Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](C(C(C(O)=O)O)O)(O)=O.[NH2:11][C@@H:12]([C:19]([OH:21])=[O:20])[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1.[ClH:22]>CO>[ClH:22].[ClH:22].[CH3:1][O:20][C:19](=[O:21])[C@@H:12]([CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)[NH2:11]
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: N[C@H](Cc1c[nH]cn1)C(=O)O
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](N)Cc1c[nH]cn1

Procedure:
A process according to claim 1, further comprising the step of reacting the crude D-histidine tartrate with hydrochloric acid and methanol at reflux temperature to produce D-histidine methylester dihydrochloride.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][C:9](=O)[NH:8][C:7](=O)[CH2:6]2)[CH2:4][CH:3]=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:4]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:1][CH:2]=[CH:3]1
Reactant: O=C1CC2(CC=CC2)CC(=O)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C1=CCC2(C1)CCNCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a solution of 8-azaspiro[4.5]dec-2-ene-7,9-dione (3.3 g, 20 mmol) [prepared according to Cipollina, J. A.; et. al. J. Med. Chem. 1991, 34, 3316.] in THF (200 mL) at 0° C. was added LAH (3.42 mg, 90 mmol) portion-wise. After 1 h at 0° C., the solution warmed to 25° C. and was then heated to 60° C. After an additional 1 h at reflux, the solution was cooled and quenched by dropwise addition of a saturated solution of Rochelle's salt. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica, 3% MeOH in DCM (1% NH4OH)) yielding the title compound (2.74 g, quant.) as a yellow oil: LCMS (ES) m/e 160 (M+Na)+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[N:5]([CH2:7][CH2:8][OH:9])[CH:6]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[Br:1][C:2]1[N:3]=[C:4]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[N:5]([CH2:7][CH2:8][O:9][S:31]([CH3:30])(=[O:33])=[O:32])[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCOS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
Combine tert-butyl 4-(4-bromo-1-(2-hydroxyethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (3.84 g, 10.26 mmol), dichloromethane (60 mL), and triethylamine (4.29 mL, 3.0 eq). Place under nitrogen and cool to 0° C. Add methanesulfonyl chloride (0.95 mL, 1.2 eq) dropwise. After 15 minutes, quench with saturated aqueous sodium bicarbonate. Wash the organics with saturated aqueous sodium chloride. Dry the organics over anhydrous magnesium sulfate, filter, and concentrate in vacuo to give the title compound (4.45 g, 96%). MS (ES) m/z=452 [M]+.
Reaction SMILES: C[Si](Cl)(C)C.BrCCBr.I[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:13][CH2:12]1.Cl[C:28]1[C:37]([O:38][CH:39]2[CH2:42][N:41]([C:43]3[CH:52]=[CH:51][C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[N:44]=3)[CH2:40]2)=[N:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=1>CC(N(C)C)=O.[Zn].[Cu]I.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.C(OCC)(=O)C>[N:44]1[C:45]2[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:51]=[CH:52][C:43]=1[N:41]1[CH2:40][CH:39]([O:38][C:37]2[C:28]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:13][CH2:12]3)=[N:29][C:30]3[C:35]([N:36]=2)=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:42]1
Reactant: Clc1nc2ccccc2nc1OC1CN(c2ccc3ccccc3n2)C1
Reactant: O=C(OCc1ccccc1)N1CCC(I)CC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CC(=O)N(C)C
Solvent: BrCCBr
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCC(c2nc3ccccc3nc2OC2CN(c3ccc4ccccc4n3)C2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
A premixed mixture of TMSCl and 1,2-dibromoethane (7:5, v/v, 0.80 mL total volume added) was added dropwise over 5 minutes to a suspension of zinc (1.62 g, 24.8 mmol) in DMA (12 mL) under argon atmosphere. The mixture was stirred for 15 minutes before benzyl 4-iodopiperidine-1-carboxylate (7.13 g, 20.67 mmol) was added dropwise over 15 minutes as a solution in DMA (6 mL). This mixture was stirred for an additional 15 min before it was added slowly to a suspension of 2-chloro-3-((1-(quinolin-2-yl)azetidin-3-yl)oxy)quinoxaline (see PREPARATION P2.8; 5.0 g, 13.8 mmol), copper(I) iodide (0.26 g, 1.38 mmol), and Pd(dppf)Cl2 dichloromethane adduct (0.56 g, 0.69 mmol) in DMA (15 mL) under argon. This mixture was stirred at 80° C. for 2 hours, then cooled to room temperature. Ethyl acetate was added and the suspension was filtered through CELITE® to remove insoluble material. The filtrate was diluted with more ethyl acetate and then washed with water (3×), brine(1×), dried (MgSO4), filtered, and concentrated in vacuo to give an oil. This oil was purified by silica gel chromatography (0 to 100% EtOAc/hexane gradient) to give benzyl 4-(3-((1-(quinolin-2-yl)azetidin-3-yl)oxy)quinoxalin-2-yl)piperidine-1-carboxylate as an off-white solid (6.93 g, 92% yield).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:15]2([CH3:18])[CH2:17][CH2:16]2)=[C:9]([CH:19]([CH3:21])[CH3:20])[CH:8]=1)(=O)=O.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26]>C(N(CC)CC)C.CN(C=O)C>[CH:19]([C:9]1[CH:8]=[C:7]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[CH:12]=[CH:11][C:10]=1[CH2:13][O:14][C:15]1([CH3:18])[CH2:17][CH2:16]1)([CH3:21])[CH3:20]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)c1cc(OS(=O)(=O)C(F)(F)F)ccc1COC1(C)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1cc(C#C[Si](C)(C)C)ccc1COC1(C)CC1
Temperature: 95 °C
Yield: 107.7 %

