Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](I)=[CH:11][C:10]([NH2:14])=[N:9]2)=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:19]=[C:20]([CH2:22][O:23][C@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:18]3[CH:19]=[C:20]([CH2:22][O:23][C@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])[CH:21]=[C:16]([F:15])[CH:17]=3)=[CH:11][C:10]([NH2:14])=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](OCc1cc(F)cc(B2OC(C)(C)C(C)(C)O2)c1)C(F)(F)F
Reactant: Nc1cc(I)n(-c2ccc(Cl)cc2)n1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: COCCOC
Product: C[C@@H](OCc1cc(F)cc(-c2cc(N)nn2-c2ccc(Cl)cc2)c1)C(F)(F)F
Temperature: 25 °C

Procedure:
Under argon atmosphere, to a solution of 1-(4-chlorophenyl)-5-iodo-1H-pyrazol-3-ylamine (35 mg) in 1,2-dimethoxyethane (0.7 ml) were sequentially added 2-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (46 mg) prepared according to the same procedures as Preparation 15, a 2M aqueous solution of sodium carbonate (0.35 ml), tricyclohexylphosphine (6.1 mg) and palladium (II) acetate (2.5 mg) at room temperature, and the mixture was stirred at 100° C. for 2 hours. This reaction mixture was cooled to room temperature, filtered through Celite, was subjected to elution with ethyl acetate. The filtrate was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (eluent: n-hexane/ethyl acetate=1/1) to give the titled compound.
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][C:11]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[CH:12][CH:13]=3)[N:8]([CH3:21])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC(C)C)(=O)C.[Br:29]Br>>[Br:29][C:7]1[N:8]([CH3:21])[C:9]2[C:14]([C:6]=1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[CH:13][CH:12]=[C:11]([C:15]([O:17][CH:18]([CH3:19])[CH3:20])=[O:16])[CH:10]=2
Reactant: CC(C)OC(=O)c1ccc2c(C3CCCC3)cn(C)c2c1
Reactant: BrBr
Solvent: CC(=O)OC(C)C
Product: CC(C)OC(=O)c1ccc2c(C3CCCC3)c(Br)n(C)c2c1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
The mixture of isopropyl 3-cyclopentyl-1-methyl-1H-indole-6-carboxylate (84 g, 0.294 mol) and isopropyl acetate (1074 g) was cooled to between −10-0° C. Bromine (50 g, 0.312 mol) was added while the batch was maintained at −10-0° C. The resulting slurry was stirred at the same temperature for additional 30 min and quenched with a pre-cooled solution of sodium thiosulfate pentahydrate (13 g) and triethylamine (64.5 g) in water (240 g) while the temperature was maintained at 0-10° C. The mixture was heated to 40-50° C. and charged with methanol (664 g). After it was stirred at the same temperature for at least 0.5 h, the batch was cooled to 0-10° C. and stirred for another 1 hr. The precipitate was filtered, rinsed with 56 wt % methanol/water solution (322 g), and dried in vacuo (≦200 Torr) at 50-60° C. until the water content was ≦0.4% to give isopropyl 2-bromo-3-cyclopentyl-1-methyl-1H-indole-6-carboxylate as a beige solid (90-95 g, 80-85% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:16])=[C:4]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C(=O)([O-])[O-:18].[K+].[K+].OO>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[C:3]([I:16])=[C:4]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:5]([C:8]([NH2:9])=[O:18])=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CCC(CC)Nc1c(C#N)ncc(Cl)c1I
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCC(CC)Nc1c(C(N)=O)ncc(Cl)c1I
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of 5-chloro-4-iodo-3-(pentan-3-ylamino)picolinonitrile (55 mg, 0.16 mmol) in DMSO (1 mL) was added solid potassium carbonate (210 mg, 0.64 mmol). The mixture was cooled in an ice water bath (0° C.) and aqueous hydrogen peroxide (30%, 0.5 mL) was added. The reaction was allowed to warm to room temperature and monitored by LCMS. After the reaction was complete, the reaction mixture was diluted with EtOAc, and the organic layer was washed repeatedly with water. The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo. The residue was filtered through a silica gel plug to provide the title compound as a white solid (50 mg, 83%). m/z=368.1 [M+H]+ and 1H NMR.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.Cl.[CH3:15][N:16]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:18]2([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:17]1=[O:30].C(=O)([O-])[O-].[K+].[K+]>>[CH3:15][N:16]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:18]2([CH2:23][CH2:22][N:21]([C:2]3[N:3]=[N:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[N:9]=4)=[CH:6][CH:7]=3)[CH2:20][CH2:19]2)[C:17]1=[O:30]
