Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]([C:14]2[N:15]=[C:16]([NH:19][C:20](=[O:36])[CH2:21][C:22]3[C:30]4[C:29](=[O:31])[N:28]([CH3:32])[C:27](=[O:33])[N:26]([CH3:34])[C:25]=4[O:24][C:23]=3[CH3:35])[S:17][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11].[C:37]([O:43][CH2:44]Cl)(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]>CC(C)=O>[CH3:39][C:38]([CH3:41])([CH3:40])[C:37]([O:43][CH2:44][N:15]1[C:14]([C:5]2[CH:6]=[CH:7][C:8]([O:9][C:10]([F:13])([F:11])[F:12])=[C:3]([Cl:2])[CH:4]=2)=[CH:18][S:17][C:16]1=[N:19][C:20](=[O:36])[CH2:21][C:22]1[C:30]2[C:29](=[O:31])[N:28]([CH3:32])[C:27](=[O:33])[N:26]([CH3:34])[C:25]=2[O:24][C:23]=1[CH3:35])=[O:42]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: Cc1oc2c(c1CC(=O)Nc1nc(-c3ccc(OC(F)(F)F)c(Cl)c3)cs1)c(=O)n(C)c(=O)n2C
Agent: [Na]
Solvent: CC(C)=O
Product: Cc1oc2c(c1CC(=O)N=c1scc(-c3ccc(OC(F)(F)F)c(Cl)c3)n1COC(=O)C(C)(C)C)c(=O)n(C)c(=O)n2C

Procedure:
The title compound was prepared by the reaction of sodium salt of N-{4-[3-chloro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide (2.0 g, 0.0036 mol) with chloromethyl pivalate (0.82 g, 0.005455 mol) in dry acetone (60 ml) to yield 390 mg of product as an off white solid. 1H NMR (300 MHz, CDCl3) δ 1.22 (s, 9H), 2.34 (s, 3H), 3.33 (s, 3H), 3.53 (s, 3H), 4.11 (s, 2H), 6.49 (s, 2H), 7.24 (s, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.98 (s, 1H). ESI-MS (m/z): 642.75 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C([NH2:21])=O.N.[OH-].[Na+]>CO>[CH3:17][CH:16]([CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:21])[C:11]=2[N:12]=[CH:13]1)[CH3:18]
Reactant: CC(C)Cn1cnc2c(Cl)nc3ccccc3c21
Reactant: NC=O
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Cn1cnc2c(N)nc3ccccc3c21
Temperature: 145 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
A mixture of 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline (100.0 g, 0.385 mole) and formamide (250 ml, 6.27 mole, 16.3 equiv.) was heated to 145° C. under nitrogen atmosphere. Then, ammonia (gas) (92 g, 5.29 mole, 14 equiv.) was bubbled (4-5 g per hour) into the reaction mixture at this temperature during a period of 20 hours. Then, the reaction mixture was cooled to ambient temperature and stirred at this temperature for 3 hours. A colorless solid was collected by filtration, washed with methanol (3×100 ml), water (3×100 ml) and again with methanol (3×50 ml) and dried at 50° C. under reduced pressure overnight to give a crude Imiquimod (74.1 g, 80.2% yield, purity by HPLC: 99.3%). The crude compound (74.1 g) was slurried in a boiling mixture of methanol (500 ml) and 47% aqueous sodium hydroxide solution (about 6 ml) for 4 hours. The hot mixture was filtered and the thus obtained cake was washed with methanol (3×40 ml), water (3×50 ml) and again with methanol (3×40 ml) and dried at 50° C. under reduced pressure to yield 72.2 g of Imiquimod in 77.9% yield, having a purity of 99.85% (by HPLC)
Reaction SMILES: CN(C)/[CH:3]=[C:4]1\[CH2:5][CH2:6][CH2:7][C:8]([OH:17])(C2C=NC=CC=2)[C:9]\1=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([NH:41][C:42]([NH2:44])=[NH:43])[CH:32]=[CH:33][C:34]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]1.C(N(CC)CC)C>C(O)C.O1CCCC1>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([NH:41][C:42]2[N:44]=[CH:3][C:4]3[CH2:5][CH2:6][CH2:7][CH:8]([OH:17])[C:9]=3[N:43]=2)[CH:32]=[CH:33][C:34]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CN(C)/C=C1\CCCC(O)(c2cccnc2)C1=O
Solvent: CCO
Solvent: O=[N+]([O-])O
Solvent: CCN(CC)CC
Product: COc1cc(Nc2ncc3c(n2)C(O)CCC3)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
A solution of crude 6-[1-dimethylamino-meth-(E)-ylidene]-2-hydroxy-2-pyridin-3-yl-cyclohexanone (1002 mg, 2.7 mmol), N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (948 mg, 3.3 mmol) and triethyl amine (546 mg, 5.4 mmol) in ethanol (13.5 mL) was heated to 160° C. for 30 minutes in a microwave oven. The reaction was concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure to yield 1340 mg of crude intermediate. This was dissolve in tetrahydrofurane (13.5 mL) and under nitrogen 1M TBAF solution in tetrahydrofurane (4.0 mL) was added. The reaction was stirred at room temperature over night and was concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified on silica gel using dichloromethane/methanol (9:1 v/v) as eluent to yield the title compound (765 mg, 81%) as a brown foam. MS ISP (m/e): 352.3 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.67 (s, 1H), 8.30 (s, 1H), 7.98 (s, 1H), 7.65 (s, 1H), 7.38 (d, 1H), 7.20 (d, 1H), 7.03 (s, 1H), 5.24 (d, 1H), 4.44 (m, 1H), 3.79 (s, 3H), 2.55-2.65 (m, 2H), 2.14 (s, 3H), 1.65-1.95 (m, 4H).
Reaction SMILES: Br.[CH3:2][N:3]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:4](=[O:7])[CH2:5][NH2:6].C(O)(=O)C>C(O)(C)C>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]1[C:9]2[N:8]([CH:12]=[CH:11][CH:10]=2)[N:3]([CH3:2])[C:4](=[O:7])[CH2:5][N:6]=1
Reactant: CN(C(=O)CN)n1cccc1C(=O)c1ccccc1Cl
Agent: Br
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CN1C(=O)CN=C(c2ccccc2Cl)c2cccn21
Yield: 26.9 %

