Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[C:13]3[C:9]([CH:10]=[CH:11][N:12]3[CH3:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:16](Cl)(=O)[C:17](Cl)=[O:18].Cl.C([O:26][C:27](=[NH:39])[CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]([CH3:38])[CH:30]=1)(C)C.CCN(CC)CC>C(Cl)Cl>[N:1]1([C:6]2[CH:14]=[C:13]3[C:9]([C:10]([C:16]4[C:17](=[O:18])[NH:26][C:27](=[O:39])[C:28]=4[C:29]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]([CH3:38])[CH:30]=4)=[CH:11][N:12]3[CH3:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cn1ccc2ccc(-n3ccnc3)cc21
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)OC(=N)Cc1cn(C)c2ccccc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(C2=C(c3cn(C)c4cc(-n5ccnc5)ccc34)C(=O)NC2=O)c2ccccc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 33 %

Procedure:
6-Imidazol-1-yl-1-methyl-1H-indole (7.0 g, 35.5 mmol) was dissolved in CH2Cl2 (100 mL) (dried under 3A molecular sieves) at 0° C. A solution of oxalyl chloride in CH2Cl2 (2 M, 35.5 mL, 71 mmol) was added dropwise over 10 min. The mixture was stirred at 0° C. for 1.5 h and evaporated. Ether (100 mL) was added to the solid residue and after the mixture was stirred for 30 min, the resulting yellow solid was filtered off, washed with ether and dried under vacuum for 30 min. 1-Methyl-3-indoleacetimidic acid isopropyl ester hydrochloride (9.6 g, 36 mmol) and CH2Cl2 (200 mL) were added to the yellow solid at 0° C. Et3N (dried over 3A° molecular sieves) (30 mL) was added dropwise over 10 min. The orange-red mixture was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 (300 mL) and washed with aqueous Na2CO3 (2×200 mL). The aqueous layer was back extracted with CH2Cl2 (100 mL). The combined organic extracts were washed with brine, dried (K2CO3) and evaporated. MeOH (100 mL) and concentrated HCl (37%, 10 mL) were added and the mixture was heated at reflux for 2 h. The reaction mixture was cooled, diluted with water (200 mL) and EtOAc (200 mL). The mixture was made basic using solid K2CO3 and extracted with EtOAc (4×200 mL). The combined organic extracts were washed with aqueous Na2CO3 (2×200 mL) brine and dried (K2CO3). The mixture was passed through a pad of silica gel (10×10 cm) and the pad was washed with 10% methanol in EtOAc. Evaporation of the combined eluates gave the crude product as an orange solid. Recrystallization of the crude product using EtOAc, MeOH and CHCI3 gave 3-(6-imidazol-1-yl-1-methyl-1H-indol-3-yl)-4-(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione (5.0 g, 33%) as an orange solid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=O)(C)(C)C.[C:19]([C:27]1[CH:35]=[CH:34][C:30](C(O)=O)=[CH:29][CH:28]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH2:36][CH2:37][CH:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[OH:39]>>[C:19]([C:20]1[CH:21]=[CH:22][C:23]([CH2:6][N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:36][CH2:37][CH:38]([OH:39])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:18])=[CH:24][CH:25]=1)(=[O:26])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:34][CH:35]=1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NCC(O)c1ccccc1
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Product: CON=C1C[C@@H](C(=O)NCC(O)c2ccccc2)N(Cc2ccc(C(=O)c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 4-benzoylbenzoic acid, and (1RS)-2-amino-1-phenylethanol, the title compound was obtained in 93% purity by HPLC. MS(ESI+): m/z=486.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH2:17])[C:14]([N:18]=O)=[C:13]([NH2:20])[N:12]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].S(=O)(=O)(O)O>O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:12]=[C:13]([NH2:20])[C:14]([NH2:18])=[C:15]([NH2:17])[N:16]=1
