Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.CS(O)(=O)=O>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]2[N:9]=[CH:8][N:7]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][O:12]3)[C:6]=2[CH:10]=1
Reactant: Cc1cc(Br)cc2[nH]cnc12
Reactant: C1=COCCC1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(Br)cc2c1ncn2C1CCCCO1
Temperature: 75 °C
Yield: 92.5 %

Procedure:
6-Bromo-4-methyl-1H-benzo[d]imidazole (1.02 g, 4.83 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature with stirring under nitrogen. 3,4-Dihydro-2H-pyran (3.5 mL, 38.4 mmol) and methanesulfonic acid (0.032 mL, 0.48 mmol) were added and the resulting mixture heated at 75° C. for 49 h. The resulting mixture was cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Flash chromatography (50-100% ethyl acetate in hexanes) gave the desired product (1.32 g, 4.47 mmol, 93% yield) as a light yellow solid. MS (ESI) m/z 295.1 [M]+, 297.3 [M+2]+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[CH2:27]([NH2:30])[CH:28]=[CH2:29]>C(#N)C>[CH3:26][S:23]([C:17]1[CH:16]=[C:15]2[C:20]([CH2:21][CH2:22][CH:13]([CH2:12][NH:30][CH2:27][CH:28]=[CH2:29])[O:14]2)=[CH:19][CH:18]=1)(=[O:24])=[O:25]
Reactant: C=CCN
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: C=CCNCC1CCc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 25: [7-(methylsulfonyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), prop-2-en-1-amine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 281 (M+, 6), 131 (8), 77 (6), 71 (5), 70 (bp).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.[CH3:17][NH:18][CH3:19]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][C:3]=1[C:4]([N:18]([CH3:19])[CH3:17])=[O:5]
Reactant: CNC
Reactant: O=Cc1ccc(F)c(C(=O)O)c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(C=O)ccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
The solution of 2-fluoro-5-formylbenzoic acid (3 g, 17.8 mmol) in methylene chloride (10 mL) was added thionyl chloride (2.0 mL, 26.7 mmol) slowly at 0° C. Then the cold reaction mixture was heated to reflux for 3 h. The solution was cooled to 0° C., added dimethylamine (40 wt. % solution in water, 5 mL) slowly, and then stirred at room temperature for 1 h. The solution was washed with water and brine, the organic layer was dried with Na2SO4 and the solvent was removed to get the desired product (2.4 g, yield 76%). LC-MS (ESI) m/z: 196 (M+1)+
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11](Cl)=[O:12].[CH2:14]([O:16][CH:17]([O:30][CH2:31][CH3:32])[CH2:18][CH2:19][CH2:20][NH:21]C(C1CCCCC1)=O)[CH3:15]>>[CH2:31]([O:30][CH:17]([O:16][CH2:14][CH3:15])[CH2:18][CH2:19][CH2:20][NH:21][C:11]([CH:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)=[O:12])[CH3:32]
Reactant: O=C(Cl)C1CCc2ccccc2C1
Reactant: CCOC(CCCNC(=O)C1CCCCC1)OCC
Product: CCOC(CCCNC(=O)C1CCc2ccccc2C1)OCC

Procedure:
1,2,3,4-Tetrahydro-naphthalene-2-carboxylic acid (4,4-diethoxy-butyl)-amide (23B) is prepared from 23A as described for 20A.
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:31][CH3:32])=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29]Cl)=[CH:23][CH:22]=3)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:7][C:5]=2[CH:6]=1.[CH3:33][NH2:34]>CO>[Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8](/[C:11](/[CH2:31][CH3:32])=[C:12](\[C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][NH:34][CH3:33])=[CH:23][CH:22]=3)/[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:7][C:5]=2[CH:6]=1
Reactant: CN
Reactant: CCC(=C(c1ccc(OC)cc1)c1ccc(OCCCl)cc1)c1ccc2oc(Cl)cc2c1
Solvent: CO
Product: CC/C(=C(\c1ccc(OC)cc1)c1ccc(OCCNC)cc1)c1ccc2oc(Cl)cc2c1