Procedure:
A solution containing 1-(N-methyl-aminoacetamido)-2-(2-chlorobenzoyl)pyrrole hydrobromide (12.6 g, 43.4 mmol) and glacial acetic acid (15 g, 0.25 mol) in 100 ml of isopropanol was refluxed under nitrogen for 12 hours and thereafter evaporated to an oil. This oil was flash chromatographed (silica, 4:1 ethyl acetate-hexane) to give 3.2 g (27%) of crystals, m.p. 132°-134°. This was combined with 0.5 g from an earlier run and recrystallized from acetone to give 3.5 g of crystals, m.p. 132°-133.5°.
Reaction SMILES: [C:1]1(C([O-])=O)[CH:6]=[CH:5]C=[CH:3][CH:2]=1.[NH2:10][C@@H:11]([C:13]([OH:15])=[O:14])[CH3:12].C(N)(C)C.P([O-])([O-])([O-])=O>>[CH:1]1[CH:6]=[CH:5][C:12]([C@@H:11]([NH2:10])[C:13]([OH:15])=[O:14])=[CH:3][CH:2]=1
Reactant: O=C([O-])c1ccccc1
Reactant: C[C@@H](N)C(=O)O
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)N
Product: N[C@@H](C(=O)O)c1ccccc1

Procedure:
D-phenylglycine was produced with a conversion of 98% by conducting reactions using 50 mL of a mixture of 0.3 M phenylformate, 20 mM D-alanine, 0.45 M isopropylamine, 0.5 mM PLP, 50 mM phosphate pH 8, 35 U/mL DATA and 30 U/mL ARmutTA. 2.02 g of pure D-phenylglycine was obtained through purification based on solubility.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13][CH3:14])[C:6]=1[CH:7]=[O:8]>O1CCOCC1>[Br:1][C:12]1[C:5]([O:4][CH3:3])=[C:6]([C:9]([S:13][CH3:14])=[CH:10][CH:11]=1)[CH:7]=[O:8]
Reactant: COc1cccc(SC)c1C=O
Reactant: BrBr
Solvent: C1COCCO1
Product: COc1c(Br)ccc(SC)c1C=O
Temperature: 50 °C
Reaction time: 6 h