Reactant: Nc1nc(SCc2cccc(F)c2F)nc(N)c1N=O
Agent: O=S(=O)(O)O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Nc1nc(SCc2cccc(F)c2F)nc(N)c1N
Temperature: 0 °C

Procedure:
To a suspension of the product of example 2, step (b) (2 g) in boiling water (40 ml) was added Na2S2O4 (5.4 g) portion-wise. The suspension was allowed to cool and then 50% sulphuric acid was added slowly and then the mixture was cooled to 0° C. The solid was isolated by filtration and washed with cold water, then dried over P2O5 at 50° C. to give the sub-titled product as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[N+:10]([O-])([OH:12])=[O:11].O>C(O)(=O)C>[OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1ccccc1O
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1cccc([N+](=O)[O-])c1O
Temperature: 25 °C
Yield: 26.3 %

Procedure:
To a solution of 2-hydroxybenzaldehyde (5.0 g, 41 mmol) in acetic acid (50 mL) at 0° C. was added nitric acid (65%, 4 g) dropwise. The reaction mixture was slowly warmed to room temperature for 2 hours and then heated at 40° C. for another 5 hours. The resulting mixture was poured into ice (75 g) and water (500 g). The precipitates were filtrated and purified by silica gel chromatography to afford the product 2-hydroxy-3-nitrobenzaldehyde (1.8 g, yield 26%). 1H NMR (400 MHz, CDCl3) δ ppm 11.44 (s, 1H), 10.42 (s, 1H), 8.34-8.37 (dd, 1H, J=2.0 Hz, 8.4 Hz), 8.10-8.13 (dd, 1H, J=2.0 Hz, 7.6 Hz), 7.12-7.16 (t, 1H, J=8.0 Hz).
Reaction SMILES: C([Mg]Br)C.C(NC(C)C)(C)C.[C:12]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[CH3:13].[CH2:20]([O:27][C:28]1[CH:35]=[C:34]2[C:31]([CH2:32][C:33]2([S:38][C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)[C:36]#[N:37])=[CH:30][C:29]=1[O:46][CH3:47])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)C.O1CCCC1>[C:16]([O:15][C:12](=[O:14])[CH:13]=[C:36]([NH2:37])[C:33]1([S:38][C:39]2[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=2)[CH2:32][C:31]2[C:34]1=[CH:35][C:28]([O:27][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[C:29]([O:46][CH3:47])[CH:30]=2)([CH3:19])([CH3:18])[CH3:17]
Reactant: COc1cc2c(cc1OCc1ccccc1)C(C#N)(Sc1ccc(Cl)cc1)C2
Reactant: CC(=O)OC(C)(C)C
Agent: CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1cc2c(cc1OCc1ccccc1)C(Sc1ccc(Cl)cc1)(C(N)=CC(=O)OC(C)(C)C)C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of ethylmagnesium bromide (3.26 mL of a 3M solution in diethyl ether, 9.8 mmol) in anhydrous tetrahydrofuran (10 mL) at 0° C. under nitrogen is added diisopropylamine (2.75 mL, 19.6 mmol). The mixture is stirred at 0° C. for 1 hour. t-Butyl acetate (0.5 mL, 3.6 mmol) and a solution of 1.0 g (2.45 mmol) of 4-benzyloxy-7-(4-chloro-phenylsulfanyl)-3-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile in anhydrous tetrahydrofuran (10 mL) are added successively, and the resulting mixture is stirred for an additional hour. The reaction is quenched with aqueous ammonium chloride and the product mixture is extracted with ethyl acetate. The ethyl acetate extract is washed with brine, dried over anhydrous sodium sulfate and passed through a plug of silica to give 3-amino-3-[4-benzyloxy-7-(4-chloro-phenylsulfanyl)-3-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-acrylic acid tert-butyl ester as a clear oil, that solidified upon standing, mp 112-115° C.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH:3]=[CH:4][C:5](=[O:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C-]#[C-].[Li+].[Li+].[CH2:17]=[CH:18]N>O1CCOCC1>[CH3:12][N:2]([CH3:1])[CH:3]([CH2:4][C:5](=[O:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:17]#[CH:18]