Procedure:
Using General Procedure D; 3-isopropyl-4-(1-methyl-cyclopropoxymethyl)-phenyl 1,1,1-trifluoromethanesulfonate (Intermediate 164, 120.0 mg, 0.34 mmol) in triethylamine (2 mL) and anhydrous DMF (5 mL) was sparged with argon for 5 minutes. Trimethylsilyl acetylene (700.0 mg, 0.71 mmol) was then added followed by dichlorobis(triphenylphosphine)palladium(I) (24.0 mg, 0.03 mmol). The resulting reaction mixture was heated to 95° C. for 60 hours. The title compound 110.0 mg, (99%) was isolated by chromatography (0-1% EtOAc-hexanes).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3[NH:16][C:17]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([C:28]6[CH:33]=[C:32]([F:34])[C:31]([OH:35])=[CH:30][C:29]=6[CH2:36][CH3:37])=[CH:25][CH:26]=5)[NH:21][N:20]=4)=[N:18][C:12]=3[CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH:38]1([NH2:44])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH:38]1([NH:44][C:2]2[N:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:15][CH2:14][C:13]4[NH:16][C:17]([C:19]5[C:27]6[C:22](=[CH:23][C:24]([C:28]7[CH:33]=[C:32]([F:34])[C:31]([OH:35])=[CH:30][C:29]=7[CH2:36][CH3:37])=[CH:25][CH:26]=6)[NH:21][N:20]=5)=[N:18][C:12]=4[CH2:11]3)=[O:9])=[N:6][CH:7]=2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(Cl)cn3)C4)n[nH]c2c1
Reactant: NC1CCCCC1
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(NC5CCCCC5)cn3)C4)n[nH]c2c1
Yield: 20.6 %

Procedure:
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (126 mg, 243 μmol) and cyclohexylamine (48 mg, 487 μmol) using the method of Example 32. The crude material was purified by HPLC Method D to afford (29 mg, 20%) of the title compound as off-white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[O:3]1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1.O>CN(C=O)C>[Si:14]([O:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[O:3]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: OC1CCC(c2ccc(F)cc2)O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CCC(c2ccc(F)cc2)O1
Reaction time: 8 h
Yield: 93.3 %