Procedure:
Bromine (28.8 g, 0.18 mol) (dissolved in dioxane (500 ml)) was added dropwise to a solution of 2-methoxy-6-methylsulfanylbenzaldehyde (22 g, 0.12 mol) in dioxane (500 ml), and the mixture was stirred at 50° C. for 6 h. The mixture was then concentrated, the residue was taken up in CH2Cl2, and the mixture was washed with H2O , dried over MgSO4 and concentrated. The solid was recrystallized from diisopropyl ether.
Reaction SMILES: [F:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[C:29]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[CH:30]=1)[N:27]=[CH:26][CH:25]=[CH:24]2.C([BH3-])#N.[Na+]>CO.[Cl-].[Na+].O>[F:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][CH:15]([N:34]3[CH2:35][CH2:36][N:31]([C:29]4[CH:30]=[C:21]([O:20][CH3:19])[CH:22]=[C:23]5[C:28]=4[N:27]=[CH:26][CH:25]=[CH:24]5)[CH2:32][CH2:33]3)[CH2:14][CH2:13]2)=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCN(c2c(F)ccc3cccnc23)CC1
Reactant: COc1cc(N2CCNCC2)c2ncccc2c1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(N2CCN(C3CCN(c4c(F)ccc5cccnc45)CC3)CC2)c2ncccc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(7-fluoroquinolin-8-yl)piperidin-4-one (Step 3, 0.26 g) and 6-methyoxy-8-(1-piperazinyl)quinoline (Example A, Step 4; 0.26 g) in anhydrous methanol (10 mL) was added sodium cyanoborohydride (0.11 g). The resulting mixture was stirred at room temperature under nitrogen for 18 hours. An additional aliquot of sodium cyanoborohydride (0.11 g) was added and stirring at room temperature was continued for another 24 hours. The resulting reaction mixture was poured into brine and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated on a rotary evaporator. The crude product was purified by flash chromatography on silica gel using hexane/acetone to give the desired product, which was converted to its trihydrochloride salt in CH2Cl2 using 1M HCl/Et2O to provide 0.12 g of a yellow solid; MS (ES) m/z (relative intensity): 472 (M+H)+ (100).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].Cl[CH2:7][C:8]1[S:12][C:11]([CH3:13])=[N:10][CH:9]=1.[OH-].[Na+]>C(#N)C>[CH3:13][C:11]1[S:12][C:8]([CH2:7][NH:1][CH2:2][CH2:3][CH2:4][NH2:5])=[CH:9][N:10]=1
Reactant: Cc1ncc(CCl)s1
Reactant: NCCCN
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1ncc(CNCCCN)s1
Yield: 89.9 %

Procedure:
Trimethylenediamine (37 g) was dissolved in 120 ml of acetonitrile, and a solution of 14.8 g of 5-chloromethyl-2-methylthiazole in 30 ml of acetonitrile was added dropwise at 10° to 15° C. After the addition, the mixture was stirred at 30° to 40° C. for a while, and then 8 g of a 50% aqueous solution of sodium hydroxide was added. Subsequently, the volatile materials were removed at a bath temperature of less than 50° C. under 5 mmHg. The inorganic materials were removed from the residue by filtration to give 16.7 g of N-(2-methyl-5-thiazolylmethyl)trimethylenediamine (purity about 90%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29](=[O:30])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=1
Reactant: COc1ccccc1N=C=O
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Product: COc1ccccc1NC(=O)Nc1ccc(-c2c(C(N)=O)[nH]c3ncccc23)cc1

