Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.O1CCOCC1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:18]1([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]4[CH2:17][CH2:16]4)=[O:14])[N:8]=[CH:9]3)=[CH:4][CH:3]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Reactant: C1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(Nc1cc2ccc(N3CCCCC3)cc2cn1)C1CC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 5.6 %

Procedure:
A solution was made of N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (66.6 mg, 0.229 mmol) and piperidine (46 uL, 0.46 mmol) in 1,4-dioxane (1.5 mL, 19 mmol). Nitrogen gas was bubbled through the mixture for 10 minutes, and then palladium (II) acetate (6.0 mg, 0.027 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (15.2 mg, 0.0244 mmol), and cesium carbonate (231 mg, 0.709 mmol) were added. The reaction mixture was stirred in a sealed vial at 100° C. for 18 hours. The reaction mixture was then cooled to room temperature, diluted in ethyl acetate, filtered through celite, washed with saturated aqueous NaHCO3, dried over MgSO4, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 3.8 mg (6%) of N-(7-(piperidin-1-yl)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT=3.481, M+H=416.2, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.89 (s, 1H), 8.27 (s, 1H), 7.67 (d, J=9.1 Hz, 1H), 7.55 (dd, J=9.1, 2.4 Hz, 1H), 7.25 (d, J=2.1 Hz, 1H), 3.27-3.20 (m, 4H), 2.03 (m, 1H), 1.66 (d, J=4.6 Hz, 4H), 1.58 (d, J=4.7 Hz, 2H), 0.81 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C[O:17][C:18](=[O:34])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]Br>C(O)(=O)C>[O:10]=[C:6]1[C:5]2[CH:11]=[CH:12][C:2]([O:1][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][O:27][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][CH2:19][C:18]([OH:34])=[O:17])=[C:3]([CH2:13][CH2:14][CH3:15])[C:4]=2[O:9][CH2:8][CH2:7]1
Reactant: COC(=O)COc1ccccc1OCCCCCBr
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Solvent: CC(=O)O
Product: CCCc1c(OCCCCCOc2ccccc2OCC(=O)O)ccc2c1OCCC2=O

Procedure:
Using the procedure of example 4, [2-[5-[3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]phenoxy]acetic acid was prepared in 72.3% overall yield starting from 0.31 g (1.5 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one and 0.53 g (1.6 mmol) of [2-[(5-bromopentyl)oxy]phenoxy]acetic acid methyl ester, as a colorless solid, mp 98°-99° C., recrystallized from hexane-ethyl acetate.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11](C2C=CC=CC=2)=[CH:10][C:9]=1[NH:20][C:21](=O)[CH2:22][C:23]([C:25]1C=C[CH:28]=[C:27]([N:31]2[CH:35]=[CH:34][N:33]=[CH:32]2)[CH:26]=1)=O)(C)(C)C.[C:38](O)([C:40](F)(F)F)=[O:39]>C(Cl)Cl>[N:31]1([C:27]2[CH:28]=[C:22]([C:21]3[CH2:40][C:38](=[O:39])[NH:7][C:8]4[CH:13]=[C:12]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[CH:11]=[CH:10][C:9]=4[N:20]=3)[CH:23]=[CH:25][CH:26]=2)[CH:35]=[CH:34][N:33]=[CH:32]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3ccnc3)c2)=Nc2ccc(-c3ccccc3)cc2N1

Procedure:
Prepared from {3-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K34) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (125 mg).
Reaction SMILES: [CH2:1]([C:8]1[CH:12]=[C:11](N2CCCCC2)[N:10]([CH2:19][CH3:20])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:21].[C:22]([Cl:25])(=O)[CH3:23]>CO>[ClH:25].[ClH:21].[CH2:1]([C:8]1[CH:12]=[C:11]([CH:23]2[CH2:22][CH2:19][NH:10][CH2:11][CH2:12]2)[N:10]([CH2:19][CH3:20])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCn1nc(Cc2ccccc2)cc1N1CCCCC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CO
Product: CCn1nc(Cc2ccccc2)cc1C1CCNCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 199.8 %

