Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:13])[CH3:12])[C:6](=[O:14])[CH2:5]2.[C:15]1([C:20](Cl)=[O:21])[S:19][CH:18]=[CH:17][CH:16]=1>CN(C1C=CN=CC=1)C.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:13])[CH3:12])[C:6](=[O:14])[CH:5]2[C:20](=[O:21])[C:15]1[S:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)N1C(=O)Cc2cc(Cl)ccc21
Reactant: O=C(Cl)c1cccs1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)N1C(=O)C(C(=O)c2cccs2)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21.7 %

Procedure:
To a stirred solution of 0.75 g (3.6 mmole) of 5-chloro-1-acetyl-2-oxindole and 0.96 ml (7.9 mmole) of 4-(N,N-dimethylamino)pyridine in 20 ml of N,N-dimethylformamide, cooled to ca. 0° C., was added a solution of 0.4 ml (3.7 mmol) of 2-thenoyl chloride in 5 ml of N,N-dimethylformamide, dropwise, during a few minutes. The reaction mixture was stirred for 30 minutes at ca. 0° C. and then for 3.5 hours at room temperature, and then it was poured into 500 ml of ice-cold 2N hydrochloric acid. The resulting solution was extracted with ethyl acetate, and the extracts were washed with water, followed by saturated sodium chloride solution, and then they were dried using magnesium sulfate. Evaporation of the dried ethyl acetate solution gave 1.1 g of crude product. The latter was purified by column chromatography using silica gel and eluting with dichloromethane-ethyl acetate mixtures, followed by recrystallization from a small volume of toluene, to give 250 mg of the title compound, m.p. 168°-170° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[C:8]([CH:11]=1)[C:9]#[N:10])([O-:3])=[O:2].[OH:19][CH2:20][CH2:21][NH2:22].C([BH3-])#N.[Na+].Cl>O1CCCC1.CO>[OH:19][CH2:20][CH2:21][NH:22][CH:15]1[CH2:16][CH2:17][N:12]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][C:8]=2[C:9]#[N:10])[CH2:13][CH2:14]1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N1CCC(=O)CC1
Reactant: NCCO
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cc([N+](=O)[O-])ccc1N1CCC(NCCO)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Nitro-2-(4-oxopiperidin-1-yl)benzonitrile (5.0 g), 2-hydroxyethylamine (1.5 g) and sodium cyanoborohydride (1.3 g) were added to a mixed solvent of methanol (100 ml) and tetrahydrofuran (50 ml) and the mixture was stirred at room temperature for 1 h. An aqueous hydrochloric acid solution was added to keep the reaction mixture acidic. The solvent was evaporated under reduced pressure. Aqueous sodium hydroxide solution was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow precipitation, whereby the title compound (3.6 g) was obtained, melting point: 115° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][OH:10].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:21]1([NH:24][C:25]([C:27]2[S:40][C:30]3=[N:31][C:32](S(C)=O)=[C:33]([Cl:36])[C:34]([CH3:35])=[C:29]3[C:28]=2[NH2:41])=[O:26])[CH2:23][CH2:22]1>C1COCC1>[CH:21]1([NH:24][C:25]([C:27]2[S:40][C:30]3=[N:31][C:32]([O:10][CH2:9][CH2:8][CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[C:33]([Cl:36])[C:34]([CH3:35])=[C:29]3[C:28]=2[NH2:41])=[O:26])[CH2:23][CH2:22]1
Reactant: OCCCc1ccccn1
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Cl)c(OCCCc2ccccn2)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 33.8 %

Procedure:
To a solution of 2-pyridinepropanol (0.960 g, 7.0 mmol) in THF (3 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl)amide (1.0 M in hexanes)(3.50 ml, 3.50 mmol). The reaction mixture is stirred for 15 minutes and then is treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (0.345 g, 1.00 mmol). The reaction mixture is heated at 75° C. in a sealed tube for 1.5 hours, cooled to room temperature, and then quenched by the addition of water (10 ml). The reaction mixture is transferred to an erlenmeyer flask and diluted to 75 ml with water. The mixture is cooled to 0° C. and stirred. During this time, a yellow precipitate is formed. This solid is collected by filtration and slurried in a 2:1 EtOAc:hexane mixture. This slurry is stirred for 10 minutes, filtered, and the collected solid is placed in the vacuum oven to dry (60° C. for 16 hours). This affords the title compound as a yellow solid (0.141 g, 34%). Mass (m/z): 417.2 (M++1), 415.1 (M+−1).
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[C:7](Cl)[C:6]([F:10])=[CH:5][N:4]=1.[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH2:11]([O:18][C:3]1[N:8]=[C:7]([O:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]([F:10])=[CH:5][N:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: OCc1ccccc1
Agent: [Na]
Solvent: Cc1ccccc1
Product: Fc1cnc(OCc2ccccc2)nc1OCc1ccccc1
Yield: 87.1 %