Reactant: Cc1noc(-c2ccc(Cl)nn2)n1
Reactant: CN1C(=O)C2(CCNCC2)c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1noc(-c2ccc(N3CCC4(CC3)C(=O)N(C)c3ccccc34)nn2)n1

Procedure:
The object product (40 mg, 53%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridazine (39 mg) obtained in Example 43(2), 1-methylspiro[indole-3,4′-piperidin]-2(1H)-one hydrochloride (51 mg) and potassium carbonate (55 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:20]([F:21])=[CH:19][CH:18]=[C:17]([F:22])[C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[F:22][C:17]1[C:15]2[N:16]=[C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[O:13][C:14]=2[C:20]([F:21])=[CH:19][CH:18]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2c(F)ccc(F)c2o1
Product: Fc1ccc(F)c2oc(CCC#Cc3ccccn3)nc12
Yield: 14.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (69 mg, 0.43 mmol) and 2-(but-3-ynyl)-4,7-difluoro-benzo[d]oxazole (90 mg, 0.43 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 98.5:1.5) to yield 17 mg (61 μmol, 14%) of 4,7-difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as an orange solid.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH3:18])[CH:12]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CO>O>[OH:10][CH:3]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1cc(C(=O)c2ccccc2)ccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(C(O)c2ccccc2)ccn1
Yield: 79.3 %

Procedure:
9.4 g of sodium borohydride was added little by little to a mixture of 130 g of 4-benzoyl-2-methoxypyridine and 300 ml of methanol under stirring in an ice bath. After the dropwise addition was completed, the mixture was stirred at room temperature overnight. The reaction solution was added to 1 L of water and then extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and then the solvent was removed, to give 104 g of the target compound.
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH3:5][C:6]1[CH:7]=[C:8]([CH:10]=[C:11]([CH3:25])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH:22]([CH3:24])[CH3:23])[CH:15]=1)[NH2:9].Cl.[Sn](Cl)Cl>O.C(O)C>[CH3:25][C:11]1[CH:10]=[C:8]([NH:9][NH2:1])[CH:7]=[C:6]([CH3:5])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH:22]([CH3:23])[CH3:24])[CH:15]=1
Reactant: O=N[O-]
Reactant: COc1ccc(Oc2c(C)cc(N)cc2C)cc1C(C)C
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(Oc2c(C)cc(NN)cc2C)cc1C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
A solution of sodium nitrite (155 mg, 2.24 mmol) in water (1 mL) was added to a suspension of 3,5-dimethyl-4-(4′-methoxy-3′-iso-propylphenoxy)-aniline (J. Med. Chem. 38:695 (1995), 640 mg, 2.24 mmol) in ethanol (3 mL) and concentrated hydrochloric acid (12 M, 1.12 mL, 13.44 mmol) at 0° C. The yellow heterogeneous solution slowly turns to an orange clear solution. After stirring at 0° C. for 30 minutes, a solution of tin dichloride (1.53 g, 8.06 mmol) in hydrochloric acid (12 M, 1.3 mL, 15.68 mmol) was added. The orange solution turned green and a white precipitate formed. Ethanol (3 mL) was added to dissolve most of the precipitate and the heterogeneous reaction mixture was stirred at 0° C. After 2 hours, water was added and the precipitate collected by filtration. The sticky solid was dissolved in ethyl acetate and washed with water, 1 N sodium hydroxide then brine. The organics were dried over sodium sulfate, concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, dichloromethane/methanol 95/5 to 90/10) to give 3,5-dimethyl-4-(4′-methoxy-3′-iso-propylphenoxy)-phenyl hydrazine (305 mg, 45%): 1H NMR (300 MHz, CDCl3) δ 6.77 (d, J=3.0 Hz, 1H), 6.67 (d, J=9.0 Hz, 1 H) 6.58 (s, 2H), 6.37 (dd, J=9.0, 3.0 Hz, 1H), 3.77 (s, 3H), 3.27 (heptuplet, J=6.9 Hz, 1H), 2.09 (s, 3H), 1.18 (d, J=6.9 Hz, 6H); TLC conditions: Merck silica gel, 250 microns; Mobile phase=dichloromethane-methanol (9:1), Rf=0.6.
