Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].[F:9][C:10]([F:17])([F:16])[C:11](OCC)=[O:12]>C1COCC1>[F:9][C:10]([F:17])([F:16])[C:11](=[O:12])[CH2:7][C:6]#[N:8]
Reactant: CC#N
Reactant: CCOC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCC(=O)C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
A flame-dried flask was charged with 20 ml (32 mmol) n-butyllithium solution (1.6 M in hexanes) in dry THF (100 ml) under inert gas atmosphere and cooled to −78° C. Next, 1.47 ml (28 mmol) acetonitrile were slowly added, and the resulting mixture was stirred for 1 h at −74° C. Then, 2.28 ml (20 mmol) ethyl trifluoroacetate were slowly added over 5 min maintaining the temperature below −69° C. The reaction mixture was stirred for 2 h at −45° C. and then quenched by addition of hydrochloric acid (2 M, 9.6 ml) while keeping the temperature below −20° C. The resulting clear solution was allowed to warm to room temperature and then concentrated under reduced pressure. The residual aqueous slurry was extracted several times with diethylether (100 ml portions), and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to yield 4.25 g (84% of th.) of the crude title compound (54% purity) which was used in the next step without further purification.
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[C:4](=[O:14])[O:3]1.[CH2:15]([NH2:18])[CH:16]=[CH2:17].C1(C)C=CC=CC=1.Cl>C(Cl)Cl.CC(O)=O>[CH2:15]([N:18]1[C:4](=[O:14])[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11]([OH:13])=[O:12])[CH:6]=2)[C:2]1=[O:3])[CH:16]=[CH2:17]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: C=CCN
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: C=CCN1C(=O)c2ccc(C(=O)O)cc2C1=O

Procedure:
To a 25 mL pear-shaped flask was added solid 1,3-dioxo-1,3-dihydroisobenzofuran-5-carboxylic acid (200 mg, 1.041 mmol) and allylamine (234 μL, 3.12 mmol, 3 eq) via syringe. Toluene (2 mL) and AcOH (1 mL) were added via syringes and the flask was refluxed for 12 h. The flask was allowed to cool and then subjected to a DCM (75 mL) and HCl (1N, 50 mL) work up. The aqueous layer was extracted with DCM (3×25 mL). The combined organic layers were washed with brine, dried with sodium sulfate, filtered and concentrated. The residue thus obtained was azeotropically dried with toluene (2×, 5 mL) and heptane (2×5 mL). The resulting reside was placed on a high vacuum for 3 to give 2-allyl-1,3-dioxoisoindoline-5-carboxylic acid.
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([O:19][CH3:20])[C:13]([S:15](Cl)(=[O:17])=[O:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH-].[NH4+:22]>>[C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([O:19][CH3:20])[C:13]([S:15](=[O:17])(=[O:16])[NH2:22])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1S(=O)(=O)Cl)CCN(C(C)=O)CC2
Reactant: [NH4+]
Agent: [OH-]
Product: COc1cc2c(cc1S(N)(=O)=O)CCN(C(C)=O)CC2
Reaction time: 2 h

Procedure:
3-Acetyl-7-chlorosulfonyl-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (3 g, 0.007 m) was treated with concentrated ammonium hydroxide (10 ml), stirred for 2 hours and filtered to give 3-acetyl-8-methoxy-7-sulfamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 260°-263°.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][N+:4]([O-:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.B(F)(F)[F:11].CCOCC.[F:19][B-:20]([F:23])([F:22])[F:21].[H+].FF>C(#N)C>[F:19][B-:20]([F:23])([F:22])[F:21].[F:19][B-:20]([F:23])([F:22])[F:21].[OH:9][N+:4]12[CH2:7][CH2:8][N+:1]([F:11])([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: FB(F)F
Reactant: [O-][N+]12CCN(CC1)CC2
Agent: FF
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CC#N
Solvent: CCOCC
Product: O[N+]12CC[N+](F)(CC1)CC2
Yield: 149.2 %

