Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:34]=[C:35]([S:40](Cl)(=[O:42])=[O:41])[CH:36]=[CH:37][C:38]=1[Cl:39]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:35]4[CH:36]=[CH:37][C:38]([Cl:39])=[C:33]([Cl:32])[CH:34]=4)(=[O:42])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(Cl)c(Cl)c4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 3,4-dichloro-benzenesulfonyl chloride. Purity (ELSD, based on MW=630.5)=100%.
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[N:6][C:5]([C:9]#[N:10])=[C:4]([C:11]#[N:12])[N:3]=1.[NH3:13].O>O1CCCC1>[NH2:13][C:7]1[C:2]([Cl:1])=[N:3][C:4]([C:11]#[N:12])=[C:5]([C:9]#[N:10])[N:6]=1
Reactant: N
Reactant: N#Cc1nc(Cl)c(Cl)nc1C#N
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1nc(N)c(Cl)nc1C#N
Reaction time: 1 h
Yield: 93.6 %

Procedure:
5.0 g (0.025 mol) of 2,3-dichloro-5,6-dicyanopyrazine was dissolved in 50 ml of dry tetrahydrofuran, and 6.1 g (0.050 mol) of 28% aqueous ammonia was dropwise added at a temperature of from -15°to 0° C. After completion of the dropwise addition, the mixture was stirred for 1 hour, and the reaction solution was poured into 500 ml of water. The precipitated solid was collected by filtration and recrystallized from a solvent mixture of toluene and ethyl acetate to obtain 4.2 g of slightly yellow crystals (yield: 93.6%, melting point: 205-208° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:13][CH2:14][CH:15]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[F:31])[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>[F:31][C:25]1[C:26]([F:30])=[CH:27][CH:28]=[CH:29][C:24]=1[CH:15]([CH2:14][NH:13][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:3]=1[O:2][CH3:1])[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: CCOC(=O)CCCC(CN)c1cccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)CCCC(CNCc1ccc(OC)cc1OC)c1cccc(F)c1F
Reaction time: 0.5 h

Procedure:
2,4-Dimethoxybenzaldehyde was added to a solution of ethyl 6-amino-5-(2,3-difluorophenyl)hexanoate (4.73 g, 17.5 mmol) in methanol (75 mL). Acetic acid was added until the pH of the reaction mixture reached pH 5. After 30 min, sodium cyanoborohydride (1.69 g, 26.9 mmol) was added. After 1 h, the mixture was diluted with ethyl acetate and saturated aqueous sodium carbonate. The mixture was extracted with ethyl acetate and the organic extracts were washed with water, saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography [100% dichloromethane→95% dichloromethane/(10% ammonium hydroxide/methanol)] gave the title compound (7.3 g). MS 422.1 (M+1).
Reaction SMILES: [CH2:1]([N:5]([CH2:13][CH2:14][CH2:15][CH3:16])[C:6]1[S:10][C:9]([CH:11]=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:17]([N:21]1[C:26]([OH:27])=[CH:25][C:24]([CH3:28])=[C:23]([C:29]#[N:30])[C:22]1=[O:31])[CH2:18][CH2:19][CH3:20]>C(OC(=O)C)(=O)C>[CH2:17]([N:21]1[C:26](=[O:27])/[C:25](=[CH:11]/[C:9]2[S:10][C:6]([N:5]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][CH:8]=2)/[C:24]([CH3:28])=[C:23]([C:29]#[N:30])[C:22]1=[O:31])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCN(CCCC)c1ccc(C=O)s1
Reactant: CCCCn1c(O)cc(C)c(C#N)c1=O
Solvent: CC(=O)OC(C)=O
Product: CCCCN1C(=O)C(C#N)=C(C)/C(=C\c2ccc(N(CCCC)CCCC)s2)C1=O