Procedure:
A 5.8 g quantity of metal sodium is dissolved in a mixture of 100 ml of benzyl alcohol and 200 ml of toluene, 16.7 g of 2,4-dichloro-5-fluoropyrimidine is added to the solution, and the mixture is refluxed for 4 hours. The resulting reaction mixture is washed with water, dried and distilled at reduced pressure to give 27.0 g of colorless oily 2,4-di(benzyloxy)-5-fluoropyrimidine in a yield of 87.1 %, b.p. 205°-206° C/3-4 mm Hg and m.p. 48.5°-49.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:1][Br:13])=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1ccc(C)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(CBr)cc1[N+](=O)[O-]
Yield: 70 %

Procedure:
A solution of 4-methyl-2-nitroanisole (25 mmol), N-bromosuccinimide (25 mmol) and benzoyl peroxide (2.5 mmol) in carbon tetrachloride (100 mL) was heated at reflux for 18 h. The heated mixture was then poured into water. A solid precipitate formed and was separated by filtration. The aqueous filtrate was extracted with carbon tetrachloride (3×50 mL). The extract was concentrated under reduced pressure to yield a solid product. The solid products (the filtered precipitate and product of evaporating the extract) were combined and recrystallized from ethyl acetate-hexane to yield 4-methoxy-3-nitro benzyl bromide as a crystalline product in 70-75% yield. m.p. 110-112° C.
Reaction SMILES: [OH-].[K+].CO.[C:5]([C:9]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].C([O:19][CH2:20][CH2:21][CH2:22][C:23]([N:26]=[N:27][C:28]([CH3:31])([CH3:30])[CH3:29])(Cl)[CH3:24])(=O)C>C(Cl)Cl.O>[C:28]([N:27]=[N:26][C:23]([S:15][C:12]1[CH:11]=[CH:10][C:9]([C:5]([CH3:8])([CH3:6])[CH3:7])=[CH:14][CH:13]=1)([CH3:24])[CH2:22][CH2:21][CH2:20][OH:19])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(=O)OCCCC(C)(Cl)N=NC(C)(C)C
Reactant: CC(C)(C)c1ccc(S)cc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(C)(C)N=NC(C)(CCCO)Sc1ccc(C(C)(C)C)cc1
Temperature: 30 °C

Procedure:
To a 250 ml 3-neck round bottom flask equipped with a magnetic stirrer, thermometer, condenser and addition funnel was added 6.6 grams (0.1 mole) of 85% potassium hydroxide pellets and 130 mls of methanol. The mixture was stirred at 30° C. until the pellets dissolved. The resulting solution was cooled to 15° C. and with rapid stirring 16.6 grams (0.1 mole) of para-t-butyl-thiophenol were added while holding the temperature at 15° to 20° C. The mixture was stirred an additional 15 minutes at 15° C. and then 24.9 grams (0.1 mole) of 4-t-butylazo-4-chloropentyl acetate were added over 20 minutes while holding the temperature at 15° to 20° C. After the addition was complete, the mixture was stirred an additional hour at room temperature and then an additional 6.6 grams (0.1 mole) of 85% potassium hydroxide was added (to saponify the acetyl group). The mixture was stirred an additional 1 hour at room temperature, poured into 300 mls of water and the organic layer taken up in 100 mls of methylene chloride. The methylene chloride layer was separated, washed with 50 ml portions of water, 10% HCl, water and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the methylene chloride stripped off on a rotary evaporator under reduced pressure. The resulting light orange liquid weighed 28 grams (83.5% crude yield). The infrared spectrum of the product contained a very broad strong OH band centered at 3350-3400 cm-1 and there was no carbonyl band.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH3:24][NH:25][O:26][CH3:27].C(N(CC)CC)C>>[CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([N:25]([O:26][CH3:27])[CH3:24])=[O:7]
Reactant: CNOC
Reactant: CN(C)c1cccc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cccc(N(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67 %