Procedure:
A solution of 1,4-diazabicyclo[2.2.2]octane N-oxide (2.56 g, 20 mmole), boron trifluoride etherate (2.4 mL, 20 mmole), and tetrafluoroboric acid (50% solution, 3.66 g, 20 mmole) in acetonitrile (250 mL) was cooled to 8° C. and treated with a mixture of fluorine in nitrogen (10% V/V, 52 mmole). The reaction was evaporated, the remaining solid washed with acetone and dried to afford 4.8 grams of 1-hydroxyl-4-fluoro-1,4-diazoniabicyclo[2.2.2 ]octane bis(tetrafluoroborate) (75% yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10]=S)[CH3:2].[NH2:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[NH2:23])[C:16]([O:18][CH3:19])=[O:17]>>[CH3:19][O:18][C:16]([C:15]1[CH:20]=[CH:21][C:22]2[N:23]=[C:10]([NH:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[CH2:1][CH3:2])[NH:12][C:13]=2[CH:14]=1)=[O:17]
Reactant: CCc1ccccc1N=C=S
Reactant: COC(=O)c1ccc(N)c(N)c1
Product: CCc1ccccc1Nc1nc2ccc(C(=O)OC)cc2[nH]1

Procedure:
2-Ethyl-1-isothiocyanatobenzene (3 mmol) and methyl 3,4-diaminobenzoate (3 mmol) were reacted, following general procedure B, to yield 2-(2-ethylphenylamino)-3H-benzimidazole-5-carboxylic acid methyl ester, which was purified by silica gel chromatography using DCM/ethyl acetate as eluent.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH3:16])[CH:14]=1)[C:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N:10][CH2:9][CH2:8]2>CCO>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH3:16])[CH:14]=1)[CH:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:10][CH2:9][CH2:8]2
Reactant: COc1cc2c(c(OC)c1)C(c1ccccc1)=NCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc2c(c(OC)c1)C(c1ccccc1)NCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
Sodium borohydride (450 mg) was added with stirring to a solution of 6,8-dimethoxy-1-phenyl-3,4-dihydroisoquinoline (1.96 g) in EtOH (50 mL) over 5 minutes. The reaction mixture was stirred at room temperature for 2 hours and then further stirred at 60° C. for 1.5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. An aqueous 3 M HCl solution (60 mL) was added to the resulting residue, followed by heating under reflux for 3 minutes. After cooling, an aqueous 20% NaOH solution was added to the mixture to have strong alkalinity, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 6,8-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (1.88 g).
Reaction SMILES: [CH2:1]([C:3]1[C:11]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].CC(C)([O-])C.[K+].CS(O[CH2:31][CH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)(=O)=O.O1CCCC1>CN(C)C=O.C(OCC)(=O)C.O>[CH2:1]([C:3]1[C:11]([N:12]([CH2:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: CS(=O)(=O)OCC1CCOCC1
Reactant: CCc1nn2ccccc2c1NC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1nn2ccccc2c1N(CC1CCOCC1)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 108.9 %

