Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.Cl.Cl.[CH2:10]([N:17]1[CH2:22][CH2:21][C:20]([NH2:26])([C:23](Cl)=[O:24])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N1CCC(N)(C(O)=O)CC1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[OH-].[Na+]>C(Cl)Cl.C(Cl)CCl>[CH3:31][C:32]1[C:33]2[CH:28]=[CH:29][CH:30]=[CH:7][C:6]=2[NH:3][C:23](=[O:24])[C:20]2([CH2:21][CH2:22][N:17]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:18][CH2:19]2)[N:26]=1
Reactant: CCN(CC)CC
Reactant: NC1(C(=O)Cl)CCN(Cc2ccccc2)CC1
Reactant: NC1(C(=O)O)CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC1=NC2(CCN(Cc3ccccc3)CC2)C(=O)Nc2ccccc21

Procedure:
A solution of 12.2 g (0.12 mole) of triethylamine in 100 ml of methylene chloride is added dropwise to a mixture of 5.4 g (0.04 mole) of 2-aminocetophenone and 13.0 g (0.04 mole) of 1-benzyl-4-amino-4-piperidine-carboxylic acid chloride dihydrochloride (prepared from 9.4 g (0.04 mole) of 1-benzyl-4-amino-4-carboxypiperidine by reaction with excess phosphorus-V chloride in methylene chloride at 25° C.) in 400 ml of ethylene chloride at 0° C., while stirring and under an N2 atmosphere, and the mixture is stirred at 0° C. for 1 hour and finally at 25° C. for 2 hours. It is then poured onto ice, the pH is brought to 10 with sodium hydroxide solution and the reaction product is extracted with methylene chloride. For purification, the product is chromatographed on silica gel 60 (Merck), a methylene chloride/methanol mixture (10:1) being used as the eluting agent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][OH:23].CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:21][CH2:22][OH:23])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cc(S(=O)O)ccc1Cl
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(S(=O)(=O)CCO)ccc1Cl

Procedure:
40 g of 4-Chloro-3-nitrobenzenesulfinic acid, 27.8 g of potassium carbonate, 24.8 g of 2-bromoethanol and 200 ml of dimethylformamide were mixed together and reacted at 50° C. for a period of 8 hours. The reaction mixture was then poured into of water and extracted with ethyl acetate. The organic layer was recovered and the solvent was removed by distillation under reduced pressure. The oily residue was refined using silica gel short-column chromatography to obtain an oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[NH2:9][CH2:10][CH2:11][CH2:12][NH2:13]>>[ClH:1].[CH3:8][C:4]1[CH:3]=[C:2]([NH:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH:7]=[CH:6][N:5]=1
Reactant: Cc1cc(Cl)ccn1
Reactant: NCCCN
Product: Cc1cc(NCCCN)ccn1
Product: Cl
Temperature: 180 °C

Procedure:
4-Chloro-2-picoline (441 μl, 4 mmol) was mixed with 1,3-diaminopropane (1.67 ml, 20 mmol) and stirred in a closed vessel at 180° C. under microwave heating for one hour. The solvent was removed under reduced pressure, toluene was added to the residue and the mixture was evaporated to dryness under reduced pressure to yield 1.076 of a solid. MS (APCI) m/z=165.8 [M+H]+.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2([CH3:43])[O:42][CH2:41][CH2:40][NH:39][CH2:38]2)=[CH:33][CH:32]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([N:39]3[CH2:40][CH2:41][O:42][C:37]([C:34]4[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=4)([CH3:43])[CH2:38]3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: CC1(c2ccc(Cl)cc2)CNCCO1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCOC(C)(c4ccc(Cl)cc4)C3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A mixture of (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate, 2-(4-chlorophenyl)-2-methylmorpholine and iPr2NEt (20.1 mg, 0.156 mmol) in DMF was heated at 100° C. for 10 hours. The mixture was evaporated to dryness and separated on CombiFlash, eluting with 0-70% EtOAc/Hex to give title compound. LCMS-ESI+: calc'd for C33H36Cl2N2O4S: 627.2, 629.2 (M+H+); found: 627.3, 629.3 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][CH2:10][OH:11])=[C:4]([F:12])[CH:3]=1.N1C=CC=CC=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>ClCCl.CN(C)C1C=CN=CC=1>[C:19]([O:11][CH2:10][CH2:9][C:5]1[C:4]([F:12])=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[F:8])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: OCCc1c(F)cc(Br)cc1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCCc1c(F)cc(Br)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.9 %

