Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6][CH2:5][CH:4]([C:7](OC)=[O:8])[CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C.CO.[Cl-].[Na+]>C1(C)C=CC=CC=1>[CH:7]([CH:4]1[CH2:5][CH2:6][N:1]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:2][CH2:3]1)=[O:8]
Reactant: COC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 1 h

Procedure:
A solution of 1-benzyl 4-methyl piperidine-1,4-dicarboxylate (10 g) in toluene (100 ml) under nitrogen was cooled to −78° C. DIBAL-H (60.9 ml) was then added dropwise at −78° C. and the mixture was stirred at this temperature for 1 h (TLC control). Because the reaction was incomplete, a further 0.2 eq. of DIBAL-H was added and the mixture was stirred for a further 30 min (TLC control: some educt and the corresponding alcohol were to be detected). Methanol (40 ml), followed by sat. sodium chloride solution (40 ml) were added slowly to the reaction mixture at −78° C. The mixture was filtered over Celite and the solvent was removed in vacuo. The residue was extracted with ethyl acetate (3×75 ml) and the extract was dried (Na2SO4) and concentrated in vacuo. The crude product obtained in this way was purified by column chromatography (silica gel, 20% ethyl acetate/hexane). Yield: 4.3 g (49%)
Reaction SMILES: [CH3:1][O:2][CH:3]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2)[C:4]([NH:6][NH2:7])=[O:5].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH:23]=O>C(O)C.C(O)(=O)C>[CH3:1][O:2][CH:3]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2)[C:4]([NH:6]/[N:7]=[CH:23]/[C:22]1[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:20]([O:19][CH3:18])[CH:21]=1)=[O:5]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: COC(C(=O)NN)c1cccc2ncccc12
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(/C=N/NC(=O)C(OC)c2cccc3ncccc23)cc(OC)c1OC
Temperature: 60 °C
Yield: 74 %

Procedure:
To a mixture of 2-methoxy-2-(quinolin-5-yl)acetohydrazide (0.149 g, 0.65 mmol) and 3,4,5-trimethoxybenzaldehyde (0.138 g, 0.70 mmol) in absolute ethanol (5 mL) was added acetic acid (1 drop). The mixture was heated at 60° C. for 17 hours. After cooling to room temperature, the solid was collected on a Büchner funnel and rinsed with ethanol and diethyl ether then dried in vacuo to give (E)-2-methoxy-2-(quinolin-5-yl)-N′-(3,4,5-trimethoxybenzylidene)acetohydrazide (6-1) as a white powder (0.197 g, 75% yield).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]Cl>C(O)CCC>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: ClCCNCCCl
Reactant: Nc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: Brc1ccc(N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Bromo-aniline (2 g, 1.162 mmol) was taken in dry nBuOH (25 mL) and dry potassium carbonate (4.8 g, 34.8 mmol) was added to it and stirred at rt for 1 h under nitrogen. Bis-(2-chloroethyl) amine hydrochloride 2 (2.49 g, 13.9 mmol) in nBuOH (10 mL) was then added to the mixture through a syringe. The reaction mass was then heated at 100° C. for 12 h. nBuOH was evaporated in vacuo and the residue was extracted with ethyl acetate. Drying of the organic layer with Na2SO4 followed by concentration afforded the crude product that on purification silica gel column (chloroform/methanol) afforded the title compound.
Reaction SMILES: [NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)#[N:31].C(=O)([O-])[O-].[K+].[K+].O>CC1CCCO1>[NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:35]2[CH:36]=[CH:37][C:32]([C:30]#[N:31])=[CH:33][CH:34]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC1CCCO1
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3ccc(C#N)cc3)cc2)C(N)=O)CCOCC1
Temperature: 78 °C
Reaction time: 10 h
Yield: 67.3 %

