Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:18][C:13]3[N:14]=[CH:15][N:16]=[CH:17][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1.C1COCC1.CO.[OH-].[Na+].Cl>O>[N:14]1[C:13]2[NH:18][C:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:19])=[O:2])=[CH:9][CH:8]=3)=[CH:11][C:12]=2[CH:17]=[N:16][CH:15]=1
Reactant: COC(=O)c1ccc(-c2cc3cncnc3[nH]2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(-c2cc3cncnc3[nH]2)cc1
Reaction time: 1 h
Yield: 61.8 %

Procedure:
To a solution of 4-(7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzoic acid methyl ester (0.601 g, 2.4 mmol) (reference example 43a) in 1:1 THF-methanol (10 mL) is added NaOH (10N) (2.4 mL, 24 mmol) and 0.5 ml H2O. The resulting solution is stirred for 1 hour then cooled to 0°-5° C. and adjusted to pH 3 with 2N HCl. The precipitated solid is filtered off, washed with a small volume of water and dried under high vacuum to give 0.355 g of title compound as a yellow solid. 1H NMR (DMSO) δ 7.59 (s, 1H), 8.10 (d, J=8 Hz, 2H), 8.20 (d, J=8 Hz, 2H), 9.22 (s, 1H), 9.50 (bs, 1H), 14.10 (bs, 1H). MS (EI) m/z 239 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21](N1C=CN=C1)([N:23]1C=CN=[CH:24]1)=O.CNC>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:23]([CH3:24])[CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(F)cc2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)Cn1c(-c2ccc(F)cc2)nc2cccnc21
Temperature: 45 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
A mixture of 2-(4-fluorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.01845 mole) and 1,1'-carbonyldiimidazole (2.99 g, 0.01845 mole) was stirred at room temperature in dry tetrahydrofuran (100 ml) for three hours with a stream of nitrogen bubbling through it. A solution of dimethylamine in tetrahydrofuran (48 ml of 2.29M solution, 0.111 mole) was added and the reaction mixture was stirred at 45° C. under nitrogen overnight. The solvents were removed under reduced pressure and the residue was triturated in water (100 ml), the solid was collected by filtration, rinsed twice with water, twice with a 5% potassium hydroxide solution and twice again with water. The solid was dissolved in hot isopropyl alcohol, filtered hot, cooled to room temperature and isopropyl ether was added to the cloud point. The resulting solid was collected by filtration, rinsed with isopropyl ether and dried under high vacuum at 42° C. overnight to give 2.15 g (39%) of title compound, mp. 180°-183° C.
Reaction SMILES: C(OC(=O)[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:28])[NH2:27])=[CH:22][C:21]=2[CH3:29])=[CH:16][C:15]=1[Cl:30])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.[ClH:32]>C(OCC)(=O)C.O1CCOCC1.CO>[ClH:30].[Cl:32][C:22]1[C:21]([CH3:29])=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([CH2:13][NH:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:15][CH:16]=2)[CH:25]=[CH:24][C:23]=1[C:26]([NH2:27])=[O:28]
Reactant: Cc1cc(C(N)=O)ccc1-c1ccc(CN(CCC(C)C)C(=O)OC(C)(C)C)c(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(-c2ccc(CNCCC(C)C)cc2)ccc(C(N)=O)c1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(4′-Carbamoyl-3-chloro-2′-methyl-biphenyl-4-ylmethyl)-(3-methyl-butyl)-carbamic acid tert-butyl ester (I-3e: 12.6 g, 28.3 mmol) was dissolved in ethyl acetate and treated with 30 ml of 4.0M hydrogen chloride in dioxane. After stirring for 24 hours at room temperature, the volatiles were removed under reduced pressure and the product was isolated by dissolving the crude material in methanol and slowly adding ethyl acetate to precipitate the product, which was isolated via filtration. The solid was crystallized by dissolving in 10 parts of hot ethanol before cooling to room temperature. After stirring for 48 hours, the resulting slurry was collected via filtration, rinsing with chilled ethanol, to provide the title compound (E3-01) as a colorless solid.
Reaction SMILES: [C:1]([O:4][C:5](=O)C)(=O)[CH3:2].[NH2:8][C:9]1[S:10][C:11]([C:20](=[O:24])[N:21]([CH3:23])[CH3:22])=[C:12]([CH3:19])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(OCC)(OCC)OCC>[CH2:1]([O:4][CH:5]=[N:8][C:9]1[S:10][C:11]([C:20](=[O:24])[N:21]([CH3:22])[CH3:23])=[C:12]([CH3:19])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:2]
Reactant: CCOC(=O)c1c(N)sc(C(=O)N(C)C)c1C
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(OCC)OCC
Product: CCOC=Nc1sc(C(=O)N(C)C)c(C)c1C(=O)OCC
Yield: 96 %

