Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]1[S:7][C:6](=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:9]#[N:10])[CH:5]=[CH:4]1.[P:18](Cl)([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[S:19].C(N(CC)CC)C.O>C1COCC1>[CH2:21]([O:20][P:18]([O:1][N:2]=[C:3]1[S:7][C:6](=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:9]#[N:10])[CH:5]=[CH:4]1)([O:23][CH2:24][CH3:25])=[S:19])[CH3:22]
Reactant: CCOP(=S)(Cl)OCC
Reactant: Cc1ccccc1C(C#N)=C1C=CC(=NO)S1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOP(=S)(OCC)ON=C1C=CC(=C(C#N)c2ccccc2C)S1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
8 g (33 mmol) of (5-Hydroxyimino-5H-thiophen-2-ylidene)-(2-methylphenyl)-acetonitrile, prepared as described in example 7.1, are dissolved in 90 ml of THF and cooled in an ice bath. After adding 6.9 g (36 mmol) of diethyl chlorothiophosphate to the solution, 5.0 g (50 mmol) of triethylamine are added dropwise, keeping the temperature below 50° C. The reaction mixture is stirred at 50° C. for 60 min, then is poured into 100 ml of water, and extracted with ethyl acetate. The organic phase is washed with 0.1N hydrochloric acid solution, water, and sodium chloride solution. The organic phase is dried over MgSO4, the solvent is distilled off, and the residue is purified by a recrystallization from 2-PrOH. The product is obtained in the form of a brown solid, melting point 86-87° C. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 1.41 (t, 6H), 2.37 (s, 3H), 4.35-4.46 (m, 4H), 6.13 (d, 1H), 6.85 (d, 1H), 7.19-7.38 (m, 4H).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>C(Cl)Cl.[Cu].C1CCCCC1.C(Cl)Cl>[Br:14][C:15]1[CH:16]=[C:17]([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Brc1cccc(I)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCCCC1
Solvent: ClCCl
Solvent: O
Product: Brc1cccc(-n2c3ccccc3c3ccccc32)c1
Temperature: 150 °C
Reaction time: 48 h
Yield: 79.2 %

Procedure:
Under nitrogen, carbazole (24.3 g, 1 eq.) is added to a flask together with 1-bromo-3-iodobenzene (98%; 75.3 g, 1.9 eq.), potassium carbonate (48.2 g, 2.5 eq.) and copper (1.77 g, 0.1 eq.). The reaction is heated to 150° C. and stirred at 150° C. for 48 h. The mixture is cooled to room temperature and diluted with 150 mL of methylene chloride. 100 mL of demineralized water are added to the mixture, which is stirred. Removal of the aqueous phase is followed by washing a further 2× with demineralized water (100 mL). The organic phase is dried over sodium sulfate and concentrated. The excess 1-bromo-3-iodobenzene is distilled off under reduced pressure. LC (SiO2; cyclohexane/methylene chloride 95:5) gives 37.1 g of product (82.4% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:20][C:21]4[NH:26][CH2:25][CH2:24][O:23][C:22]=4[N:27]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:20][C:21]4[N:26]([C:42](=[O:44])[CH3:43])[CH2:25][CH2:24][O:23][C:22]=4[N:27]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NCCO4)cc2)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCOc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To a solution of tert-butyl(1-(4-(7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (22 mg, 0.05 mmol) in dry DCM (1 ml) was added triethyl amine (10 μl, 0.07 mmol) and acetyl chloride (5 μl, 0.07 mmol) under nitrogen. The resulting mixture was stirred for 1 h at room temperature. A saturated solution of NaHCO3 was added and the mixture was extracted with dichloromethane (3×10 ml) using a phase separator (Isolute® SPE). The combined organic phases were concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 80% EtOAc in cyclohexane) to give the title compound (20 mg, 83%). 1H NMR (500 MHz, CDCl3): 8.50 (1H, br s), 7.25 (2H, d), 7.19-7.17 (5H, m), 7.11-7.10 (2H,m), 4.95 (1H, s), 4.43 (2H, t), 3.94 (2H, br s), 2.55-2.25 (7H, m), 2.06-1.98 (1H, m), 1.82-1.73 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([Br:31])[C:15]=2[N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:18]2)[NH:10][CH:9]=1.C(N(CC)CC)C.[Li+].[OH-]>ClCCl.CN1C(=O)CCC1.C1COCC1.CC#N.O>[Br:31][C:14]1[C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:18]2)=[C:16]2[C:8]([NH:7][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[CH:9][NH:10][C:11]2=[N:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(N)c23)C1
Reactant: CCCC(=O)Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
Butyryl chloride (234 mg, 2.19 mmol) in anhydrous dichloromethane (0.5 mL) was added dropwise to a solution of (R)-tert-butyl 1-(3-amino-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (150 mg, 0.366 mmol) and triethylamine (259 mg, 0.357 mL, 2.56 mmol) in NMP (0.900 mL) cooled on an ice-bath. The mixture was stirred at ambient temperature for 1 hour. The mixture was diluted with THF (10 mL), treated with an aqueous 2N LiOH solution (3 mL) and stirred for 1 hour. The THF was evaporated. The residue was stirred with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated. The residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 15-80% CH3CN/water, 25CV) to give (R)-tert-butyl 1-(5-bromo-3-butyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (176 mg, 100% yield) as a solid. LCMS (APCI+) m/z 482.1, 382, 380 (M+H)+, Retention time=3.80 minutes.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[O:8][C:4]=2[CH:3]=1.[C:12](=O)(O)[O-].[Na+].S(OC)(OC)(=O)=O>O>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([S:9][CH3:12])[O:8][C:4]=2[CH:3]=1
Reactant: Oc1ccc2nc(S)oc2c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CSc1nc2ccc(O)cc2o1
Yield: 25.2 %

