CH2:17][CH2:16][N:15]([CH3:18])[C:14]4=[O:19])[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[CH:30][CH:31]=2)=[O:25])[CH2:23][CH2:22][CH2:21]1
Reactant: O=C(c1ccc(Br)cn1)N1CCC1
Reactant: COC(=O)c1cc(O)cc(O[C@H]2CCN(C)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(O[C@H]2CCN(C)C2=O)c1
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A mixture of methyl 3-hydroxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoate (Intermediate 8) (530 mg, 2 mmol), azetidin-1-yl-(5-bromopyridin-2-yl)methanone (CAS no. 845306-16-3) (531 mg, 2.2 mmol), caesium carbonate (1.956 g, 6 mmol) and tris(triphenylphosphine)copper bromide (CAS no. 15709-74-7) (373 mg, 0.4 mmol) in DMA (5 mL) was stirred at 160° C. for 6 hours. The DMA was evaporated under reduced pressure and the residue was dissolved in water (520 mL) washed with ethyl acetate (3×20 mL). The aqueous fraction was acidified with 2N hydrochloric acid and extracted with ethyl acetate (3×100 mL), the combined organic layers were washed with water (2×20 mL) and brine (20 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was dissolved in THF (6 mL) and methanol (3 mL) and was treated dropwise with 2M (trimethylsilyl)diazomethane in hexane (1.1 mL). The reaction was stirred for 30 min then treated with 1 drop of acetic acid, stirred for another 15 minutes and evaporated to dryness under reduced pressure. The residue was purified by chromatography eluting with 0-100% ethyl acetate/hexane to give afford the product (439 mg, 52%). 1H NMR δ (300 MHz, CDCl3) 2.10-2.24 (m, 1H), 2.35 (quintet, 2H), 2.52-2.67 (m, 1H), 2.93 (s, 3H), 3.34-3.56 (m, 2H), 3.89 (s, 3H), 4.25 (t, 2H), 4.70 (t, 2H), 4.91 (t, 1H), 6.99 (s, 1H), 7.32 (s, 1H), 7.35 (d, 1H), 7.53 (s, 1H), 8.10 (d, 1H), 8.31 (s, 1H); m/z 426 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@@H:15]([C:19]#[N:20])[CH2:14]2)=[CH:9][CH:8]=1.Cl.[NH2:25][OH:26].C(N(CC)C(C)C)(C)C>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@@H:15]([C:19]([NH:25][OH:26])=[NH:20])[CH2:14]2)=[CH:9][CH:8]=1
Reactant: N#C[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: N=C(NO)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 25 °C

Procedure:
(R)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carbonitrile (0.211 g, 0.001 mol) and hydroxylamine hydrochloride (0.047 g, 0.001 mol) were dissolved in ethanol (4 ml) and N,N-diisopropylethylamine (0.120 ml, 0.001 mol) was added. The reaction mixture was stirred under reflux for three hours. The reaction was cooled to room temperature, the solvent was evaporated and the residue extracted with dichloromethane and purified by column chromatography on silica gel using a 19:1-mixture of dichloromethane and methanol as the eluent to yield (0.220 g, 94% of theory) of a yellow oil. MS (m/e)=344.3(M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1)[NH:8][CH2:7][CH2:6]2.F[C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1)[N:8]([C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCNC2Cc1ccc(OCc2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc2c(c1)CCN(c1ccc([N+](=O)[O-])cc1)C2Cc1ccc(OCc2ccccc2)cc1
Temperature: 120 °C
Yield: 89.1 %