Procedure:
To a stirred solution of (S)-tert-butyl 4-(1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (produced in step (i), 27 g) in 2-methyltetrahydrofuran (8 rel. vol.) was added 4-cyanophenyl boronic acid (1.1 mol. eq.), potassium carbonate (2 mol. eq.), water (2 rel. vol.) and 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.0065 mol. eq) at room temperature. Reaction mixture was heated to 78° C. and stirred for 10 h under nitrogen. The reaction mixture was cooled to room temperature and passed through a pad of celite. Water was added to the mixture and the layers separated. The organic layer was separated and concentrated to 5 rel. vol. under vacuum. The concentrated organic portion was stirred for 6 h at room temperature and the resulting solid filtered and washed with 2-methyltetrahydrofuran (2 rel. vol.). The solid was dried at 50° C. under vacuum to afford the sub-titled compound (17.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH2:21][N:22]([CH3:24])[CH3:23])=[N:19][N:18]=[C:17]2[CH2:25]O)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].CS(Cl)(=O)=O.[CH:32]1([CH2:35][NH2:36])[CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH2:21][N:22]([CH3:24])[CH3:23])=[N:19][N:18]=[C:17]2[CH2:25][NH:36][CH2:35][CH:32]2[CH2:34][CH2:33]2)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: CN(C)Cc1nnc(CO)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: NCC1CC1
Agent: CS(=O)(=O)Cl
Product: CN(C)Cc1nnc(CNCC2CC2)n1-c1ccc(Cl)cc1C(=O)c1ccccc1

Procedure:
In the manner given in Example 47, 5-chloro-2-[3-(hydroxymethyl)-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-4- yl]benzophenone is treated first with methanesulfonyl chloride followed by (cyclopropylmethyl)amine to give 5-chloro-2-[3-[[(cyclopropylmethyl)amino]methyl]-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: I.[CH:2]12[CH2:13][CH2:12][CH:5]([CH2:6][CH:7]1[C:8]([O:10]C)=[O:9])[CH2:4][NH:3]2.[CH3:14][N:15]1[CH:19]=[C:18]([S:20](Cl)(=[O:22])=[O:21])[N:17]=[CH:16]1>>[CH3:14][N:15]1[CH:19]=[C:18]([S:20]([N:3]2[CH2:4][C@H:5]3[CH2:12][CH2:13][C@@H:2]2[C@H:7]([C:8]([OH:10])=[O:9])[CH2:6]3)(=[O:22])=[O:21])[N:17]=[CH:16]1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: COC(=O)C1CC2CCC1NC2
Agent: I
Product: Cn1cnc(S(=O)(=O)N2C[C@H]3CC[C@@H]2[C@H](C(=O)O)C3)c1

Procedure:
The title compound was synthesized as in Production Example 1, using methyl 2-azabicyclo[2.2.2]octane-6-carboxylate hydroiodide and 1-methyl-1H-imidazole-4-sulfonyl chloride as the raw material.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[H-].[Na+].Br[CH2:24][CH2:25][O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1.O>CN(C)C=O>[Br:1][C:2]1[N:3]([CH2:24][CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2
Reactant: BrCCOC1CCCCO1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CCOC3CCCCO3)c2c1

Procedure:
To a solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (5.00 g, 14.8 mmol) in N,N-dimethylformamide (50 ml) was added sodium hydride (60% in oil, 713 mg, 17.8 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr. 2-(2-Bromoethoxy)tetrahydropyran (2.90 ml, 19.2 mmol) was added to the reaction mixture under ice-cooling, and the mixture m was stirred at room temperature for 4 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give methyl 2-bromo-3-cyclohexyl-1-[2-(tetrahydropyran-2-yloxy)ethyl]-1H-indole-6-carboxylate as a crude product. The obtained crude product was used for Step 2 without purification.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[C:5]([CH:9]([OH:12])[CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.[CH2:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>C1C=CC=CC=1>[OH:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:10][NH:11][C:13]3([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[O:12]2)[CH:6]=[CH:7][CH:8]=1
Reactant: C1CCCCC1
Reactant: NCC(O)c1cccc(O)c1
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Product: Oc1cccc(C2CNC3(CCCCC3)O2)c1

Procedure:
A suspension of 20 g. of 1-(3'-hydroxyphenyl)-2-amino-ethanol hydrochloride in 100 ml. of cyclohexane is heated, while stirring vigorously, in a three-necked flask equipped with a dropping funnel, water separator, and thermometer. Above a temperature of 80° C., up to 100 ml. of benzene are added dropwise in such a manner so that the water of reaction formed together with the benzene is distilled of azeotropically. The temperature of the flask contents is, at the finish, about 130° C. After cooling, the crystalline reaction product is separated off, digested with benzene, and collected on a frit. There is obtained 20.3 g. (71.5% of theory) of 2-(3'-hydroxyphenyl)-1-oxa-4-azospiro[4,5]decane hydrochloride. After recrystallization from isopropanol/ethyl acetate, the product is obtained in the form of colorless crystals with a melting point of 138° - 139° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH3:12])[C:9]#[N:10])=[CH:4][CH:3]=1.[CH2:13](N)[CH2:14][NH2:15]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:9]2[NH:15][CH2:14][CH2:13][N:10]=2)[CH2:11][CH3:12])=[CH:6][CH:7]=1
Reactant: NCCN
Reactant: CCC(C#N)c1ccc(Cl)cc1
Product: CCC(C1=NCCN1)c1ccc(Cl)cc1