Procedure:
To a 100 ml flask, 3.0 g of 5-(dibutylamino)thiophene-2-carbaldehyde, 2.59 g of 1-butyl-6-hydroxy-4-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile and 10 ml of acetic anhydride are added, followed by heating while refluxing. After completion of the reaction, the resulting material is cooled and the solvent is removed to obtain (E)-1-butyl-5-((5-(dibutylamino)thiophen-2-yl)methylene)-4-methyl-2,6-dioxo-1,2,5,6-tetrahydropyridine-3-carbonitrile in solid phase.
Reaction SMILES: [H-].[Na+].FC(F)(F)C(O)=O.[C:10]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[CH2:10]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(c1ccccc1)c1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(Cc2cccc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Sodium hydride pellets (98% NaH; 3.5 g; 5.3 eq) were added to 50 mL of trifluoroacetic acid at ice-water bath temperature, under nitrogen atmosphere. 1-Benzoylnaphthalene (4.0 g; 17.2 mMol), as prepared above, in 25 mL of methylene chloride, was added dropwise. The mixture was allowed to stir overnight while warming to room temperature. The mixture was poured onto ice, the layers were separated, and the aqueous layer was extracted with methylene chloride. The combined organic extractions were washed with saturated sodium bicarbonate, and brine; then dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to medium pressure chromatography on silica gel, eluting with ethyl acetate:hexane/5:95. The desired product was obtained as a white powder (3.0 g; 80% yield).
Reaction SMILES: [C:1]([C:3]1[C:4](=[C:11]([C:14]#[N:15])[C:12]#[N:13])[O:5][C:6]([CH3:10])([CH3:9])[C:7]=1[CH3:8])#[N:2].[C:16]([SiH2:20][O:21][C:22]([CH3:49])([CH3:48])[CH:23]1[CH2:28][O:27][C:26]2=[C:29]([CH:34]=[CH:35][C:36]3[CH:41]=[CH:40][C:39]([N:42]([CH2:46][CH3:47])[CH2:43][CH2:44][OH:45])=[CH:38][CH:37]=3)[S:30][C:31]([CH:32]=O)=[C:25]2[O:24]1)([CH3:19])([CH3:18])[CH3:17].O>N1CCCCC1.C(Cl)(Cl)Cl>[C:16]([SiH2:20][O:21][C:22]([CH3:48])([CH3:49])[CH:23]1[CH2:28][O:27][C:26]2=[C:29]([CH:34]=[CH:35][C:36]3[CH:37]=[CH:38][C:39]([N:42]([CH2:46][CH3:47])[CH2:43][CH2:44][OH:45])=[CH:40][CH:41]=3)[S:30][C:31]([CH:32]=[CH:8][C:7]3[C:6]([CH3:9])([CH3:10])[O:5][C:4](=[C:11]([C:12]#[N:13])[C:14]#[N:15])[C:3]=3[C:1]#[N:2])=[C:25]2[O:24]1)([CH3:17])([CH3:19])[CH3:18]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Reactant: CCN(CCO)c1ccc(C=Cc2sc(C=O)c3c2OCC(C(C)(C)O[SiH2]C(C)(C)C)O3)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: C1CCNCC1
Product: CCN(CCO)c1ccc(C=Cc2sc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C)c3c2OCC(C(C)(C)O[SiH2]C(C)(C)C)O3)cc1
Reaction time: 2 h
Yield: 31.3 %

Procedure:
15 mL of anyhdrous chloroform was added to 1.99 g (0.010 mol) of 2-(3-cyano-4,5,5-trimethyl-5H-furan-2-ylidene)-malononitrile, and 2.91 g of 4 (0.007 mol). Once in solution, 5 drops of piperidine were added and the reaction mixture was stirred at reflux. The reaction went to completion in 2 h. The crude reaction mixture was poured into water, and an equal amount of chloroform was added. The organic layered was washed three times with water, dried over MgSO4, and filtered. The solvent was removed under reduced pressure. The compound was purified on a silica column with a hexane/ethyl acetate mobile phase to yield 1.5 g of 5 (37.5% yield).
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH:18]=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C.O1CCCC1>[CH2:20]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH2:18][OH:19])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=Cc1c(N(Cc2ccccc2)Cc2ccccc2)cccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: O=[N+]([O-])c1cccc(N(Cc2ccccc2)Cc2ccccc2)c1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
The product from Example 46A (1.5 g, 4.33 mmoles) in ethanol (10 mL) and tetrahydrofuran (4 mL) was treated with sodium borohydride (0.164 g, 4.33 mmoles). After stirring for 30 minutes at room temperature, the mixture was quenched with saturated ammonium chloride and diluted with diethyl ether. The diethyl ether was washed with saturated ammonium chloride, brine, dried with sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 10:1 to 4:1 hexanes:ethyl acetate) to provide the title compound (1.39 g, 92%). MS (ESI+) m/z 348 (M+H)+.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].[CH3:18][O:19][C:20]1[CH:21]=[C:22](I)[CH:23]=[CH:24][CH:25]=1>>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([C:2]#[C:1][C:3]2([CH3:17])[CH2:8][CH2:7][C:6]3[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=3[O:4]2)[CH:23]=[CH:22][CH:21]=1
Reactant: COc1cccc(I)c1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Product: COc1cccc(C#CC2(C)CCc3c(C)c(O)c(C)c(C)c3O2)c1

