Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[O:8].C[Si](C)(C)[C:11]([F:14])([F:13])[F:12].Cl>CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([OH:8])[C:11]([F:14])([F:13])[F:12]
Reactant: O=CCCCCCBr
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: OC(CCCCCBr)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.9 %

Procedure:
Subsequent treatment of 6-bromo-hexanal with trimethyl(trifluoromethyl)silane in the presence of a catalytic amount of tertrabutyl ammonium fluoride (TBAF) resulted in the nucleophilic addition to the carbonyl and afforded the corresponding α-trifluoromethyl alcohol in a single step, a modification of Krishnamurti et al., J. Org. Chem. 1991, 56, 984. A 1.12 g sample of 6-bromo-hexanal (6.26 mmol) was combined with 8 mL freshly distilled THF and trimethyl(trifluoromethyl)silane (1.07 g, 7.51 mmol), all in a 50 mL round bottomed flask under a nitrogen atmosphere. The solution was allowed to stir for 20 min at rt and then cooled to 0° C. for 15 min prior to the addition of 20 mg of TBAF. After observation of initial yellow color formation, the ice bath was removed and solution allowed to warm to room temperature and stirred overnight. Disappearance of the carbonyl band of the starting material was confirmed by FTIR. The resulting reaction mixture was hydrolyzed upon addition of 1 mL of 5 M HCl followed by stirring at rt for 5 hr. The resulting reaction mixture was extracted with Et2O (3×75 mL), washed with di-H2O (50 mL), washed with brine (50 mL) and dried over MgSO4. The resulting organic layer was concentrated to afford the desired product (1.48 g). FTIR: 3283, 2946, 2862, 1633, 1463, 1379, 1272, 1161, 1118, 841 cm−1; 19F NMR—79.93 δ (d, J=7, CF3); 1H NMR: 4.09 (t, J=6, 1H), 3.43 (t, J=7, 2H), 2.35 (bs, 1-OH), 1.91 (t, J=7, 2H), 1.87–1.41 δ (m, 6H); 13C NMR: 121.7 (q, CF3), 82.3, 34.7, 28.7, 25.4, 23.0, 20.8 δ. Anal. Calcd for C7H12BrF3O: C, 33.76; H, 4.86. Found: C, 33.91; H, 4.57.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[C:9]([C:12]2([CH2:18][NH2:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[S:10][CH:11]=1.[F:20][C:21]([F:37])([F:36])[C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[N:23]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[C:9]([C:12]2([CH2:18][NH:19][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([C:24]4[N:23]=[C:22]([C:21]([F:37])([F:36])[F:20])[O:26][N:25]=4)[CH:28]=3)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[S:10][CH:11]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCC1(c2nc(-c3ccccn3)cs2)CCOCC1
Product: O=C(NCC1(c2nc(-c3ccccn3)cs2)CCOCC1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 13 %