Procedure:
2-Hydroxy-5-(4-fluorophenyl)-tetrahydrofuran (550 mg, 3.0 mmol), t-butyldimethylsilyl chloride (498 mg, 3.3 miol) and imidazole (450 mg, 6.6 mmol) were dissolved in 2 mL of dry DMF. This solution was stirred under dry argon overnight, poured into 200 mL of water and extracted with a 2:1 mixture of ethyl acetate( and hexane (3×100 mL). The combined organic extracts were washed with water (4×200 mL) and brine (100 mL), dried over sodium sulfate and evaporated to give 830 mg (93%) of 2-(t-butyldimethylsilyloxy)-5-(4-fluorophenyl) tetrahydrofuran (202, mixture of cis and trans isomers) as a colorless oil, which did not need any purification. 1H-NMR (CDCl3) δ 7.40-7.50(2H, m, minor isomer), 7.25-7.35 (2H, m, major isomer), 7.00-7.10 (2H, m, both major and minor isomers), 5.71-5.75 (1H, m, major isomer), 5.59-5.62 (1H, m, minor isomer), 5.12-5.20 (1H, m, major isomer), 4.90-4.98 (1H, m, minor isomer), 2.40-2.55 (1H, m, both major and minor isomers), 2.05-2.17 (1H, m, both major and minor isomers), 1.87-2.00 (1H, m, both major and minor isomers), 1.67-1.70 (1H, m, both major and minor isomers), 0.92 (s, 9H, both major and minor isomers), 0.16 (s, 6H, both major and minor isomers).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:30]=[CH:29][C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:28])[CH3:27])[CH2:22]3)=[CH:17][CH:16]=2)=[O:13])=[CH:10][N:9]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1.O>CN(C=O)C.C(OCC)(=O)C>[CH3:27][N:26]([CH3:28])[CH:23]1[CH2:24][CH2:25][N:21]([C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:12](=[O:13])[C:11]3[CH:29]=[CH:30][C:8]([O:38][C:35]4[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=4)=[N:9][CH:10]=3)=[CH:16][CH:17]=2)[CH2:22]1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(Cl)nc3)cc2)C1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(Oc4ccc(F)cc4)nc3)cc2)C1
Temperature: 140 °C

Procedure:
49 mg of potassium carbonate were added to a solution of 0.041 g of 6-chloro-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]nicotinamide and 4-fluorophenol (30 mg) in 0.8 ml of DMF, and the reaction was heated at 140° C. in a microwave apparatus for 90 minutes. After addition of water and ethyl acetate, the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated in vacuo and purified by preparative HPLC. This resulted in the product with the molecular weight of 420.2 (C24H25FN4O2); MS (ESI): 421 (M+H+) as hydrotrifluoroacetate.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][C:40]3[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=3[O:47][CH3:48])=[CH:30][CH:29]=2)[C@H:10]([O:49][CH2:50][C@H:51]2[CH2:55][O:54]C(C)(C)[O:52]2)[CH2:9]1)=O)(C)(C)C.Cl>CO>[F:46][C:44]1[CH:43]=[CH:42][C:41]([O:47][CH3:48])=[C:40]([CH:45]=1)[CH2:39][O:38][CH2:37][CH2:36][CH2:35][O:34][C:31]1[CH:32]=[CH:33][C:28]([C@@H:11]2[C@@H:12]([O:14][CH2:15][C:16]3[CH:25]=[C:24]([O:26][CH3:27])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH2:13][NH:8][CH2:9][C@H:10]2[O:49][CH2:50][C@H:51]([OH:52])[CH2:55][OH:54])=[CH:29][CH:30]=1
Reactant: COc1ccc(F)cc1COCCCOc1ccc([C@@H]2[C@@H](OCc3cc(OC)c4ccccc4c3)CN(C(=O)OC(C)(C)C)C[C@H]2OC[C@H]2COC(C)(C)O2)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(F)cc1COCCCOc1ccc([C@@H]2[C@@H](OCc3cc(OC)c4ccccc4c3)CNC[C@H]2OC[C@H](O)CO)cc1