Procedure:
83.6 mg of solid beige-coloured 3-{4-[3-(2-methoxyphenyl)ureido]phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 2-methoxyphenyl isocyanate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([CH3:31])([S:27]([CH3:30])(=[O:29])=[O:28])[C:17]([NH:19][O:20]C2CCCCO2)=[O:18])=[CH:10][CH:9]=1.Cl.CO>C(Cl)Cl>[OH:20][NH:19][C:17](=[O:18])[C:16]([CH3:31])([S:27]([CH3:30])(=[O:28])=[O:29])[CH2:15][CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[OH:1])=[CH:13][CH:12]=1
Reactant: CC(CCc1ccc(-c2ccccc2O)cc1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC(CCc1ccc(-c2ccccc2O)cc1)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-(2′-Hydroxybiphenyl-4-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (19.6 mg, 0.044 mmol) was dissolved in methylene chloride (1 mL) at ambient temperature. To this solution was added HCl (4M in 1,4-dioxane, 0.33 mL, 1.32 mmol) and the solution was stirred at RT for 5 minutes. Methanol (100 uL) was added followed by silica gel and the mixture was concentrated to dryness. The crude material was purified via silica gel chromatography and eluted with methylene chloride/methanol to afford N-hydroxy-4-(2′-hydroxybiphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide as a solid. 6.5 mg
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:4]2[CH2:3]1.[C-:22]#N.[K+]>CC(O)C>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])=[C:4]2[CH2:3]1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Reactant: [C-]#N
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)OC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2

Procedure:
285 mg (1 mmol) of ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate and 50 mg of potassium cyanide are stirred at 60° C. for 72 hours in 10 ml of 2-propanol. Then, the mixture is concentrated on a rotary evaporator, the residue is partitioned between water and chloroform, extracted twice with chloroform, the chloroform phase is dried over magnesium sulphate and evaporated. There is obtained isopropyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine 3-carboxylate of melting point 190°-192° C. This product is uniform according to thin-layer chromatography.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10]2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[C:13]1([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[C:4]([NH2:1])[CH:12]=3)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1ccc2cc(-c3ccccc3)[nH]c2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc2cc(-c3ccccc3)[nH]c2c1
Temperature: 70 °C
Yield: 35.5 %

Procedure:
6-Nitro-2-phenyl-1H-indole (175 mg, 0.73 mmol), ammonium chloride (80 mg, 1.47 mmol) and iron powder (205 mg, 3.68 mmol) were suspended in ethanol/water (4 mL/2 mL) and heated at 70° C. for 2 h. After cooling, the solution was filtrated through a pad of Celite®, which was washed with ethanol. The organic layer was evaporated into vacuo to obtain a solid, which was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 10:90 v/v to ethyl acetate/hexanes 50:50 v/v) to afford 54 mg (35%) of the title compound.
Reaction SMILES: Br[CH2:2][CH:3](Br)[C:4](=O)[CH2:5][CH2:6][CH2:7][Cl:8].O.[NH2:12][NH2:13]>C(O)(C)C>[Cl:8][CH2:7][CH2:6][CH2:5][C:4]1[CH:3]=[CH:2][NH:13][N:12]=1
Reactant: O=C(CCCCl)C(Br)CBr
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: ClCCCc1cc[nH]n1
Reaction time: 16 h

Procedure:
To a solution of 1,2-dibromo-6-chlorohexan-3-one in isopropanol (80% solution in water, 30 mL) at ambient temperature was added hydrazine hydrate (8.4 g, 170 mmol). After 16 hours, the reaction mixture was quenched with water (15 mL) and extracted with ethyl acetate (3×30 mL). The organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 3-(3-chloropropyl)-1H-pyrazole, which was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:28])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[S:17][C:18]([CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[C:19]([CH3:21])[CH:20]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1.[C:29](O)(=[O:32])[CH2:30][OH:31]>>[CH2:26]([N:23]([CH2:22][C:18]1[S:17][C:16]([C:14]2[O:13][N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][CH:3]([OH:28])[CH2:2][NH:1][C:30](=[O:31])[CH2:29][OH:32])=[CH:6][CH:7]=3)[N:15]=2)=[CH:20][C:19]=1[CH3:21])[CH2:24][CH3:25])[CH3:27]
Reactant: O=C(O)CO
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(CC(O)CN)cc3)no2)cc1C
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(CC(O)CNC(=O)CO)cc3)no2)cc1C
Yield: 54.1 %