Procedure:
According to the same procedure as example 1, step E described, 2-chloro-5-(1-(4-(2-chloroethoxy)phenyl)-1-(4-methoxyphenyl)but-1-en-2-yl)benzofuran (440 mg, 1.0 eq) was reacted with MeNH2 (30% wt in water, 10 mL) in MeOH (20 mL) under reflux to give the desired (Z)-product (Z and E isomer can be separated via column chromatography). 1H NMR (400 MHz, CDCl3) δ 7.24 (d, J=2.0 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.15 (d, J=8.8 Hz, 2H), 7.01 (dd, J=8.4 Hz, 2.0 Hz, 1H), 6.88 (d, J=8.8 Hz, 2H), 6.74 (d, J=8.8 Hz, 2H), 6.51 (d, J=8.8 Hz, 2H), 6.45 (s, 1H), 3.92 (t, J=5.2 Hz, 2H), 3.83 (s, 3H), 2.88 (t, J=5.2 Hz, 2H), 2.50 (q, J=7.6 Hz, 2H), 2.45 (s, 3H), 0.92 (t, J=7.6 Hz, 3H); m/z=462[M+1]+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4](Cl)[N:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:26][C:25]2[CH:24]=[CH:23][C:22]([N:19]3[CH2:18][CH2:17][N:16]([CH3:15])[CH2:21][CH2:20]3)=[CH:28][CH:27]=2)[N:3]=1
Reactant: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1cnc2c(Nc3ccc(N4CCN(C)CC4)cc3)nc(Cl)nc21
Temperature: 78 °C
Yield: 86.4 %

Procedure:
To a reaction vial was added 2,6-dichloro-9-isopropyl-9H-purine (containing 6.3 mmol), 4-(4-methylpiperazin-1-yl)aniline (1.2 g, 6.3 mmol), isopropanol (32 mL, 0.2 M), and TFA (1 mL, 13 mmol). The reaction vial was capped, stirred and heated at 78° C. (block temperature) for 20 hr. The volatiles were removed to give a dark residue. Sat. aq. NaHCO3 (40 mL) was added. There was dark gummy solid precipitated out. Ethyl acetate (2×120 mL) and DCM (2×80 mL) were used to extract product. The combined organic layers were dried over Na2SO4 and evaporated to give a dark residue that was purified on silica with a gradient of 100% ethyl acetate to 10% ammonia (7 N in methanol)-90% ethyl acetate to give the title product as a light yellow solid (2.1 g, 86% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.04 (s, 1 H) 8.38 (s, 1 H) 7.61 (d, J=8.56 Hz, 2 H) 6.93 (d, J=8.93 Hz, 2 H) 4.71 (dt, J=13.39, 6.63 Hz, 1 H) 3.10 (br. s., 4 H) 2.45 (m, J=4.16 Hz, 4 H) 2.22 (s, 3 H) 1.52 (d, J=6.72 Hz, 6 H). m/z (APCI+) for C19H24ClN7 386.2 (M+H)+ with Cl isotope pattern. The regiochemistry of the product was also confirmed by small molecule X-ray crystallography.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[BH4-].[Na+].C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Br:17])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1ccc(Br)cc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cc(Br)ccc1CBr
Yield: 73.4 %