Procedure:
2.0 ml of acetic anhydride were added to 30.6 g (119 mmol) of 2-amino-3-carboethoxy-4-methyl-5-dimethylcarbamoyl-thiophene in 150 ml of triethyl orthoformate, and the mixture was boiled under nitrogen and at reflux for 2 h. The mixture was then evaporated right down at 80° C. on a rotary evaporator. 35.6 g (96%) of crude product were isolated as a dark oil, which is sufficiently pure for further reaction.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][NH:11][C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([O:8][C:9]1[C:10]([CH3:16])=[N:11][CH:12]=[C:13]([Br:17])[C:14]=1[OH:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1[nH]ccc(=O)c1OCc1ccccc1
Solvent: CC#N
Product: Cc1ncc(Br)c(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.4 %

Procedure:
The above compound 3 (129 g, 599 mmol) was suspended in acetonitrile (1300 ml), and N-bromosuccinic acid imide (117 g, 659 mmol) was added, followed by stirring at room temperature for 90 minutes. Precipitated crystals were filtered, and washed with acetonitrile and diethyl ether to obtain 3-benzyloxy-5-bromo-2-methyl-pyridine-4-ol 4 (154 g, 88%) as a colorless crystal. NMR (DMSO-d6) δ: 2.06 (3H, s), 5.04 (2H, s), 7.32-7.42 (5H, m), 8.03 (1H, d, J=5.5 Hz), 11.82 (1H, brs).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:19])[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](/[C:11](=[CH:20]\[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)/[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[O:19]
Reactant: COc1ccc(C(=O)CC(=O)OC(C)(C)C)c(O)c1
Reactant: O=Cc1ccccc1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COc1ccc(C(=O)/C(=C\c2ccccc2)C(=O)OC(C)(C)C)c(O)c1
Yield: 45.3 %

Procedure:
Prepared according to general procedure A using tert-butyl 3-(2-hydroxy4-methoxyphenyl)-3-oxopropanoate (532 mg, 2.0 mmol), benzaldehyde (200 μL, 2.00 mmol), 12.0 mL benzene, piperidine (10 μL, 0.10 mmol) and glacial acetic acid (5.7 μL, 0.10 mmol), refluxed for 3 h. Purified via recrystallization from hexanes/CH2Cl2, yielding 321 mg (46%) of white solid. mp=105-107° C.; IR (film) 2977.5; 1712.8; 1624.0; 1155.6 cm−1; 1H NMR (500 MHz, CDCl3) δ 12.41 (bs, 1H), 7.81 (s, 1H), 7.41 (d, J=9.1 Hz, 1H), 7.37-7.25 (m, 5H), 6.46 (d, J=2.1 Hz, 1H), 6.34 (dd, J=8.8, 2.1 Hz, 1H), 3.83 (s, 3H), 1.42 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 199.4, 166.8, 165.8, 164.0, 141.8, 133.6, 133.1, 131.6, 130.5, 130.3, 129.1, 114.3, 108.4, 101.1, 82.6, 55.8, 28.1; LRMS (electrospray): Mass calculated for C21H22O5 [M]+, 354.14. Found [M+23]+, 377.5.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[CH:10]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH-].[Na+].[C:18]([O:22][C:23](=O)[O-:24])([CH3:21])([CH3:20])[CH3:19].O>O1CCOCC1>[C:18]([O:22][C:23]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[CH:10]3)[CH2:2][CH2:3]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: c1cc2[nH]ncc2cc1N1CCNCC1
Reactant: CC(C)(C)OC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3[nH]ncc3c2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
To a solution of 5-Piperazin-1-yl-1H-indazole (0.34 g, 1.3 mmol) in 1,4-dioxane (5 mL) was added 3N NaOH (0.42 mL, 1.3 mmol). After cooling to 0° C., a solution of tert-butylcarbonate (0.25 g, 1.3 mmol) in 1,4-dioxane (1 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight and then poured into water and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3, water, brine, dried and concentrated. The residue was purified by column chromatography (EtOAc:hexanes, 1:1) to give 4-(1H-Indazol-5-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.31 g, 82%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 10.01 (s, 1H), 7.80 (s, 1H), 7.42 (d, J=9.2 Hz, 1H), 7.21 (dd, J=9.2 Hz, J=2.0 Hz, 1H), 7.16 (d, J=2.0 Hz, 1H), 3.62 (m, 4H), 3.09 (m, 4H), 1.50 (s, 9H). LCMS (APCI+) m/z 303 [M+H]+; Rt=2.50 minutes.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][CH:8]1[C:12](=[O:13])[N:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:10]2([CH2:23][CH2:22][C:21](=[CH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:20][CH2:19]2)[S:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:30](O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[CH2:7][CH:8]1[C:12](=[O:13])[N:11]([CH2:14][CH2:15][C:16]([O:18][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:17])[C:10]2([CH2:19][CH2:20][C:21](=[CH:24][CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:23]2)[S:9]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)CC=C1CCC2(CC1)SC(CC(=O)OC(C)(C)C)C(=O)N2CCC(=O)O
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)CC=C1CCC2(CC1)SC(CC(=O)OC(C)(C)C)C(=O)N2CCC(=O)OCc1ccccc1
Reaction time: 24 h
Yield: 25.1 %