Procedure:
The title compound (31 mg) is prepared in analogy to Example 163 starting from rac-1-amino-3-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-propan-2-ol (50 mg, 125 μmol) and glycolic acid (13 mg, 175 μmol); LC-MS: tR=0.68 min; [M+1]+=458.68. 1H NMR (CDCl3): δ1.09 (t, J=7.0 Hz, 6H), 2.23 (s, 3H), 2.62 (q, J=7.0 Hz, 4H), 2.75-2.87 (m, 2H), 3.18-3.28 (m, 1H), 3.50-3.58 (m, 1H), 3.70 (s, 2H), 3.94-4.02 (m, 1H), 4.06 (s, 2H), 7.14 (t, J=5.5 Hz, 1H), 7.33 (d, J=8.3 Hz, 2H), 7.64 (s, 1H), 8.03 (d, J=8.0 Hz, 2H).
Reaction SMILES: N1([CH:10]=[O:11])C2C=CC=CC=2N=N1.[Cl:12][C:13]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:14]=1[NH2:15]>O1CCCC1>[Cl:12][C:13]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:14]=1[NH:15][CH:10]=[O:11]
Reactant: O=Cn1nnc2ccccc21
Reactant: Nc1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: O=CNc1ccc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 22.5 h
Yield: 95 %

Procedure:
1H-1,2,3-benzotriazole-1-carbaldehyde (327 mg, 2.22 mmol, Sigma-Aldrich) was added to a solution of 2,4-dichloroaniline (300 mg, 1.85 mmol) in tetrahydrofuran (THF) (6 mL). The solution was heated to 60° C. and stirred for 22.5 h before concentrating in vacuo. The resulting solid was dissolved in DCM (30 ml), washed with 2M HCl (15 ml), the organic layer was passed through a hydrophobic frit and reduced in vacuo. Purification was carried out by silica column chromatography (Biotage SP4, gradient elution 0-100% EtOAc in iso-hexane) to yield the title compound (334 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:30]1[CH2:29][CH2:28][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[F:20])[CH2:32][CH2:31]1)=[O:19])=[N:5]2
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Product: COc1nc2ccc(F)cc2nc1NC(=O)N1CCN(c2ccccc2F)CC1
Yield: 91 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound (yield, 91%). 1H NMR (200 MHz, CDCl3): δ 3.18 (s, 4H), 3.78 (s, 3H), 4.13 (s, 4H), 6.93-7.10 (m, 5H), 7.20-7.34 (m, 1H), 7.46-7.60 (m, 1H), 7.67-7.74 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH3:12][NH:13][C@@H:14]1[CH2:31][N:18]2[C:19]3[C:24]([C:25]([CH2:26][C:27]([O:29]C)=[O:28])=[C:17]2[CH2:16][CH2:15]1)=[CH:23][CH:22]=[CH:21][CH:20]=3>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([N:13]([CH3:12])[C@@H:14]2[CH2:31][N:18]3[C:19]4[C:24]([C:25]([CH2:26][C:27]([OH:29])=[O:28])=[C:17]3[CH2:16][CH2:15]2)=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: CN[C@H]1CCc2c(CC(=O)OC)c3ccccc3n2C1
Product: CN(C(=O)Cc1ccc(F)cc1)[C@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from (4-fluorophenyl)acetic acid and methyl [(7S)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 395.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:25]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[C:12]2[N:13]=[C:14]([CH3:24])[N:15]=[C:16]([N:17]3[CH2:22][C@@H:21]4[CH2:23][C@H:18]3[CH2:19][NH:20]4)[N:11]2[N:10]=1.C(N(C(C)C)CC)(C)C.[CH2:42]([S:44](Cl)(=[O:46])=[O:45])[CH3:43]>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:25]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[C:12]2[N:13]=[C:14]([CH3:24])[N:15]=[C:16]([N:17]3[CH2:22][C@@H:21]4[CH2:23][C@H:18]3[CH2:19][N:20]4[S:44]([CH2:42][CH3:43])(=[O:46])=[O:45])[N:11]2[N:10]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Cc1nc(N2C[C@@H]3C[C@H]2CN3)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)N1C[C@@H]2C[C@H]1CN2c1nc(C)nc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Reaction time: 8 h