Procedure:
To a solution of tert-butyl N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)carbamate (12 g, 46 mmol) and potassium tert-butoxide (6.2 g, 55 mmol) dissolved in N,N-dimethylformamide (120 mL) was added tetrahydropyran-4-ylmethyl methanesulfonate (10.7 g, 55 mmol) while cooling with ice, the reaction mixture was stirred for 1 hour, and then tetrahydrofuran (200 mL) was further added and the reaction mixture was additionally stirred for 18 hours. Water (200 mL) and ethyl acetate (500 mL) were then added to the reaction mixture, and the aqueous layer was separated and extracted with ethyl acetate (300 mL). The combined organic extracts were washed with water (300 mL, 3 times) and brine, dried over magnesium sulfate and evaporated under reduced pressure to afford 18 g of the title compound as a yellow oil (>99% yield).
Reaction SMILES: C(OCCl)(=O)C(C)(C)C.[Na+].[CH2:11]([C:14]1[C:23]2[O:22][C:21]([C:24]([O-:26])=[O:25])=[CH:20][C:19](=[O:27])[C:18]=2[C:17]([O:28][CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[CH:16][CH:15]=1)[CH:12]=[CH2:13].[I-].[Na+]>CC(C)=O>[CH2:11]([C:14]1[C:23]2[O:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][C:19](=[O:27])[C:18]=2[C:17]([O:28][CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[CH:16][CH:15]=1)[CH:12]=[CH2:13]
Reactant: C=CCc1ccc(OCCC(C)C)c2c(=O)cc(C(=O)[O-])oc12
Agent: CC(C)(C)C(=O)OCCl
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C=CCc1ccc(OCCC(C)C)c2c(=O)cc(C(=O)O)oc12

Procedure:
To a solution of 5.4 parts of chloromethyl pivalate in 60 parts of dry acetone were added 6 parts of 8-allyl-5-(3-methyl-n-butoxy)-4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt and 0.1 parts of sodium iodide. The mixture was refluxed for 10 hurs, cooled and evaporated to an oil which was dissolved in diethyl ether. The ethereal solution was filtered and evaporated under vacuum to give an oil which solidified when triturated with petroleum ether (b.p. 40°-60° C). The solid was filtered off and crystallised from petroleum ether (b.p. 60°-80° C) to give 4.5 parts of 8-allyl-5-(3-methyl n-butoxy)-4-oxo-4H-1-benzopyran-2-carboxylic acid pivaloyoxymethyl ester, m.p. 79°-80° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:34][CH:35]([C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:47])=[O:46])=[CH:41][CH:40]=2)[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[S:51][CH:52]=[CH:53][N:54]=1>C(Cl)Cl>[CH:28]1([CH2:34][CH:35]([C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:47])=[O:46])=[CH:41][CH:40]=2)[C:36]([NH:49][C:50]2[S:51][CH:52]=[CH:53][N:54]=2)=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: Nc1nccs1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCCC2)C(=O)O)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCCC2)C(=O)Nc2nccs2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
A solution of triphenylphosphine (416 mg, 1.58 mmol) in methylene chloride (8 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (281 mg, 1.58 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of 3-cyclohexyl-2-(4-methanesulfonyl-phenyl)-propionic acid (290 mg, 0.93 mmol) in methylene chloride (5 mL). The clear solution was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (233 mg, 2.32 mmol), and the resulting suspension was stirred for 20 h at 25° C. The reaction mixture was concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (50 mL) and a 1N aqueous hydrochloric acid solution (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×30 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and, concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 4/1 to 1/1 hexanes/ethyl acetate) afforded 3-cyclohexyl-2(-4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (337 mg, 92%) as an amorphous solid: EI-HRMS m/e calcd for C19H24N2O3S2 (M+) 392.1228, found 392.1230.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[CH3:11][S:12]([N:15]1[CH2:19][CH2:18][C@H:17](OS(C)(=O)=O)[CH2:16]1)(=[O:14])=[O:13]>>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][C@@H:17]2[CH2:18][CH2:19][N:15]([S:12]([CH3:11])(=[O:14])=[O:13])[CH2:16]2)=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: CS(=O)(=O)O[C@H]1CCN(S(C)(=O)=O)C1
Product: Cc1cc(O[C@@H]2CCN(S(C)(=O)=O)C2)cc(C)c1Br

