Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:4]2([O:8][CH2:7][CH2:6][O:5]2)[CH2:3][CH:2]1[N:9]1[C:13]([CH3:14])=[C:12](I)[CH:11]=[N:10]1.C1COCC1.C([Mg]Cl)(C)C.CO[B:28]1[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]1.[NH4+].[Cl-]>>[CH2:1]1[C:4]2([O:8][CH2:7][CH2:6][O:5]2)[CH2:3][CH:2]1[N:9]1[C:13]([CH3:14])=[C:12]([B:28]2[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]2)[CH:11]=[N:10]1
Reactant: Cc1c(I)cnn1C1CC2(C1)OCCO2
Reactant: COB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1C1CC2(C1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(5,8-dioxaspiro[3.4]oct-2-yl)-4-iodo-5-methyl-1H-pyrazole (50.0 mg, 0.156 mmol) in THF (3 mL, 40 mmol) at was added 2 M isopropylmagnesium chloride in THF (0.23 mL, 0.46 mmol), and the mixture was stirred at rt for 1 h. The reaction was quenched with 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.10 mL, 0.62 mmol) and allowed to stir at rt for 1 h. Sat. NH4Cl was added, and the organic solvent was removed in vacuo. The material was extracted with DCM and water. The organic layer was concentrated in vacuo to afford the title compound as a white solid. The material was used in the next step without further purification.
Reaction SMILES: [OH-].[K+].[CH2:3]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([C:23]([OH:25])=[O:24])[CH:17]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH3:26]S(C)=O>O>[CH3:26][N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[C:18]([C:23]([OH:25])=[O:24])[CH:17]=2)[CH:22]=[C:14]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCc1cc2ccc(C(=O)O)cc2[nH]1
Reactant: CS(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCc1cc2ccc(C(=O)O)cc2n1C

Procedure:
Potassium hydroxide (9.0 g) was added to a solution of 2-(n-undecyl)indole-6-carboxylic acid (22.1 g) in dimethylsulphoxide (100 ml) and water (5 ml), and the mixture was stirred and warmed on a steam bath to give a suspension. After 15 minutes the suspension was removed from the steam bath, methyl iodide (15 ml) was added, and the mixture was stirred for 2 hours with occasional warming. Methyl iodide (10 ml) was added and the mixture was stirred for 1 hour. The mixture was left to cool overnight and was then poured into water and acidified with 2N hydrochloric acid. The product was collected and washed. This product was then added to a mixture of ethanol (150 ml), water (50 ml), and sodium hydroxide (6.5 g), and the mixture was heated under reflux for 1 hour and then poured into water containing acetic acid (50 ml). The product was twice recrystallised from ethanol to give 1-methyl-2-(n-undecyl)indole-6-carboxylic acid (9.6 g), in the form of a white powder, m.p. 165°-168° C.
Reaction SMILES: C(N=S(C1C=CC(CN2C(=O)C3C(=CC=CC=3)C2=O)=CC=1)(C)=[O:5])#N.[C:25]([N:27]=[S:28]([C:30]1[CH:31]=[CH:32][C:33]([N:36]2[C:44](=[O:45])[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37]2=[O:46])=[N:34][CH:35]=1)[CH3:29])#[N:26]>>[C:25]([N:27]=[S:28]([C:30]1[CH:31]=[CH:32][C:33]([N:36]2[C:44](=[O:45])[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37]2=[O:46])=[N:34][CH:35]=1)([CH3:29])=[O:5])#[N:26]
Reactant: CS(=O)(=NC#N)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Reactant: CS(=NC#N)c1ccc(N2C(=O)c3ccccc3C2=O)nc1
Product: CS(=O)(=NC#N)c1ccc(N2C(=O)c3ccccc3C2=O)nc1

Procedure:
The title compound is prepared in analogy to preparation 6c, substituting 2-(4-(N-cyano-S-methylsulfinimidoyl)benzyl)isoindoline-1,3-dione with 2-(5-(N-cyano-S-methylsulfinimidoyl)pyridin-2-yl)-isoindole-1,3-dione (preparation 16c). ESI mass spectrum: [M+H]+=341; r.t. HPLC: 0.88 min (Z018_S04).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][CH2:11][NH2:12].[CH:13]([CH:15]=O)=O.O>C1(C)C=CC=CC=1>[CH2:11]1[N:12]2[C@@H:7]([C@@H:6]3[N:1]([CH2:13][CH2:15]2)[CH2:2][CH2:3][CH2:4][NH:5]3)[NH:8][CH2:9][CH2:10]1
Reactant: NCCCNCCNCCCN
Reactant: O=CC=O
Solvent: Cc1ccccc1
Solvent: O
Product: C1CN[C@@H]2[C@H]3NCCCN3CCN2C1