Procedure:
To a stirred solution of 3-(dimethylamino)benzoic acid (16.5 g, 100 mmol), cooled to 0° C. with a brine/ice bath, was added N,N-dimethylformamide (0.39 mL, 5 mmol) followed by oxalyl chloride (10.5 mL, 120 mmol). The resulting mixture was stirred 4 h at room temperature, until gas evolution stopped and a clear solution was obtained. The mixture was cooled to 0° C. with a brine/ice bath, N,O-Dimethylhydroxylamine (13.7 g, 140 mmol) was added at once, followed by dropwise addition of triethylamine (55.8 mL, 400 mmol) through a dropping funnel, while keeping the internal temperature under 20° C. The resulting suspension was stirred overnight at room temperature, then washed with brine. The aqueous layers were extracted with dichloromethane (2×50 mL), then the combined organic layers were dried over MgSO4 and concentrated in vacuo to afford 3-(dimethylamino)-N-methoxy-N-methylbenzamide as an oil [15.5 g, yield 67%; HPLC/MS: m/z=209 (M+H); logP(HCOOH)=0.95].
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:7]=1)[C:3](=O)[CH3:4].[C:17]([NH:20][C:21]([NH2:23])=[S:22])(=[O:19])[CH3:18].O.C(OCC)(=O)C>C(O)C>[F:12][C:9]1[CH:10]=[CH:11][C:6]([C:2]2[S:22][C:21]([NH:20][C:17](=[O:19])[CH3:18])=[N:23][C:3]=2[CH3:4])=[CH:7][C:8]=1[S:13]([CH3:16])(=[O:15])=[O:14]
Reactant: CC(=O)C(Br)c1ccc(F)c(S(C)(=O)=O)c1
Reactant: CC(=O)NC(N)=S
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc(C)c(-c2ccc(F)c(S(C)(=O)=O)c2)s1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
A mixture of 1-bromo-1-(4-fluoro-3-methanesulfonyl-phenyl)-propan-2-one (Example 47c) (0.17 g, 0.55 mmol) and N-acetylthiourea (0.065 g, 0.55 mmol) in ethanol is heated at 70° C. for 3 hours then at room temperature over two days. The reaction mixture is poured into water (200 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers are dried over MgSO4, filtered and concentrated to afford a viscous solid. This solid in a minimum amount of ethyl acetate is sonicated to give a suspension which is then heated until all solid has dissolved then left to cool to room temperature overnight. The white crystalline solid is filtered off to afford the titled compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[CH:9]1([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C1CNCCN1
Reactant: Brc1ccccc1OC1CCCCC1
Product: c1ccc(N2CCNCC2)c(OC2CCCCC2)c1

Procedure:
NaH (8.4 g, 210 mmol, 60% in mineral oil) was slurred in DMF (40 mL) and heated to about 65° C. To the slurry was added cyclohexanol (7 g, 69.9 mmol) dissolved in DMF (50 mL). The mixture was stirred at 65° C. for about 1 hour. Ortho-fluoro bromobenzene (9.2 mL, 83.9 mmol) was added dropwise in DMF (10 mL) and the mixture was stirred at 65° C. for about 16 hours, and quenched with water and diluted with DCM. The mixture was concentrated to an oily solid and extracted between water and 1/1 EtOAc/hex. The organic layer was dried, filtered and concentrated. Chromatography on silica gel (EtOAc/hexanes) gave 1-bromo-2-cyclohydroxy-benzene (6.13 g, 34%) as a yellow oil. 1-Bromo-2-cyclohexyloxy-benzene was coupled to piperazine using the Buchwald chemistry described in preparation 1A. LRMS (ESI+): 261.1 (M+1)
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH3:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:34]3[CH:35]=[CH:36][C:31]([CH3:30])=[CH:32][CH:33]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(OC4CCN(C(C)C)CC4)ccc32)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 4-methylphenylboronic acid. The title compound was obtained in 59% yield as light yellow foam. MS (m/e): 496.1 (MH+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([C@H:13]1[C@:17]([CH3:22])([CH2:18][C:19]([OH:21])=[O:20])[C@@H:16]([OH:23])[CH2:15][CH2:14]1)[CH2:7][CH2:6]2.[CH:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH2:25].CS(O)(=O)=O>C1COCC1>[CH2:27]([O:26][CH:24]([O:23][CH:16]1[CH2:15][CH2:14][CH:13]([CH:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:9]2)[C:17]1([CH3:22])[CH2:18][C:19]([O:21][CH:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH3:25])=[O:20])[CH3:25])[CH2:28][CH2:29][CH3:30]
Reactant: C=COCCCC
Reactant: COc1ccc2c(c1)CCC([C@@H]1CC[C@H](O)[C@@]1(C)CC(=O)O)C2
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Product: CCCCOC(C)OC(=O)CC1(C)C(OC(C)OCCCC)CCC1C1CCc2cc(OC)ccc2C1