Procedure:
In analogy to the procedure described in example 1) (g) the (3S,4R,5R)-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-4-[4-[3-(5-fluoro-2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester was deprotected with HCl in methanol to yield the (R)-3-[(3S,4R,5R)-4-[4-[3-(5-fluoro-2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy]-piperidin-3-yloxy]-propane-1,2-diol as amorphous solid; MS: 650 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][CH2:16][C@H:15]([CH3:18])[N:14]3[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:26][O:27][CH2:28][C@@H:29]1[CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:31]([C:41]2[NH:42][C:43]([C:46]3[CH:51]=[CH:50][C:49](B4OC(C)(C)C(C)(C)O4)=[CH:48][CH:47]=3)=[CH:44][N:45]=2)[CH2:30]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:22]([O:21][C:19]([N:14]1[C@@H:15]([CH3:18])[CH2:16][CH2:17][C@H:13]1[C:11]1[NH:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:49]3[CH:48]=[CH:47][C:46]([C:43]4[NH:42][C:41]([C@@H:31]5[CH2:30][C@H:29]([CH2:28][O:27][CH3:26])[CH2:33][N:32]5[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[N:45][CH:44]=4)=[CH:51][CH:50]=3)=[CH:3][CH:4]=2)=[CH:9][N:10]=1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: C[C@H]1CC[C@@H](c2ncc(-c3ccc(Br)cc3)[nH]2)N1C(=O)OC(C)(C)C
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc(-c4ccc(-c5cnc([C@@H]6CC[C@H](C)N6C(=O)OC(C)(C)C)[nH]5)cc4)cc3)[nH]2)N(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Yield: 70.3 %

Procedure:
To a solution of (2S,5S)-tert-butyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate (1.0 g, 2.5 mmol) and (2S,4S)-tert-butyl 4-(methoxymethyl)-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (1.4 g, 2.8 mmol) in DME (12.5 mL) was added tetrakis(triphenylphosphine)-palladium (0.28 g, 0.24 mmol) and aqueous potassium phosphate (2M, 3.7 mL, 7.4 mmol). The resulting slurry was degassed with argon for 5 min and heated to 80° C. for 18 h. The reaction was cooled to room temperature and diluted with a mixture of CH2Cl2 (10% MeOH). The solution was washed with water and brine. The aqueous layer was backextracted with CH2Cl2 (10% MeOH). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude oil was purified by column chromatography (SiO2, 50 to 100% EtOAc (5% MeOH)/Hexanes) to provide (2S,4S)-tert-butyl 2-(5-(4′-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (1.2 g, 73%). LCMS-ESI+: calc'd for C39H50N6O5: 688.38 (M+). Found: 683.51 (M+H+).
Reaction SMILES: FC(F)(F)[C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.CC1N=CC(CO)=C[N:16]=1>>[CH3:4][C:3]1[N:16]=[CH:5][C:6]([CH2:9][C:10]#[N:11])=[CH:7][N:8]=1
Reactant: Cc1ncc(CO)cn1
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Product: Cc1ncc(CC#N)cn1

Procedure:
(2-Methyl-pyrimidin-5-yl)-acetonitrile was prepared as described above for the synthesis of (6-trifluoromethyl-pyridin-3-yl)-acetonitrile starting from (2-methyl-pyrimidin-5-yl)-methanol
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:16]2[C:11](=[C:12]([CH3:21])[C:13]([CH3:20])=[C:14]([OH:19])[C:15]=2[CH2:17][CH3:18])[O:10][C:6]2([CH2:9][CH2:8][CH2:7]2)[CH2:5]1.Cl>C1COCC1.O1CCOCC1>[CH2:17]([C:15]1[C:14]([OH:19])=[C:13]([CH3:20])[C:12]([CH3:21])=[C:11]2[C:16]=1[CH:4]([NH:3][O:2][CH3:1])[CH2:5][C:6]1([O:10]2)[CH2:9][CH2:8][CH2:7]1)[CH3:18]
Reactant: CCc1c(O)c(C)c(C)c2c1C(=NOC)CC1(CCC1)O2
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCc1c(O)c(C)c(C)c2c1C(NOC)CC1(CCC1)O2
Reaction time: 8 h