Procedure:
A solution of 2-(4-bromo-2,6-difluorophenyl)ethanol (1.392 mmol) in dichloromethane (2 mL) was treated with pyridine (4.00 mL), acetic anhydride (4.18 mmol), and 4-(dimethylamino)pyridine (0.070 mmol). The reaction was stirred at room temperature for three days. At this point, the reaction contents were concentrated to in vacuo to minimum volume. The material was diluted with water (50 mL) and was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aq sodium bicarbonate, twice with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a beige oil (330 mg, 76% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.95 (s, 3 H) 2.91 (t, J=6.32 Hz, 2 H) 4.18 (t, J=6.44 Hz, 2 H) 7.47 (d, J=7.07 Hz, 2 H).
Reaction SMILES: [OH2:1].[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.O.[CH3:14][C:15]([CH3:17])=[O:16]>C(OCC)C>[C:15]1([O:16][CH2:4]/[CH:3]=[C:2](\[CH3:12])/[CH:7]=[O:1])[C:17]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:2]=[CH:12][CH:14]=1
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)=O
Solvent: CCOCC
Product: C/C(C=O)=C\COc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 11.5 g (E)-4-(bromo-1,1-diethoxy)-2-methyl-2-butene, 13.8 g potassium carbonate and 7.20 g 1-naphthol in 50 ml sieve dried dimethyl formamide is stirred at room temperature under nitrogen for about 64 hours. The reaction mixture is poured into 300 ml distilled water and the mixture stirred for about 30 minutes before being extracted with two 200 ml portions of diethylether. The ether extracts are combined and washed with 200 ml of a 10% aqueous potassium carbonate solution and with 200 ml distilled water and is then treated with magnesium sulfate and activated carbon. Filtration yields a deep red solution which is evaporated to dryness to yield 12.05 g red oil. The oil is dissolved in 60 ml of a 1:5 water-acetone mixture and the solution is stirred at room temperature under nitrogen as 1.5 g p-toluenesulfonic acid monohydrate is added. After about one hour, the acetone is removed on the rotary evaporator and the red oily mixture is treated with 50 ml diethylether and distilled water and the phases separated. The water phase is washed with an additional 50 ml diethylether and the organic phases combined, treated with magnesium sulfate and activated carbon and filtered. The filtrate is evaporated to dryness and yields a red brown oil which gradually solidifies and is dissolved in 80 ml diethylether and the solution is reduced in volume to 40 ml by heating under a stream of nitrogen. Then 10 ml hexanes is added and the solution allowed to cool to room temperature before being placed in a freezer. A yellow solid precipitates and is collected by nitrogen pressure filtration and dried under a stream of nitrogen to yield 2.09 g solid product, m.p. 81.5°-82.5° C. Elemental Analysis. Calculated: C,79.62; H,6.24. Found: C,79.32; H,6.27.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.O.[NH2:11][NH2:12].C1COCC1>C(O)CCC>[NH:11]([C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1)[NH2:12]
Reactant: N#Cc1ccnc(Cl)c1
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCO
Product: N#Cc1ccnc(NN)c1
Temperature: 60 °C
Yield: 18 %

Procedure:
To a solution of 2-chloropyridine-4-carbonitrile (20.0 g, 144 mmol) in 1-butanol (150 mL) was added 1M solution of hydrazine hydrate in THF (303 mL, 303 mmol) dropwise at rt. It was then heated at 60° C. overnight. The mixture was concentrated, and the residue was purified by flash column chromatography (CH2Cl2/MeOH=20/1) to afford the title compound (3.5 g, 18%) as a white solid. [M+H] Calc'd for C6H6N4, 135; Found, 135.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.C1(C)C=CC=CC=1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]1[O:30][CH2:29][CH2:28][O:27]1>O.CN(C=O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:11][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]1[O:27][CH2:28][CH2:29][O:30]1
Reactant: Brc1ccccc1C1OCCO1
Reactant: COc1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cccc(Oc2ccccc2C2OCCO2)c1
Temperature: 80 °C
Yield: 87 %