Procedure:
rac-2-[1-(4-Chloro-phenyl)-propyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(4-chloro-phenyl)butyronitrile and ethylene diamine in analogy to Example 22: colourless powder; MS (ISP): 223.0 ((M+H)+.).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH2:19]([CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22]1)[CH3:20].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH2:19]([CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]1[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1)[CH3:20]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CCC1Cc2ccccc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCC1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 62 %

Procedure:
(±)-2-[2-(2-Ethyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one is prepared by following the procedure described in example 1c using 0.40 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 0.25 g of 2-ethylindoline [which can be prepared according to patent WO2009065920] and 0.39 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 250 ml of pyridine and 6.5 ml of N,N-dimethylformamide. After purification by chromatography on a 25 g cartridge of 15-40 μm silica, elution being carried out successively with 99/1 then 98/2 and 97/3 v/v dichloromethane/methanol mixtures, at a flow rate of 30 ml/min, 0.35 g of (±)-2-[2-(2-ethyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one is obtained in the form of a white foam, the characteristics of which are the following:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[C:7]([CH:14]=[O:15])=[CH:8][NH:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)=O.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>CO>[CH3:1][O:2][C:3](=[N:17][OH:18])[C:5]1[C:6]2[C:7]([CH:14]=[O:15])=[CH:8][NH:9][C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1cccc2[nH]cc(C=O)c12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=NO)c1cccc2[nH]cc(C=O)c12

Procedure:
A mixture of 3-formyl -4-indolecarboxylic acid methyl ester (2.03 g), described in Example 1, 10 ml of a 5M aqueous solution of hydroxylamine hydrochloride, 10 of 5M aqueous sodium acetate and 20 ml. of methanol is stirred at 45°-55°C for 1 hr. The precipitate is collected and washed with cold water. Recrystallization from methanol-water gives the title compound, mp 178°-179°C.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].Cl.[CH3:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][NH:15][CH2:16]2)=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][N:15]([S:1]([Cl:5])(=[O:3])=[O:2])[CH2:16]2)=[CH:11][CH:10]=1
Reactant: COc1ccc2c(c1)CNCC2
Reactant: O=S(=O)(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CN(S(=O)(=O)Cl)CC2
Reaction time: 1 h

Procedure:
To a stirred, precooled solution (-40° C.) of 0.41 mL of sulfuryl chloride in 10 mL of chloroform was added a mixture of 1.0 g of 7-methoxy-1,2,3,4-tetrahydro-isoquinoline-hydrochloride and 2.1 mL of triethylamine in 25 mL of chloroform at −40° C. Stirring was continued at −30° C. for one hour and additionally at 5° C. for one hour. The mixture was poured on ice, the organic layer extracted with cold water, dried (sodium sulfate) and concentrated. The residue was redissolved in diethyl ether and chromatographed on silica gel (isohexane/ethyl acetate=8/2 v/v) yielding 0.62 g of 7-methoxy-3,4-dihydro-1H-isoquinoline-2-sulfonyl chloride as an oil. EI-MS: 261 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:10])=[CH:4][CH:3]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1>>[Cl:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][N:15]1[CH2:16][CH2:17][O:18][CH:13]([CH2:12][NH:11][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:10])[CH2:14]1
Reactant: O=C(NCC1CNCCO1)Nc1ccc(Cl)cc1
Reactant: Clc1cccc(CBr)c1
Product: O=C(NCC1CN(Cc2cccc(Cl)c2)CCO1)Nc1ccc(Cl)cc1