Procedure:
1-(t-Butoxycarbonyl)4-(3-benzyl-1-ethyl-(1H)-pyrazol-5-ylpiperidine 5 from Step D (18.5 g, 50 mmol) was added to a solution of HCl (530 mmol) in methanol (300 mL) prepared by the slow addition of acetyl chloride (38 mL, 530 mmol) and aged for 90 min. The reaction was stirred at rt for 16 h and then evaporated to dryness to afford 17.1 g (100%) of the title compound as a hygroscopic white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]1[C:19]2[NH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH2:10][CH:9]([C:20]([OH:22])=[O:21])[CH2:8]1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>CN(C)C=O>[CH2:7]1[C:19]2[NH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH2:10][CH:9]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:8]1
Reactant: O=C(O)C1CCc2[nH]c3ccccc3c2C1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1CCc2[nH]c3ccccc3c2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.1 %

Procedure:
5.53 g of powdered potassium carbonate was added to a solution of 4.34 g of 1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, as obtained in Example 49, in 100 ml of N,N-dimethylformamide. 3.76 g of benzyl bromide were added to the reaction mixture, which was then stirred for 1.5 hours at room temperature, after which the mixture was neutralized by the addition of a 0.5N aqueous solution of hydrochloric acid. The aqueous layer was extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 150 g of silica gel with a 4:1 v/v mixture of hexane and ethyl acetate as the eluent, and recrystallized from ethyl acetate and hexane, to yield 6.04 g of the title compound, melting at 104°-105° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[C:9](Cl)(=[O:11])[CH3:10].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[CH3:8][C:3]1[CH:4]=[C:5]([C:9]([CH3:10])=[O:11])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: CC(=O)Cl
Reactant: Cc1ccccc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(F)c(C)c1
Yield: 98.2 %

Procedure:
A mixture of 50 grams (454 millimoles) of ortho-fluorotoluene and 42.8 grams (545 millimoles) of acetyl chloride was dissolved in 250 milliliters of methylene chloride, and then 72.7 grams (545 millimoles) of anhydrous aluminum chloride was gradually added thereto while cooling with ice and stirring. The resulting mixture was further stirred for 2 hours while cooling with ice. Then the reaction mixture was added to 1,200 milliliters of 5% hydrochloric acid, which was then allowed to separate into aqueous and organic layers. The organic layer thus obtained was washed with a 5% aqueous solution of sodium carbonate and dried over anhydrous sodium sulfate and, thereafter, the methylene chloride was distilled away under reduced pressure. Thus, as a product, 67.9 grams (446 millimoles) of 3-methyl-4-fluoroacetophenone was obtained (yield, 98%).
Reaction SMILES: CNC.[C:4]([O:7][CH2:8][CH:9]=O)(=[O:6])[CH3:5].[CH:11](=[O:15])[CH2:12][CH2:13][CH3:14]>C(O)(=O)C>[C:4]([O:7][CH2:8][CH:9]=[C:12]([CH2:13][CH3:14])[CH:11]=[O:15])(=[O:6])[CH3:5]
Reactant: CC(=O)OCC=O
Reactant: CCCC=O
Agent: CNC
Solvent: CC(=O)O
Product: CCC(C=O)=CCOC(C)=O
Yield: 54.2 %

Procedure:
To a mixture of 225 g of a 40% strength by weight aqueous solution of dimethylamine and 120 g of acetic acid was added with stirring and cooling, in the course of 15 min, a solution of 204 g of acetoxyacetaldehyde in 288 g (4 mol) of n-butyraldehyde, and the reaction mixture was subsequently stirred at 50° C. for 30 min. The reaction solutions were cooled down and the aqueous catalyst solution separated off to give, by fractional distillation, 169 g of 4-acetoxy-2-ethyl-2-butenal (b.p.=83°-93° C./6 mbar), corresponding to a yield of 54% of theory, based on acetoxyacetaldehyde, and 181 g of 2-ethyl-2-hexanal (b.p.=38°-70° C./20-60 mbar).
Reaction SMILES: [CH3:1]C1CCOC(=O)CCCCCCOCC1.[CH3:17][CH:18]1[CH2:33][CH2:32][O:31][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[CH3:17][C:18]1([CH3:1])[CH2:33][CH2:32][O:31][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: CC1CCOCCCCCCC(=O)OCC1
Reactant: CC1CCOCCCCCCCC(=O)OCC1
Product: CC1(C)CCOCCCCCCCC(=O)OCC1

