Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[N:17]=2)=[C:6]([CH:14]=1)[C:7](N(CC)CC)=[O:8].[CH:23]([N-:26][CH:27](C)[CH3:28])(C)[CH3:24].[Li+]>C1COCC1>[Br:1][C:2]1[CH:14]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:15][C:16]1=[N:17][C:18]([F:22])=[CH:19][CH:20]=[C:21]1[C:7]2=[O:8].[Br:1][C:2]1[CH:14]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:15][C:16]1=[N:17][C:18]([N:26]([CH2:27][CH3:28])[CH2:23][CH3:24])=[CH:19][CH:20]=[C:21]1[C:7]2=[O:8]
Reactant: CCN(CC)C(=O)c1cc(Br)ccc1Oc1cccc(F)n1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(CC)c1ccc2c(=O)c3cc(Br)ccc3oc2n1
Product: O=c1c2cc(Br)ccc2oc2nc(F)ccc12
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 5-bromo-N,N-diethyl-2-(6-fluoropyridin-2-yloxy)benzamide (2.90 g, 7.90 mmol) in 50 mL of dry THF at −78° C. was added dropwise lithium diisopropylamide (2.0 M heptane/THF/ethylbenzene, 11.8 mL, 23.69 mmol) and the reaction was stirred at −78° C. for 2 hours. The reaction quenched at −78° C. with 30 mL of 1 N HCl in ether. After warming to rt, the reaction was further quenched with saturated NH4Cl (250 mL) extracted with ethyl acetate (3×250 mL). The combined organics were washed with brine, and evaporated to dryness. Purification by silica gel chromatography (hexane to hexane/CH2Cl2=1:1 to CH2Cl2 to CH2Cl2/EA=10:1) gave 7-bromo-2-fluoro-5H-chromeno[2,3-b]pyridin-5-one as a white solid and 7-bromo-2-(diethylamino)-5H-chromeno[2,3-b]pyridin-5-one as a white solid.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C:12]1[S:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23]CC3C=CC=CC=3)=[CH:19][CH:18]=2)=[N:15][N:16]=1)C1C=CC=CC=1>Br.C(O)(=O)C.C(OCC)C>[NH2:10][CH2:11][C:12]1[S:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[N:15][N:16]=1
Reactant: O=C(NCc1nnc(-c2ccc(OCc3ccccc3)cc2)s1)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: NCc1nnc(-c2ccc(O)cc2)s1

Procedure:
A solution of benzyl((5-(4-(benzyloxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)carbamate (7.4 g, 17.1 mmol) in 33% HBr in acetic acid (100 mL) and was stirred for 2 h. The resulting mixture was diluted with diethyl ether and the precipitate was collected and washed with diethyl ether to yield 4-(5-(aminomethyl)-1,3,4-thiadiazol-2-yl)phenol (MS m/z=408 MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][C@H:11]([NH:16]C(OC(C)(C)C)=O)[C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1.C(Cl)(C)=O>CCOC(C)=O.CO>[NH2:16][C@@H:11]([CH2:10][C:9]#[C:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)[C@H](CC#Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)Cl
Solvent: CO
Product: COC(=O)[C@@H](N)CC#Cc1ccc(Br)cc1
Yield: 96 %