Procedure:
Potassium hydroxide pellets (35.2 g; 0.63 mol) were dissolved in water (50 ml) and 3-methoxyphenol (78 g; 0.63 mol) was added together with toluene (250 ml). The mixture was heated to and maintained at reflux temperature until water ceased to distil over (a total of 65 ml of water was collected). The mixture was cooled to 80° C. and 2-(2-bromophenyl)-1,3,-dioxolane (120 g; 0.524 mol), DMF (200 ml) and cuprous chloride (0.2 g) were added. The mixture was slowly heated to 150°-155° C. and toluene was distilled off. The mixture was maintained at 150°-155° C. for 6 hours then cooled to 25° C. and water (500 ml) was added. The mixture was filtered and the residue was washed with ether (200 ml ). The filtrate was extracted with ether (3×150 ml). The combined ether extracts were washed with 2N sodium hydroxide solution (2×150 ml), water (4×150 ml) and saturated brine (1×200 ml). After drying and filtration the ether solution on evaporation gave 2-[2-(3-methoxyphenoxy)phenyl]-1,3-dioxolane (124.1 g, 87.1% yield) as an oil.
Reaction SMILES: CO.C([O:10][C:11]1[CH:30]=[CH:29][C:14]([CH:15]([OH:28])[CH2:16][N:17](CC2C=CC=CC=2)[CH:18]([CH3:20])[CH3:19])=[CH:13][C:12]=1[NH:31][C:32](=[O:42])[CH2:33][O:34]CC1C=CC=CC=1)C1C=CC=CC=1.[ClH:43]>C(O)C.[C].[Pd]>[ClH:43].[OH:10][C:11]1[CH:30]=[CH:29][C:14]([CH:15]([OH:28])[CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])=[CH:13][C:12]=1[NH:31][C:32](=[O:42])[CH2:33][OH:34]
Reactant: CC(C)N(Cc1ccccc1)CC(O)c1ccc(OCc2ccccc2)c(NC(=O)COCc2ccccc2)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CC(C)NCC(O)c1ccc(O)c(NC(=O)CO)c1

Procedure:
In 100 ml. of methanol there was dissolved 2.3 g. of 4-benzyloxy-3-benzyloxyacetylamino-α-(N-benzyl-N-isopropylaminomethyl)benzyl alcohol and after adding to the solution 4.3 ml. of 1N hydrogen chloride in ethanol solution and then 0.3 g. of 10% palladium carbon, the catalytic reduction was conducted at normal temperature and pressure. When 300 ml. of hydrogen was absorbed, the reaction was stopped. Thereafter, the catalyst was filtered off and then the solvent was distilled off under reduced pressure to provide a white crystalline material. By crystallizing the crystals from methanol-n-hexane, 600 mg. of 4-hydroxy-3-hydroxyacetylamino-α-(isopropylaminomethyl)benzyl alcohol hydrochloride melting at 188°-190° C was obtained.
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].C(Cl)(=O)C([Cl:16])=O.CN(C=O)C>ClC(Cl)C>[ClH:16].[CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:16])=[O:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)c1cccc(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: CN(C)c1cccc(C(=O)Cl)c1
Product: Cl
Reaction time: 16 h
Yield: 124.3 %

Procedure:
To a solution of 3-(dimethylamino) benzoic acid (5.0 g. 30.0 mmol) in dichloroethane (50 mL) was added oxalyl chloride (5.6 g, 44.6 mmol) drop wise followed by catalytic amount of DMF. The reaction was stirred for 16 h. The excess oxalyl chloride and solvent were removed under reduced pressure. The residue was chased with benzene to give the desired product (6.1 g, 92%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:12]3[O:13][C:14]([CH3:16])=[CH:15][C:11]=3[C:10]([C:17]([OH:19])=[O:18])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:20][O:18][C:17]([C:10]1[C:11]2[CH:15]=[C:14]([CH3:16])[O:13][C:12]=2[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[CH:8][CH:9]=1)=[O:19]
Reactant: Cc1cc2c(C(=O)O)ccc(OC3CCCC3)c2o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1ccc(OC2CCCC2)c2oc(C)cc12
Temperature: 5 °C
Yield: 102.5 %

Procedure:
To a suspension of 7-cyclopentyloxy-2-methylbenzo[b]furan-4-carboxylic acid (40.0 g, 0.153 moles) and potassium carbonate (42.0 g, 0.184) in acetone (400 mL) added dimethyl sulfate (24.0 g, 0.307 moles) and refluxed for 4-5 hrs. acetone (305 mL) was distilled off and reaction mixture was cooled to 5° C., ice cold water (500 mL) was and the solid separated was filtered, washed with water (2×100 mL0 and dried to get off white solid (43.0 g).
Reaction SMILES: [C:1]([C:4]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)=[CH:22][C:5]=1[O:6][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[CH2:8][CH2:9][C:10]([O:12]CC)=[O:11])(=[O:3])[CH3:2].[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH:39]=O.[OH-].[Na+].Cl>C(O)C.O>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH:7]([O:6][C:5]1[CH:22]=[C:23]([O:26][CH2:27][C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)[CH:24]=[CH:25][C:4]=1[C:1](=[O:3])/[CH:2]=[CH:39]/[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=1)[CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: O=Cc1ccccn1
Reactant: CCOC(=O)CCC(Oc1cc(OCc2ccsc2)ccc1C(C)=O)c1ccccc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1C(CCC(=O)O)Oc1cc(OCc2ccsc2)ccc1C(=O)/C=C/c1ccccn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38.8 %