Reactant: C=CN
Reactant: CCCCCC(=O)C=CN(C)C
Agent: [C-]#[C-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C#CC(CC(=O)CCCCC)N(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 1-(dimethylamino)-1-octen-3-one (4.0 g), described in Example 37, and lithiumacetylide-ethyleneamine (4.0 g) in dry dioxane (25 ml) is stirred at room temperature for 45 min. The mixture is added to ice. The mixture is extracted with ether. The extract is dried (Na2SO4) and then evaporated. The residue is distilled to afford the title compound, b.p. 80°-85° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:27]=1.C(=O)([O-])O.[Na+].[CH:33]1([S:36](Cl)(=[O:38])=[O:37])[CH2:35][CH2:34]1>O1CCCC1>[CH:33]1([S:36]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[C:13]([NH:17][C:18]([C:20]5[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=5)=[O:19])[CH:14]=[CH:15][CH:16]=4)=[CH:6][N:5]3[CH:27]=2)(=[O:38])=[O:37])[CH2:35][CH2:34]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(N)cn3c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(NS(=O)(=O)C4CC4)cn3c2)c1
Temperature: 25 °C
Reaction time: 61 h
Yield: 22.6 %

Procedure:
To N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-3-methylpyridine-2-carboxamide (150 mg, 0.417 mmol), tetrahydrofuran (10 mL) and aqueous sodium hydrogen carbonate solution (5 mL) was added cyclopropanesulfonyl chloride (348 μL, 2.48 mmol), and the mixture was stirred at room temperature for 61 hr. The reaction mixture was concentrated under reduced pressure, diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0%→70% ethyl acetate-hexane) to give the title compound (43.7 mg, 23%) as a pale-yellow solid.
Reaction SMILES: [CH:1]([C:3]([CH3:5])=[O:4])=[CH2:2].C#[N:7].P(=O)(O)(O)O.C[C:14]1[C:15](O)=[C:16](C)[C:17](C)=[C:18]([CH:20]=1)O.B(F)(F)F>C1(C)C=CC=CC=1.C(N(CC)CC)C.[N+](C)([O-])=O>[C:5]([CH:3]1[CH2:1][CH2:2][C:18]2[C:20](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:4]1)#[N:7]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: C=CC(C)=O
Reactant: C#N
Agent: FB(F)F
Agent: O=P(O)(O)O
Solvent: C[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: N#CC1CCc2ccccc2O1
Reaction time: 1.5 h
Yield: 78 %

Procedure:
23.7 g (0.338 mole) of methyl vinyl ketone were added over 5 minutes to a solution of 9.7 g (0.36 mole) of liquid hydrocyanic acid and 34 g of nitromethane whilst stirring, and thereafter 0.5 g of triethylamine was added slowly, first at -20° C. and then at -25° C. The reaction mixture was then kept at -20° C. for 1.5 hours. After acidifying the mixture with 1 g of phosphoric acid, 51.4 g (0.338 mole) of trimethylhydroquinone and 180 g of toluene were added, and 23.0 g (0.338 mole) of BF3 were then passed in over 1.5 hours at -10° C. After stirring for one hour at -5° C., the mixture was brought to room temperature and stirred for 5 hours. Working up by the method described in Example 1 gave pure 2-cyanochromane in 78% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:16]([N:23]1[CH:27]=[N:26][C:25]([NH2:28])=[N:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:23]1[CH:27]=[N:26][C:25]([NH:28][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([CH:9]=2)[C:7]#[N:8])=[N:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Reactant: Nc1ncn(Cc2ccccc2)n1
Product: Cc1cn(-c2ccc(Nc3ncn(Cc4ccccc4)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-benzyl-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a white solid (Yield=25%). MS ISP (m/e): 356.1 (100) [(M+H)+].