Reaction SMILES: CN(C=O)C.Br[CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:13]=[C:14]([CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]3[CH:30]=[N:31][CH:32]=[C:33]([CH:38]=3)[C:34]([O:36][CH3:37])=[O:35])=[O:27])[CH2:22][CH2:21]2)[CH:15]=[CH:16][CH:17]=1)=[O:11].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CCOC(C)=O>[N:9]1([C:10]([C:12]2[CH:13]=[C:14]([CH2:18][CH2:19][CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]4[CH:30]=[N:31][CH:32]=[C:33]([CH:38]=4)[C:34]([O:36][CH3:37])=[O:35])=[O:27])[CH2:22][CH2:21]3)[CH:15]=[CH:16][CH:17]=2)=[O:11])[CH2:7][CH2:8]1
Reactant: COC(=O)c1cncc(OC(=O)N2CCC(CCc3cccc(C(=O)NCCBr)c3)CC2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cncc(OC(=O)N2CCC(CCc3cccc(C(=O)N4CC4)c3)CC2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
A DMF (10 ml) suspension of methyl 5-[{(4-[2-(3-{[(2-bromoethyl)amino]carbonyl}phenyl)ethyl]piperidin-1-yl}carbonyl)oxy]nicotinate (750 mg), potassium carbonate (300 mg) and potassium iodide (361 mg) was stirred at 80° C. for 1 hour. The reaction liquid was left cooled, then EtOAc was added thereto, washed with aqueous saturated sodium hydrogencarbonate solution and saturated brine in that order, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform:methanol=20:1 (v/v)) to obtain methyl 5-{[(4-{2-[3-(aziridin-1-ylcarbonyl)phenyl]ethyl}piperidin-1-yl)carbonyl]oxy}nicotinate (630 mg) as a colorless oil.
Reaction SMILES: [OH-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]#[N:14])=[CH:4]1.[CH3:15]I.O>CO>[CH3:15][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]#[N:14])=[CH:4]1
Reactant: CI
Reactant: N#CCc1c[nH]c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1cc(CC#N)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
20 cm3 of 50% aqueous sodium hydroxide solution are added to a mixture of 7.8 g (0.05 mol) of 3-indolylacetonitrile, 14.2 g (0.1 mol) of methyl iodide and 0.83 g of a solution of Triton B in methanol at a rate such that the temperature of the reaction mixture does not exceed 35° C. (approximately 1 h 30 min), and the reaction mixture is then stirred for 3 hours at room temperature; thereafter, 100 cm3, of water are added while cooling and the mixture is extracted with diethyl ether, the ether extract is thereafter washed with water to neutrality, dried over sodium sulphate and then filtered, the ether is evaporated off and the residue is crystallised in a sufficient quantity of pentane; the solid thereby obtained is drained and then dried.
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][C@H:18]([C:25]1[CH:26]=[N:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:19][C:20]([O:22]CC)=[O:21])=[O:16].[Li+].[OH-].Cl>CCO>[N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[C:25]([C@@H:18]([NH:17][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[CH2:6][CH2:7][CH2:8][NH:9][C:10]=3[N:1]=2)[CH2:19][C:20]([OH:22])=[O:21])[CH:26]=1
Reactant: CCOC(=O)C[C@H](NC(=O)CCCCc1ccc2c(n1)NCCC2)c1cnc2ccccc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C[C@H](NC(=O)CCCCc1ccc2c(n1)NCCC2)c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ester 5-8 (145 mg, 0.320 mmol) was dissolved in 1 mL EtOH and treated with 1N LiOH (352 mL, 0.35 mnmol) and stirred at room temperature overnight. The reaction solution was neutralized with 1N HCl (352 mL), evaporated, and purified by chromatography on silica gel (60% 20:1:1 EtOH/NH4OH/H2O--40% EtOAc) to afford 5-9 as a white solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([O:7][C:8]2[C:9]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:10][C:11]([C:18]([OH:20])=[O:19])=[CH:12][C:13]=2[S:14]([NH2:17])(=[O:16])=[O:15])=[CH:5][CH:6]=1.Cl[CH2:27][C:28]([N:30]([CH3:32])[CH3:31])=[O:29].C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[NH2:17][S:14]([C:13]1[CH:12]=[C:11]([CH:10]=[C:9]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[C:8]=1[O:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[C:18]([O:20][CH2:27][C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[O:19])(=[O:16])=[O:15]
Reactant: CN(C)C(=O)CCl
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(N2CCCC2)c1Oc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)COC(=O)c1cc(N2CCCC2)c(Oc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
In a similar manner to Example 11, piretanide can be reacted with 2-chloro-N,N dimethylacetamide, triethylamine and sodium iodide in DMF to yield N,N-dimethylaminocarbonylmethyl 3-aminosulfonyl-4-phenoxy-5-(1-pyrrolidinyl)benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1)[CH3:9].Br[C:36]1[CH:41]=[CH:40][C:39]([CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:38][CH:37]=1>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:46]([O:45][C:43](=[O:44])[CH2:42][C:39]1[CH:40]=[CH:41][C:36]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:33])[C:13]=3[NH:12][C:11]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:34])=[CH:19][CH:20]=2)=[CH:37][CH:38]=1)[CH3:47]
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Reactant: Cc1noc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccccc3Cl)cc2)cc1

Procedure:
Following the procedure described in Example 17, Step 2, {3-methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-isoxazol-4-yl}-carbamic acid 1-(2-chloro-phenyl)-ethyl ester, ethyl 4-bromophenylacetate, and (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) were reacted to provide (4′-{4-[1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 17, Step 3.