Procedure:
Treat a mixture of 4-bromo-2-(trifluoromethyl)benzaldehyde (6.52 g, 25.8 mmol) and methanol (250 mL) in a 500 mL flask with sodium borohydride (778 mg, 20.6 mmol). Stir the reaction at room temperature for 1 hour then dilute with ethyl acetate (300 mL). Wash with water (2×200 mL) and saturated sodium chloride solution (1×200 mL), then dry over anhydrous magnesium sulfate. After filtering, concentrate the solution under vacuum to dryness. Add dimethylformamide (250 mL) to the residue and cool in an ice bath before treating with carbon tetrabromide (12.78 g, 38.5 mmol) and triphenylphosphine (10.11 g, 38.5 mmol) for 3 hours. Add ethyl acetate (300 mL) and wash with water (2×200 mL) then saturated sodium chloride solution (1×200 mL). Dry over anhydrous magnesium sulfate and concentrate under vacuum. Purify the crude product via silica gel chromatography eluting with hexanes to afford 6.02 g (74%) of the product as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.78 (d, 1H, J=1.9 Hz), 7.68 (dd, 1H, J=1.9 Hz, J=8.3 Hz), 7.47 (d, 1H, J=8.3 Hz), 4.57 (s, 2H).
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Li+].C[CH:13]([N-:15]C(C)C)C.C(P(=O)(OCC)OCC)#N>C1COCC1>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]([C:13]#[N:15])=[CH:2]1
Reactant: CC(C)[N-]C(C)C
Reactant: O=C1CCc2ccccc21
Agent: CCOP(=O)(C#N)OCC
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1=CCc2ccccc21
Temperature: -10 °C
Yield: 829.2 %

Procedure:
A solution of 1-indanone (100 g, 0.756 mole) in 1 L of dry THF was cooled to −10° C. followed by the addition of 38.7 ml of 2M LDA (75.6 mmole). After 20 min of stirring at −10° C. diethyl cyanophosphonate (126.28 ml, 0.8323 moles) was added over 1 hour. The reaction was warmed to room temperature until no indanone was visible by TLC. The reaction was again cooled to −10° C. and borotrifluoride diethyl etherate (191 ml, 1.513 moles) was added dropwise. After warming to room temperature THF was evaporated and the resulting dark oil dissolved in EtOAc, washed with water and dried over MgSO4. Evaporation of the EtOAc and distillation of the resulting oil afforded 88.4908 g of 1H-indene-3-carbonitrile (83% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH:7]([NH2:28])[CH2:8][C:9]1([C:14](=[O:27])[NH:15][C@H:16]2[CH2:21][CH2:20][C@@H:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:37]1([S:43](Cl)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[C:1]([O:5][C:6](=[O:29])[CH:7]([NH:28][S:43]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:45])=[O:44])[CH2:8][C:9]1([C:14](=[O:27])[NH:15][C@H:16]2[CH2:17][CH2:18][C@@H:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20][CH2:21]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(N)C(=O)OC(C)(C)C)CCCC2)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(NS(=O)(=O)c3ccccc3)C(=O)OC(C)(C)C)CCCC2)CC1

Procedure:
2-Amino-3-{1-[(cis-4-ethoxycarbonyl-cyclohexyl)carbamoyl]cyclopentyl}propanoic acid t-butyl ester (0.605 g, 1.48 mmole) was dissolved in dry dichloromethane (25 ml) and treated at 0° C. with triethylamine (0.45 g, 4.4 mmole) and benzene sulphonyl chloride (0.24 ml, 1.84 mmole). After stirring for 16 hours at room temperature under nitrogen the dichloromethane was removed under vacuum, the residue taken up in diethyl ether (25 ml), washed with dilute hydrochloric acid, dilute sodium hydrogen carbonate and water, dried (Na2SO4) and the solvent evaporated under vacuum to give the crude product. Purification by column chromatography on silica, eluting with diethyl etherdichloromethane mixtures, gave pure title compound as a white foam (0.60 g, 74%). Found: C,61.38; H,7.85; N,5.06. C28H42N2O7S requires C,61.06; H,7.69; N,5.09%.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:25][C:26]([NH2:28])=[O:27])[C:14]([Cl:29])=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3].[C:30](OC(=O)C)(=[O:32])[CH3:31].Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:30]([NH:1][CH:2]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:25][C:26]([NH2:28])=[O:27])[C:14]([Cl:29])=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3])(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: CC(N)c1cccc(Nc2ncc(Cl)c(CCc3ccccc3CC(N)=O)n2)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)NC(C)c1cccc(Nc2ncc(Cl)c(CCc3ccccc3CC(N)=O)n2)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 70.4 %