Procedure:
To a suspension of (1S,4S)-7-(2-chlorophenyl)-8-(4-chlorophenyl)-4-(2,5-diazabicyclo[2.2.1]hept-2-yl)-2-methylpyrazolo[1,5-a][1,3,5]triazine, hydrochloride salt (9A-1; 24.3 mg, 0.0463 mmol) in methylene chloride (1 ml) was added diisopropylethylamine (0.028 ml, 0.16 mmol), followed by a 0.56 M solution of ethanesulfonyl chloride in methylene chloride (0.1 ml, 0.056 mmol). After stirring overnight, the reaction directly loaded and then purified on a Biotage™ Flash 12S column using 0-20% methanol in methylene chloride as eluant to afford 10A-1 (18 mg, 72%) as a solid: +ESI MS (M+1) 543.3; 1H NMR (400 MHz, CD3OD) δ 7.50-7.36 (m, 4H), 7.32 (d, J=8.3 Hz, 2H), 7.21 (d, J=8.3 Hz, 2H), 4.58 (br s, 1H), 3.62 (s, 2H), 3.11 (q, J=7.5 Hz, 2H), 2.46 (s, 3H), 2.18-2.21 (br m, 2H), 1.30 (t, J=7.5 Hz, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=2)[CH:17]=1)=O)(C)(C)C.[NH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([Cl:39])[CH:33]=1>>[Cl:39][C:34]1[CH:33]=[C:32]([CH2:31][CH2:30][NH:29][C:24]2[N:23]=[C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][N:11]4[CH2:10][CH:9]5[CH2:14][CH:12]4[CH2:13][NH:8]5)[CH:17]=3)[CH:27]=[CH:26][N:25]=2)[CH:37]=[CH:36][C:35]=1[OH:38]
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1ccc(O)c(Cl)c1
Product: Oc1ccc(CCNc2nccc(-c3cccc(CN4CC5CC4CN5)c3)n2)cc1Cl

Procedure:
Intermediate 143 was coupled with 4-(2-amino-ethyl)-2-chloro-phenol following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 436. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.38 (s, 1H) 8.26 (d, 2H) 7.87 (d, 1H) 7.72 (m, 1H) 7.48 (d, 1H) 7.20 (s, 1H) 7.00 (d, 1H) 6.79 (d, 1H) 4.62 (s, 2H) 3.92 (d, 2H) 3.74 (d, 2H) 3.61 (t, 2H) 3.24 (t, 2H) 2.88 (t, 2H) 2.76 (d, 1H) 2.37 (d, 1H).
Reaction SMILES: [C:1]1([S:7]([C:10]([CH:19]2[CH2:31][C:22]3[NH:23][C:24]4[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][C:29]=4[C:21]=3[CH2:20]2)([F:18])[C:11]2[O:15][N:14]=[C:13]([CH2:16][NH2:17])[N:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:32]([C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1)=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:41][O:40][C:38](=[O:39])[C:37]1[CH:42]=[CH:43][C:34]([CH2:32][NH:17][CH2:16][C:13]2[N:12]=[C:11]([C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])([CH:19]3[CH2:31][C:22]4[NH:23][C:24]5[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][C:29]=5[C:21]=4[CH2:20]3)[F:18])[O:15][N:14]=2)=[CH:35][CH:36]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: NCc1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(CNCc2noc(C(F)(C3Cc4[nH]c5ccc(Cl)cc5c4C3)S(=O)(=O)c3ccccc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 49.3 %

Procedure:
To a stirred solution of 50 mg (0.1 mmol) of (RS,SR)-C-{5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazol-3-yl}-methylamine in 5 mL MeOH at 0° C. was added 19 mg (0.1 mmol, 1 eq) of methyl 4-formylbenzoate, 7 mg (0.1 mmol, leg) sodium cyanoborohydride and one drop of acetic acid. The reaction mixture was stirred at 0° C. for 20 minutes and then the temperature was raised to RT and the reaction quenched with saturated aqueous solution of NaHCO3. The reaction mixture was poured on water and extracted with EtOAc. The organic phase were dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel (heptane/EtOAc 1:1) yielded 30 mg (45%) of (RS,SR)-4-[({5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazol-3-ylmethyl}-amino)-methyl]-benzoic acid methyl ester as a light yellow powder, MS: 609 (MH+).