Procedure:
A solution of 87.2 g of 1,10-diamino-4,7-diazadecane in 500 ml of toluene was admixed with 72.3 g of a 40% aqueous glyoxal solution, and the mixture was refluxed, with a water separator fitted, for 3 hours. When the solution was cooled, a solid precipitated out which was filtered off with suction, washed three times with 50 ml of toluene each time and dried under reduced pressure. This gave 34.9 g of pale yellow needles.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:24])([CH2:17][C:18]1=[O:23])[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.CCOCC.[C:30]([CH2:32][CH2:33][OH:34])#[N:31].C(=O)(O)[O-].[Na+]>B(F)(F)F.CCOCC.C(OCC)(=O)C>[C:30]([CH2:32][CH2:33][O:34][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:1])#[N:31]
Reactant: N#CCCO
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCCC#N)C[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
2α,3α-Epoxy-5α-pregnane-11,20-dione (2 g), dry ether (50 ml) and 2-cyanoethanol (10 ml.) were sirred at room temperature until the solid had dissolved. Boron trifluoride diethyl etherate (10 drops) was added. After 2 hours at room temperature a further quantity of etherate (10 drops) was added. After 1 hour further etherate (10 drops) was added and after a further hour, the mixture was neutralised with saturated sodium bicarbonate solution, ethyl acetate (50 ml.) added and the organic layer washed with water (3 × 200 ml.). The washed solution was dried over anhydrous sodium sulphate and evaporated to a white foam which was purified by preparative T.L.C. using ethyl acetate. The main band (Rf 0.4) gave the title compound (740 mg;) m.p. 194°-196°C. [α]D + 85° .
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[NH2:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[C:16]([Cl:21])[N:15]=1>CS(C)=O>[Cl:21][C:16]1[CH:17]=[C:18]([O:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[NH:9][CH:8]=[CH:7]3)[N:19]=[C:14]([NH2:13])[N:15]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Oc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1nc(Cl)cc(Oc2ccc3[nH]ccc3c2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 22.1 %

Procedure:
Sodium hydride (1.0 g, 25 mmol) was suspended in dimethyl sulfoxide (40 ml) under nitrogen atmosphere, and 5-hydroxyindole (3.33 g, 25 mmol) was gradually added while the reaction mixture was stirred at room temperature. After 20 minutes, 2-amino-4,6-dichloropyrimidine (3.28 g, 20 mmol) was added. The reaction mixture was heated at 100° C. and was stirred for 3 hours. After the reaction mixture was cooled to room temperature, the reaction mixture was partitioned between ethyl acetate and 10% aqueous ammonia solution. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by NH silica gel column chromatography (eluent; ethyl acetate:hexane=2:1). The crystals were precipitated from ethyl acetate, filtered off, and dried under aeration to yield the title compound (1.15 g, 4.41 mmol, 22.0%) as white crystals.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[CH:7][CH:8]=1)N.C(O)C.[H][H]>[Ni].O>[NH2:1][C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: NNc1ccc(-c2cccc(C(F)(F)F)c2)nn1
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: Nc1ccc(-c2cccc(C(F)(F)F)c2)nn1

Procedure:
Alternatively, 5.0 g of 3-hydrazino-6-[3-(trifluoromethyl)phenyl]pyridazine, 100 ml of ethanol, 10 ml of water and Raney nickel catalyst was shaken with hydrogen under 40 pounds of pressure in a Parr apparatus for 18 hours. The mixture was cooled and filtered and the filtrate concentrated to a gummy soid which was crystallized from dichloromethane-hexane to give 3-amino-6-[3-(trifluoromethyl)phenyl]pyridazine as off-white crystals, mp 138°-139° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH:20]=[C:19]2[C@@H:9]([CH2:10][C:11]3[C:21]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]2=4)[NH:13][CH:12]=3)[N:7]([CH3:8])[CH2:6]1)=[O:4].[N:22]#CBr>ClCCl.CO.ClCCl>[CH3:1][O:2][C:3]([C@@H:5]1[CH:20]=[C:19]2[C@@H:9]([CH2:10][C:11]3[C:21]4[C:14]([NH:13][CH:12]=3)=[CH:15][CH:16]=[CH:17][C:18]=42)[N:7]([C:8]#[N:22])[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1C=C2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Reactant: N#CBr
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@@H]1C=C2c3cccc4[nH]cc(c34)C[C@H]2N(C#N)C1