Procedure:
The title compound is prepared in analogy to Intermediate 36 from 4-Bromo-3,5-dimethylphenol (626 mg, 3.08 mmol) and Methanesulfonic acid (S)-1-methanesulfonyl-pyrrolidin-3-yl ester (300 mg, 1.23 mmol). (Yield: 350 mg).
Reaction SMILES: [Br-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2-].[Na+].[CH2:24]([O:31][C:32]1[CH:44]=[CH:43][CH:42]=[C:41]2[C:33]=1[C:34]1[C:35]([CH2:57][O:58][CH3:59])=[C:36]([CH:55]=O)[N:37]=[CH:38][C:39]=1[N:40]2[S:45]([C:48]1[CH:54]=[CH:53][C:51]([CH3:52])=[CH:50][CH:49]=1)(=[O:47])=[O:46])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[CH2:24]([O:31][C:32]1[CH:44]=[CH:43][CH:42]=[C:41]2[C:33]=1[C:34]1[C:35]([CH2:57][O:58][CH3:59])=[C:36]([CH:55]=[CH2:2])[N:37]=[CH:38][C:39]=1[N:40]2[S:45]([C:48]1[CH:54]=[CH:53][C:51]([CH3:52])=[CH:50][CH:49]=1)(=[O:46])=[O:47])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COCc1c(C=O)ncc2c1c1c(OCc3ccccc3)cccc1n2S(=O)(=O)c1ccc(C)cc1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=Cc1ncc2c(c1COC)c1c(OCc3ccccc3)cccc1n2S(=O)(=O)c1ccc(C)cc1
Yield: 0 %

Procedure:
1.0 g of methyltriphenylphosphoniumbromide+sodium amide (condition-ylide) in 8 ml of absolute tetrahydrofuran is stirred at room temperature under argon for 15 minutes. To it is added 500 mg of 5-benzyloxy-4-methoxymethyl-9-tosyl-beta-carboline-3-carbaldehyde and the reaction mixture is refluxed for 4 hours. After evaporation of the solvent, the residue is chromatographed over silica gel with cyclohexane/acetic acid=8+2 as eluant. 0.153 mg of 5-benzyloxy-4-methoxymethyl-9-tosyl-3-vinyl-beta-carboline with a melting point of 141°-143° C. is obtained.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)C.O.[NH2:14][NH2:15]>CO>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([NH:14][NH2:15])=[O:3])=[CH:6][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)c1ccc(Br)cc1
Solvent: CO
Solvent: O
Product: NNC(=O)c1ccc(Br)cc1

Procedure:
Ethyl-4-bromobenzoate is treated with hydrazine monohydrate in methanol under reflux conditions to obtain product X, 4-bromobenzoic hydrazide. Reaction of compound X with bromobenzoic acid in pyridine at 120° C. gives product XI, bis-(4-bromophenyl) hydrazine. Compound XI is then treated with sulfonyl chloride to afford 2,5-bis-(4-bromophenyl)-1,3,4-oxadiazole (Compound XII), which is further reacted 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane under conditions similar to step-3 in Example 1. The resulting product thus obtained is subjected to Suzuki coupling conditions similar to step-5 in Example 1 to obtain the desired product XIII. Other alligator clips which can be introduced are CN, SCN, NH2, pyridine.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.Cl[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([O:33][CH3:34])[CH:28]=1.[O:35]1[C:39]2([CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[O:38][CH2:37][CH2:36]1.CC(C)([O-])C.[Na+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:34][O:33][C:29]1[CH:28]=[C:27]([N:42]2[CH2:43][CH2:44][C:39]3([O:38][CH2:37][CH2:36][O:35]3)[CH2:40][CH2:41]2)[CH:32]=[CH:31][N:30]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: COc1cc(Cl)ccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: COc1cc(N2CCC3(CC2)OCCO3)ccn1
Temperature: 130 °C