Procedure:
A solution of 2-(2-(2-(2-((3-(1-aminoethyl)phenyl)amino)-5-chloropyrimidin-4-yl)ethyl)phenyl)acetamide (38) (0.045 g, 0.11 mmol) in pyridine (3 mL) containing acetic anhydride (62 μL, 0.66 mmol) and 4-dimethylaminopyridine (2.6 mg, 0.022 mmol) was stirred at room temperature for 22 hours under a nitrogen atmosphere. The mixture was acidified with 1 M hydrochloric acid (30 mL) and extracted with DCM (3×20 mL). The combined organic phases were washed with water, brine, dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was adsorbed onto silica gel and the product was purified by column chromatography (CombiFlash Rf, 4 g SiO2 Cartridge, 0-10% MeOH in DCM) to yield the title compound (39) as a white solid (0.035 g, 70%). LCMS-B: rt 6.20 min; m/z 452 [M+H]+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1COCC1.[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][OH:24].[OH-].[Na+]>O>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH3:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCCOCCO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCCOCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 1.5 h
Yield: 101.7 %

Procedure:
Under ice cooling, a mixture of 515 g of p-toluenesulfonyl chloride and 500 ml of THF was added dropwise to a mixture of 295 g of 2-(2-methoxyethoxy)ethanol, 589 g of 25 wt % NaOH aqueous solution, and 2,500 ml of THF. The reaction solution was aged for 1.5 hours, after which 1,500 ml of water was added to quench the reaction. The organic layer was separated and concentrated in vacuum. The concentrate was dissolved in a mixture of 660 ml toluene and 330 ml hexane, and washed with water. The organic layer was concentrated in vacuum, obtaining 684.74 g of the target compound, 2-(2-methoxyethoxy)ethyl p-toluenesulfonate as oily matter. Yield 97%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:3][CH:4]=1
Reactant: C1CNCCN1
Reactant: Brc1ccc(Br)nc1
Product: Brc1ccc(N2CCNCC2)nc1
Temperature: 25 °C

Procedure:
The pyridine intermediate was prepared by treating a suspension of 5-bromo-2-(piperazin-1-yl)pyridine (7.0 g, 28.9 mmol) with di-tert-butyldicarbonate (6.30 g, 28.9 mmol) and the resulting mixture stirred for 2 h. The solvent was removed under reduced pressure to give the desired product (8.76 g as a beige solid after recrystallisation from aqueous ethanol, m.p. 88-90°. δH (CDCl3) 8.18 (1 H, d, J 2.5 Hz), 7.52 (1H, dd, J 9.0, 2.5 Hz), 6.52 (1H, d, J 9.0 Hz), 3.50 (8H, m) and 1.47 (9H, s). The 5-bromo-2-(piperazin-1-yl)pyridine was prepared by heating a mixture of 2,5-dibromopyridine (10.0 g, 42.4 mmol) and piperazine (7.98g, 92.8 mmol) as a melt at 125° for 3 h. On cooling to room temperature the mixture was triturated with methanol-dichloromethane to afford the desired product (7.0g) as a beige solid. δH (CDCl3) 8.18 (1H, d, J 2.1 Hz), 7.25 (1H, dd, J 9.1, 2.1 Hz), 6.52 (1H, d, J 9.1 Hz), 3.47 (4H, m), 2.97 (4H, m) and 1.75 (1H br s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Cl.[NH2:17][CH2:18][CH:19]([NH:28][S:29]([C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=1)(=[O:31])=[O:30])[C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21]>>[CH:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:40]=[CH:41][C:32]=1[S:29]([NH:28][CH:19]([C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21])[CH2:18][NH:17][C:13]([CH:10]1[CH2:11][CH2:12][N:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:8][CH2:9]1)=[O:14])(=[O:30])=[O:31]
Reactant: NCC(NS(=O)(=O)c1ccc2ccccc2c1)C(=O)N1CCCCC1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Agent: Cl
Product: O=C(NCC(NS(=O)(=O)c1ccc2ccccc2c1)C(=O)N1CCCCC1)C1CCN(c2ccncc2)CC1
Yield: 17 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with 1-[3-amino-2-(2-naphthalenesulphonamido)propionyl]piperidine hydrochloride salt to give N-[2-(2-naphthalenesulphonamido)-2-(piperidinocarbonyl)ethyl]-1-(4-pyridyl)-piperidine-4-carboxamide in 17% yield;
Reaction SMILES: N(OC(C)(C)C)=O.[Br:8][C:9]1[CH:15]=[CH:14][C:12](N)=[C:11]([S:16][CH3:17])[C:10]=1[CH3:18].[CH3:19][S:20]SC>[Cu]>[CH3:18][C:10]1[C:11]([S:16][CH3:17])=[C:12]([S:20][CH3:19])[CH:14]=[CH:15][C:9]=1[Br:8]
Reactant: CSSC
Reactant: CSc1c(N)ccc(Br)c1C
Agent: [Cu]
Agent: CC(C)(C)ON=O
Product: CSc1ccc(Br)c(C)c1SC
Temperature: 50 °C
Reaction time: 4 h