Procedure:
In 10 ml of methylene chloride was dissolved 0.56 g of 3-[2-[2-(tert-butoxy)-2-oxoethyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionic acid. At ambient temperature, 0.21 g of benzyl alcohol, 0.23 g of 1-hydroxybenzotriazole monohydrate and 0.31 g of dicyclohexyl carbodiimide were successively added. After stirring the resulting mixture for 24 hours at the same temperature as above, the insoluble matter was filtered off. The filtrate was washed successively with 2 mol/L hydrochloric acid, water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: hexane:ethyl acetate=6:1] gave 0.17 g of benzyl 3-[2-[2-(tert-butoxy)-2-oxoethyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionate as a light yellow oily product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][N:14]([CH:18]2[CH2:23][CH:22]3[CH2:24][CH:19]2[CH2:20][CH2:21]3)[C:15](Cl)=[O:16])=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][N:14]([CH:18]2[CH2:23][CH:22]3[CH2:24][CH:19]2[CH2:20][CH2:21]3)[C:15]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:16])=[CH:11][CH:10]=1
Reactant: O=C(Cl)N(Cc1ccc(Cl)cc1)C1CC2CCC1C2
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)N(Cc1ccc(Cl)cc1)C1CC2CCC1C2
Yield: 64.4 %

Procedure:
Aniline (19 g) was dissolved in 400 ml of toluene, and with stirring and cooling, a solution of 30 g of N-4-chlorobenzyl-N-2-norbornylcarbamoyl chloride in 50 ml of toluene was added dropwise. After the addition, the temperature of the mixture was gradually raised, and it was stirred for about 10 hours at about 70° to 80° C. After cooling, the precipitated aniline hydrochloride was separated by filtration. The toluene layer was washed successively with water, a 1% aqueous solution of sodium carbonate, 1% hydrochloric acid and then water, and then dried over anhydrous sodium sulfate. Toluene was evaporated, and the residue was recrystallized from a mixture of hexane and ethanol to give 23 g of the desired 1-(4-chlorobenzyl)-1-(2-norbornyl)-3-phenylurea. mp. 111°-113° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:11]=1[CH:17]([CH3:19])[CH3:18])([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][N:23]=1.C([O-])([O-])=O.[K+].[K+]>>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][N:23]=2)[C:11]=1[CH:17]([CH3:18])[CH3:19])([CH3:3])([CH3:4])[CH3:2]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)c1c(O)cccc1CCNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)c1c(CCNC(=O)OC(C)(C)C)cccc1Oc1ccc(C#N)cn1
Yield: 74.8 %