Procedure:
5-Ethyl-6-hydroxy-7,8-dimethylspiro[chromene-2,1′-cyclobutan]-4(3H)-one O-methyloxime was dissolved in 10 mL of THF. To this solution at 0° C. was added BH3/pyrine complex (2.27 mL). Subsequently, a solution of 9 mL of HCl in dioxane (4.0 M) was added over a period of 1 hour. The reaction mixture was allowed to stir overnight. The mixture was extracted with ethyl acetate and washed with saturated NaHCO3. After evaporation of the solvents, the residue was purified by flash chromatography eluted with 5-8% ethyl acetate in hexane to give 136.4 mg of the product 5-ethyl-4-(methoxyamino)-7,8-dimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol. 1H-NMR (300 MHz, CDCl3) δ=4.40 (b, 1H), 4.30 (m; 1H), 3.66 (s, 3H), 2.19 (s, 3H), 2.17 (s, 3H), 2.70-1.60 (m, 6H), 1.25 (t, 3H) ppm. 13C-NMR (75 MHz, CDCl3) δ=146.3, 145.2, 126.1, 124.1, 123.4, 114.1, 76.8, 61.8, 52.4, 36.0, 35.0, 32.9, 19.2, 14.9, 13.9, 13.4, 12.4 ppm. MS: (m/z)=245.1 (M−NH2OMe+).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])[C:3]([OH:5])=[O:4].C(OC(N1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32])=O)C>C(=O)([O-])[O-].[Na+].[Na+]>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][CH2:6][CH:2]([N:1]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32])[C:3]([OH:5])=[O:4])([O-:16])=[O:15]
Reactant: NC(CCc1ccccc1[N+](=O)[O-])C(=O)O
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)C(CCc1ccccc1[N+](=O)[O-])N1C(=O)c2ccccc2C1=O
Yield: 70.3 %

Procedure:
In an aqueous solution (150 ml) of 6.1 g of sodium carbonate is dissolved 11.7 g of 2-amino-4-(2-nitrophenyl)butyric acid, and 15 g of N-ethoxycarbonylphthalimide is added to the solution under stirring. After stirring at room temperature overnight, the insoluble material is removed by filtration, and the filtrate is made weakly acidic with concentrated hydrochloric acid. The viscous material, which separates out, is admixed with 50 ml of ethanol, followed by stirring, whereby there separate out crystals. The crystals are collected by filtration and dried to give 13 g of 4-(2-nitrophenyl)-2-phtalimidobutyric acid as colorless crystals. m.p. 177°-179° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[N:9]3[C:10](=[N:15][C:16]([CH3:17])=[C:8]3[C:7]1=[O:18])[CH:11]=[CH:12][CH:13]=2.C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:17][C:16]1[N:15]=[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[N:9]2[C:8]=1[C:7](=[O:18])[N:6]3[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1nc2cccc3n(CCCCN)c(=O)c1n23
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2cccc3n(CCCCNC(=O)c4ccccc4)c(=O)c1n23

Procedure:
To a solution of 2.44 g (10.0 mmol) of 1-[4-(amino)butan-1-yl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one and 2.09 ml (15.0 mmol) of triethylamine in 80 ml of methylene chloride was added, while stirring under ice-cooling, 1.39 ml (12.0 mmol) of benzoyl chloride. The mixture was stirred for 0.5 hour at the same temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate/ethanol=10:1).
Reaction SMILES: C(N(CC)[CH:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:5])C.[C:20]([O:23][C:24]1[C:25](=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:26](Cl)=[O:27])(=[O:22])[CH3:21]>C(C(C)=O)C>[CH2:4]([N:6]([CH2:5][CH2:4][N:6]1[CH2:11][CH2:10][N:9]([C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=2[O:23][C:20](=[O:22])[CH3:21])[CH2:8][CH:7]1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:7][CH3:8])[CH3:5]
Reactant: CCN(CC)C(C)N1CCNCC1c1ccccc1
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Solvent: CCC(C)=O
Product: CCN(CC)CCN1CCN(C(=O)c2ccccc2OC(C)=O)CC1c1ccccc1