Procedure:
A solution of ethyl (RS)-4-[2-acetyl-5-(3-thienylmethoxy)phenoxy]-4-(2-methylphenyl)-butanoate (0.5 g) in ethanol (5 mL) is treated with pyridine-2-carboxaldehyde (0.12 g) and aqueous sodium hydroxide solution (0.95 g; 33% w/w) and stirred at 25° C. for 90 minutes. The solution is diluted with water and then brought to pH 7 by treatment with hydrochloric acid (2 M), forming a yellow gum. This gum is extracted with ethyl acetate, and the extract is washed with water, dried and evaporated. The resulting residue is subjected to flash chromatography on silica gel, eluting with a mixture of ethyl acetate and pentane (65:35 v/v), followed by trituration with pentane, to give (E)-(RS)-4-(2-methylphenyl)-4-[2-{3-(2-pyridyl) prop-2-enoyl}-5-(3-thienylmethoxy)phenoxy]butanoic acid (0.22 g) in the form of a yellow solid, m.p. 65-70° C. [NMR(CDCl3):- 2.1-2.9 (4H,m),2.4(3H,s),4.9(2H,q),5.6(1H,q), 6.2-7.6(12H),7.7(1H,d,J=16 Hz),7.8(1H,t), 8.0(1H,d,J=16 Hz),8.6(1H,d)].
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=[C:29]([N:36]2[CH2:40][CH2:39][C:38](F)(F)[CH2:37]2)C2N=NNC=2N=1)(C)(C)C.Br.BrCCC1C=CN=CC=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH2:15][C:38]3[CH:37]=[CH:29][N:36]=[CH:40][CH:39]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: Br
Agent: BrCCc1ccncc1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CCc3ccncc3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 4-(2-bromoethyl)pyridine hydrobromide and isolated as brown solid. MS(m/e): 388.3 (MH+).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[S:14]([OH:17])(=O)=[O:15].P(Cl)(Cl)([Cl:20])=O>>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[S:14]([Cl:20])(=[O:17])=[O:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1ccc2oc3ccccc3c2c1
Product: O=S(=O)(Cl)c1ccc2oc3ccccc3c2c1
Yield: 85 %

Procedure:
2-Dibenzofuransulfonic acid (12.8 mmol) was heated at 70° C. with phosphorus oxychloride (1.30 ml, 14.0 mmol) for 2 h. Excess phosphorus oxychloride was removed under reduced pressure. The residue was decomposed with ice water and extracted with ethyl acetate. The extract was washed with 5% sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated to yield 2.9 g crude 2-dibenzofuransulfonyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[ClH:13].[CH3:14][NH:15][CH3:16].[CH2:17]=O>Cl.C(O)C>[ClH:13].[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:14][N:15]([CH3:17])[CH3:16])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: C=O
Reactant: O=C1CCCc2ccc(Br)cc21
Reactant: CNC
Agent: Cl
Solvent: CCO
Product: CN(C)CC1CCc2ccc(Br)cc2C1=O

Procedure:
A mixture of 7-bromo-1-tetralone (4.50 g), dimethylamine hydrochloride (2.50 g), paraformaldehyde (1.0 g), ethanol (6 ml) and concentrated hydrochloric acid (4 drops) was heated under reflux for two hours and cooled. The mixture was diluted with a few ml. of acetone and the solid was filtered off, washed with a little acetone and dried to give 7-bromo-2-dimethylaminomethyl-1-tetralone hydrochloride, m.p. 169°-171°, pure enough for further reaction.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH2:16])=[C:9]2[C:4]=1[CH2:5][CH2:6]N[CH2:8]2.[C:17]([BH3-])#[N:18].[Na+]>CO.O>[Br:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH2:16])=[C:9]2[C:4]=1[CH2:5][CH2:6][N:18]([CH2:17][CH2:5][C:4]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:3]=1)[CH2:8]2
Reactant: [BH3-]C#N
Reactant: Nc1c([N+](=O)[O-])cc(Br)c2c1CNCC2
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1c([N+](=O)[O-])cc(Br)c2c1CN(CCc1ccccc1)CC2
Reaction time: 1 h
Yield: 190.3 %