Procedure:
This compound was synthesized from (4-(4-(pyridin-2-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (35 mg, yield 13%). 1H NMR (400 MHz, MeOD) δ 8.54 (d, J=5.5 Hz, 1H), 8.44 (m, 1H), 8.25 (d, J=8.0 Hz, 1H), 8.17 (s, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.97 (d, J=7.8 Hz, 1H), 7.79 (td, J=7.7 Hz, 1.6 Hz, 1H), 7.62 (t, J=7.8 Hz, 1H), 7.32 (m, 1H), 3.97-3.93 (dt, J=11.8 Hz, 3.8 Hz, 2H), 3.75 (m, 2H), 3.62-3.56 (m, 2H), 2.47-2.44 (m, 2H), 2.12-2.08 (ddd, J=14.1 Hz, 10.5 Hz, 4.3 Hz, 2H). MS (ESI) m/z: Calculated for C24H20F3N5O3S: 515.12. found: 516.0 (M+H)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH2:9][C@@H:10]1[O:14][C:13](=[O:15])[N:12]([C:16]2[CH:21]=[CH:20][C:19]([NH:22]C(OC(C)(C)C)=O)=[C:18]([F:30])[CH:17]=2)[CH2:11]1.N1C=CC=CC=1>C(Cl)Cl>[C:1]([NH:8][CH2:9][C@@H:10]1[O:14][C:13](=[O:15])[N:12]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([F:30])[CH:17]=2)[CH2:11]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(N2C[C@H](CN)OC2=O)cc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(N)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Acetic anhydride (0.15 mL) was added to a solution of 5-(S)-aminomethyl-3-[4′-(tert-butoxycarbonyl)amino-3′-fluorophenyl]oxazolidine-2-one (0.325 g, 1.0 mmol) and pyridine (0.25 mL) in DCM (4.0 mL). The mixture was stirred at r.t. for 4 h, and solvent was removed under vacuum. The resulted 5-(S)-acetamidomethyl-3-[4′-(tert-butoxycarbonyl)amino-3′-fluorophenyl]oxazoli-dine-2-one was washed with water (2×3 mL), diethyl ether (3 mL), and dried under vacuum. 50% TFA in DCM (3 mL) was added, and the mixture was kept at r.t. for 1 h. Solvents were removed under vacuum, and the residue distributed between ethyl acetate (40 mL) and saturated aq. sodium bicarbonate (20 mL). Organic layer was washed with aq. sodium bicarbonate, water, brine, dried (MgSO4). Solvent was removed under vacuum to afford the product as a white solid. Yield 0.25 g (95%). MS (m/z): [M+H]+=268.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.[C:12]([O:16][C:17](=[O:28])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22][N:21]=1)([CH3:15])([CH3:14])[CH3:13].[OH-].[K+]>CCO>[C:12]([O:16][C:17](=[O:28])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:10]/[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=2)=[O:11])=[CH:22][N:21]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(=O)c1ccc(CO)cc1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C=O)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)/C=C/c1ccc(/C=C/C(=O)c2ccc(CO)cc2)cn1
Temperature: 0 °C
Reaction time: 5 h
Yield: 34.5 %

Procedure:
A solution of 1-(4-hydroxymethyl-phenyl)-ethanone (750 mg, 5 mmol) in EtOH (15 ml) was added dropwise at 0° C. to a stirred solution of (E)-3-(5-formyl-pyridin-2-yl)-acrylic acid tert-butyl ester (described in Example 11 STEP A-D, 1.16 g, 5 mmol) and 1.7 M KOH (4.4 ml) in EtOH (10 ml). The mixture was stirred at 0° C. for 5 h and the resulting precipitate was filtered and triturated with di-isopropylether to give 630 mg of desired (E)-3-{5-[(E)-3-(4-hydroxymethyl-phenyl)-3-oxo-propenyl]-pyridin-2-yl}-acrylic acid tert-butyl ester. The mother liquors were diluted with water and extracted with AcOEt. The organic layer was dried over Na2SO4 and evaporated in vacuo. The residue was triturated with EtOH to give additional 70 mg of (E)-3-{5-[(E)-3-(4-hydroxymethyl-phenyl)-3-oxo-propenyl]-pyridin-2-yl}-acrylic acid tert-butyl ester.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[C:15]#[N:16])[CH2:9][CH2:8]1.[F:21][C:22]1[CH:23]=[C:24]([C@@H:29]2[C:34]([C:35](O)=[O:36])=[C:33]([CH3:38])[NH:32][C:31](=[O:39])[NH:30]2)[CH:25]=[CH:26][C:27]=1[F:28]>>[C:15]([C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[CH:10]1[CH2:9][CH2:8][N:7]([CH2:6][CH2:5][CH2:4][NH:3][C:35]([C:34]2[C@@H:29]([C:24]3[CH:25]=[CH:26][C:27]([F:28])=[C:22]([F:21])[CH:23]=3)[NH:30][C:31](=[O:39])[NH:32][C:33]=2[CH3:38])=[O:36])[CH2:12][CH2:11]1)#[N:16]
Reactant: N#Cc1ccccc1C1CCN(CCCN)CC1
Reactant: CC1=C(C(=O)O)[C@@H](c2ccc(F)c(F)c2)NC(=O)N1
Agent: Cl
Product: CC1=C(C(=O)NCCCN2CCC(c3ccccc3C#N)CC2)[C@@H](c2ccc(F)c(F)c2)NC(=O)N1