Procedure:
Reaction of 1.15 g (5 mmol) of rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol and 1.5 ml (12.5 mmol) of 3-methoxy-iodobenzene as described in Example 4 yielded after isolation by chromatography over 60 g of silica gel with methylene chloride and crystallization from ether/hexane 1.05 g (62.5%) of colorless crystals with m.p. 108°-112° C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].ClS(C1C=CC=CC=1C(O)=O)(=O)=[O:16].[OH-].[Na+:28]>O.ClC1C=CC=CC=1>[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([O-:10])=[O:9])([OH:16])(=[O:4])=[O:3].[Na+:28]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: O=C(O)c1ccccc1S(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Solvent: O
Product: O=C([O-])c1cccc(S(=O)(=O)O)c1
Temperature: 100 °C
Yield: 93.3 %

Procedure:
273.6 g of 3-(chlorosulfonyl)benzoic acid containing 28.6% water (corresponding to 195.3 g (0.89 mol) of 100% chlorosulfonylbenzoic acid) are admixed with 50 g of water and 500 g of chlorobenzene and heated in a water separator. A total of 106 ml of water are expelled. After cooling the reaction mixture to 100° C., 108 g (0.89 mol) of 33% strength sodium hydroxide solution are added dropwise over 30 minutes. Subsequently a further 90 ml of water are expelled. After cooling, the precipitated product is filtered off with suction. After drying at 100° C./100 torr (13.16 kPa) 190.4 g of sodium 3-sulfobenzoate are obtained, the purity determined by titration being 97.3%; this corresponds to a yield of 93.3%.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:8]=1)=O.[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][C:35]=2[NH:37][NH2:38])[CH:30]=[CH:29][N:28]=1>>[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][C:35]=2[N:37]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[C:16]([S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=4)[N:8]=3)=[CH:4][CH:3]=[N:38]2)[CH:30]=[CH:29][N:28]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N(C)C)c2)ccc1=O
Reactant: NNc1cccc2ccncc12
Product: CN(C)S(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3cccc4ccncc34)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N,N-dimethyl-benzenesulfonamide (A-12) and isoquinolin-8-yl-hydrazine according to the method described for example 91. MS: M=473.3 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@:9]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][C@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].B1([O-])O[O:27]1.O.O.O.O.[Na+]>O1CCCC1.C(OCC)(=O)C.O>[C:1]([O:5][C:6]([N:8]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[C@:9]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][C@H:10]1[CH2:12][CH2:13][OH:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C[C@@H]1C[C@@]1(C(=O)OCC)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: [O-]B1OO1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@]1(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@H]1CCO
Temperature: -15 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To (1R,2S)-ethyl 1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylate (10 g, 39.2 mmol) and Boc anhydride (22.73 mL, 98 mmol) dissolved in tetrahydrofuran (25 mL) at room temperature was added portionwise DMAP (3.83 g, 31.3 mmol) and the mixture was stirred for 3 h. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with 0.1 N HCl followed by saturated aqueous sodium chloride solution, separated, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The residual oil was purified by flash chromatography on silica gel eluting with a 5-15% ethyl acetate/hexane gradient to provide (1R,2S)-ethyl 1-(bis(tert-butoxycarbonyl)amino)-2-vinylcyclopropanecarboxylate (13.2 g, 37.1 mmol, 95% yield) as a clear oil. MS (ESI): m/z=378.0 [M+Na]. To a solution of (1R,2S)-ethyl 1-(bis(tert-butoxycarbonyl)amino)-2-vinylcyclopropane carboxylate (13.2 g, 37.1 mmol) in tetrahydrofuran (50 mL) at -15° C. was added dropwise 1 N borane tetrahydrofuran complex (74.3 mL, 74.3 mmol) and the mixture was stirred for 2 h at −15° C. To the resulting mixture stirring at 0° C. was added dropwise water (100 mL) followed by sodium perborate tetrahydrate (11.43 g, 74.3 mmol), and the mixture was stirred for 16 hr at rt. The reaction mixture was diluted with ethyl acetate and water, and the resulting organic layer was washed with saturated aqueous sodium chloride solution, separated, dried over anhydrous magnesium sulfate, filtered, and the solvent evaporated under reduced pressure. The residue was purified via flash chromatography on silica gel (10-20% acetone/hex). The resulting impure material was repurified by flash chromatography on silica gel (eluting with a 25%-50% ethyl acetate/hexane gradient) to give (1R,2S)-ethyl 1-(bis(tert-butoxycarbonyl)amino)-2-(2-hydroxyethyl)cyclopropanecarboxylate (9.15 g, 24.50 mmol, 66.0% yield) as an oil. MS (ESI): m/z=396.0 [M+Na].