Procedure:
To a 50 ml round-bottom flask containing a solution of lysergic acid methyl ester (1.0 g, 3.54 mmol) in anhydrous dichloromethane (50 ml) is slowly added cyanogen bromide (2.02 g, 19.11 mmol) and the resulting black-coloured reaction mixture is stirred at room temperature for 4 hours by which time TLC in 10% methanol/dichloromethane showed partial conversion of starting material to give two faster-running products. The reaction mixture is left stirring over the weekend and monitored by TLC showing no change. The reaction mixture is then stirred at 50° C. for 4 hours and is then extracted between tartaric acid and dichloromethane. The aqueous phase is re-extracted with dichloromethane (100 ml) and the combined organic phases washed with brine (200 ml), dried over MgSO4, filtered and concentrated in vacuo to give a dark brown (tar-coloured) oil. Purification is carried out by Normal Phase Flash column chromatography (Biotage Flash 40, 90 g cartridge) using 40% ethyl acetate/hexane to achieve separation of the fast-running product which is isolated as a pale yellow solid. The product is crystallized from tert. Butyl methylether and slowly evaporated. The resulting crystallized material is filtered at the pump to give pale yellow crystals.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH3:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([CH:26]=O)[CH:21]=1.O>O1CCCC1>[CH3:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22](/[CH:26]=[CH:9]/[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH:21]=1
Reactant: Cc1ccnc(C=O)c1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccnc(/C=C/C(=O)OC(C)(C)C)c1
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
A solution of tert-butyl diethylphosphonoacetate (6.2 g, 24 mmol) in tetrahydrofuran (20 ml) was added dropwise to a mixture of sodium hydride (60% in oil, 1.1 g, 26 mmol) and tetrahydrofuran (120 ml) at 0° C., and the mixture was stirred at the same temperature for 30 minutes. Successively, a solution of 4-methyl-2-pyridinecarbaldehyde (1.5 g, 12 mmol) in tetrahydrofuran (30 ml) was added dropwise to the mixture at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was combined with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was subjected to a silica gel column chromatography. The fractions eluted with ethylacetate-hexane (1:5, v/v) were collected and concentrated to give the titled compound (1.9 g, 70%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(Cl)[CH2:11][N:10]([CH:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9]2)=[CH:4][CH:3]=1>[Ni].C(O)(C)(C)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:11][N:10]([CH:12]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2(Cl)CN(C(c3ccccc3)c3ccccc3)C2)cc1
Agent: [Ni]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: Fc1ccc(C2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 80 °C
Yield: 87.5 %

Procedure:
To a stirred suspension of Raney Nickel (2.0 g, wet slurry) in tertiary butanol (10 mL) and toluene (50 mL) was added a solution of 3-(4-fluorophenyl)-3-chloro-1-(diphenylrnethyl)azetidine (16) (1.9 g) in toluene (20 mL). The mixture was heated to 80° C. for 6 hours, cooled and filtered through kieselguhr. The filtrate was concentrated in vacuo and partitioned between diethyl ether (3×30 mL) and aqueous potassium carbonate solution (50 mL). The combined organic extracts were washed (water, brine), dried (Na2SO4), and concentrated in vacuo. Recrystallisation from diisopropyl ether gave 3-(4-fluorophenyl)-1-(diphenylmiethyl)azetidine (17) (1.5 g), m.p. 65-66° C. (diisopropyl ether). Found: C, 83.25; H1 6.35; N, 4.41. C22H20FN requires C, 8325; H, 6.35; N, 4.41%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][Si:11]([CH3:23])([CH3:22])[CH2:12][CH2:13][O:14][CH2:15][N:16]1[CH:20]=[CH:19][C:18]([NH2:21])=[N:17]1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)C.O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:21][C:18]2[CH:19]=[CH:20][N:16]([CH2:15][O:14][CH2:13][CH2:12][Si:11]([CH3:23])([CH3:22])[CH3:10])[N:17]=2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: C[Si](C)(C)CCOCn1ccc(N)n1
Reactant: Cc1cc(Cl)nc(Cl)n1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2ccn(COCC[Si](C)(C)C)n2)nc(Cl)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 405.9 mg of 2,4-dichloro-6-methylpyrimidine, 585.5 mg of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine (WO2006/046734, page 132, Reference 2), 231.9 mg of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, 208.6 mg of tris(dibenzylideneacetone)dipalladium(0)-chloroform complex, 751.2 mg of potassium phosphate and 20 ml of 1,4-dioxane was stirred at 80° C. overnight, followed by cooling to room temperature. The reaction mixture was diluted with ethyl acetate. An insoluble matter was filtered off using Celite, and washed with ethyl acetate. The filtrate was washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=10/1−2/3) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[CH3:27][Si](C)(C)N[Si](C)(C)C.[K].IC.[Cl-].[NH4+]>CN(C=O)C>[CH2:18]([C:17]1[O:16][N:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]=1[C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[O:25][CH3:26])=[N:12][N:11]=1)[CH3:27]
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Agent: [K]
Agent: [NH4+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(F)cc2OC)o1
Reaction time: 1 h
Yield: 1.3 %