Procedure:
To a solution of methyl (2S)-5-(4-bromophenyl)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-pentynoate (D74, 1.199 g, 3.136 mmol) in dry EtOAc (18 ml) and dry methanol (2 ml) was added AcCl (1.14 ml, 1.25 g, 15.98 mmol). After solvent removal the residue was purified using a SCX cartridge affording the title compound (849 mg, 95%). UPLC: Rt 0.51 min, MS: (ES/+) m/z: 282, 284 [MH+], C12H12BrNO2 requires 282.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:14])[S:10](Cl)(=[O:12])=[O:11].[CH3:15][C:16]([CH3:27])([CH2:25][CH3:26])[CH2:17][C:18]1[N:19]=[C:20]([CH3:24])[N:21]([OH:23])[CH:22]=1>C(Cl)Cl>[CH3:15][C:16]([CH3:27])([CH2:25][CH3:26])[CH2:17][C:18]1[N:19]=[C:20]([CH3:24])[N:21]([O:23][S:10]([N:9]([CH3:14])[CH3:8])(=[O:12])=[O:11])[CH:22]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CCC(C)(C)Cc1cn(O)c(C)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)(C)Cc1cn(OS(=O)(=O)N(C)C)c(C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
Triethylamine (100 mL, 0.72 mol) followed by N,N-dimethylsulfamoyl chloride (42 mL, 0.38 mol) were added to a 0° C. solution of 4-(2,2-dimethylbutyl)-2-methyl-1H-imidazol-1-ol in methylene chloride (100 mL). After stirring at ambient temperature for 2 h, the reaction mixture was washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography over silica eluting with ethyl acetate/hexane followed by methanol afforded N-({[4-(2,2-dimethylbutyl)-2-methyl-1H-imidazol-1-yl]oxy}sulfonyl)-N-methylmethanamine (ca. 50% purity by HPLC) which was dissolved in 7:1 methanol/acetic acid (400 mL), and 10% Palladium (10% on activated carbon) (6 g) was added. After stirring under 40 psi hydrogen for 2 h, the reaction mixture was filtered through celite, rinsing with methanol and concentrated in vacuo. The residue was redissolved in ethyl acetate and washed with 1 N aqueous sodium hydroxide and brine, dried (magnesium sulfate), filtered and concentrated in vacuo. Chromatography over silica eluting with 5-20% methanol/methylene chloride afforded 4-(2,2-dimethylbutyl)-2-methyl-1H-imidazole.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[O:9][C:8](=[O:10])[NH:7][C:6]([CH3:12])([CH3:11])[CH2:5]1.[Cl:13]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>ClCCl.CO>[Cl:13][N:7]1[C:6]([CH3:12])([CH3:11])[CH2:5][CH:4]([CH2:3][CH2:2][OH:1])[O:9][C:8]1=[O:10]
Reactant: CC1(C)CC(CCO)OC(=O)N1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: CO
Solvent: ClCCl
Product: CC1(C)CC(CCO)OC(=O)N1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.5 %

Procedure:
To a solution of 6-(2-hydroxyethyl)-4,4-dimethyl-1,3-oxazinan-2-one (278 mg, 1.6 mmol) in 4 mL dichloromethane and 250 uL methanol was added trichloroisocyanuric acid (370 mg, 1.6 mmol). The reaction mixture was stirred at room temperature for 4 hours and then directly purified by column chromatography (0 to 10% methanol in dichloromethane) to give a white solid (291 mg, 1.40 mmol, 87%). 1H NMR (D2O, 400 MHz) δ 1.35 (s, 6H), 1.78-1.83 (m, 2H), 1.97-2.03 (dd, J=11.9, 14.2 Hz, 1H), 2.13-2.17 (dd, J=2.1, 14.2 Hz, 1H), 3.64-3.68 (m, 2H), 4.55-4.60 (m, 2H). 13C NMR (D2O, 100 MHz) δ 24.3, 27.9, 35.8, 41.5, 63.0, 72.5, 155.15. LRMS (ESI/APCI) m/z 208 [M+H]+.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)=[O:5].C[Mg+].[Br-].[C:21](O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[C:4]([CH:6]1[CH2:7][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:9]1)(=[O:5])[CH3:21]
Reactant: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 70 %

Procedure:
To a solution of tert-butyl 3-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate (7.0 g, 28.7 mmol) in THF (150 mL) was added CH3MgBr (43 mL, 43 mmol) at 0° C., then slowly warmed to RT for about 2 hr. 10% aqueous of citric acid (30 mL) was added to the mixture, and extracted with EA (50 mL×3), the combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography on silica gel (200-300 mesh, PE/EA=2/1), to give the crude product (4.0 g, 70%) as a colorless oil. MS (ESI) m/e [M−55]+ 144.0.
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:3]=1[C:4]([N:6]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)=[O:5].[Cl:35]N1C(=O)CCC1=O.O.C(Cl)Cl>C(#N)C>[NH2:1][C:2]1[C:33]([Cl:35])=[CH:32][C:31]([CH3:34])=[CH:30][C:3]=1[C:4]([N:6]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:24][CH:25]=1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=1)=[O:5]
Reactant: Cc1ccc(N)c(C(=O)N(CCc2cccc(C(F)(F)F)c2)Cc2ccc(C(C)(C)C)cc2)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cc(Cl)c(N)c(C(=O)N(CCc2cccc(C(F)(F)F)c2)Cc2ccc(C(C)(C)C)cc2)c1
Temperature: 95 °C
Yield: 28 %