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[O:13]([CH2:20][CH2:21][NH2:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH2:23][CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>>[O:13]([CH2:20][CH2:21][NH:22][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[CH:8]=2)[N:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccncc1
Reactant: NCCOc1ccccc1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Product: c1ccc(OCCNc2ccc3cc(NCc4ccncc4)ccc3n2)cc1

Procedure:
The title compound, MS: m/e=371.1 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-phenoxyethylamine and 4-(aminomethyl)pyridine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([Br:15])[CH:11]=[CH:12][CH:13]=2)[C:8]([C:18]2[C:19]([OH:29])=[CH:20][C:21]3[O:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22]=3[CH:28]=2)([CH2:16]O)[C:7]1=[O:30])[CH3:2].C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([Br:15])[CH:11]=[CH:12][CH:13]=2)[C:8]2([CH2:16][O:29][C:19]3[CH:20]=[C:21]4[C:22](=[CH:28][C:18]2=3)[CH2:23][C:24]([CH3:27])([CH3:26])[O:25]4)[C:7]1=[O:30])[CH3:2]
Reactant: CCOC(=O)CN1C(=O)C(CO)(c2cc3c(cc2O)OC(C)(C)C3)c2c(Br)cccc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)CC(C)(C)O4)c2c(Br)cccc21
Yield: 52 %

Procedure:
Following the procedure as described in EXAMPLE 1, and making non-critical variations using ethyl[4-bromo-3-(6-hydroxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained in 52% yield: 1H NMR (300 MHz, CDCl3) δ 7.22-7.10 (m, 2H), 6.70 (d, 1H), 6.48 (s, 1H), 6.30 (s, 1H), 5.0 (d, 1H); 4.86 (d, 1H), 4.63 (d, 1H), 4.35 (d, 1H), 4.28-4.18 (m, 2H), 2.79 (s, 2H), 1.43 (s, 3H), 1.39 (s, 3H), 1.28 (t, 3H); MS (ES+) m/z 472.5 (M+1), 474.5 (M+1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([NH:18][C:19]([CH2:38][OH:39])([CH2:25][CH2:26][CH2:27][CH2:28][B:29]1[O:33][C:32]([CH3:35])([CH3:34])[C:31]([CH3:37])([CH3:36])[O:30]1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16]([NH:18][C:19]([CH:38]=[O:39])([CH2:25][CH2:26][CH2:27][CH2:28][B:29]1[O:30][C:31]([CH3:37])([CH3:36])[C:32]([CH3:35])([CH3:34])[O:33]1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CCOC(=O)C(CO)(CCCCB1OC(C)(C)C(C)(C)O1)NC(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C=O)(CCCCB1OC(C)(C)C(C)(C)O1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.5 %

Procedure:
While under an argon atmosphere, a solution of oxalyl chloride (1.46 g, 0.88 mL, 11.6 mmol) in dichloromethane (15 mL) was cooled to −78° C. and treated with dimethyl sulfoxide (1.8 g, 1.64 mL, 23.2 mmol) and stirred for 10 minutes. To this mixture ethyl 2-(tert-butoxycarbonylamino)-2-(hydroxymethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (2.4 g, 5.78 mmol) in anhydrous dichloromethane (15 mL) was added and the mixture was stirred for 30 minutes. The reaction mixture was quenched by adding triethylamine (3.5 g, 4.8 mL, 34.7 mmol) at −78° C. and slowly warming the reaction mixture to room temperature. The mixture was diluted with dichloromethane (25 mL) and washed successively with water (2×25 mL) and saturated aqueous sodium chloride (25 mL). Organic layer was dried over magnesium sulfate, filtered and evaporated to dryness. The resulting residue was purified using a combiflash system (40 g column, eluted with 20-40% ethyl acetate in heptanes) to give ethyl 2-(tert-butoxycarbonylamino)-2-formyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (1.35 g, 57%). 1HNMR (CDCl3) δ 9.58 (s, 1H), 5.64 (bs, 1H), 4.25 (m, 2H), 2.13 (m, 2H), 1.45 (m, 9H), 1.28 (m, 4H), 1.24 (s, 12H), 0.88 (t, J=6.4 Hz, 3H), 0.77 (t, J=7.9 Hz, 2H). MS found for C20H36BNO7 m/z[436(M+Na)].