Procedure:
To a solution of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (1.00 g, 2.85 mmol) in DMF (10 mL) was added potassium hexamethyldisilazane (0.91 M in tetrahydrofuran, 3.44 mL, 3.13 mmol) at ambient temperature and the resulting mixture was stirred for 1 h. After addition of iodomethane (0.20 mL, 3.13 mmol) the reaction mixture was stirred for 20 h at this temperature. Further potassium hexamethyldisilazane (0.91 M in tetrahydrofuran, 3.44 mL, 3.13 mmol) and iodomethane (0.20 mL, 3.13 mmol) were added and stirring was continued for another 1.5 h. The reaction mixture was poured onto aqueous ammonium chloride (saturated, 50 mL) and was extracted with ethyl acetate. Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 0:80:20) afforded the title compound (14 mg, 1%) as a white solid. MS: m/e=366.1 [M+H]+.
Reaction SMILES: F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)CC)(C)C.[N:34]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([C:44]([OH:46])=O)[CH:42]=2)[CH:37]=[CH:36][CH:35]=1.[CH3:47][O:48][C:49](=[O:58])[C:50]1[CH:55]=[CH:54][C:53]([NH2:56])=[CH:52][C:51]=1[Cl:57]>O1CCCC1>[CH3:47][O:48][C:49](=[O:58])[C:50]1[CH:55]=[CH:54][C:53]([NH:56][C:44]([C:41]2[CH:42]=[C:43]3[C:38]([CH:37]=[CH:36][CH:35]=[N:34]3)=[CH:39][CH:40]=2)=[O:46])=[CH:52][C:51]=1[Cl:57]
Reactant: O=C(O)c1ccc2cccnc2c1
Reactant: COC(=O)c1ccc(N)cc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)c2ccc3cccnc3c2)cc1Cl
Temperature: 25 °C
Yield: 35 %

Procedure:
Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (6.03 g, 12.9 mmol, 1.1 equiv.) and diisopropyl ethyl amine (3.19 g, 12.9 mmol, 1.1 equiv.) were added to a solution of quinoline-7-carboxylic acid (2.03 g, 11.75 mmol) in tetrahydrofuran (100 ml) and the resultant mixture stirred for 10 minutes. 4-Amino-2-chlorobenzoic acid methyl ester (2.40 g, 12.9 mmol, 1.1 equiv.) in tetrahydrofuran (20 ml) was added and the mixture refluxed for 16 hours. Additional Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (1.10 g, 2.36 mmol, 0.2 equiv.) and diisopropyl ethyl amine (0.61 g, 4.7 mmol, 0.4 equiv.) were added and the mixture refluxed for a further 16 hours. The mixture was evaporated then dissolved in isopropanol (100 ml). Water (5 ml) and 60% aqueous perchloric acid (0.5 ml) were added and the mixture was refluxed for 24 hours. The mixture was filtered while hot then left to cool to room temperature whereupon a crystalline solid was formed. The solid was filtered and washed with cold isopropanol (20 ml) and dichloromethane (20 ml) to give 2-chloro-4-[(quinoline-7-carbonyl)-amino]-benzoic acid methyl ester, 1.42 g (35% yield), as a tan solid. LC @215 nm; Rt 1.11: 100%, m/z (ES+): 341 (M+H+.); δH (400 MHz; d6-DMSO) 10.96 (1H, br.s), 9.05 (1H, m), 8.73 (1H, s), 8.49 (1H, d), 8.18-8.10 (3H, m), 7.94 (2H, s), 7.68 (1H, dd), 3.86 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:26](=[CH:27][CH:28]=1)[O:25][C:11]1([CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20]C(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:29].[C:31](Cl)(=O)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:30])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:26](=[CH:27][CH:28]=1)[O:25][C:11]1([CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:20])[CH3:31])[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:29]
Reactant: CC(=O)Cl
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(=O)OC(C)(C)C)CC1)O2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(C)=O)CC1)O2
Temperature: 25 °C
Yield: 98.4 %