Procedure:
A solution of the product from Example 5 (1 g, 3.24 mmol) and phenylacetylaldehyde (0.82 ml, 7 mmol) in 2:1 MeOH/H2O (50 mL) was treated with sodium cyanoborohydride (0.56 g, 9 mmol) portionwise under nitrogen and stirred for one hour. The reaction mixture was then cooled under an ice bath and precipitate filtered off. The solids were washed with hexane and oven dried to give the title compound (1.16 g, 95% yield) as an orange solid, mp=120-122° C.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[C:3]=1[CH3:11].C(OC)(OC)OC.[CH2:19]([O:21][C:22](=[O:28])[CH:23]=[C:24]1[CH2:27][CH2:26][CH2:25]1)C>CO.S(=O)(=O)(O)O>[CH3:19][O:21][C:22](=[O:28])[CH2:23][C:24]1([S:1][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[C:3]=2[CH3:11])[CH2:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)C=C1CCC1
Reactant: Cc1cc(S)c(C)c(C)c1O
Agent: O=S(=O)(O)O
Solvent: COC(OC)OC
Solvent: CO
Product: COC(=O)CC1(Sc2cc(C)c(O)c(C)c2C)CCC1
Yield: 71.8 %

Procedure:
4-Mercapto-2,3,6-trimethyl-phenol (1.8 g) was dissolved in anhydrous methanol (30 mL) containing trimethyl orthoformate (2 mL). To this solution was added cyclobutylidene-acetic acid ethyl ester (4.0 g) and then 5 drops of concentrated sulfuric acid. The solution was deoxygenated by bubbling with nitrogen, and was allowed to reflux for 4 days. The mixture was concentrated, washed with NaHCO3 and extracted with ethyl acetate. After concentration in vacuo, the residue was purified by flash chromatography eluted with 10-20% ethyl acetate in hexane to give 2.26 g of [1-(4-Hydroxy-2,3,5-trimethyl-phenylsulfanyl)-cyclobutyl]-acetic acid methyl ester as a white solid.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl.[CH3:14][C:15]1[CH:16]=[C:17]([NH:22]N)[CH:18]=[C:19]([CH3:21])[CH:20]=1.[C:24]([O:29][CH2:30][CH3:31])(=[O:28])[C:25]([CH3:27])=O.O>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:30]([O:29][C:24]([C:25]1[NH:22][C:17]2[C:16]([CH:27]=1)=[C:15]([CH3:14])[CH:20]=[C:19]([CH3:21])[CH:18]=2)=[O:28])[CH3:31]
Reactant: CCOC(=O)C(C)=O
Reactant: Cc1cc(C)cc(NN)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)c1cc2c(C)cc(C)cc2[nH]1
Reaction time: 8 h
Yield: 81.9 %

Procedure:
In a flask fitted with a Dean-Stark trap, p-toluenesulfonic acid monohydrate (132 g, 0.69 mol) in 500 ml of benzene was heated at reflux for 2 hours. A solution of 3,5-dimethylphenylhydrazine hydrochloride (34.5 g, 0.2 mol), ethyl pyruvate (23.2 g, 0.2 mol), and p-toluenesulfonic acid monohydrate (0.85 g, 0.005 mol) in 500 ml of benzene, which had been refluxed for 2 hours with water removed through a Dean-Stark apparatus was then added. The resulting mixture was heated at reflux and stirred overnight. After cooling, the solution was treated with saturated sodium bicarbonate solution and diluted with methylene chloride. The organic portion was washed twice with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by ISCO (hexane/EtOAc, 0-30%, 40 min) to give yellow solids, which was recrystallized from hexane/ethyl acetate (10%) to give colorless needles (35.6 g, 82%). 1H NMR (DMSO-d6, 400 MHz): δ 11.68 (brs, 1H, exchangeable with D2O, NH), 7.12 (s, 1H), 7.05 (s, 1H), 6.71 (s, 1H), 4.33 (q, J=6.8 Hz, 2H), 2.44 (s, 3H), 2.35 (s, 3H), 1.34 (t, J=6.8 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[N:37]1([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[N:37]1([CH:43]2[CH2:48][CH2:47][N:46]([C:13](=[O:14])[CH:12]([NH:16][C:17]([N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[CH2:31][CH2:30][C:29]5[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=5[NH:27][C:26]4=[O:36])[CH2:21][CH2:20]3)=[O:18])[CH2:11][C:5]3[CH:6]=[CH:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:1][CH3:2])[CH:4]=3)[CH2:45][CH2:44]2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: CCc1ccc(CC(NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Product: CCc1ccc(CC(NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc1CC

Procedure:
Prepared analogously to Example 3f) from 3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and [1,4′]-bipiperidinyl.