Procedure:
A mixture of 6-hydroxy-2-mercaptobenzoxazole (165 mg), sodium bicarbonate (84 mg) and dimethyl sulfate (94 μl) was dissolved in water (2 ml) with stirring and under an argon atmosphere. The reaction mixture was stirred at RT overnight and HPLC showed that all starting material was gone. The reaction mixture was evaporated to dryness to give a dark brown solid (one can also extract the reaction mixture with chloroform to give the crude product). Chromatography on silica gel using 10% ethyl acetate/hexane gave the pure product as a near-white crystalline solid (45 mg, 25%).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH2:14]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19]2)[CH3:15].N1CCCCC1>C(O)C>[CH2:14]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[CH:11][C:8]1[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=1[CH3:13])[CH3:15]
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Reactant: CCc1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: CCc1ccc2c(c1)C(=Cc1[nH]cc(CCC(=O)O)c1C)C(=O)N2
Yield: 32.1 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90.6 mg), 80.5 mg 5-ethyl-2-oxindole, and 75 μL of piperidine in 2 mL of ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N of aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight. The crude solid was purified by a chromatography on a silica gel column eluting with ethyl acetate-hexane-acetic acid to give 52 mg (32%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:5]([CH:13]=[O:14])[C:4](=[O:15])[N:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC(=CC)C.Cl([O-])=[O:28].[Na+].OP([O-])(O)=O.[K+]>CC(O)(C)C.O>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)=[C:5]([C:13]([OH:28])=[O:14])[C:4](=[O:15])[N:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cn1c(-c2ccncc2)c(C=O)c(=O)n1-c1ccccc1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cn1c(-c2ccncc2)c(C(=O)O)c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 9 h
Yield: 52 %