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:19])[CH2:15][C:16]([OH:18])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:21]1([CH2:27][CH2:28][CH2:29][CH:30]([NH2:40])[CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:34]1([CH2:33][CH2:32][CH2:31][CH:30]([NH:40][C:16](=[O:18])[CH2:15][C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:19])[CH2:29][CH2:28][CH2:27][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CC(=O)O)CC1
Reactant: NC(CCCc1ccccc1)CCCc1ccccc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CC(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-3-oxopropionic acid (36) (1.20 g; 4.41 mmol) is dissolved in methylene chloride (40 mL) at ambient temperature. 1,7-Diphenyl-4-aminoheptane hydrochloride (1) (1.61 g; 5.29 mmol), N,N-diisopropylethylamine (1.82 g; 14.1 mmol) and PyBOP (2.75 g; 5.29 mmol) are added sequentially. The reaction is stirred for 14 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography (40%<70% ethyl acetate in hexanes) affording the desired product as a solid. ESMS: MH+ 522.4
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][CH2:2]1.[CH3:15][NH:16][C:17]([N:19]1[C:27]2[C:22](=[CH:23][C:24]([O:28][C:29]3[CH:34]=[CH:33][N:32]=[C:31]([N:35](C(OC4C=CC=CC=4)=O)[C:36](=O)[O:37]C4C=CC=CC=4)[CH:30]=3)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1)=[O:18]>CN(C)C=O>[CH3:15][NH:16][C:17]([N:19]1[C:27]2[C:22](=[CH:23][C:24]([O:28][C:29]3[CH:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]([N:1]4[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][CH2:2]4)=[O:37])[CH:30]=3)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1)=[O:18]
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N(C(=O)Oc4ccccc4)C(=O)Oc4ccccc4)c3)ccc21
Reactant: CCOC(=O)CCCC1CCNCC1
Solvent: CN(C)C=O
Product: CCOC(=O)CCCC1CCN(C(=O)Nc2cc(Oc3ccc4c(ccn4C(=O)NC)c3)ccn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
Ethyl 4-(piperidin-4-yl)butyrate (650 mg, 2.0 mmol, Production example 43-2) was suspended in N,N-dimethylformamide (3.35 ml); phenyl N-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (350 mg, 0.67 mmol, Production example 5-2) was added; and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300, hexane-ethyl acetate-methanol system) to yield the title compound (271 mg, 0.54 mmol, 80%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][C@H:16]2[C@H:13]([CH2:14][NH:15]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:20](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][C@H:16]2[C@H:13]([CH2:14][N:15]2[CH3:20])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C(OCc1ccccc1)N1C[C@H]2CN[C@H]2C1
Agent: C=O
Agent: [Na+]
Solvent: O
Product: CN1C[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]21
Temperature: 25 °C
Yield: 90.4 %

Procedure:
To a solution of (1R,5R)-3,6-diazabicyclo[3.2.0]heptane-3-carboxylic acid benzyl ester (14.2 g, 61.2 mmol; prepared according to patent WO 2001081347) and aqueous formaldehyde (38%, 100 mL, 1.38 mol; Fisher) in water (100 mL) was added sodium triacetoxyborohydride (25.8 g, 122 mmol; Aldrich). The mixture was stirred at room temperature until the reaction was complete according to HPLC analysis. The mixture was extracted with chloroform (3×100 mL) and the organic phase was washed with brine (100 mL) and concentrated under reduced pressure to afford the title compound (13.6 g, 55.3 mmol; 90% yield): 1H NMR (300 MHz, CD3OD) δ ppm 7.26-7.42 (5H, m), 5.15 (2H, s), 3.85 (1H, dd, J=7, 4 Hz), 3.69-3.79 (1H, m), 3.42-3.55 (1H, m), 3.13-3.25 (4H, m), 2.98-3.09 (1H, m), 2.32 (3H, s); MS (DCl/NH3) m/z 247 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>ClCCl>[CH2:18]([O:17][C:15]([N:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1CSCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCSCC1
Temperature: 25 °C
Yield: 4.2 %