Procedure:
Odor: Relatively weak, powdery musk-like, woody-herby.--IR (film): ν=1734 cm-1 (νC=O), 1117/1154 cm-1 (νasO--C--C), 1252 cm-1 (νasC--C(=O)--O), 1366 cm31 1 (δCH3), 1046 cm-1 (νasC--O--C).--1H-NMR (CDCl3): δ=0.94 (s, 6H, 12-Me2), 1.31-1.42 (m, 6H, 4-H2 -6-H2), 1.50-1.57 (m, 4H, 3-,7-H2), 1.69 (t, J=7.2 Hz,2H, 11-H2), 1.71 (dd, J=10.0 and 6.8 Hz, 2H, 13-H2), 2.30 (t, J=6.6 Hz, 2-H2), 3.39 (t, J=5.2 Hz, 8-H2), 3.46 (t, J=6.2 Hz, 10-H2), 4.16 (t, J=7.0 Hz, 2H, 14-H2). --13C-NMR (CDCl3): δ=23.72, 24.91 (t, C-3,-6), 26.41/27.89 (t, C-4,-5), 28.59 (2q, 12-Me2), 29.05 (t, C-7), 31.77 (s, C-12), 34.59 (t, C-2), 38.86/40.57 (t, C-11,-13), 61.93 (t, C-14), 67.66/69.88 (t, C-8,-10), 174.15 (s, C-1).--MS (El): m/z (%)=55 (100) [C4H7⊕ ], 69 (72) [C5H9⊕!, 81 (40) [C6H9⊕ ], 97 (59) [C6H9O⊕]113 (27) [C7H13O⊕]125 (27) [C8H13O⊕ ], 141 (15) [M⊕ --C6H9O--H2O], 183 (2) [M⊕ --C4H7 --H2O]227 (1)[M⊕ --CHO], 256 (1) [M⊕].--C15H28O3 (256.39): calculated C 70.27, H 11.01; found C 70.15, H 10.87.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:18]([OH:20])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([OH:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.O.O.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37](S(O)(=O)=O)=[CH:36][CH:35]=1>C(O)C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:21]1([CH3:31])[CH:22]=[CH:23][C:24]([S:27]([OH:30])(=[O:28])=[O:29])=[CH:25][CH:26]=1.[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:18]([O:20][CH2:44][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: OCc1ccccc1
Solvent: O
Product: NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Yield: 62 %