Procedure:
2-[1-(3-amino-propyl)-piperidine-4-yl]-benzonitrile dihydrochloride as used in place of 2-[1-(3-amino-propyl)-piperidine-4-yl]-5-fluoro-enzonitnile dihydrochloride and (R)-4-(3,4-difluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid was used in place of (4R)-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15](O)=[O:16])=[CH:9][CH:8]=1.[CH3:21][NH2:22]>>[CH3:21][NH:22][C:15](=[O:16])[C:14]#[C:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[C:2]([F:1])[CH:3]=2)=[CH:8][CH:9]=1
Reactant: O=C(O)C#Cc1ccc(OCc2cccc(F)c2)cc1
Reactant: CN
Product: CNC(=O)C#Cc1ccc(OCc2cccc(F)c2)cc1
Yield: 45 %

Procedure:
The title compound is prepared in analogy to example 5 d), starting from [4-(3-fluoro-benzyloxy)-phenyl]-propynoic acid and aqueous methylamine. Colorless solid. Yield=45%. MS: m/e=284.1 (M++H).
Reaction SMILES: [CH:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C)C=O>[CH2:24]([N:13]1[CH2:14][CH2:15][CH:10]([C:8](=[O:9])[C:7]2[CH:16]=[CH:17][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)[CH2:11][CH2:12]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)c1ccc(C(=O)C2CCNCC2)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1ccc(C(=O)C2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 66 %

Procedure:
To a solution of 4-(4-isopropylbenzoyl)piperidine in N,N-dimethylformamide (100 mL), potassium carbonate (9.60 g, 69.5 mmol) and benzyl bromide (8.50 g, 71.5 mmol) were added, and the resulting mixture was stirred for 20 hours at room temperature. The mixture was poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium hydrogencarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from hexane to obtain the title compound (13.53 g, yield 66%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2.[CH2:20]([O:22]C1C=CC=C2C=1NC=C2)[CH3:21]>>[CH2:20]([O:22][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2)[CH3:21]
Reactant: CCOc1cccc2cc[nH]c12
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Product: CCOc1cccc2cc(B3OC(C)(C)C(C)(C)O3)[nH]c12

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 7-ethoxy-1H-indole.
Reaction SMILES: [N:1]1([C:6]2[N:7]=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:9]3[CH2:15][NH:14][CH2:13][CH2:12][C:10]=3[N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:27](C)=O.[Na+]>CO.[OH-].[Na+]>[CH3:27][N:14]1[CH2:13][CH2:12][C:10]2[N:11]=[C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[N:7]=[C:8]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)[C:9]=2[CH2:15]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1ccc(-c2nc(N3CCCC3)nc3c2CNCC3)cc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2nc(N3CCCC3)nc3c2CN(C)CC3)cc1
Yield: 89.2 %

Procedure:
To a solution of 2-pyrrolidin-1-yl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (0.034 g, 0.12 mmol) in MeOH (2 mL) was added formaldehyde (37% in water; 0.10 mL) and NaBH(OAc)3 (0.030 g, 0.14 mmol). After the reaction was judged complete, the mixture was diluted with 1 N NaOH and extracted with CH2Cl2 (3×). The combined organic layers were dried and concentrated. The resulting residue was purified by FCC (2 M NH3 in MeOH/CH2Cl2) to give 0.033 g (91%) of the title compound. HPLC: Rt=8.2 min. MS (ESI): mass calcd. for C19H24N4, 308.4; m/z found, 309.5 [M+H]+. 1H NMR (CDCl3): 7.44 (d, J=8.1, 2H), 7.24 (d, J=7.9, 2H), 3.61-3.58 (m, 4H), 3.42 (5, 2H), 2.92 (dd, J=6.1, 6.0, 2H), 2.74 (dd, J=6.1, 6.0, 2H), 2.40 (5, 3H), 2.39 (5, 3H), 1.97-1.94 (m, 4H).
Reaction SMILES: [F:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:16])[C:12]=2[C:13]([OH:15])=O)=[O:7])[CH2:3]1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:25]2[N:26]=[C:27]3[N:32]=[C:31]([NH2:33])[CH:30]=[CH:29][N:28]3[CH:34]=2)[CH:22]=[CH:23][CH:24]=1>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:25]2[N:26]=[C:27]3[N:32]=[C:31]([NH:33][C:13]([C:12]4[N:11]([CH3:16])[N:10]=[CH:9][C:8]=4[C:6]([N:4]4[CH2:3][CH:2]([F:1])[CH2:5]4)=[O:7])=[O:15])[CH:30]=[CH:29][N:28]3[CH:34]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: COc1cccc(-c2cn3ccc(N)nc3n2)c1
Reactant: Cn1ncc(C(=O)N2CC(F)C2)c1C(=O)O
Product: COc1cccc(-c2cn3ccc(NC(=O)c4c(C(=O)N5CC(F)C5)cnn4C)nc3n2)c1