Procedure:
2-Amino-N-(4-tert-butyl-benzyl)-5-methyl-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide (60 mg, 0.128 mmol) was dissolved in acetonitrile (2 ml) and N-chlorosuccinimide (23 mg, 0.128 mmol) was added. The reaction was heated to 95° C. for 4 h. The reaction mixture was cooled to RT and partitionated between water and methylene chloride. The aqueous layer was extracted with methylene chloride and the combined organic phase was dried (MgSO4), filtered and concentrated in vacuo to give a residue which was purified by flash column chromatography (heptane/ethyl acetate 7:3) to yield the desired product (18 mg, 28%) as a brown gum. MS (ISP) 503.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](=S)[NH:9][C:8]=2[C:7]([C:17]#[N:18])=[C:6]1[N:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20]1.C(O)(=O)C.O.OO>CO.O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[Cl:1][C:2]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[CH:10]=[N:9][C:8]=2[C:7]([C:17]#[N:18])=[C:6]1[N:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20]1
Reactant: Cn1c(=S)[nH]c2c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n(Cc3cc(F)ccc3Cl)c2c1=O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: Cn1cnc2c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n(Cc3cc(F)ccc3Cl)c2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 113.3 %

Procedure:
Sodium tungstate dihydrate (0.91 g) was added to a solution of tert-butyl {(3R)-1-[5-(2-chloro-5-fluorobenzyl)-7-cyano-3-methyl-4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (1.51 g) in a mixture of methanol (9 ml), acetic acid (3 ml) and water (1 ml), and a 30% aqueous hydrogen peroxide solution (0.29 ml) was added dropwise thereto at room temperature and stirred for 2 hours. After the reaction mixture was allowed to cool, the methanol was distilled off under reduced pressure and the residue was adjusted to pH 9 with an aqueous potassium carbonate solution. A 10% aqueous sodium hydrogensulfite solution was added thereto and stirred for 30 minutes, followed by extraction with ethyl acetate (200 mL). The organic layer was washed with a 10% aqueous potassium carbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was dried under reduced pressure to obtain the title compound (1.61 g).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[O:5]1[C:9]2([CH2:14][CH2:13][CH:12]([N:15]3[CH:19]=[C:18]([C:20]4[CH:21]=[C:22]([NH:27][C:28]5[N:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][N:29]=5)[CH:23]=[C:24]([CH3:26])[CH:25]=4)[CH:17]=[N:16]3)[CH2:11][CH2:10]2)OCC1.CS(O)(=O)=O.[OH-].[Na+]>C(Cl)(Cl)Cl.O>[CH3:26][C:24]1[CH:25]=[C:20]([C:18]2[CH:17]=[N:16][N:15]([CH:12]3[CH2:11][CH2:10][NH:1][C:9](=[O:5])[CH2:14][CH2:13]3)[CH:19]=2)[CH:21]=[C:22]([NH:27][C:28]2[N:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[CH:30][N:29]=2)[CH:23]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(C3CCC4(CC3)OCCO4)c2)c1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(C3CCNC(=O)CC3)c2)c1
Temperature: 65 °C

Procedure:
Sodium azide (155 mg, 2.39 mL) was added to a solution of N-{3-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-4-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (732 mg, 1.59 mmol) in chloroform (8.0 mL) followed by methanesulfonic acid (1.24 mL, 19.1 mmol). The reaction was heated to 65° C. for 2 h. The reaction was cooled to room temperature and water was added, followed by NaOH (1N). The organic layer was extracted with EtOAc (3×). The combined layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (10% methanol/dichloromethane) to afford racemic 5-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]azepan-2-one as a white solid. MS ESI calcd. for C21H21F3N6O [M+H]+ 431. found 431.
Reaction SMILES: NC1[C:3]([O:17]C)=[C:4](NS(C)(=O)=O)[CH:5]=[C:6]([C:8](C)(C)C)C=1.C([N:21](CC)CC)C.O[N:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2N=N1>CN(C=O)C.CCOC(C)=O>[CH:6]([C:5]1[C:30]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:27][C:4]=1[C:3]([NH2:21])=[O:17])=[CH2:8]
Reactant: CCN(CC)CC
Reactant: On1nnc2ccccc21
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=Cc1c(C(N)=O)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 508.3 %