Procedure:
Example 26 was prepared in an analogous manner to Example 19 using a mixture of Intermediate 9 (0.01 g) and 1-(bromomethyl)-3-chlorobenzene (5.4 μl) to give the title compound (0.0023 g). LC-MS (System A): Rt 2.72 mins, Mass Spectrum m/z 394 [MH+].
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].B.[Na].O>C(O)(C)C>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C=O)cc2)cc1
Agent: B
Agent: [Na]
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCOc1ccc(-c2ccc(CO)cc2)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 94.4 %

Procedure:
4'-Octyloxy-4-formyl-biphenyl (30 g) was suspended in isopropyl alcohol (100 ml), followed by pouring in the resulting suspension, a suspension of sodium boron hydride (1.22 g) in isopropyl alcohol (100 ml), stirring the mixture at 70° C. for 4 hours, adding 6H-HCl (20 ml) and water (10 ml), stirring the mixture at 70° C. for 2 hours, allowing to stand overnight, filtering and collecting the resulting crystals and recrystallizing from ethanol to obtain 4'-octyloxy-4-hydroxymethyl-biphenyl (28.5 g) having a m.p. of 141.6° C. This product (16 g) together with thionyl chloride (12 g) were heated for 6 hours, followed by distilling off excess thionyl chloride and recrystallizing the residue from toluene-heptane to obtain 4'-octyloxy-4-chloromethyl-biphenyl (IIa-8) (14.8 g) having a m.p. of 101° C.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH:31]1(B(O)O)[CH2:34][CH2:33][CH2:32]1.N1C=CC=CC=1>C(Cl)(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:31]1([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:30])[CH2:3][CH2:4]2)=[O:9])[CH2:34][CH2:33][CH2:32]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OB(O)C1CCC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3C2CCC2)CC1
Yield: 14 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), cyclobutylboronic acid (commercially available), copper(II) acetate and pyridine using chloroform as solvent and stirring under reflux for 6 days, to give the desired product as a light brown foam (14%).
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1>C1(C)C(C)=CC=CC=1>[N+:7]([C:6]1[CH:5]=[CH:4][C:3]([O:10][CH2:2][CH:3]([OH:10])[CH2:4][O:10][C:3]2[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=2)=[CH:2][CH:1]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1ccc(OCC(O)COc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
76.5 g (0.55 mole) of p-nitrophenol, 32.3 g (0.25 mole) of glycerol-αα′-dichlorohydrin, and 500 ml of xylene were added to a reaction solution, and the reaction mixtures were heated with stirring under a nitrogen current. After dissolving the solid, 345 g (2.5 moles) of potassium carbonate anhydride was added, and the reaction mixtures were refluxed with stirring for 12 hours. The reacted solution was separated by filtration while it was warm. After cooling, hexane was added to the filtrate. A yellow viscous liquid was obtained. After column purification and drying this liquid, a 55 g-yellow viscous liquid (1,3-bis(4-nitrophenoxy)-2-propyl alcohol) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([OH:23])[CH2:5][N:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1)[NH:7]C(OC(C)(C)C)=O.O1CCOCC1>CC#N.Cl>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([OH:23])[CH2:5][N:6]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([Br:22])=[CH:20][CH:21]=1)[NH2:7]
Reactant: COC(=O)[C@H](O)CN(Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: COC(=O)[C@H](O)CN(N)Cc1ccc(Br)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
(R)-3-[N-(4-Bromobenzyl)-N′-t-butoxycarbonyl-hydrazino]-2-hydroxy-propionic acid methyl ester (1.1 g, 2.8 mmol) was dissolved in MeCN (10 mL) and of 4N HCl in dioxane (6 mL, 20 mmol). The mixture was stirred at room temperature until deprotection was complete (1 hour). The precipitate was filtered and dried to yield the title compound (840 mg) as an HCl salt.
Reaction SMILES: [CH3:1][C:2]1([CH3:41])[CH2:11][C:10]2[N:9]=[C:8]([CH:12]([OH:14])[CH3:13])[C:7]3[C@@H:15]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[O:16][C:17]4([CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:6]=3[C:5]=2[C@@H:4]([O:33][C:34]([CH3:40])([C:36]([CH3:39])([CH3:38])[CH3:37])[CH3:35])[CH2:3]1.[CH3:42]I>O1CCCC1>[CH3:42][O:14][CH:12]([C:8]1[C:7]2[C@@H:15]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=3)[O:16][C:17]3([CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:6]=2[C:5]2[C@@H:4]([O:33][C:34]([CH3:40])([C:36]([CH3:39])([CH3:38])[CH3:37])[CH3:35])[CH2:3][C:2]([CH3:1])([CH3:41])[CH2:11][C:10]=2[N:9]=1)[CH3:13]
Reactant: CC(O)c1nc2c(c3c1[C@@H](c1ccc(C(F)(F)F)cc1)OC31CCOCC1)[C@@H](OC(C)(C)C(C)(C)C)CC(C)(C)C2
Reactant: CI
Solvent: C1CCOC1
Product: COC(C)c1nc2c(c3c1[C@@H](c1ccc(C(F)(F)F)cc1)OC31CCOCC1)[C@@H](OC(C)(C)C(C)(C)C)CC(C)(C)C2
Reaction time: 0.08 h