Procedure:
A suspension of (±)-(E)-3-[4-oxo-spiro(chromane-2,4′-azepane)-6-yl]acrylic acid methyl ester hydrochloride salt (500 mg, 1.43 mmol, Intermediate 3) in DCM (15 ml) was treated with acetyl chloride (0.121 ml, 1.72 mmol) and DIPEA (0.507 ml, 2.86 mmol) and was stirred at RT for 1. The solution was evaporated under vacuum and the crude product was purified by chromatography column (eluent: DCM/MeOH 95:5) to give (±)-(E)-3-[1′-acetyl-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid methyl ester (503 mg).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br>>[CH3:16][C:13]1([CH3:17])[N:12]([CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[C:20]([C:19]([F:18])([F:28])[F:29])[CH:21]=2)[N:11]([CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[C:14]1=[O:15]
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: FC(F)(F)c1cccc(CBr)c1
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1cccc(C(F)(F)F)c1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 3-(trifluoromethyl)benzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C@H:13]3[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24](O)=[N:25][CH:26]=1>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([O:19][C@@H:16]2[CH2:17][CH2:18][C@H:13]([C:11]([N:8]3[CH2:9][CH2:10][N:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)[CH2:6][CH2:7]3)=[O:12])[CH2:14][CH2:15]2)=[N:25][CH:26]=1
Reactant: Oc1ccc(Cl)cn1
Reactant: O=C([C@H]1CC[C@H](O)CC1)N1CCN(C2CCC2)CC1
Product: O=C([C@H]1CC[C@@H](Oc2ccc(Cl)cn2)CC1)N1CCN(C2CCC2)CC1

Procedure:
According to the procedure described for example 1, the title compound had been synthesized from trans-(4-cyclobutyl-piperazin-1-yl)-(4-hydroxy-cyclohexyl)-methanone and 5-chloro-2-hydroxypyridine. MS (m/e): 378.3 (MH+).
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][N:10](CC3C=CC=CC=3)[CH2:9][CH:8]2[CH2:19][NH2:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].CO>[C:1]1([CH:7]2[CH2:11][NH:10][CH2:9][CH:8]2[CH2:19][NH2:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCC1CN(Cc2ccccc2)CC1c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NCC1CNCC1c1ccccc1
Yield: 86.4 %

Procedure:
A mixture of 4.79 g (0.018 mole) of 4-phenyl-1-(phenylmethyl)-3-pyrrolidinemethanamine, 0.7 g of 20% palladium on carbon, and 250 ml of methanol was shaken in an atmosphere of hydrogen at about 50 psi and at room temperature for 24 hours. The catalyst was filtered and the filtrate evaporated under reduced pressure to give 2.74 g of 4-phenyl-3-pyrrolidinemethanamine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CCN(C2C=CC(O[CH2:41][CH2:42][CH2:43][Cl:44])=CC=2)CC1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:41][CH2:42][CH2:43][Cl:44])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(OCCCCl)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(O)c2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(OCCCCl)c2)CC1

Procedure:
Prepared from 4-(3-hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (D12) using the same method described in Description 9 (D9).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:10]=[C:11]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20])[S:12][CH:13]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[I:27]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[CH2:7]([O:6][P:4]([C:9]1[CH:10]=[C:11]([C:14]2[S:15][C:16]([I:27])=[CH:17][C:18]=2[P:19]([O:21][CH2:22][CH3:23])([O:24][CH2:25][CH3:26])=[O:20])[S:12][CH:13]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(OCC)c1csc(-c2sccc2P(=O)(OCC)OCC)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(OCC)c1csc(-c2sc(I)cc2P(=O)(OCC)OCC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
In a mixed solvent of chloroform and acetic acid at 1:1, 0.0877 g (0.2 mmols) of 4,3′-bis(diethoxyphosphoryl)-[2,2′]-bithiophene was dissolved, to which 0.2250 g (1.0 mmol) of commercially available N-iodosuccinimide was added at room temperature. Thereafter, the reaction mixture was stirred at room temperature for 8 hours. After the reaction, a sodium thiosulfate aqueous solution was added, followed by extraction with chloroform. The organic phase was washed with a 0.2 N sodium hydroxide aqueous solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting crude product was purified with a PTLC plate (developed with ethyl acetate:hexane=2:1) to obtain the specified substance in the form of a yellow solid at a yield of 0.0880 g (yield: 78%). The thus obtained product was used as it is for reaction in Example 12(12).