Procedure:
To a solution of the above carboxylic acid (1.6 g, 8.2 mmol) in DMF (80 mL) was added N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide (2.21 g, 8.14 mmol.), O-(7-azobenzotriazol-1-yl)-N,N,N′,N′-tetrauroniumhexafluorophosphate (HATU, 3.15 g, 8.260 mmol), 2.56 mL of triethylamine (2.56 mL, 18.4 mmol), and 1-hydroxybenzotriazole (HOAT, 307.4 mg, 2.240 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was then diluted with EtOAc, washed with water, dried with sodium sulfate and concentrated. The crude product was purified by silica gel chromatography to afford 2.12 g (56.8%) of the desired ethenylindole amide.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[CH:12][CH:13]=2)[CH:8]=1)(=O)=O.[CH3:21][O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[CH3:18][O:17][C:11]1[CH:12]=[CH:13][C:14]2[C:9](=[CH:8][C:7]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([O:22][CH3:21])[CH:28]=3)=[CH:16][CH:15]=2)[CH:10]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: COc1ccc2ccc(OS(=O)(=O)C(F)(F)F)cc2c1
Product: COc1cccc(-c2ccc3ccc(OC)cc3c2)c1

Procedure:
The title compound was prepared by reacting 7-methoxy-2-naphthyl trifluoromethanesulfonate (2.20 g, 7.18 mmol) with 3-methoxyphenylboronic acid (1.20 g, 7.90 (mmol) according to method A above to yield a white solid: mp 58–59° C.; 1H NMR (CDCl3): δ 3.89 (3H, s), 3.93 (3H, s), 6.91–6.94 (1H, m), 7.15 (1H, dd, J=2.42 Hz, J=8.83 Hz), 7.19 1H, d, J=2.27 Hz), 7.23–7.25 (1H, m), 7.28–7.31 (1H, m), 7.37–7.42 (1H, m), 7.59 (1H, dd, J=1.56 Hz, J=8.46 Hz), 7.75 (1H, d, J=8.84 Hz), 7.83 (1H, d, J=8.45 Hz), 7.94 (s1H, s); MS (ESI) m/z 265 (M+H)−.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[Br:6][C:7]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][C:11]([CH3:18])=[N:12]2>S(=O)(=O)(O)O.ClCCl>[Br:6][C:7]1[C:16]([F:17])=[CH:15][C:14]([N+:1]([O-:4])=[O:2])=[C:13]2[C:8]=1[CH:9]=[CH:10][C:11]([CH3:18])=[N:12]2
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1ccc2c(Br)c(F)ccc2n1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc2c(Br)c(F)cc([N+](=O)[O-])c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.8 %

Procedure:
A solution of 11.5 g of potassium nitrate in 30 ml of concentrated sulfuric acid was added to 21.0 g of 5-bromo-6-fluoroquinaldine in 117 ml of concentrated sulfuric acid dropwise at -5° C. After stirring at room temperature for 5 hours, the reaction mixture was poured into 2 l of ice water to precipitate solids which were then collected by filtration. The filtrate was rendered alkaline to form a small amount of solids, which together with the former solids were dissolved in dichloromethane. After the solution was dried over sodium sulfate the solvent was distilled off. Recrystallization of the residue from isopropanol gave 22.9 g of 5-bromo-6-fluoro-8-nitroquinaldine. m.p. 135°-137° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:4][CH:3]=1.O.[NH2:16][NH2:17]>C(O)C>[NH:16]([C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:4][CH:3]=1)[NH2:17]
Reactant: NN
Reactant: CC(C)(C)OC(=O)c1ccc(Cl)nc1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(NN)nc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
18.0 g (84.2 mmol) of tert-butyl 6-chloropyridine-3-carboxylate are initially charged in 85 ml of ethanol. 42.2 g (842.0 mmol) of hydrazine hydrate are added, and the mixture is stirred at 100° C. for 2 h. The mixture is then concentrated, and the residue is taken up in a mixture of ethyl acetate and water. The phases are separated, and the organic phase is washed once with water and once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated again. The residue is triturated with petroleum ether, and the solid formed is filtered off and dried under high vacuum.
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:5][NH:4][C:3]=1[NH2:12].[C:13]([N:21]=[C:22]=[S:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCOCC1>[S:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:6]1[C:2]2[S:23][C:22]([NH:21][C:13](=[O:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[N:12][C:3]=2[NH:4][N:5]=1
Reactant: Nc1[nH]nc(-c2cccs2)c1Br
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1nc2[nH]nc(-c3cccs3)c2s1)c1ccccc1
Temperature: 90 °C
Reaction time: 17 h
Yield: 80.7 %