Procedure:
The crude 1-methyl-3-oxo-2-phenyl-5-(pyridin-4-yl)-2,3-dihydro-1H-pyrazole-4-carbaldehyde was dissolved in t-BuOH (˜70 ml) and 2-methyl-2-butene (25 ml, 236 mmol) was added, followed by sodium chlorite (2.43 g, 27 mmol) in water (30 ml) with ˜5 ml water rinse. Then, potassium phosphate monobasic (10.35 g, 76 mmol) was added as a suspension in water (˜70 ml), and the reaction was stirred at room temperature. After 9 hours, the reaction was poured into water (400 ml) and the aqueous phase was then extracted with EtOAc, DCM, and 10:1 DCM/MeOH exhaustively until most of the product had been extracted. The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated to give desired 1-methyl-3-oxo-2-phenyl-5-(pyridin-4-yl)-2,3-dihydro-1H-pyrazole-4-carboxylic acid (1.98 g, 6.7 mmol, 52% yield over two steps). MS (ESI pos. ion) m/z: 296 (MH+). Calc'd exact mass for C16H13N3O3: 295.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:9]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[CH:39]=[CH:38][C:21]([O:22][C:23]3[N:27](CC(OCC)=O)[C:26]4[CH:34]=[CH:35][CH:36]=[CH:37][C:25]=4[N:24]=3)=[CH:20][CH:19]=2)=[N:10]1)[CH3:8].[O-]S([O-])(=O)=O.[Na+].[Na+].C1C[O:50][CH2:49][CH2:48]1>>[CH2:7]([N:9]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[CH:19]=[CH:20][C:21]([O:22][C:23]3[N:27]([CH:49]([OH:50])[CH3:48])[C:26]4[CH:34]=[CH:35][CH:36]=[CH:37][C:25]=4[N:24]=3)=[CH:38][CH:39]=2)=[N:10]1)[CH3:8]
Reactant: CCOC(=O)Cn1c(Oc2ccc(-c3nn(CC)c4cccnc34)cc2)nc2ccccc21
Reactant: C1CCOC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Product: CCn1nc(-c2ccc(Oc3nc4ccccc4n3C(C)O)cc2)c2ncccc21
Reaction time: 0.5 h

Procedure:
LiAlH4 (24.8 mg) was added to a solution of ethyl 2-{2-[4-(1-ethyl-1H-pyrazolo[4,3-b]pyridin-3-yl)phenoxy]-1H-benzo[d]imidazol-1-yl}acetate (144 mg) in THF (3.5 ml) at 0° C. After stirring for 1 h at the same temperature, Na2SO4.10H2O was added to the reaction mixture at 0° C. and stirred for 30 min. After Na2SO4 was added to this mixture, the precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane). The solid was crystallized from AcOEt/hexane to give the title compound (81 mg).
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]=[CH:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:4]=2[N:5]=[N:6][CH:7]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][C:16]=1[C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[C:3]3[N:10]=[CH:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:4]=3[N:5]=[N:6][CH:7]=2)=[CH:17][C:16]=1[C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:37])=[O:38])=[CH:32][CH:31]=1
Reactant: CC(C)n1cnc2c(Cl)cnnc21
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccc(S(N)(=O)=O)cc3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1cnc2c(-c3ccc(F)c(-c4ccc(S(N)(=O)=O)cc4)c3)cnnc21
Temperature: 90 °C
Yield: 50 %

Procedure:
To 4-Chloro-7-isopropyl-7H-imidazo[4,5-c]pyridazine (Preparation 6, 50 mg, 0.254 mmoles) and 2′-fluoro-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-sulfonamide (Preparation 2, 131 mg, 0.254 mmoles) in dioxane (2.5 mL) was added Na2CO3 (80 mg, 0.759 mmol) pre dissolved in water (0.5 mL) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7.3 mg, 0.009 mmol). The reaction was degassed with nitrogen and heated under microwave irradiation at 90° C. for 15 minutes. After cooling, ethyl acetate and Na2SO4 were added and the mixture decanted and washed with ethyl acetate. Purification by silica gel column chromatography eluting with DCM: MeOH 1:0 to 9:1 yielded the title product in 50% yield, 57 mg.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C.CCOC(C)=O>CS(C)=O.O>[Br:1][C:2]1[CH:9]=[C:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: N#Cc1ccc(F)cc1Br
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1ccc(C#N)c(Br)c1
Yield: 464.5 %

Procedure:
A solution of 2-bromo-4-fluorobenzonitrile (0.761 g, 3.80 mmol), tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (1.00 g, 0.808 mmol) and DIEA (1.00 mL, 5.76 mmol) in DMSO (6 mL) was stirred at 100 C for 18 h. EtOAc and water were added. The organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give tert-butyl (1S,2R)-2-(3-bromo-4-cyanophenylamino)cyclohexylcarbamate (1.48 g) as an off-white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]#[N:9])=[CH:3][CH:2]=1.[CH2:10](Br)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:8]#[N:9])=[CH:3][CH:2]=1
Reactant: N#CCc1ccncc1
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCCCCCCC(C#N)c1ccncc1
Yield: 68.6 %