Reaction SMILES: [CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[CH2:25]([OH:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>O1CCOCC1>[C:1]([O:33][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCCCCCCO
Reactant: O=CC=Cc1ccccc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=[Si]=O
Agent: [Al+3]
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCCOC(=O)C=Cc1ccccc1
Yield: 86 %

Procedure:
A homogeneous mixture containing cinnamaldehyde (7.5 mmol), DDQ (11.3 mmol), octanol (15 mL) and dioxane (10 mL) is taken in a round bottom flask and catalytic amount of AMBERLYST® 15 (0.1 g) is added to it. The mixture is refluxed for 6 hrs under Dean Stark apparatus. After completion of the reaction (observed by TLC and by GC analysis), the reaction mixture is filtered and washed with ethylacetate (5 ml×2). Concentrate the filtrate under reduced pressure and the crude product thus obtained is loaded on a neutral alumina column and eluted with diethyl ether. Octyl cinnamate (from formula I where X1═H, X2═H, X3═H, X4═H, X5═H, R═C8H17) is isolated in 86% yield. 1H-NMR (CDCl3, 300 MHz) δ7.51 (1H, d), 7.46 (2H, m), 7.26 (3H, m), 6.24 (1H, d), 3.93 (2H, m), 1.43 (2H, m), 1.16 (8H, m), 0.73 (5H, m); 13C-NMR (CDCl3, 75.4 MHz) δ166.5, 144.2, 134.4, 129.9, 128.6, 127.9, 118.2, 66.5, 38.8, 30.4, 28.9, 23.8, 22.9, 13.9, 10.9.
Reaction SMILES: [C:1]1([C@H:7]([N:9]2[CH2:13][CH2:12][C@H:11]([CH2:14][OH:15])[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CN=C1.[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22].O>CN(C)C=O>[Si:25]([O:15][CH2:14][C@H:11]1[CH2:12][CH2:13][N:9]([C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH3:8])[CH2:10]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@H](c1ccccc1)N1CC[C@H](CO)C1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](c1ccccc1)N1CC[C@H](CO[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a solution of {(3S)-1-[(1R)-1-phenylethyl]pyrrolidin-3-yl}methanol (6.62 g, 32 mmol) and imidazole (4.77 g, 70 mmol) in N,N-dimethylformamide (90 ml) was added tert-butyldimethylchlorosilane (5.28 g, 35 mmol) at 0° C. and the resulting mixture was warmed to room temperature. The reaction mixture was stirred overnight and poured into water. Extraction with ethyl acetate was performed. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solution was concentrated and the residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=90/10 to 75/25) to afford (3S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-[(1R)-1-phenylethyl]pyrrolidine (8.81 g, 27.6 mmol, 86%) as a colorless oil.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)[O:25][C:26]=1[CH3:27]>>[CH2:17]([O:16][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:21][C:22]1[N:23]=[C:24]([C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)[O:25][C:26]=1[CH3:27])[CH:11]=[CH:10]2)[C:4]([OH:3])=[O:19])[CH3:18]
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Reactant: Cc1oc(-c2cccs2)nc1CCl
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3cccs3)oc2C)c1)C(=O)O
Yield: 31 %

Procedure:
Starting from rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-chloromethyl-5-methyl-2-thiophen-2-yl-oxazole, the title compound was obtained in 31% yield as a yellow solid. MS: (M+H)+ 411.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23](F)=[CH:22][C:21]=2[O:27][CH2:28][CH2:29][O:30][CH3:31])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].[CH3:33][N:34]1[CH2:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23]([N:37]3[CH2:38][CH2:39][CH2:40][N:34]([CH3:33])[CH2:35][CH2:36]3)=[CH:22][C:21]=2[O:27][CH2:28][CH2:29][O:30][CH3:31])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: COCCOc1cc(F)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Reactant: CN1CCCNCC1
Product: COCCOc1cc(N2CCCN(C)CC2)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1

Procedure:
Prepared from 5-fluoro-2-[4-fluoro-2-(2-methoxyethoxy)-benzoylamino]-N-(5-chloropyridin-2-yl)-benzamide and 1-methyl-hexahydro-1,4-diazepine to afford 91 mg (72%).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:14])[CH2:4][CH2:5][CH2:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13].[B]1OC2C(=CC=CC=2)O1.[OH-].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]([OH:14])[CH2:4][CH2:5][CH2:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13]
Reactant: COCCCCC1=C(Br)C(=O)CCC1
Agent: [B]1Oc2ccccc2O1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COCCCCC1=C(Br)C(O)CCC1
Temperature: -78 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
To a solution of 2-bromo-3-(4-methoxy-butyl)-cyclohex-2-enone (2) (32.0 g, 123 mmol) in dry toluene (480 mL) at −95° C. was added (S)-methyl-oxazaborolidi-none (for making isomer 3) or(R)-methyl-oxazaborolidinone (for making isomer 3″) (1 M solution in toluene; 25 mL, 25 mmol). Catecholborane (1 M solution in toluene; 160 mL, 160 mmol) was added dropwise at −95° C. over a period of 10 hours and the reaction mixture stirred at −78° C. overnight. A 1 M NaOH solution (500 mL) was added and the temperature allowed to rise to room temperature. The organic layer was separated and the aqueous layer extracted with Et2O. The combined organic layers were washed with a 1 M NaOH solution and dried over anhydrous MgSO4. The solvent was removed in vacuo, and the resulting residue purified over silica (isooctane/EtOAc, 8:2) to afford 31.5 g (97% yield) of the desired product as a colorless oil which was characterized as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[Br:16]Br>CC(O)=O>[Br:16][CH:11]1[C:12](=[O:14])[CH2:13][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:9][C:10]1=[O:15]
Reactant: BrBr
Reactant: O=C1CC(=O)CC(c2ccc(Cl)cc2)C1
Solvent: CC(=O)O
Product: O=C1CC(c2ccc(Cl)cc2)CC(=O)C1Br
Yield: 29.3 %

Procedure:
To a stirred solution of 5-(4-chlorophenyl)cyclohexane-1,3-dione (5 g, 22.6 mmol) in AcOH (40 mL) at r.t. was added bromine (3.61 g, 1.15 mL, 22.6 mmol) dropwise. The reaction was then carried out according to Method A to give the title compound (2.0 g, 66%) as a white solid. δH (DMSO-d6) 7.38 (4H, m), 3.41-3.38 (1H, m), 2.97-2.85 (2H, m), 2.67 (2H, dd, J 16.4 and 4.2 Hz), 2.50 (1H, bs).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH2:18])=[CH:4][CH:3]=1.[OH:19][S:20](O)(=[O:22])=[O:21].O=S(=O)=O.N1C=CC=CC=1>O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH2:18])=[CH:4][C:3]=1[S:20]([OH:22])(=[O:21])=[O:19]
Reactant: Nc1ccc(N)c2c1C(=O)c1ccccc1C2=O
Reactant: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: c1ccncc1
Solvent: O
Product: Nc1cc(S(=O)(=O)O)c(N)c2c1C(=O)c1ccccc1C2=O
Temperature: 120 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
60 parts of 1,4-diaminoanthraquinone are added to 228 parts of 25% oleum over one hour and then 20 parts of pyridine are added. The temperature of the reaction mixture is 70°-80° C. and is further raised to 120° C. The reaction mixture is stirred at this temperature for 3 hours, then cooled to 70°-80° C., and 220 parts of water are slowly added dropwise. The resultant thick suspension is filtered at room temperature and the filter cake is washed with 100 parts of 50% sulfuric acid and subsequently dispersed in water. The pH of the aqueous suspension is then adjusted to 7.5 with 35% sodium hydroxide solution, whereupon the 1,4-diaminoanthraquinone-2sulfonic acid goes into solution. The solution is then heated to 85°-90° C. and 40 parts of magnesium sulfate are added. Upon cooling the reaction solution, the 1,4-diaminoanthraquinone-2-sulfonic acid crystallises in the form of the magnesium salt, which is isolated by filtration, washed with a 5% solution of magnesium sulfate and dried, affording 72.4 parts of the magnesium salt of 1,4-diaminoanthraquinone-2-sulfonic acid, corresponding to a yield of 85%. According to chromatographic analysis, the product is homogeneous with a trace of starting material. The Rf value is 0.57, which confirms that this product is identical with that obtained in Example 1.