Procedure:
Using a method similar to Example 221, Step 1, using [2-(3-hydroxy-2-isopropyl-phenyl)-ethyl]-carbamic acid tert-butyl ester (4.02 g, 14.4 mmol), 6-chloronicotinonitrile (1.99 g, 14.4 mmol) and K2CO3 (2.98 g, 21.5 mmol) gives {2-[3-(5-cyano-pyridin-2-yloxy)-2-isopropyl-phenyl]-ethyl}-carbamic acid tert-butyl ester (4.11 g) as a yellow foam. 1HNMR (CDCl3): 8.50 (s, 1H), 7.92 (d, 1H), 7.17 (t, 1H), 7.06 (d, 1H), 7.01 (d, 1H), 6.86 (d, 1H), 4.63 (br. s, 1H), 3.34 (m, 2H), 3.27 (m, 1H), 2.91 (t, 2H), 1.44 (s, 9H), 1.24 (d, 6H).
Reaction SMILES: [Sn:1]([Cl:3])[Cl:2].[C:4]([CH2:7][C:8](=[O:10])[CH3:9])(=O)[CH3:5].C([Cl:14])(=O)C>C(OCC)C>[CH3:5][C:4]([Sn:1]([Cl:14])([Cl:3])[Cl:2])=[CH:7][C:8](=[O:10])[CH3:9]
Reactant: CC(=O)Cl
Reactant: CC(=O)CC(C)=O
Reactant: Cl[Sn]Cl
Solvent: CCOCC
Product: CC(=O)C=C(C)[Sn](Cl)(Cl)Cl
Yield: 57.1 %

Procedure:
94.8 g (0.5 mol) of tin(II) chloride and 50 g (0.5 mol) of acetylacetone in 200 ml of diethyl ether were placed in a reactor at room temperature. 39.3 g (0.5 mol) of acetyl chloride were metered in over 15 min, the temperature rising to 36° C. After a postreaction time of 2 h at room temperature, the white crystals which had precipitated out were filtered off and washed twice with 50 ml of diethyl ether. After drying under vacuum, 88 g (57% of theory) of 1-methylbut-1-en-3-onyltin trichloride (Cl3Sn--C(CH3)=CH--CO--CH3) melting at 129°-130° C. were isolated.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([NH:20][CH:21]([CH2:25][N:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[C:22](O)=[O:23])=[O:19])=[CH:13][CH:12]=3)[CH:6]=[CH:5][N:4]=1.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:58]([CH2:60][NH2:61])[OH:59]>CN(C=O)C.C(Cl)CCl>[OH:59][CH2:58][CH2:60][NH:61][C:22]([CH:21]([NH:20][C:18]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:7]1[CH:6]=[CH:5][N:4]=[C:3]([NH:2][CH3:1])[N:8]=1)=[CH:17]2)=[O:19])[CH2:25][N:26]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[N:28]=[CH:29][CH:30]=[CH:31][N:32]=1)=[O:23]
Reactant: NCCO
Reactant: CNc1nccc(-c2cc3cc(C(=O)NC(CN(c4ccccc4)c4ncccn4)C(=O)O)ccc3[nH]2)n1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nccc(-c2cc3cc(C(=O)NC(CN(c4ccccc4)c4ncccn4)C(=O)NCCO)ccc3[nH]2)n1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
200 mg of the acid 48 were dissolved in 2 ml of absolute DMF, 94 mg of HOAt and 158 μl of DIEA were added 56 μl of ethanolamine were then added dropwise and the mixture was cooled down to 0° C.; 195 mg of EDC were then added. After 2 days of stirring at room temperature, the solvent was evaporated and the crude product was purified by means of MPLC (eluent: DCM:MeOH=9:1).
Reaction SMILES: C[O-].[Na+].C([O:6][C:7](=O)[CH2:8][C:9](=O)[CH3:10])C.[N+]([O-])([O-])=O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:29][C:30]([NH2:32])=[NH2+:31])[CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26]>CO>[CH3:10][C:9]1[N:32]=[C:30]([NH:29][C:21]2[CH:22]=[C:23]([O:27][CH3:28])[C:24]([O:25][CH3:26])=[C:19]([O:18][CH3:17])[CH:20]=2)[NH:31][C:7](=[O:6])[CH:8]=1
Reactant: COc1cc(NC(N)=[NH2+])cc(OC)c1OC
Reactant: CCOC(=O)CC(C)=O
Agent: C[O-]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Nc2nc(C)cc(=O)[nH]2)cc(OC)c1OC
Temperature: 25 °C
Yield: 47.9 %