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][N:13]3[C:21]4[C:16](=[CH:17][C:18]([C:22](O)=[O:23])=[CH:19][CH:20]=4)[C:15]([CH3:25])=[C:14]3[CH3:26])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[Br:29][C:30]1[CH:31]=[C:32]([C@@H:36]([NH2:38])[CH3:37])[CH:33]=[CH:34][CH:35]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[Br:29][C:30]1[CH:31]=[C:32]([C@@H:36]([NH:38][C:22]([C:18]2[CH:17]=[C:16]3[C:21](=[CH:20][CH:19]=2)[N:13]([CH2:12][C:11]2[CH:27]=[CH:28][C:8]([C:5]4([C:3]([O:2][CH3:1])=[O:4])[CH2:7][CH2:6]4)=[CH:9][CH:10]=2)[C:14]([CH3:26])=[C:15]3[CH3:25])=[O:23])[CH3:37])[CH:33]=[CH:34][CH:35]=1
Reactant: COC(=O)C1(c2ccc(Cn3c(C)c(C)c4cc(C(=O)O)ccc43)cc2)CC1
Reactant: C[C@H](N)c1cccc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1(c2ccc(Cn3c(C)c(C)c4cc(C(=O)N[C@@H](C)c5cccc(Br)c5)ccc43)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-(1-(methoxycarbonyl)cyclopropyl)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid (50 mg, 0.13 mmol) in DMF (1 mL) was added (S)-1-(3-bromophenyl)ethylamine (21 μL), DIEA (45 μL) and HATU (54 mg). The reaction mixture was allowed to stir at rt for 30 min, and then was diluted by ethyl acetate. The resulting mixture was washed with a 0.5 N HCl solution, a saturated solution of NaHCO3, and brine, dried on MgSO4, and concentrated to afford a yellow oil (73 mg) which was directly used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[CH3:16]N(C=O)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](C)=[CH:24][C:23]=1[S:29](Cl)(=[O:31])=[O:30]>>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:16])[C:23]=1[S:29]([N:8]1[C:9]2[C:5](=[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])[C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1)(=[O:30])=[O:31]
Reactant: Cc1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: CN(C)C=O
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Product: COc1ccc2c(ccn2S(=O)(=O)c2c(C)cccc2Cl)c1CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 25.5 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 2-chloro-5-methylbenzene-1-sulfonyl chloride (25 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (7 mg, 24%) as a white solid. MS (ESI+) for C19H21ClN2O3S m/z 394 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[CH2:20][CH2:19][C@@:18]3([CH2:24][CH2:23][NH:22][C:21]3=[O:25])[N:17]2C(OC(C)(C)C)=O)=[CH:12][CH:11]=1.C([Cl:36])(C)=O>C(OCC)(=O)C.CO>[ClH:36].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C@@H:16]2[CH2:20][CH2:19][C@@:18]3([CH2:24][CH2:23][NH:22][C:21]3=[O:25])[NH:17]2)=[CH:14][CH:15]=1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1[C@H](c2ccc(OCc3ccccc3F)cc2)CC[C@@]12CCNC2=O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cl
Product: O=C1NCC[C@@]12CC[C@@H](c1ccc(OCc3ccccc3F)cc1)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
To a solution of 1,1-dimethylethyl (2S,5S)-2-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate (D79, 130 mg, 0.295 mmol) in a mixture of ethyl acetate (2.7 ml) and methanol (0.3 ml) at 0° C. was added AcCl (130 μl, 1.82 mmol). The mixture was stirred for 4 hours at room temperature. The solvent was evaporated and the residue was triturated with Et2O to afford the title compound as a white solid (80 mg, 82%); Rt (HPLC) 3.60 min; MS: (ES/+) m/z: 341 [MH+] C20H21FN2O2 requires 340; 1H NMR (500 MHz, DMSO-d6) δ(ppm): 10.37 (br. s, 1H), 8.78 (br. s, 1H), 8.42 (s, 1H), 7.53-7.58 (m, 1H), 7.54 (d, 2H), 7.42 (dd, 1H), 7.25 (t, 1H), 7.23 (t, 1H), 7.10 (d, 2H), 5.13-5.21 (m, 2H), 4.65-4.76 (m, 1H), 3.25-3.33 (m, 2H), 2.48-2.55 (m, 1H), 2.31-2.42 (m, 2H), 2.27-2.34 (m, 2H), 2.04-2.14 (m, 1H).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:15]2[C:16]3[C:21]([CH:22]=[C:23]4[C:28]=2[CH:27]=[CH:26][CH:25]=[CH:24]4)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:2]=1.C1C(=O)N([Br:36])C(=O)C1>C1COCC1>[Br:36][C:22]1[C:21]2[C:16]([C:15]([C:3]3[CH:2]=[CH:1][C:14]4[CH:13]=[CH:12][C:11]5[C:6]([C:5]=4[CH:4]=3)=[CH:7][CH:8]=[CH:9][CH:10]=5)=[C:28]3[C:23]=1[CH:24]=[CH:25][CH:26]=[CH:27]3)=[CH:17][CH:18]=[CH:19][CH:20]=2