Procedure:
14.8 g (129 mmol) of tert-butyl nitrite and 20 g of copper powder are initially charged in 50 ml of dimethyl disulfide, and a solution of 20 g (86 mol) of 4-bromo-3-methyl-2-methylthioaniline in 100 ml of dimethyl disulfide is added dropwise at 50-55° C. The mixture is then stirred at 50° C. for 4 hours. For work-up, the solid is filtered off with suction and the solution is diluted with methylene chloride and extracted with dilute hydrochloric acid. The organic phase is washed with saturated aqueous NaHCO3 solution, dried over sodium sulfate, filtered off and concentrated using a rotary evaporator. Excess dimethyl disulfide is removed under oil pump vacuum.
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[CH2:3]1.[O-]CC.[Na+].[CH3:21][C:22]([CH:24]=[CH2:25])=[O:23].Cl>C(O)C>[O:23]=[C:22]1[CH2:24][CH2:25][C:3]2[C:4]3[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=3[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2]=2[CH2:21]1
Reactant: O=C1Cc2ccccc2Oc2ccccc21
Reactant: C=CC(C)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C1CCC2=C(C1)c1ccccc1Oc1ccccc12

Procedure:
To a solution of 42 g of the compound 10-keto-10,11-dihydrodibenzo(b,f)-oxepine in 200 ml of dry ethanol a solution of sodiumethoxide (7 g of sodium in 500 ml of ethanol) is added dropwise. After stirring the mixture for 30 minutes 16.2 ml of methylvinylketon in 50 ml of ethanol are added, whereupon the solution is refluxed for 1 hour. The solution is cooled then and poured into 2 N HCl. After extracting into ether, washing the ether layer with water (till neutral) and drying the etherial phase, the solvent is evaporated.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[ClH:10].[CH2:11]([Cl:13])[CH3:12].[OH-].[Na+]>O>[ClH:13].[ClH:10].[ClH:13].[CH2:3]([N:4]([CH2:11][CH3:12])[CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]1)[CH3:2]
Reactant: CCCl
Reactant: OCCN1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)CCN1CCN(CCO)CC1
Reaction time: 18 h
Yield: 51 %

Procedure:
To a stirred solution of 76.0 g (0.58 mol) of 1-(2-hydroxyethyl)piperazine in 200 ml of water was added dropwise 201.0 g (0.58 mol) of a 50% aqueous solution of 2-diethylamino)ethyl chloride hydrochloride. The pH was maintained at 10 by addition of 25% NaOH while the solution was stirred for 18 hours. Water was removed to give a thick oil which was extracted with ethanol. The ethanolic solution was filtered, then the ethanol was removed. The resulting liquid was distilled to give 67.7 g (51%) (b.p. 110°-112° C./0.1 Torr) of the alcohol as a light brown liquid. The trihydrochloride salt was prepared by acidifying the free base to a pH of 1 and removing the water.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17][C:16]2([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.O>[CH3:24][C:16]1([CH3:25])[C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=3)[C:1]#[N:2])[CH:14]=2)[NH:19][C:18](=[O:23])[CH2:17]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CC1(C)CC(=O)Nc2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)Nc2ccc(-c3cccc(C#N)c3)cc21