Procedure:
Nα-Benzyloxycarbonyl (L) lysine (10 g; 35.7 mmol) in benzyl alcohol (30 cm3), toluene (30 cm3) and para toluene sulphonic acid (6.93 g) was heated under reflux. The water evolved from the reaction and from the p-toluene sulphonic acid monohydrate was collected azeotropically using a Dean and Stark apparatus. Refluxing was continued until the water was no longer collected. The reaction mixture was allowed to cool, when crystals formed. The crystals were filtered off and dried, yield=5 g. The proton magnetic resonance and infrared spectra showed this compound to be the p-toluene sulphonic acid salt of the starting material. The filtrate was poured into ether (300 cm3) forming an oil. The ether was decanted off and the oil washed with ether and dried under reduced pressure. The resultant oil slowly crystallised to afford 12 g (62%) of the title compound, ν (Nujol) 3370, 1735, 1692, 1040, 1015, 820, 745, 735, 700, 685 cm-1.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1.ClC(Cl)(Cl)C(=N)O[C:13]([CH3:16])([CH3:15])[CH3:14].C([O-])(O)=O.[Na+]>CCCCCC.C1COCC1>[CH:1]1([CH2:4][CH2:5][C:6]([O:8][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:7])[CH2:3][CH2:2]1
Reactant: O=C(O)CCC1CC1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)CCC1CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a cool (0° C., precooled for at least 15 min), stirred solution of 3-cyclopropylpropanoic acid (5 g, 43.8 mmol) in hexane (30.0 mL) and THF (30 mL) under N2 was added tert-butyl 2,2,2-trichloroacetimidate (15.7 mL, 88 mmol) portion wise over 5 min. The reaction mixture was stirred for 15 min. Boron trifluoride ether complex (0.555 mL, 4.38 mmol) was added and the reaction mixture was allowed to warm to room temperature as the bath warmed overnight. To the clear reaction mixture was added NaHCO3 (5 g) and stirred for 60 min. The suspension was filtered through MgSO4 and washed with 300 mL hexane. The filtrate was allowed to sit, then the formed solid was filtered through the same MgSO4 filter, washed with hexane (100 mL). The filtrate was concentrated under vacuo with the water bath not turned on. The residue was purified by silica gel chromatography (hexanes/EtOAc) to provide Intermediate I1B (6.05 g, 81%) as clear oil: 1H NMR (400 MHz, CDCl3) δ 2.29 (2H, t, J=7.48 Hz), 1.35-1.54 (11H, m), 0.60-0.75 (1H, m), 0.29-0.46 (2H, m), −0.06-0.10 (2H, m).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[CH3:11].[O:12]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:14][CH2:13]1>>[CH3:11][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[N:21]1[CH2:22][CH2:23][CH:18]([N:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)[CH2:19][CH2:20]1)[NH2:8]
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: Cc1cc([N+](=O)[O-])ccc1Cl
Product: Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthesis Example 40 using 4-chloro-3-methylnitrobenzene and 4-morpholinopiperidine, the title compound was obtained, melting point: 199–200° C.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:10]=3[CH:9]=2)=[CH:5][CH:4]=1)[CH3:2].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:22][C@H:23]1[O:25][CH2:24]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([C:3]1[S:7][C:6]([C:8]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH2:22][C@H:23]4[O:25][CH2:24]4)[C:10]=3[CH:9]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(-c2cc3c(O)cccc3o2)s1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1ccc(-c2cc3c(OC[C@@H]4CO4)cccc3o2)s1

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 1 using 2-(5-ethylthiophen-2-yl)-4-hydroxybenzo(b)furan (750 mg), (S)-glycidyl nosylate (875 mg) and potassium carbonate (1.27 g), a crude product of the title compound was quantitatively obtained as a yellow oil.
Reaction SMILES: B(F)(F)F.C([NH:12][C@@H:13]([CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH:14](O)[CH2:15][Si](C)(C)C)(OC(C)(C)C)=O.C(=O)([O-])[O-].[Na+].[Na+]>CCOCC.C(Cl)Cl>[CH:22]1([CH2:21][C@H:13]([NH2:12])[CH:14]=[CH2:15])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(O)C[Si](C)(C)C
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: C=C[C@@H](N)CC1CCCCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
42.2 ml (336 mmol) of an approximately 48% solution of boron trifluoride in ether are added at 5° C. to a solution of 23.1 g (67.2 mmol) of 3(S)-(Boc-amino)-2(R,S)-hydroxy-4-cyclohexyl-1-trimethylsilyl-butane in 460 ml of methylene chloride. The reaction mixture is then stirred for 6 h at RT and 3M sodium carbonate solution is added. The aqueous phase is removed and extracted twice with methylene chloride. The organic extracts are washed with brine, dried over sodium sulfate and concentrated by evaporation. The title product is further used without additional purification.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([N:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[I:22])[CH:13]1[CH2:23][C:24]([O:26]CC)=O)=[O:11])=O)(C)(C)C.IC1C=CC=C2C=1CCNC2CC(OCC)=O.N(C(OC(C)(C)C)=O)CC(O)=O.CCN(CC)CC.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CN(C=O)C.C([O-])(O)=O.[Na+]>CCOC(C)=O.O>[I:22][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[CH2:20][CH2:21][N:12]1[C:10](=[O:11])[CH2:9][NH:8][C:24](=[O:26])[CH:23]=[C:13]12
Reactant: CCOC(=O)CC1c2cccc(I)c2CCN1C(=O)CNC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CCOC(=O)CC1NCCc2c(I)cccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C1C=C2c3cccc(I)c3CCN2C(=O)CN1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
ethyl 2-(2-(2-((tert-butoxycarbonyl)amino)acetyl)-5-iodo-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate. A mixture of ethyl 2-(5-iodo-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (39.5 g, 114 mmol), Boc-Gly-OH (20.1 g, 114 mmol) and Et3N (32 mL, 230 mmol) in AcOEt (570 mL) was treated with a solution of T3P in DMF (80 mL, 137 mmol)—exothermic. The mixture was stirred at RT for 15 h and H2O (200 mL) was then added. The pH was adjusted to 8 by addition of saturated aq. solution of NaHCO3, and the aq. phase was extracted with AcOEt. The combined org. phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (57.4 g) that was used as it is in the next step. UPLC-MS: MS 503.2 (M+H+); UPLC rt 1.20 min.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]\[CH2:5]Cl.[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:7]([N:14]1[CH2:5][CH:4]=[CH:3][CH2:2]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCc1ccccc1
Reactant: ClC/C=C\CCl
Product: C1=CCN(Cc2ccccc2)C1