Reactant: c1ccc2c(-c3ccc4ccc5ccccc5c4c3)c3ccccc3cc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: Brc1c2ccccc2c(-c2ccc3ccc4ccccc4c3c2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
30 g (80 mmol) of 9-phenanthren-3-ylanthracene are suspended in 300 ml of THF, 14.2 g (80 mmol) of NBS are added, and the mixture is stirred at RT for 2 h with exclusion of light. The solvent is subsequently removed in vacuo, and the residue is boiled in EtOH and recrystallised twice from dioxane, leaving 32.9 g (95%) of bromide as yellow crystals.
Reaction SMILES: [CH3:1]/[C:2](/[NH2:6])=[CH:3]\[C:4]#[N:5].[Cl:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)N.C(O)(=O)C>O>[Cl:7][C:8]1[CH:14]=[C:13]([NH:6][C:2]([CH3:1])=[CH:3][C:4]#[N:5])[CH:12]=[CH:10][CH:9]=1
Reactant: C/C(N)=C\C#N
Reactant: Nc1cccc(Cl)c1
Solvent: O
Solvent: CC(=O)O
Product: CC(=CC#N)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Aminocrotonitrile (5.0 g, 60.9 mmol), 3-chloroaniline (8.55 g, 66.99 mmol) and acetic acid (6.22 g, 103.5 mmol) are dissolved in water (20 ml). The reaction mixture is stirred at room temperature for 60 minutes and the precipitate is isolated.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:10].[CH3:11][C:12](OC(C)=O)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:11]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:10])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: NCCCCCCCCN
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCNCCCCCCCCN
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Ten mmole of 1,8 diaminooctane is dissolved in 50 ml of pyridine. Five mmole of Ac2O is added to the solution dropwise at 10° C. The organic solvent is then evaporated. Using column chromatography, N-monoacetoamide-1,8-diaminooctane subsequently is separated out. The N-monoacetoamide-1,8-diaminooctane is dissolved in 25 ml 1,2-dichloroethane. To this solution, 6 mmole of LiAlH4 is added. The solution is then stirred under nitrogen gas at room temperature for 1 day. Subsequently, the solution is diluted with 100 ml of ethyl acetate. The resulting solution is washed with 20 ml of saturated sodium chloride solution. The solution is dried over MgSO4 and evaporated to produce a residue of N-monoethyl-1,8-diaminooctane. The obtained N-monoethyl-1,8-diaminooctane is dissolved in 80 ml of 1,2-dichloroethane containing about 15 mmole of 2-methyl-5-nitro-imidazolyl-1-yl-acetaldehyde. This reaction mixture is stirred for 30 minutes and then acidified with 15 mmole of acetic acid. Eighteen mmole of sodium triacetoxyborohydride is added as a reducing agent and the solution is stirred for 48 hours at room temperature. The resulting mixture is diluted with 80 ml of ethyl acetate, and the mixture solution is washed with 100 ml of saturated aqueous NaHCO3 and 50 ml of water. The organic layer is dried over anhydrous MgSO4, and the solvent is evaporated to leave residual oil which solidified at 4° C. for 2 days. The obtained solid is recrystallized from ethyl acetate/hexane to give N,N,N′-tri[2′-(2-methyl-5-nitro-1-imidazolyl)ethyl]-N′-ethyl-1,8-octanediamine.