Procedure:
Prepared by coupling 3-cyanophenylboronic acid with an equivalent amount of 6-bromo-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one using a catalytic amount of tetrakis(triphenylphosphine)palladium(0) as a catalyst with overnight refluxing in toluene containing an equivalent amount of potassium carbonate dissolved in water in the usual manner followed by recrystallization from ethanol gave a grey solid: mp. 190-192° C.; 1H-NMR (DMSO-d6) δ 10.29 (s,1H), 8.17 (s, 1H), 8.00 (d,1H, J=7.9 Hz), 7.77 (d, 1H, J=6.4 Hz), 7.65 (m, 2H), 7.55 (d, 1H, J=8.2 Hz), 6.97 (d, 1H, J=8.3 Hz), 2.40 (s, 2H), 1.30 (s, 6H); MS (APCI (−)) m/z 275 [M−-H]− Anal. Calc. For C18H16N2O 0.25H2O: C, 75.77, H, 6.01, N, 9.82. Found: C, 75.45, H, 5.65, N 9.20.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:30]=[C:31]([CH3:41])[C:32]3[N:36]=[C:35]([CH2:37][O:38][CH3:39])[NH:34][C:33]=3[CH:40]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([O:28][C:29]5[CH:30]=[C:31]([CH3:41])[C:32]6[N:36]=[C:35]([CH2:37][O:38][CH3:39])[NH:34][C:33]=6[CH:40]=5)[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: COCc1nc2c(C)cc(Oc3cc(Cl)ncn3)cc2[nH]1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCc1nc2c(C)cc(Oc3cc(N4CCC(N5CCc6cc(OC)ccc6NC5=O)CC4)ncn3)cc2[nH]1

Procedure:
52 mg (0.19 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 50 mg (0.16 mmol) 6-(6-chloropyrimidin-4-yloxy)-2-(methoxymethyl)-4-methyl-1H-benzo[d]imidazole and 0.07 mL (0.40 mmol) DIPEA in 2.0 mL DMF were stirred at RT over the weekend. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were partially evaporated down i.vac. and neutralised with 4M sodium hydroxide solution. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][C:4]([C:7]2[S:11][C:10]([C:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=3)=[CH:9][CH:8]=2)=[N:3]1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>ClCCl>[Cl:18][CH2:19][C:20]([N:15]1[CH2:14][CH:13]=[C:12]([C:10]2[S:11][C:7]([C:4]3[N:5]=[CH:6][N:2]([CH3:1])[N:3]=3)=[CH:8][CH:9]=2)[CH2:17][CH2:16]1)=[O:21]
Reactant: Cn1cnc(-c2ccc(C3=CCNCC3)s2)n1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Product: Cn1cnc(-c2ccc(C3=CCN(C(=O)CCl)CC3)s2)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a cold (0° C.) solution of 4-[5-(1-methyl-1H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-1,2,3,6-tetrahydro-pyridine (7BW) (1.5 g, 4.72 mmol) in dichloromethane (50 ml) was added TEA (4.5 ml, 28.32 mmol) dropwise. After stirred at 0° C. for 10 min, chloroacetyl chloride (1.12 ml, 14.2 mmol) was added to the reaction mixture. The resulting mixture was stirred at 0° C. for 1 hr., and quenched with water (15.6 ml). The reaction mixture was diluted with dichloromethane (200 ml). The organic layer was separated and washed with brine, dried over MgSO4. Reaction mixture was concentrated to ˜50 ml, ether was added and the solid was filtered out to get the desired product (8BW).