Procedure:
4-Pyridylacetonitrile (1.18 g, 0.01 mole) dissolved in acetonitrile (20 ml) was heated under reflux with n-octyl bromide (1.73 ml, 0.01 mole) and caesium carbonate (4 g) for 1 hour, filtered and concentrated. Elution from a column of silica gel as described in Example 1 gave 2-(4-pyridyl)decanonitrile (1.58 g, 69% yield).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[CH:12][N:11](COCC[Si](C)(C)C)[N:10]=2)[CH:6]=[C:5]([C:22]([F:25])([F:24])[F:23])[N:4]=1.C(OCC)(=O)C.CCCCCC>Cl.O1CCOCC1>[NH:11]1[CH:12]=[N:13][C:9]([C:7]2[CH:6]=[C:5]([C:22]([F:23])([F:24])[F:25])[N:4]=[C:3]([C:2]([F:27])([F:1])[F:26])[CH:8]=2)=[N:10]1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2cc(C(F)(F)F)nc(C(F)(F)F)c2)n1
Agent: Cl
Solvent: CCCCCC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cc(-c2nc[nH]n2)cc(C(F)(F)F)n1
Temperature: 60 °C
Yield: 58.5 %

Procedure:
In a 10 mL seal tube, 2,6-bis(trifluoromethyl)-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)pyridine (2) (0.15 g, 1 eq.) was dissolved in dioxane HCl (5 mL) and seal tube was heated to 60° C. for 6 h. Reaction completion was monitored on TLC using ethyl acetate:hexane (5:5) as mobile phase. The reaction mixture was quenched into the ice-water NaHCO3 solution (50 mL) and was extracted with ethyl acetate (3×50 mL). Organic layer was washed with brine solution (3×50 mL). The organic layer was dried using anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide the 0.3 g of crude compound. The compound was purified by column chromatography using ethyl acetate/hexane as mobile phase. Compound was eluted out at 30% ethyl acetate in hexane to afford 4-(1H-1,2,4-triazol-3-yl)-2,6-bis(trifluoromethyl)pyridine (3) 0.060 g. Yield: 58.4%.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[CH3:5][C:6]1[C:11]2=[CH:12][C:13]3[CH2:14][CH2:15][C:16]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:17]=4[C:18]=3[N:10]2[CH2:9][CH2:8][N:7]=1.FC(F)(F)S(O)(=O)=O.[OH-].[Na+].[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38]>C(Cl)Cl.C(O)C.CO>[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38].[C:2]([O:23][C:21]1[CH:20]=[CH:19][C:17]2[C:18]3[N:10]4[CH2:9][CH2:8][N:7]=[C:6]([CH3:5])[C:11]4=[CH:12][C:13]=3[CH2:14][CH2:15][C:16]=2[CH:22]=1)([CH3:3])([CH3:1])[CH3:4]
Reactant: C=C(C)C
Reactant: CC1=NCCn2c1cc1c2-c2ccc(O)cc2CC1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: CC1=NCCn2c1cc1c2-c2ccc(OC(C)(C)C)cc2CC1
Temperature: -78 °C
Yield: 6 %