Procedure:
The title compound was prepared in analogy to example 82 from 4-(3-fluoroazetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (100 mg, 440 μmol) and 2-(3-methoxyphenyl)imidazo[1,2-a]pyrimidin-7-amine (106). Yellow solid (142 mg, 72%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([OH:25])=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:23](=[O:25])[CH2:22][O:21][C:18]2[CH:19]=[N:20][C:15]([C:12]3[CH:11]=[CH:10][C:9]([F:8])=[CH:14][CH:13]=3)=[CH:16][CH:17]=2)=[CH:29][CH:28]=1
Reactant: O=C(O)COc1ccc(-c2ccc(F)cc2)nc1
Reactant: Nc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1ccc(-c2ccc(F)cc2)nc1)Nc1ccc(F)cc1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 95 mg (0.26 mmol) of [6-(4-fluoro-phenyl)-pyridin-3-yloxy]-acetic acid trifluoroacetic acid salt and 43.8 mg (0.39 mmol) of 4-fluoroaniline. Yield: 31 mg.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17]>>[Cl:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:17])[C:10]=1[CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: ClCc1c(Cl)cccc1Cl
Reactant: O=C1CCNCC1
Product: O=C1CCN(Cc2c(Cl)cccc2Cl)CC1

Procedure:
1-(2,6-Dichlorobenzyl)-4-piperidone is prepared from 4-piperidone and α,2,6-trichlorotoluene essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:36]=[CH:35][C:12]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][C:18]4[CH:19]=[C:20]([CH:32]=[CH:33][CH:34]=4)[O:21][C:22]([CH3:31])([CH3:30])[C:23]([O:25]C(C)(C)C)=[O:24])=[CH:11][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.Cl[C:38]1[O:39][C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:41][N:42]=1>>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:10]=[CH:11][C:12]([CH2:13][N:14]([C:38]4[O:39][C:40]([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)=[CH:41][N:42]=4)[CH2:15][CH2:16][CH2:17][C:18]4[CH:19]=[C:20]([CH:32]=[CH:33][CH:34]=4)[O:21][C:22]([CH3:30])([CH3:31])[C:23]([OH:25])=[O:24])=[CH:35][CH:36]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: Clc1ncc(-c2ccccc2)o1
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CCCNCc2ccc(-c3noc(C4CC4)n3)cc2)c1
Product: CC(C)(Oc1cccc(CCCN(Cc2ccc(-c3noc(C4CC4)n3)cc2)c2ncc(-c3ccccc3)o2)c1)C(=O)O

Procedure:
Similarly prepared from tert-butyl 2-[3-(3-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl]amino}propyl)phenoxy]-2-methylpropanoate and 2-chloro-5-phenyl-oxazole (ref. GB1552125).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][C:5]=2[N:6]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:16]=1[CH:17]=O>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:16]=1[CH:17]1[N:12]([CH2:11][C:8]2[CH:9]=[CH:10][C:4]3[O:3][C:2]([CH3:1])=[N:6][C:5]=3[CH:7]=2)[C:4](=[O:3])[CH2:5][CH2:7][CH2:8]1
Reactant: Cc1nc2cc(CN)ccc2o1
Reactant: COc1cccc(OC)c1C=O
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc2oc(C)nc2c1