Procedure:
A solution of 6-methoxy-1-[4-(phenylmethoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline (2.10 g, 5.84 mmol) and 1-fluoro-4-nitrobenzene (1.65 g, 11.7 mmol) in 40 mL of DMSO was treated with powdered K2CO3 (1.62 g, 11.7 mmol) and the reaction mixture was warmed at 120° C. for 12 h. The reaction mixture was cooled to room temperature and 300 mL of water was added. The aqueous layer was extracted with CH2Cl2 and the combined organic layer was washed with water, dried over MgSO4, then concentrated under reduced pressure. The crude product was purified by flash chromatography to provide the title compound (2.50 g, 89%). ES-MS, (m/z) 481 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])#[CH:13].N>>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: C#Cc1ccc(F)cc1F
Reactant: ON=C(Cl)c1cncc(Cl)c1
Agent: N
Product: Fc1ccc(-c2cc(-c3cncc(Cl)c3)no2)c(F)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 69B (57 mg, 0.3 mmol) and 1-ethynyl-2,4-difluorobenzene (Aldrich, 41 mg, 0.3 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.30-7.43 (m, 1H), 7.61 (ddd, J=11.4, 9.2, 2.8 Hz, 1H), 7.68 (d, J=3.2 Hz, 1H), 8.07 (td, J=8.5, 6.3 Hz, 1H), 8.54 (t, J=2.0 Hz, 1H), 8.80 (d, J=2.4 Hz, 1H), 9.15 (d, J=2.0 Hz, 1H) ppm; MS (DCI/NH3) m/z 293 (M+H)+, 295 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.C([O:11][C:12](=[O:17])[CH2:13][N:14]=[C:15]=[O:16])C>C1COCC1>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:15](=[O:16])[NH:14][CH2:13][C:12]([OH:17])=[O:11])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(N)ccn1
Reactant: CCOC(=O)CN=C=O
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)NCC(=O)O)ccn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2-Methyl-pyridin-4-ylamine (1.08 g, 10 mmol) is dissolved in dry THF (30 mL) and isocyanatoacetic acid ethyl ester (1.29 g, 10 mmol) is added. The mixture is stirred at r.t. for 15 h. The mixture is evaporated and 6N aq. HCl (20 mL) is added. The mixture is stirred at 50° C. for 6 h, evaporated and the residue purified by reversed phase MPLC to provide the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH:8]([S:9]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[O:20][C:21]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[F:40][C:41]([F:51])([F:50])[C:42]1[CH:43]=[C:44]([NH2:49])[C:45]([NH2:48])=[CH:46][CH:47]=1.OS([O-])=O.[Na+]>CCO>[F:40][C:41]([F:50])([F:51])[C:42]1[CH:47]=[CH:46][C:45]2[NH:48][C:16]([C:15]3[CH:14]=[CH:13][C:12]([S:9]([CH:8]4[CH2:7][CH2:6][CH2:5][CH2:4][N:3]([O:20][C:21]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:2]4=[O:1])(=[O:11])=[O:10])=[CH:19][CH:18]=3)=[N:49][C:44]=2[CH:43]=1
Reactant: O=Cc1ccc(S(=O)(=O)C2CCCCN(OC(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C1C(S(=O)(=O)c2ccc(-c3nc4cc(C(F)(F)F)ccc4[nH]3)cc2)CCCCN1OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
4-(2-Oxo-1-trityloxy-azepane-3-sulfonyl)-benzaldehyde prepared from step G (17.4 mg, 0.0322 mmol) and 4-Trifluoromethyl-benzene-1,2-diamine (23.6 mg, 0.13 mmol) in 5.0 ml of anhydrous EtOH was heated to reflux and a 1.2 ml aqueous solution of NaHSO3 (100.1 mg) was added in one portion. The resulting solution was stirred and heated to reflux for overnight. The reaction mixture was concentrated under reduced pressure and diluted with EtOAc and water. The organic phase was washed sequentially with water and saturated NaCl solution, and then dried over anhydrous Na2SO4. The EtOAc solution was concentrated under reduced pressure to give a crude material, which was then purified by a column chromatography (0˜10% EtOAc in hexane and dichloromethane 1:1). MS: 696.2 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:32])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[S:27][C:26]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:33]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[CH2:34][CH2:35][CH3:36]>>[CH2:33]([N:37]1[CH2:42][CH2:41][N:40]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:32])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]4[S:27][C:26]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:25][CH:24]=4)(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:39][CH2:38]1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCN1CCNCC1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)s3)cc2)c1
Product: CCCCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)s4)cc3)c2)CC1
Yield: 58 %

Procedure:
The title compound was prepared from 5-((4-(3-(3-cyanophenyl)ureido) phenylsulfonamido)methyl)thiophene-2-sulfonamide following procedure C and using 2.2 equivalent of n-butylpiperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:13]([NH2:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH4-].[Na+]>CO.Cl>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:21][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCc1ccccc1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
0.65 ml of 4-tert-butylbenzaldehyde (3.7 mmol) and 0.32 ml of phenethylamine (2.5 mmol) were dissolved in 7.5 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 2¼ h. After cooling down to rt, 142 mg (3.7 mmol) of sodium borohydride were added and after stirring for 15 min at rt, the reaction mixture was then refluxed for 3.5 h. After cooling down to rt, the reaction mixture was treated with 6 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:2) to give 609 mg of colorless oil (91%). MS (ISP) 268.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH3:16]>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH:14][C:21]([NH:20][C:18]([O:17][CH2:15][CH3:16])=[O:19])=[S:22])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Nc1ncccc1-c1ccc(F)cc1
Reactant: CCOC(=O)N=C=S
Solvent: C1COCCO1
Product: CCOC(=O)NC(=S)Nc1ncccc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3-(4-fluoro-phenyl)-pyridin-2-ylamine (200 mg, 1.06 mmol) in dioxane (10 mL) was added ethoxycarbonyl isothiocyanate (141 μL, 1.17 mmol) and stirred at room temperature for 12 hours. The solvent was evaporated and the residue was used for the next step without purification. The title compound was obtained as a light yellow solid (340 mg, 100%).
Reaction SMILES: [CH3:1][N:2]1[C:14]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:6]2=[CH:7][CH:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[N:5]2[CH2:4][CH2:3]1.C1C(=O)N([Br:34])C(=O)C1>C(#N)C>[Br:34][C:7]1[CH:8]=[C:9]([C:10]([F:11])([F:13])[F:12])[N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[C:14]3([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[C:6]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1CCn2c(C(F)(F)F)ccc2C12CCN(C(=O)OC(C)(C)C)CC2
Solvent: CC#N
Product: CN1CCn2c(C(F)(F)F)cc(Br)c2C12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
To a solution of tert-butyl 2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (5.60 g, 15.0 mmol) in acetonitrile (50 mL) was added NBS (2.80 g, 15.8 mmol). The mixture was stirred at room temperature overnight. The solvent was removed and the residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4 and concentrated to dryness. The crude material was purified by column chromatography (10-20% EtOAc-Hex) to provide tert-butyl 8-bromo-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (5.40 g, 73%) as a light yellow solid. ESI-MS m/z calc. 452.3. found 454.5 (M+1)+; Retention time: 1.60 minutes (3 minute run).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]2[CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][C:7]=2[N:8]=1)#[N:2]>FC(F)(F)C(O)=O.ClCCl>[N:8]1[C:7]2[CH2:9][NH:10][CH2:11][C:6]=2[CH:5]=[N:4][C:3]=1[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cnc(C#N)nc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ncc2c(n1)CNC2

Procedure:
A solution of tert-butyl 2-cyano-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (150 mg) in trifluoroacetic acid and dichloromethane (1:1, 1 mL) was stirred for one h and evaporated. The residue was purified by flash column chromatography (silica, 0-4% methanol containing 10% ammonium hydroxide in dichloromethane) to yield 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-2-carbonitrile.