Procedure:
Isobutylene (11.0 g) was condensed under argon into a solution of 1.0 g of 5,6,10,11-tetrahydro-8-methyl-benzo[g]pyrazino[1,2-a]indol-3-ol in 50 ml of methylene chloride. The solution was cooled to -78° C. and treated with 0.4 ml of trifluoromethanesulphonic acid while stirring. The mixture was stirred at -78° C. for 8 hours and at -5° C. for 30 minutes. Subsequently, 50 ml of methanol were added and the mixture was neutralized with powdered sodium hydroxide. The reaction mixture was freed from solvent and chromatographed over 100 g of aluminium oxide (neutral, III) with methylene chloride as the eluent. The crude product, 0.3 g of yellow oil, was dissolved in a 20-fold amount of ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. The solution was concentrated to half and treated with 5 ml of ethyl acetate. There was obtained 0.11 g (6%) of 3-tert-butoxy-5,6,10,11-tetrahydro-8-methyl-benzo[g]pyrazino[1,2-a]indole fumarate (1:1); m.pt.: 179°-181° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH2:19]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[C:20]#[CH:21]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C.[I-]>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:21]#[C:20][CH2:19][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Reactant: C#CCN1CCOCC1
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(CC1CCCC1)c1ccc(C#CCN2CCOCC2)cc1
Temperature: 70 °C
Yield: 81.9 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (716 mg, 2.0 mmol) and triethylamine (2 mL, 0.01 mmol) in N,N-dimethylformamide (2 mL) was treated with 4-prop-2-ynyl morpholine (626 mg, 5.0 mmol). The resulting reaction mixture was degassed with argon and then treated with cooper iodide (10 mg, 0.05 mmol) and bis(triphenylphosphine)palladium (II) chloride (15 mg, 0.02 mmol). The reaction was then heated at 70° C. for 24 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The residue was diluted with ethyl acetate (40 mL) and a half-saturated aqueous sodium chloride solution (1×20 mL). The aqueous layer was back extracted with ethyl acetate (1×40 mL). The combined organic extracts were washed with a half-saturated aqueous sodium chloride solution (1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 ethyl acetate/hexanes) afforded 3-cyclopentyl-2-[4-(3-morpholin-4-yl-prop-l-ynyl)-phenyl]-propionic acid methyl ester (582 mg, 82%) as an amber oil: EI-HRMS m/e calcd for C22H29NO3 (M+) 355.2147, found 355.2150.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:26]([CH3:33])([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[CH3:32][C:26]([O:24][C:21]1[CH:20]=[CH:19][C:18]([C:15]2[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:13][CH:14]=2)=[CH:23][CH:22]=1)([CH3:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=C(NCCc1ccc(-c2ccc(O)cc2)cc1)c1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(-c2ccc(CCNC(=O)c3ccccc3)cc2)cc1
Yield: 16 %

Procedure:
Ethyl 2-Methyl-2-{4-[2-benzamido-ethyl]-biphenyl-4'-oxy}-propionate was prepared from 4-(2-benzamido-ethyl)-4'-hydroxybiphenyl and ethyl 2-bromo-2-methyl-propionate analogous to Example 1. Yield: 16% of theory; m.p. 100° C.
Reaction SMILES: [NH2:1][C:2](=[O:40])[C@@H:3]([NH:24][C:25]([C@@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:23]=[CH:22][C:14]3[N:15]([CH2:19][CH2:20][OH:21])[C:16](=[O:18])[S:17][C:13]=3[CH:12]=2)=[CH:7][CH:6]=1.[Si:41](Cl)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42].N1C=CN=C1.O>CN(C=O)C>[NH2:1][C:2](=[O:40])[C@@H:3]([NH:24][C:25]([C@@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])=[O:26])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:23]=[CH:22][C:14]3[N:15]([CH2:19][CH2:20][O:21][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[C:16](=[O:18])[S:17][C:13]=3[CH:12]=2)=[CH:9][CH:10]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc3c(c2)sc(=O)n3CCO)cc1)C(N)=O
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc3c(c2)sc(=O)n3CCO[Si](C)(C)C(C)(C)C)cc1)C(N)=O
Reaction time: 4 h
Yield: 78.4 %

Procedure:
A solution of (S)-tert-butyl 2-((S)-1-amino-3-(4-(3-(2-hydroxyethyl)-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)phenyl)-1-oxopropan-2-ylcarbamoyl)piperidine-1-carboxylate (138 mg), tert-butyldimethylsilyl chloride (40.2 mg) and imidazole (41.3 mg) in DMF (1 mL) was stirred for 16 h. Further tert-butyldimethylsilyl chloride (40.2 mg) and imidazole (41.3 mg) were added and stirred for 4 h. Water was added and the mixture was extracted thrice with ethyl acetate. The organic layers were washed twice with water, combined, dried over magnesium sulfate, evaporated and purified by flash silica chromatography eluting with 1:2 acetone/isohexane to give the subtitle compound (130 mg) as a colourless gum.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]1([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([O:25][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: OC1CCCCC1
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Product: O=C(NC(=O)C(c1ccccc1)c1ccccc1)OC1CCCCC1

Procedure:
The title compound, white solid, m.p. 117-119° C. and MS: m/e 337.4 (M+H+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and cyclohexanol.