Procedure:
To a solution of sodium methoxide (0.96 g, 1.79 mmol) in methanol was added ethyl-3-oxo-butanoate (0.23 g, 1.79 mmol) and 3,4,5-trimethoxyphenylguanidinium nitrate (0.5 g, 1.79 mmol). The mixture was stirred at reflux for 17 h. The reaction mixture was cooled to room temperature and evaporated in vacuo to give a dark grey solid. Recrystallisation from ethanol gave the title compound (0.25 g, 49%) as a light grey solid, m.p. 228-230° (dec). δH (d6DMSO) 2.12 (3H, s), 3.61 (3H, s), 3.74 (6H, s), 5.69 (1H, s), 7.02 (2H, s), 8.70 (1H, br s) and 10.47 (1H, br s).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:11]=[CH:12][C:13]3[C:14]4[N:22]=[C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:20]=[C:19]([C:29]([O:31]C)=O)[C:15]=4[NH:16][C:17]=3[CH:18]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1.[NH3:33]>CO>[O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:11]=[CH:12][C:13]3[C:14]4[N:22]=[C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:20]=[C:19]([C:29]([NH2:33])=[O:31])[C:15]=4[NH:16][C:17]=3[CH:18]=2)(=[O:8])=[O:9])[CH2:3][CH2:2]1
Reactant: N
Reactant: COC(=O)c1cc(-c2ccccc2)nc2c1[nH]c1cc(S(=O)(=O)N3CCOCC3)ccc12
Solvent: CO
Product: NC(=O)c1cc(-c2ccccc2)nc2c1[nH]c1cc(S(=O)(=O)N3CCOCC3)ccc12
Temperature: 80 °C
Yield: 62 %

Procedure:
A suspension of methyl 7-(morpholinosulfonyl)-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxylate (106 mg, 0.235 mmol) in 7 N NH3 in MeOH (5 mL) in a sealed microwave vial was heated at 80° C. overnight. After cooling to RT, the precipitate was collected, washed with MeOH, and dried to leave 7-(morpholinosulfonyl)-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxamide (67 mg, 0.15 mmol, 62% yield) as yellow fluffy solid. MS (ESI) m/z 435.1 (M−H). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.03 (1H, s), 8.70 (1H, s), 8.59 (1H, s), 8.52 (1H, d, J=8.06 Hz), 8.33 (2H, d, J=7.30 Hz), 8.21 (1H, d, J=1.01 Hz), 8.00 (1H, s), 7.52-7.64 (3H, m), 7.46 (1H, t, J=7.30 Hz), 3.60-3.69 (4H, m), 2.88-2.97 (4H, m).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Br:12]Br.C(=O)([O-])[O-].[Na+].[Na+]>[N+](C1C=CC=CC=1)([O-])=O>[Br:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1cc2ccccc2cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1ncc2ccccc2c1Br
Temperature: 180 °C
Yield: 72.3 %