Procedure:
To a stirring solution of 4-bromo-5-thiophen-2-yl-2H-pyrazol-3-ylamine (50 mg, 0.205 mmol) in dioxane (1 mL) was added benzoylisothiocyanate (30 μL, 0.225 mmol) dropwise. The reaction mixture was stirred at 90° C. for 17 h. It was then cooled to room temperature and partitioned between ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The organic layer was washed twice with a saturated aqueous solution of sodium bicarbonate, then with brine, and adsorbed on silica gel. Purification on silica gel with 0-80% ethyl acetate in hexane as eluent provided 54 mg (80%) of N-(3-thiophen-2-yl-1H-pyrazolo[3,4-d]thiazol-5-yl)-benzamide as a beige solid. 1H-NMR (d6-DMSO) δ: 13.5 and 13.6 (2 broad s, 1H, NH+tautomer), 12.9 (broad s, 1H, NH), 8.1 (d, 2H), 7.68 and 7.85 (2 dd, 1H, tautomers), 7.66 (t, 1H), 7.58 (t, 2H), 7.34 and 7.53 ( 2 d, 1H, tautomers), 7.17 and 7.22 (2 t, 1H, tautomers); HPLC/MS m/z: 327 [MH]+.
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:15]=[C:14]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(N(CC)CC)C>C1COCC1.O>[Br:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:15]=[C:14]([C:16]3[N:17]=[N:18][N:19]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:20]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: Fc1ccc(Br)c(OC2CCN(c3cc(-c4nnn[nH]4)on3)CC2)c1
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)Cn1nnc(-c2cc(N3CCC(Oc4cc(F)ccc4Br)CC3)no2)n1

Procedure:
A mixture of 4-(2-bromo-5-fluorophenoxy)-1-[5-(1H-tetrazol-5-yl)isoxazol-3-yl]piperidine (1.2 g, 2.93 mmol), ethyl bromoacetate (0.45 mL, 4.04 mmol) and triethylamine (0.75 mL, 5.38 mmol) in THF (12 mL) was heated at reflux temperature for 2 h. After cooling, the mixture was diluted with water and extracted with EtOAc. The EtOAc extract was washed with water, dried (Na2SO4) and concentrated. Combi-Flash chromatography (40 g, 25-40% EtOAc in hexanes for 20 min, 35 mL/min, 18 mL/fraction) gave the title compound as a colorless gum, containing about 20% of 1-alkylated isomer.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:22]=[CH:21][C:11]3[NH:12][C:13]([C:15]4[C:19]([NH2:20])=[CH:18][NH:17][N:16]=4)=[N:14][C:10]=3[CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>C1COCC1>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]3[C:11](=[CH:21][CH:22]=2)[N:12]=[C:13]2[N:14]3[C:23](=[O:24])[NH:20][C:19]3[C:15]2=[N:16][NH:17][CH:18]=3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c2c[nH]nc2c2nc3ccc(CN4CCOCC4)cc3n12
Temperature: 25 °C
Yield: 67.4 %