Procedure:
A mixture of 1,4-dichloro-cis-2-butene and benzylamine is heated at reflux to give 1-benzyl-3-pyrroline (2), which is converted to the epoxide (3) by first reacting (2) with chlorine in dilute hydrochloric acid and then with sodium hydroxide. The epoxide is opened to give the corresponding hydroxy amine (4) with either ammonia and water or sodium azide followed by reduction of the resulting azide. The resulting trans 1-benzyl-3-amino-4-hydroxypyrrolidine (4) is acetylated with acetic anhydride to give N-acetyl derivative (5) in which N-benzyl group is removed by hydrogenation in the presence of Pd/C under acidic conditions to give (6), and further alkylated with bromoethyl acetate to give N-ethoxycarbonyl methyl derivative (7). The basic hydrolysis of the ester (7) gives the target (8).
Reaction SMILES: [O:1]=[C:2]1[NH:18][C:5]2=[N:6][CH:7]=[C:8]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=3)[N:9]=[C:4]2[N:3]1[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.BrC1N=C2N(CCN3CCCCC3)C(=O)[NH:36][C:31]2=[N:30]C=1.C(C1C=CC(B(O)O)=CC=1)#N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[N:30]1[N:15]=[C:14]([C:13]2[CH:12]=[CH:11][C:10]([C:8]3[N:9]=[C:4]4[N:3]([CH2:19][CH2:20][N:21]5[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]5)[C:2](=[O:1])[NH:18][C:5]4=[N:6][CH:7]=3)=[CH:17][CH:16]=2)[NH:36][CH:31]=1
Reactant: N#Cc1ccc(-c2cnc3[nH]c(=O)n(CCN4CCCCC4)c3n2)cc1
Reactant: O=c1[nH]c2ncc(Br)nc2n1CCN1CCCCC1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: N#Cc1ccc(B(O)O)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=c1[nH]c2ncc(-c3ccc(-c4nnc[nH]4)cc3)nc2n1CCN1CCCCC1
Temperature: 100 °C
Yield: 39 %