Procedure:
Prepared according to the described general procedure 6 (GP6) with (2-methylbenzo[d]oxazol-5-yl)methanamine and commercially available 2,6-dimethoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.70 min.; [M+H]+: 381.27 g/mol.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:20]1[CH2:44][CH:21]1[CH2:22][O:23][CH:24]1[CH2:29][CH2:28][CH:27]([C:30]([CH:33]2[CH2:38][CH2:37]C(OCC3OC3)CC2)([CH3:32])[CH3:31])[CH2:26][CH2:25]1>>[OH:20][CH:21]([CH2:44][N:13]1[C:12]([CH3:19])([CH3:18])[CH2:11][CH:10]([O:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:15][C:14]1([CH3:17])[CH3:16])[CH2:22][O:23][CH:24]1[CH2:25][CH2:26][CH:27]([C:30]([CH:33]2[CH2:26][CH2:25][CH:24]([O:23][CH2:22][CH:21]([OH:20])[CH2:44][N:13]3[C:14]([CH3:17])([CH3:16])[CH2:15][CH:10]([O:9][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:11][C:12]3([CH3:19])[CH3:18])[CH2:37][CH2:38]2)([CH3:32])[CH3:31])[CH2:28][CH2:29]1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1
Reactant: CC(C)(C1CCC(OCC2CO2)CC1)C1CCC(OCC2CO2)CC1
Product: CC(C)(C1CCC(OCC(O)CN2C(C)(C)CC(OC(=O)c3ccccc3)CC2(C)C)CC1)C1CCC(OCC(O)CN2C(C)(C)CC(OC(=O)c3ccccc3)CC2(C)C)CC1

Procedure:
A mixture of 30.0 g of 4-benzoyloxy-2,2,6,6-tetramethylpiperidine and 15.0 g of 2,2-bis[4-(2,3-epoxypropoxy)cyclohexyl]propane was reacted folowing the procedure described in Example 5, giving the desired Compound No. 78 in the form of a colourless, viscous liquid. The Compound had an Rf value of 0.70 on thin-layer chromatography on silica gel developed with a 15:5:1 by volume mixture of n-hexane, triethylamine and ethanol.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[Ca+2].[OH-].Cl[CH:13]([CH3:21])[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15]>CS(C)=O>[OH:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][CH:13]([CH3:21])[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: CCCCOC(=O)C(C)Cl
Agent: [Ca+2]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCOC(=O)C(C)Oc1ccc(O)cc1
Reaction time: 1 h
Yield: 46.2 %

Procedure:
121 g (1.1 moles) of hydroquinone were dissolved in 500 ml of dimethylsulfoxide, 37 g (0.5 mole) of calcium hydroxide were added to the solution, and the mixture was stirred for 1 hour at 45°-50° C. Thereafter, 82.3 g (0.455 mole) of optically active n-butyl 2-chloropropionate (αD20 =-13.0°) were added dropwise in the course of 1 hour at the same temperature. The mixture was stirred for a further 3 hours at 45°-50° C., cooled, and worked up as described in Example 1. 49.7 g (0.21 mole) of optically active n-butyl 2-(4-hydroxyphenoxy)-propionate were obtained. Yield: 46.2%; bp. =150°-152° C./0.22 mbar; αD20 =+11.8° ##STR7##
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH2:7][OH:8])[NH:4][N:3]=1.CCO/[CH:12]=[C:13](/[CH:15]=O)\[CH3:14]>C(O)(=O)C>[CH3:15][C:13]1[CH:12]=[N:1][C:2]2[N:3]([N:4]=[C:5]([CH2:7][OH:8])[N:6]=2)[CH:14]=1
Reactant: Nc1n[nH]c(CO)n1
Reactant: CCO/C=C(\C)C=O
Solvent: CC(=O)O
Product: Cc1cnc2nc(CO)nn2c1
Temperature: 80 °C

Procedure:
To a solution of (3-amino-1H-1,2,4-triazol-5-yl)methanol (16.6 g, 87.6 mmol) in acetic cid was added 3-ethoxymethacrolein (10.0 g, 87.6 mmol), and the mixture was heated to 80° C. for 4 hours. Upon cooling of the reaction, the product crystallized out of solution. The collected product was a white solid (14.0 g, 92%). 1H NMR (300 MHz, DMSO-D6) δ: 2.38 (m, 3H) 4.63 (m, 2H) 5.52 (m, 1H) 8.75 (m, 1H) 9.21 (m, 1H). MS (APCI, M+H+): 163.1, 165.1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:10][CH2:11][CH2:12][C@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)O>CO>[Cl:10][CH2:11][CH2:12][C@H:13]([N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1cnc2cc[nH]c2c1
Reactant: O[C@H](CCCl)c1ccccc1
Solvent: CO
Product: ClCC[C@@H](c1ccccc1)n1ccc2ncccc21
Yield: 24 %