Procedure:
Contacting (1S, 2S, 5S) -5-(1,2,3,4 -tetrahydro-6-methoxy-2-naphthyl)-2-hydroxy-1-methylcyclopentaneacetic acid with butyl vinyl ether in THF containing methanesulfonic acid affords the stereochemically corresponding α-butoxyethyl 2-(α-butoxyethoxy)-5-(1,2,3,4-tetrahydro-6-methoxy-2-naphthyl)-1 -methylcyclopentaneacetate, in which the ester linkage is cleaved and the carboxyl reduced to hydroxy by contacting with lithium tetrahydroaluminate (1-) in THF. From the resultant alcohol, on esterification with acid chloride or anhydride in pyridine, followed by cleavage of the ether linkage via hydrochloric acid in acetone, the corresponding mono ester of the invention wherein the ester grouping is on the ethanolic side chain eventuates. Contacting such a mono ester with acid chloride or anhydride affords a di-ester of the invention.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13]CC)=[O:12])=[C:5]2[CH3:16].[OH-].[K+].Cl>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[C:5]2[CH3:16]
Reactant: CCOC(=O)c1[nH]c2ccc(F)cc2c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)O)[nH]c2ccc(F)cc12

Procedure:
Ethyl 5-fluoro-3-methyl-1H-indole-2-carboxylate (8.3 g, 37.5 mmol) and potassium hydroxide (6.3 g, 112.5 mmol) in a mixture of ethanol (20 mL) and water (15 mL) was heated at reflux for 1 hour . The volume was reduced to 10 mL under reduced pressure and the solution brought to an acidic pH with a 3N aqueous solution of hydrochloric acid. The resulting precipitate was filtered, washed with water (100 mL) and dried in vacuo at 80° C. overnight to afford 5-fluoro-3-methyl-1H-indole-2-carboxylic acid as a white solid. MS (ES) m/z 192.0
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])=[O:26].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:31]4[CH:32]=[CH:33][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:29][CH:30]=4)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Cl)ncc3o2)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3o2)CC1
Temperature: 170 °C

Procedure:
A mixture of 4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (390 mg), 4-(methanesulfonyl)phenyl boronic acid (350 mg), aqueous Na2CO3 solution (2 M; 1.50 mL), and dioxane (10 mL) is sparged with argon for 10 min and Pd(PPh3)4 (100 mg) is added. The resulting mixture is heated to 170° C. in a microwave oven until the conversion is complete. The reaction mixture is concentrated in vacuo, diluted with water and extracted with ethyl acetate. The organic phase is washed with brine, dried over MgSO4, and the solvent is evaporated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 60:40→40:60) to give the title compound. LC (method 5): tR=1.32 min; Mass spectrum (ESI+): m/z=457 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[S:4][N:3]=1.[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[N:6]=[C:5]([NH:7][C:8]([N:30]2[CH2:31][CH2:32][N:27]([C:25]3[S:24][N:23]=[C:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:26]=3)[CH2:28][CH2:29]2)=[O:15])[S:4][N:3]=1
Reactant: Cc1nsc(NC(=O)OCC(Cl)(Cl)Cl)n1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nsc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)n1
Temperature: 70 °C
Reaction time: 15 h
Yield: 36.9 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3-methyl-1,2,4-thiadiazol-5-yl)carbamate (260 mg, 0.893 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.156 ml, 0.893 mmol) in dimethylsulfoxide (2.7 ml) was stirred at 70° C. for 15 hours. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and ethyl acetate to obtain the desired product (116 mg, 36.8%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8](C(OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1.CS(C)=O.[Cl-].[Na+]>O>[Cl:1][C:2]1[C:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ncccc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1ncccc1Cl
Temperature: 142.5 °C
Reaction time: 0.33 h
Yield: 94.5 %