Procedure:
To a solution of thiomorpholine (5 g, 1 mol. equiv.) and triethylamine (5.4 g, 1.1 mol. equiv.) in dichloromethane (200 ml) at 0° C. under nitrogen was slowly added benzyl chloroformate (8.68 g, 1.05 mol. equiv.) over fifteen minutes. The reaction was then allowed to warm to room temperature and stirred for a further sixteen hours. The reaction was washed with a saturated aqueous sodium bicarbonate solution. The organic layer was dried using magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane to give the title compound (10 g). TLC=Rf 0.3 (silica, dichloromethane). Found: C, 59.24; H, 6.49; N, 5.78. C12H15NO2S requires C, 59.12; H, 6.23: N, 5.70%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19]Cl)[C:10]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][N:32]2[CH2:33][CH2:34][N:29]([C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:30][CH2:31]2)[C:10]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(CCl)nc2ccccc2c1OCc1ccccc1
Reactant: CCCCCC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCC(=O)N1CCN(Cc2nc3ccccc3c(OCc3ccccc3)c2C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
A mixture of 4-(benzyloxy)-2-(chloromethyl)-3-methylquinoline (200 mg), 1-hexanoylpiperazin (130 mg), potassium carbonate (111 mg), and DMF (6 mL) was stirred at room temperature for 2 hours. Water (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (50 mL). The organic layer was washed sequentially with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/1) to obtain 4-(benzyloxy)-2-[(4-hexanoylpiperazin-1-yl)methyl]-3-methylquinoline (241 mg).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:15]2[N:19]=[CH:18][N:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[N:16]=2)=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:6]=1.C([Sn](CCCC)(CCCC)[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1)CCC.[Cl-].[Li+]>O1CCOCC1.[Cu]I.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>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:5]2[N:6]=[C:2]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[S:3][C:4]=2[C:15]2[N:19]=[CH:18][N:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[N:16]=2)=[CH:9][CH:10]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: Clc1ccc(Cc2nc(Br)sc2-c2ncn(C3CCCCO3)n2)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: Clc1ccc(Cc2nc(-c3ccncc3)sc2-c2ncn(C3CCCCO3)n2)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 150.3 %

Procedure:
To a 20 mL vial was added a solution of 3-[2-bromo-4-(4-chlorobenzyl)-1,3-thiazol-5-yl]-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole (0.1500 g, 0.3411 mmol) and 4-(tributylstannyl)pyridine (0.2511 g, 0.6822 mmol) in anhydrous 1,4-dioxane (5.000 mL). The solution was degassed for 10 minutes. Lithium chloride (0.108 g, 2.56 mmol) and copper (I) iodide (0.0487 g, 0.256 mmol) were added followed by tetrakis(triphenylphosphine)palladium(0) (0.0492 g, 0.0426 mmol). The reaction mixture was heated to 90° C. and allowed to stir for 18 h. The reaction was cooled to ambient temperature and quenched by the addition of a saturated aqueous solution of sodium bicarbonate (10 mL). The quench mixture was extracted with EtOAc (10 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography on silica (gradient DCM to 10% MeOH over 30 min) to afford the product (0.2245 g, 73%) as a yellow solid. LC/MS (AA) ES+ 438. 1H NMR (400 MHz, d6-DMSO) δ: 8.92 (s, 1H), 7.90 (d, J=4.8 Hz, 2H), 7.65 (d, J=1.2 Hz, 2H), 7.38-7.32 (m, 4H), 5.66 (dd, J=9.6, 2.8 Hz, 1H), 4.65 (s, 2H), 3.97-3.94 (m, 1H), 3.72-3.66 (m, 1H), 1.59-1.48 (m, 2H), 1.32-1.23 (m, 2H), 1.10-1.06 (m, 2H).