Procedure:
1-(3-Chloro-1-(S)-phenyl-propyl)-1H-pyrrolo[3,2-b]pyridine was prepared from 1H-pyrrolo[3,2-b]pyridine and 3-chloro-1-(R)-phenyl-propan-1-ol following the procedure described in steps 1 and 2 of Example 11 (24% yield [268 mg, αD=−111.0° (MeOH, c=1)].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[N:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[C:31](Cl)=[O:32]>CN(C)C(=O)C>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([F:24])=[C:2]([NH:1][C:31]([C:26]5[CH:27]=[N:28][CH:29]=[CH:30][N:25]=5)=[O:32])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: O=C(Cl)c1cnccn1
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F)c1cnccn1
Yield: 26.1 %

Procedure:
Using a solution of N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (327 mg, 1.0 mmol) and 2-pyrazinecarbonylchloride (171 mg, 1.2 mmol) in N,N-dimethylacetamide (6.0 mL), and by a reaction in the same manner as in Example 148, the title compound (113 mg, 26%) was obtained as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)=[CH:16][C:15]=2[CH:26]=O)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:29]([NH2:31])[CH3:30]>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)=[CH:16][C:15]=2[CH2:26][NH:31][CH2:29][CH3:30])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCN
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3cnn(C)c3)cc2C=O)c1
Product: CCNCc1cc(-c2cnn(C)c2)ccc1-c1cc(CC(=O)OCC)ccc1OC

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using the following starting materials: [2′-formyl-6-methoxy-4′-(1-methyl-1H-pyrazol-4-yl)-biphenyl-3-yl]-acetic acid ethyl ester and ethylamine (2M in THF).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]([CH3:12])([OH:11])[CH3:10])[C:6]=1[CH3:7].C1COCC1.C([Mg]Cl)(C)C.CO[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1.[NH4+].[Cl-]>>[CH3:10][C:9]([OH:11])([CH3:12])[CH2:8][N:5]1[C:6]([CH3:7])=[C:2]([B:25]2[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]2)[CH:3]=[N:4]1
Reactant: COB1OC(C)(C)C(C)(C)O1
Reactant: Cc1c(I)cnn1CC(C)(C)O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1CC(C)(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-(4-iodo-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (150.0 mg, 0.5355 mmol) in THF (8 mL, 100 mmol) was added 2 M isopropylmagnesium chloride in THF (0.80 mL, 1.6 mmol) at 0° C., and the reaction was allowed to warm to rt over 30 min. 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.35 mL, 2.1 mmol) was then added, and the mixture was stirred at rt overnight. Sat. NH4Cl was added to quench, and the organic solvent was removed in vacuo. The material was extracted with DCM and water, and the organic layer was concentrated in vacuo to afford the title compound as a white solid. The material was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([CH3:13])=[C:7]([OH:12])[CH:8]=2)[N:3]=1.[Br:14]Br>C(O)(=O)C>[Br:14][C:8]1[C:7]([OH:12])=[C:6]([CH3:13])[CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]2
Reactant: BrBr
Reactant: Cc1ccc2cc(O)c(C)cc2n1
Solvent: CC(=O)O
Product: Cc1ccc2c(Br)c(O)c(C)cc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2,7-dimethylquinolin-6-ol (200 mg, 1.2 mmol) in acetic acid (10 mL) was added Br2 (0.062 mL, 1.21 mmol) at ambient temperature. The mixture was stirred at ambient temperature for 0.5 hour. The solid formed was filtered and collected, washed with 2 mL acetic acid to give the product as an HBr salt. LCMS-ESI+: calc'd for C11H10BrNO: 252.0 (M+H+); Found: 252.2 (M+H+).