Procedure:
70 mg 1-((3R,9S)-7,7-Dimethyl-3-(4-(trifluoromethyl)phenyl)-9-(2,3,3-trimethylbutan-2-yloxy)-2′,3′,5′,6,6′,7,8,9-octahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran]-4-yl)ethanol are dissolved in 1.5 ml tetrahydrofurane. 27 mg Potassium-tert.-butylate are added, the mixture is stirred for 5 minutes and the 11 μl methyliodide are added. The mixture is stirred for 20 minutes and then partitioned between 0.1 M hydrochloric acid and dichloromethane. The aqueous phase is extracted with dichloromethane and the combined organic phases are dried with sodium sulphate. The solvents are evaporated in vacuo and the residue is purified by preparative HPLC (Gemini C18, water/methanol/ammonia 90:10:0.1 to 0:100:0.1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:21]([NH:23][C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@@H:27]([O:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:41]([N:44]5[CH2:49][CH2:48][CH2:47][CH2:46][C@@H:45]5[CH3:50])=[N:42][N:43]=4)[CH:40]=3)[CH2:26][CH2:25]2)=[O:22])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18]O)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C[CH2:52][N:53](C(C)C)[CH:54](C)C.CS(Cl)(=O)=O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:21]([NH:23][C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@@H:27]([O:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:41]([N:44]5[CH2:49][CH2:48][CH2:47][CH2:46][C@@H:45]5[CH3:50])=[N:42][N:43]=4)[CH:40]=3)[CH2:26][CH2:25]2)=[O:22])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][N:53]([CH3:54])[CH3:52])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN(C(C)C)C(C)C
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCN(C)C)c4)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
To a solution of Intermediate 186c (293 mg, 0.44 mmol) and DIPEA (304 pit, 1.76 mmol) in DCM (10 mL) was added methanesulfonyl chloride (103 μL, 1.33 mmol). The reaction mixture was stirred at RT for 1 hour. The mixture was concentrated in vacuo. The residue was taken up in THF (2 mL) and dimethylamine solution in THF (2M, 3.3 mL) was added. The reaction mixture was heated at 60° C. in a sealed tube for 72 h. The reaction mixture was cooled to RT and concentrated in vacuo. The product was purified by HPLC using a gemini C18 column and using a gradient of 20-35%+0.1% Formic acid over 10 minutes. The combined fractions were evaporated under reduced pressure and crystallised by MeCN/Et2O to afford the title compound as a white solid (90 mg, 30%). LCMS (Method 3): Rt 3.01 min, m/z 706 [MH+]. 1H NMR (300 MHz, d6-DMSO): 0.91 (3H, d, J=6.7 Hz), 1.23 (9H, s), 1.46-1.54 (2H, m), 1.63-1.72 (2H, m), 1.75-1.76 (2H, m), 2.00-2.18 (2H, m), 2.43 (6H, s), 2.66 (2H, t, J 5.8 Hz), 2.85-2.95 (2H, m), 3.12-3.20 (4H, m), 4.10 (2H, t, J=5.4 Hz), 4.78-4.86 (1H, m), 5.52 (1H, t, J=4.0 Hz), 6.33 (1H, s), 6.95-6.99 (2H, m), 7.06-7.14 (2H, m), 7.19 (1H, dd, J=10.0 Hz), 7.25-7.32 (3H, m), 7.33-7.42 (2H, m), 7.58 (1H, d, J=10.6 Hz), 7.63 (1H, d, J=1.8 Hz), 8.17 (1H, s).