Procedure:
A solution of palladium(II) acetate (62.5 mg, 279 μmol) and 2-(dicyclohexylphosphino) biphenyl (201 mg, 557 μmol) in dioxane (1.5 mL) was stirred under argon at room temperature for 10 minutes, then added to a solution of 4-chloro-2-methoxypyridine (500 mg, 3.48 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (499 mg, 446 μL, 3.48 mmol) and sodium tert-butoxide (502 mg, 5.22 mmol) in dioxane (1.5 mL), degassed and argon bubbled through the reaction during 5 minutes. The reaction mixture was heated in the microwave to 130° C. for 30 minutes. The reaction mixture was filtered through dicalite, water was added to the filtrate and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were dried over Na2SO4 and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, 70 g, 80% to 100% ethyl acetate in heptane). The title compound was obtained as brown oil (700 mg, 80%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCCCCCCCCCCS.C[CH:22]1[CH2:28][C:27](C)(C)[CH2:26][C:24](=[O:25])[CH2:23]1.Cl.[OH-].[Na+]>O>[CH:28]1[CH:27]=[C:26]([C:3]2[CH:4]=[CH:5][CH:6]=[C:1]([OH:7])[CH:2]=2)[C:24]([OH:25])=[CH:23][CH:22]=1
Reactant: CC1CC(=O)CC(C)(C)C1
Reactant: Oc1ccccc1
Agent: CCCCCCCCCCCCS
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Oc1cccc(-c2ccccc2O)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
1692 g (18 mol) of phenol, 60.6 g (0.3 mol) of dodecylthiol and 420 g (3 mol) of dihydroisophorone (3,3,5-trimethylcyclohexan-1-one) are introduced into a stirring apparatus equipped with a stirrer, thermometer, reflux condenser and gas inlet pipe at 28°-30° C. Dry HCl gas is introduced into this solution over a period of 5 hours at 28°-30° C. The mixture is then left to react for about 10 h at 28°-30° C. When 95% of the ketone has been converted (examined by GC), 2.5 l of water are added to the reaction mixture and a pH value of 6 is adjusted by adding a 45% NaOH solution. The reaction mixture is stirred for one hour at 80° C. and then cooled to 25° C. The aqueous phase is decanted off and the remaining residue is washed with water at 80° C. The resulting crude product is filtered off and hot-extracted twice with n-hexane and twice with methylene chloride and then filtered. The residue is recrystallised twice from xylene.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:9]=[CH:10][C:11]2=[C:12]([CH:35]=1)[N:13]=[C:14]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:15][C:16]([C:18](=[O:26])[N:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])=[CH:17]2.O.[K].[K].C1(P(C2C=CC(S(O)(=O)=O)=CC=2)C2C=CC(S(O)(=O)=O)=CC=2)C=CC=CC=1.N#N.[CH3:68][N:69]([CH3:81])[C:70]([C:72]1[CH:77]=[CH:76][C:75](B(O)O)=[CH:74][CH:73]=1)=[O:71]>CCO.O.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:68][N:69]([CH3:81])[C:70]([C:72]1[CH:77]=[CH:76][C:75]([C:8]2[CH:9]=[CH:10][C:11]3=[C:12]([CH:35]=2)[N:13]=[C:14]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:15][C:16]([C:18](=[O:26])[N:19]([CH2:20][CH2:21][CH3:22])[CH2:23][CH2:24][CH3:25])=[CH:17]3)=[CH:74][CH:73]=1)=[O:71]
Reactant: CCCN(CCC)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
Reactant: CN(C)C(=O)c1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(C(=O)N(C)C)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Temperature: 65 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
To Na2CO3 (129 mg, 1.214 mmol) in a 50 mL round-bottom flask was added water (3.7 mL) was bubbled with N2 for 10 min. To this mixture was added tert-butyl (1E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate (200 mg, 0.40 mmol) in EtOH (4.9 mL) at room temperature. The resulting mixture was bubbled with N2 for 10 min. Pd(OAc)2 (9.3 mg, 0.040 mmol) and 4,4′-(phenylphosphinidene)bisbenzenesulfonic acid dipotassium hydrate (45 mg, 0.081 mmol) were added. The resulting mixture was warmed to 65° C. with N2 bubbling. To this mixture was added a solution of 4-(dimethylcarbamoyl)phenylboronic acid (97 mg, 0.49 mmol) in EtOH (0.6 mL). The resulting mixture was stirred at 65° C. for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude material that was diluted with water (5 mL) and EtOAc (10 mL). The mixture was filtered through GF/F filter. The aqueous layer was separated and extracted with EtOAc (10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude product that was purified by silica gel flash column chromatography (CH2Cl2 to 2% MeOH in CH2Cl2) to afford 178 mg (83%) of tert-butyl (1E,4E)-8-(4-(dimethylcarbamoyl)phenyl)-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate. MS APCI(+) m/z 533 (M+1) detected.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([NH:44][CH2:45][CH2:46][F:47])=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH2:41][CH2:42][NH:44][CH2:45][CH2:46][F:47])[CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=2[CH2:17]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Reactant: O=C(CCl)NCCF
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCNCCF)c(F)c2)C(C)C)c1
Yield: 22.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (26 mg) and 2-chloro-N-(2-fluoroethyl)acetamide (14 mg) according to an analogous synthetic method to Example 567 and purified by LC-MS, the title compound (5.8 mg) was obtained.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH:7]=1.CO>>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[NH:13][S:12]([C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]([OH:26])=[O:2])[CH:11]=[CH:10][CH:9]=1)(=[O:24])=[O:25]
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2ccc3ccccc3c2)c1
Solvent: CO
Product: O=C(O)C=Cc1cccc(S(=O)(=O)Nc2ccc3ccccc3c2)c1
Reaction time: 0.5 h