Procedure:
To 3-methylisoquinoline (0.500 g, 3.49 mmol) in 1 ml nitrobenzene, bromine (0.196 ml, 3.84 mmol) was added and the contents heated in a sealed tube at 180° C. for 4 hours. The solution was cooled to room temperature, neutralized with solid sodium carbonate (pH=8) and extracted with ethyl acetate (2×20 ml). The organic layer was dried over sodium sulfate, filtered, concentrated and column purified (hexane:EtOAc; 4.5:0.5) to give 0.560 g (72%) of the product as syrup.
Reaction SMILES: [N:1]1([CH2:15][C:16]2[O:20][C:19]([CH2:21][OH:22])=[N:18][CH:17]=2)[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:30][S:31]([O:22][CH2:21][C:19]1[O:20][C:16]([CH2:15][N:1]2[CH2:6][CH2:5][C:4]3([C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH:8]=[CH:7]3)[CH2:3][CH2:2]2)=[CH:17][N:18]=1)(=[O:33])=[O:32]
Reactant: OCc1ncc(CN2CCC3(C=Cc4ccccc43)CC2)o1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ncc(CN2CCC3(C=Cc4ccccc43)CC2)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
To a 0° C. stirred solution of [5-(spiro[indene-1,4′-piperidine]-1′-ylmethyl)oxazol-2-yl]methanol (0.15 g, 0.51 mmol) in DCM (10.0 mL) is added triethylamine (0.18 mL, 1.26 mmol) and methane sulphonyl chloride (0.05 mL, 0.61 mmol). The reaction mixture is stirred at 0° C. for 1 hour. The reaction mixture is washed with water (20.0 mL) and brine (10.0 mL), extracted with DCM, dried over Na2SO4, and evaporated to dryness to give the crude product (0.18 g) as a brown liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH2:23][C:24]1[S:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[S:25]1[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=[C:24]1[NH:23][C:13](=[O:15])/[C:12](/[C:4]1[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=1)=[N:16]/[O:17][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Nc1nc2ccccc2s1
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)Nc2nc3ccccc3s2)cc1Cl
Reaction time: 2 h
Yield: 69.5 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 96 mg, 0.28 mmol), 2-aminobenzothiazole (42 mg, 0.28 mmol) and N,N-diisopropylethylamine (145 μL, 0.83 mmol) were combined in acetonitrile (1.25 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (106 mg, 0.28 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 40% ethyl acetate/hexanes) to afford (E)-N-benzothiazol-2-yl-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-acetamide (93 mg, 70%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C21H20ClN3O4S2 [M+] 477.06, found 478 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.68 (m, 4 H, 2×CH2), 1.90 (m, 4 H, 2×CH2), 3.32 (s, 3 H, SO2CH3), 4.96 (m, 1 H, OCH), 7.35 (ddd, Jo=7.9, Jo=7.3, Jm=1.2 Hz, 1 H, Ar), 7.48 (ddd, Jo=8.2, Jo=7.3, Jm=1.2 Hz, 1 H, Ar), 7.61 (dd, Jo=8.2, Jm=1.6 Hz, 1 H, Ar), 7.72 (d, Jm=1.6 Hz, 1 H, Ar), 7.84 (m, 2H, Ar), 8.23 (d, Jo=8.2 Hz, 1 H, Ar), 10.21 (s, 1 H, NH).
Reaction SMILES: [CH2:1]([C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]C.C(#N)CCCCCCCCCC.N[CH:27]([OH:29])[CH3:28]>C(O)CCC.O.O.C([O-])(=O)C.[Cd+2].C([O-])(=O)C>[CH2:1]([C:12]1[O:29][CH2:27][CH2:28][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CC(N)O
Reactant: CCCCCCCCCCCC#N
Agent: CC(=O)[O-]
Agent: CCCCCCCCCCC#N
Agent: [Cd+2]
Solvent: O
Solvent: CCCCO
Product: CCCCCCCCCCC1=NCCO1
Yield: 64.3 %

Procedure:
Undecyl cyanide in Example 1 was substituted with 18.13 g (108.4 mmoles) of undecanenitrile and allowed to react with 7.5 ml (121.3) mmoles of aminoethanol in presence of cadmium acetate dihydrate (667 mg; 2.5 mmoles) in 1-butanol under identical reaction conditions. The reaction mixture was worked up following Example 1 and the residue was distilled at 118°-120°/1.2 mm to give 14.72 g (64.3%) of 2-decyl-2oxazoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8]/[C:9]/2=[N:12]\[OH:13])=[CH:5][CH:4]=1.CCN(CC)CC.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:21][S:22]([O:13]/[N:12]=[C:9]1\[CH2:8][CH2:7][C:6]2[C:10]\1=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2c(c1)/C(=N/O)CC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)/C(=N/OS(C)(=O)=O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 7750 %

Procedure:
To the solution of intermediate 16 (6.6 g, 37.2 mmol) in CH2Cl2 (120 mL) was added Et3N (20.6 mL, 149 mmol), DMAP (455 mg, 3.73 mmol) and MsCl (4.35 mL, 55.87 mmol). The mixture was stirred at rt overnight. The reaction mixture was washed successively with water, saturated aq NH4Cl, brine, dried over anhydrous MgSO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel column (elution with PE/CH2Cl2=1:1) to give (E)-6-methoxy-2,3-dihydro-1H-inden-1-one O-methylsulfonyl oxime (intermediate 17) (736 g, 82%) as a white solid.