Procedure:
4-Diethylaminoethyl-3-phenyl-1-(o-acetoxy benzoyl)piperazine is prepared by boiling under reflux 15 g. of 1-diethylaminoethyl-2-phenyl-piperazine dissolved in 100 ml. of methyl ethyl ketone with 11 g. of acetyl salicyclic acid chloride dissolved in 50 ml. methyl ethyl ketone, for 6 hours. The solvent is removed by distillation. The residue is dissolved in water. The aqueous solution is extracted with benzene. Ammonia is added to the aqueous layer until its reaction is alkaline and the thus precipitated oil is extracted with benzene. The benzene extract is dried by means of potassium carbonate and the benzene is distilled off. The residue is distilled in a vacuum. Boiling point: 190° C./0.01 mm. (bath temperature). Light yellow, viscous oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([N:15]=[N+:16]=[N-:17])[C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1)[CH3:2].[C:20]1([C:26]#[CH:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:18]([N:3]([CH2:1][CH3:2])[C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([N:15]3[CH:27]=[C:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:17]=[N:16]3)[C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1)[CH3:19]
Reactant: C#Cc1ccccc1
Reactant: CCN(CC)c1ccc2cc(N=[N+]=[N-])c(=O)oc2c1
Product: CCN(CC)c1ccc2cc(-n3cc(-c4ccccc4)nn3)c(=O)oc2c1

Procedure:
This example illustrates the fluorogenic conjugation of 7-diethylamino-3-azidocoumarin and phenylacetylene to form 7-diethylamino-3-(4-phenyl-[1,2,3]triazol-1-yl)-chromen-2-one.
Reaction SMILES: [OH:1][C:2]1([CH2:16][CH2:17][N:18]([CH3:32])[CH2:19][CH2:20][CH2:21][C:22]2[NH:23][C:24]3[C:30]([OH:31])=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)[CH2:7][CH:6]2[CH2:8][CH2:9][CH:3]1[CH:4]=[C:5]2[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:33](Cl)(=[O:37])[CH:34]([CH3:36])[CH3:35]>>[C:33]([O:31][C:30]1[C:24]2[NH:23][C:22]([CH2:21][CH2:20][CH2:19][N:18]([CH3:32])[CH2:17][CH2:16][C@:2]3([O:1][C:2](=[O:1])[CH:3]([CH3:9])[CH3:4])[CH2:7][C@H:6]4[CH2:8][CH2:9][C@@H:3]3[CH:4]=[C:5]4[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[N:26][C:25]=2[CH:27]=[CH:28][CH:29]=1)(=[O:37])[CH:34]([CH3:36])[CH3:35]
Reactant: CC(C)C(=O)Cl
Reactant: CN(CCCc1nc2cccc(O)c2[nH]1)CCC1(O)CC2CCC1C=C2c1ccccc1
Product: CC(C)C(=O)Oc1cccc2nc(CCCN(C)CC[C@]3(OC(=O)C(C)C)C[C@H]4CC[C@@H]3C=C4c3ccccc3)[nH]c12

Procedure:
Prepared according to procedure P1.4 in Example 1A using rac-(1R*,2R*,4R*)-2-(3-{[2-(2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-ethyl]-methyl-amino}-propyl)-3H-benzoimidazol-4-ol and 5 eq. of isobutyryl chloride.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)=O.[CH:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(C1C=CC=CC=1)(=O)C>O.C(O)C>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([CH:4]=[CH:3][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:20])=[CH:7][CH:8]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)c1ccccc1
Solvent: CCO
Product: O=C(C=Cc1ccc(Br)cc1)c1ccccc1
Reaction time: 8 h
Yield: 93 %

Procedure:
Sodium hydroxide (1.88 g, 47 mmol) and 4-bromoacetophenone (7.47 g, 37.5 mmol) were dissolved in water (15 mL) and ethanol (50 mL). Benzaldehyde (4.00 g, 37.5 mmol) dissolved in ethanol (20 mL) was added dropwise to the acetophenone solution. A slurry quickly formed, which was allowed to stir overnight. The slurry was filtered, was with water until the filtrate was neutral to pH paper, and dried at 100° C. for 12 hours. A light tan solid was obtained (10.0 g, 93% yield).