Procedure:
To a suspension of 3-[3-(naphthalen-2-ylsulfamoyl)-phenyl]-acrylic acid methyl ester (14e) (0.25 g, 0.68 mmol) in methanol (3.5 ml) 2N NaOH solution (1.0 ml, 2.0 mmol) was added and the resultant mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified with 2N HCl solution and stirred for 30 min. The precipitated solid was filtered, washed with water and dried in desiccator over P2O5. The title compound was obtained as a white solid (0.21 g, 87%). 1H NMR (DMSO-d6, HMDSO), δ: 6.56 (1H, d, J=16.0 Hz); 7.21-8.01 (11H, m); 8.12 (1H, s); 10.56 (1H, br s); 12.54 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][CH2:9][C:10]3([CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.[H-].[Na+].F[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([F:29])([F:28])[F:27].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]\[C:33]([OH:35])=[O:34]>CS(C)=O.O.CCOCC>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]\[C:33]([OH:35])=[O:34].[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])[CH2:9][C:10]3([CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1
Reactant: Fc1ccccc1C(F)(F)F
Reactant: CN1CCC2(CC1)CNc1cc(Cl)ccc12
Agent: O=C(O)/C=C\C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOCC
Product: CN1CCC2(CC1)CN(c1ccccc1C(F)(F)F)c1cc(Cl)ccc12
Reaction time: 0.5 h

Procedure:
A mixture of 2.4 g of 6-chloro-1'-methylspiro[indoline-3,4'-piperidine], 0.5 g of sodium hydride and 6 g of 2-fluorobenzotrifluoride in 30 ml of dimethylsulfoxide is stirred under nitrogen for 30 minutes. An exothermic reaction occurs during this time. Thereafter, the mixture is diluted with water, and the diluted mixture thrice with ether. The combined ether extracts are extracted with 2 N hydrochloric acid. The acidic extracts are basified providing a colorless oil. The oil is dissolved in ether and the solution is dried. The product is passed through an alumina column, ether eluant, to provide a colorless oil which is converted, in ether, to its maleic acid salt. The salt is recrystallized from an acetone-ether mixture to provide white platelets, mp 209°-211° C. of 6-chloro-1-(2-trifluoromethylphenyl)-1'-methylspiro[indoline-3,4'-piperidine] maleate.