Procedure:
3.70 g of diethyl (3-chloro-2-pyridyl)malonate and 15 ml of dimethyl sulfoxide were mixed. To the mixture was added 0.95 g of sodium chloride and 0.49 g of water. The mixture was stirred for about 20 minutes at an inner temperature of 135 to 150° C. The reaction mixture was allowed to cool to room temperature, then, water was added to the reaction mixture, and extracted with ethyl acetate. After liquid separation, the organic layer was washed with saturated brine twice, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure to obtain 2.57 g of ethyl (3-chloro-2-pyridyl)acetate.
Reaction SMILES: CO[CH:3](OC)[CH2:4][C:5](=O)[CH3:6].[NH2:10][C:11]1[NH:15][N:14]=[C:13]2[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][C:12]=12>C(O)(=O)C>[CH3:6][C:5]1[N:15]2[N:14]=[C:13]3[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][C:12]3=[C:11]2[N:10]=[CH:3][CH:4]=1.[CH3:6][C:5]1[CH:4]=[CH:3][N:15]2[N:14]=[C:13]3[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][C:12]3=[C:11]2[N:10]=1
Reactant: COC(CC(C)=O)OC
Reactant: CC(C)(C)OC(=O)N1Cc2n[nH]c(N)c2C1
Solvent: CC(=O)O
Product: Cc1ccn2nc3c(c2n1)CN(C(=O)OC(C)(C)C)C3
Product: Cc1ccnc2c3c(nn12)CN(C(=O)OC(C)(C)C)C3
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 0.30 mL (2.4 mmol) of 4,4-dimethoxy-2-butanone in 2 mL of glacial acetic acid at 95° C. was added 448 mg (2.0 mmol) of tert-butyl 3-amino-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate as a solution in 8 mL of glacial acetic acid over 40 min. The reaction mixture was stirred for an additional 1.5 h, cooled to ambient temperature and the solvent evaporated in vacuo to afford the title compound as a 5:3 mixture with tert-butyl 2-methyl-7H-pyrrolo[3′,4′:3,4]pyrazolo[1,5-a]pyrimidine-8(9H)-carboxylate and was used in Step B without purification. LC/MS 275.2 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=O)[C:5]=2[CH2:4][CH2:3]1.P(Cl)(Cl)(Cl)(Cl)Cl.[Cl-:20].[Al+3].[Cl-].[Cl-].Cl>ClC1C=CC=CC=1>[Cl:20][C:5]1[CH:6]=[CH:7][C:8]([C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH2:4][CH2:3][C:2]3=[O:1])=[O:13])=[CH:9][CH:10]=1
Reactant: [Cl-]
Reactant: O=C(O)c1cccc2c1CCC2=O
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: O=C1CCc2c1cccc2C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 200 ml. of chlorobenzene are added 17.6 g. of 1-oxoindan-4-carboxylic acid and 23 g. of phosphorus pentachloride. The mixture is stirred at room temperature for 3 hours, after which time 40 g. of aluminum chloride is added. The mixture is stirred at about 65°C for 3 hours. After cooling, the mixture is poured into ice and hydrochloric acid, followed by extraction with chloroform. The extract is washed with water, a saturated aqueous solution of sodium bicarbonate and water in the order mentioned. After drying, the solvent is distilled off under reduced pressure and the residue is purified by column chromatography on silica gel (200 g. silica gel; eluted with chloroform). Finally, recrystallization from a 20:5 mixture of benzene and hexane gives 4-(p-chlorobenzoyl)indan-1-one as crystals melting at 144.5°-146°C.
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([O:7][C:8](=[O:13])[C:9]([CH2:11]O)=[CH2:10])[CH3:6].O>CCOCC>[CH2:5]([O:7][C:8](=[O:13])[C:9]([CH2:11][Br:2])=[CH2:10])[CH3:6]
Reactant: BrP(Br)Br
Reactant: C=C(CO)C(=O)OCC
Solvent: CCOCC
Solvent: O
Product: C=C(CBr)C(=O)OCC
Reaction time: 3 h
Yield: 123.1 %

Procedure:
Phosphorus tribromide (17.16 g, 63.41 mmol) was added to a stirred solution of the compound of example 30 (17.92 g, 138.1 mmol) in dry ether (132 mL) at −10° C. The temperature was allowed to rise to 20° C. and stirring was continued for 3h. Water (80 mL) was then added at −10° C. and the mixture was extracted with hexane (3×45 mL). The organic extracts were washed with saturated sodium chloride solution (2×45 mL) and dried with anhydrous MgSO4. Evaporation of solvent under vacuum gave 15.07 g (yield 56.6%) of the crude product, which was used directly in the next reaction without any further purification. 1H NMR (CDCl3, 400 MHz) δ 6.25 (s, 1H), 5.88 (s, 1H), 4.2 (q, 2H), 4.11 (s, 2H), 1.25 (t, 3H); 13C NMR (CDCl3, 400 MHz) 166.7, 140.1, 125.3, 61.1, 53.9, 14.4.