Procedure:
4-(2-Oxo-3-(2-(piperidin-1-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzonitrile. 6-Bromo-1-(2-(piperidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (1.2 g., 3.68 mmol), 4-cyanophenylboronic acid (0.595 g., 4.05 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.3 g., 0.368 mmol) and potassium phosphate (3.12 g., 14.7 mmol) were combined in DMF (9 mL) and heated in a sealed tube to 100° C. overnight. The flask was cooled to rt and the reaction mixture was filtered through celite, washed with methanol and ethyl acetate. The filtrate and washes were combined, concentrated and treated with water. The product was extracted into ethyl acetate, the organic layer was concentrated and the resulting material was subjected to silica gel chromatography (60-100% ethyl acetate in hexanes) to yield the title compound (0.5 g., 39% yield). MS (ESI) m/z 349.3 [M+1]+.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[NH:13][CH2:14][C:15]#[N:16].[F:18][C:19]([F:34])([F:33])[C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:23](O)=[O:24]>>[C:15]([CH2:14][N:13]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:7]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:17])[C:23](=[O:24])[C:22]1[CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=[C:20]([C:19]([F:18])([F:33])[F:34])[CH:21]=1)#[N:16]
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1ccccc1-c1ccncc1NCC#N
Product: Cc1ccccc1-c1ccncc1N(CC#N)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from (4-o-tolyl-pyridin-3-ylamino)-acetonitrile and 3,5-bis-trifluoromethyl-benzoic acid (CAS RN 725-89-3) after a reaction time of 18 hours. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). The product-containing fractions were pooled and evaporated until a suspension formed. The colorless solid was filtered off and washed with a small amount of a mixture of EtOAc:n-heptane (1:6). Colorless solid (37%). MS (ESI): m/z=464.12 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:14]=3[O:15][C@H:16]([CH3:20])[C:17](O)=[O:18])=[N:7][CH:8]=[N:9]2)=[C:4]([F:26])[CH:3]=1.CCN(C(C)C)C(C)C.[F:36][C:37]([F:41])([F:40])[CH2:38][NH2:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:14]=3[O:15][C@H:16]([CH3:20])[C:17]([NH:39][CH2:38][C:37]([F:41])([F:40])[F:36])=[O:18])=[N:7][CH:8]=[N:9]2)=[C:4]([F:26])[CH:3]=1
Reactant: NCC(F)(F)F
Reactant: C[C@@H](Oc1cc(F)ccc1Nc1ncnc2cc(Br)cc(F)c12)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Oc1cc(F)ccc1Nc1ncnc2cc(Br)cc(F)c12)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 300 mg (0.78 mmol) (2R)-2-[2-[(7-bromo-5-fluoro-quinazolin-4-yl)amino]-5-fluoro-phenoxy]propanoic acid and DMF, 0.3 ml (1.8 mmol) DIPEA, 105 mg (0.89 mmol) 2,2,2-trifluoro-ethylamine and 344 mg (0.9 mmol) HATU are added. The mixture is stirred at RT for 3 h, water is added and the precipitate is filtered and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[S:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:4][CH:3]=1.[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32]Cl)[CH3:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[S:17]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:32][CH2:31][CH2:30][N:29]([CH2:34][CH3:35])[CH2:27][CH3:28])=[CH:24][CH:25]=2)(=[O:19])=[O:18])=[CH:6][CH:7]=1
Reactant: CCN(CC)CCCCl
Reactant: O=S(=O)(c1ccc(O)cc1)c1oc2ccccc2c1-c1ccc(Cl)cc1
Product: CCN(CC)CCCOc1ccc(S(=O)(=O)c2oc3ccccc3c2-c2ccc(Cl)cc2)cc1

Procedure:
Reaction of 3-(4-chlorophenyl)-2-(4-hydroxyphenylsulfonyl)benzofuran with 3-diethylaminopropyl chloride by the method described in Example 1 gives the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[CH:4][C:5]([CH3:12])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1.BrC1C=C([F:23])C(C)=C(N)C=1>>[Br:1][C:2]1[CH:3]=[C:4]([F:23])[C:5]([CH3:12])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: Cc1cc(F)c(Br)cc1CC(=O)O
Reactant: Cc1c(N)cc(Br)cc1F
Product: Cc1c(F)cc(Br)cc1CC(=O)O

Procedure:
(5-Bromo-3-fluoro-2-methyl-phenyl)-acetic acid was prepared analogously to the synthesis of (5-bromo-4-fluoro-2-methyl-phenyl)-acetic acid (preparation example P5, step P5.3) starting from 5-bromo-3-fluoro-2-methyl-phenylamine (preparation example P7, step P7.1) by making use of the procedures described under step P5.1, step P5.2 and step P5.3. The title acid was obtained as a solid, mp: 147° C.