Procedure:
To a mixture of 3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine (3.2 g, 10.7 mmol) in anhydrous THF (50 mL) stirring at ambient temperature was added 1,1′-carbonyldiimidazole (1.78 g, 11 mmol). The mixture was heated at reflux for 14 h and then cooled to ambient. The solid formed was collected by filtration, washed with THF (20 mL) and dried in vacuo to give 7-morpholin-4-ylmethyl-2,4-dihydro-1,2,4,5a,10-pentaaza-cyclopenta[a]fluoren-5-one (2.34 g, 67% ) as a pink solid.
Reaction SMILES: C(OC([NH:8][S:9]([CH:12]1[NH:17][CH2:16][C:15]2[S:18][C:19]([C:21]([N:23]3[CH2:28][CH2:27][N:26]([S:29]([C:32]4[NH:33][C:34]5[C:39]([CH:40]=4)=[CH:38][C:37]([Cl:41])=[CH:36][CH:35]=5)(=[O:31])=[O:30])[CH2:25][CH:24]3[CH2:42][C:43]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[O:44])=[O:22])=[N:20][C:14]=2[CH2:13]1)(=[O:11])=[O:10])=O)(C)(C)C.FC(F)(F)C(O)=O.C(OCC)C>C(Cl)Cl>[NH2:8][S:9]([CH:12]1[NH:17][CH2:16][C:15]2[S:18][C:19]([C:21]([N:23]3[CH2:28][CH2:27][N:26]([S:29]([C:32]4[NH:33][C:34]5[C:39]([CH:40]=4)=[CH:38][C:37]([Cl:41])=[CH:36][CH:35]=5)(=[O:31])=[O:30])[CH2:25][CH:24]3[CH2:42][C:43]([N:45]3[CH2:46][CH2:47][O:48][CH2:49][CH2:50]3)=[O:44])=[O:22])=[N:20][C:14]=2[CH2:13]1)(=[O:10])=[O:11]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)C1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4cc5cc(Cl)ccc5[nH]4)CC3CC(=O)N3CCOCC3)sc2CN1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)C1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4cc5cc(Cl)ccc5[nH]4)CC3CC(=O)N3CCOCC3)sc2CN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.9 %

Procedure:
In methylene chloride (3 ml) was dissolved 1-[[6-(tert-butoxycarbonylaminosulfonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazine (275 mg), followed by the addition of trifluoroacetic acid (3 ml). The resulting mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure. A saturated solution of hydrochloride. in ethanol (3 ml) was added and the resulting mixture was stirred at room temperature for 1.5 hours. The residue obtained by distilling off the solvent under reduced pressure was added with methylene chloride and water to separate into layers. The water layer was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by preparative thin-layer chromatography (methanol:methylene chloride=1:9) using silica gel. The solid thus obtained was dissolved in a small amount of methylene chloride, followed by solidification by the addition of diethyl ether, whereby the title compound (50 mg) was obtained as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][CH2:8][C@H:9]([NH2:28])[C:10](=[O:27])[N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[OH:40][C:41]1[N:45]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[N:44]=[C:43]([C:52](O)=[O:53])[CH:42]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:29])[CH2:7][CH2:8][C@H:9]([NH:28][C:52]([C:43]1[CH:42]=[C:41]([OH:40])[N:45]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[N:44]=1)=[O:53])[C:10](=[O:27])[N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=2)[CH2:13][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC[C@H](N)C(=O)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Reactant: O=C(O)c1cc(O)n(-c2ccccc2)n1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(O)n(-c2ccccc2)n1)C(=O)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Yield: 84.8 %

Procedure:
To 2.2 g of (S)-4-Amino-5-oxo-5-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-pentanoic acid tert-butyl ester in 30 ml of DMF, 892 mg of HOBT, 1.08 g of 5-Hydroxy-1-phenyl-1H-pyrazole-3-carboxylic acid 1.12 g EDC Hydrochlorid and 1.90 ml DIPEA was added. After 3 h at RT the mixture was diluted with ethyl acetate and washed with saturated sodium hydrogen carbonate solution. Drying of the organic layer over sodium sulfate and evaporation under reduced pressure afforded a brownish powder that was purified by chromatography over silica gel eluting with ethyl acetate/heptane 1:1 to 100% ethyl acetate to give 2.7 g of the desired product. Yield: 2.7 g MS (ES+): m/e=416.