Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7](=O)[CH2:8][C:9]1[CH:13]=[CH:12][S:11][CH:10]=1.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25]=1[OH:26])[CH:21]=O)[CH3:16].[NH2:30][C:31]([NH2:33])=[O:32].[ClH:34]>C(O)C>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:21]2[C:8]([C:9]3[CH:13]=[CH:12][S:11][CH:10]=3)=[C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)[NH:33][C:31](=[O:32])[NH:30]2)[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25]=1[OH:26])[CH3:16].[ClH:34]
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: NC(N)=O
Reactant: O=C(Cc1ccsc1)c1cnccn1
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3cnccn3)=C2c2ccsc2)cc([N+](=O)[O-])c1O

Procedure:
To a solution of 1-(pyrazin-2-yl)-2-(thiophen-3-yl)ethanone (Intermediate 66) (30 mg, 0.15 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (31 mg, 0.15 mmol) and urea (27 mg, 0.45 mmol) in 2 mL of ethanol was added 0.2 mL of conc. HCl, and was stirred at reflux overnight. The mixture was cooled and then purified by preparative HPLC (30-60% acetonitrile+0.15% trifluoroacetic acid in water, over 15 min.), the desired eluting solution was treated with HCl/MeOH (2 mL, 2M) and concentrated in vacuo to give Compound 131 as HCl salt (8.3 mg, yield 12.3%). 1H NMR (CD3OD 400 MHz): δ 8.69 (dd, J=1.6 Hz, 2.4 Hz, 1H), 8.48 (d, J=3.6 Hz, 1H), 8.17 (d, J=1.6 Hz, 1H), 7.60 (d, J=2.0 Hz, 1H), 7.37 (dd, J=3.2 Hz, 5.2 Hz, 1H), 7.18 (d, J=2.0 Hz, 1H), 7.02 (dd, J=1.2 Hz, 2.8 Hz, 1H), 6.66 (dd, J=1.2 Hz, 5.2 Hz, 1H), 5.42 (s, 1H), 4.11-4.06 (m, 2H), 1.42 (t, J=7.2 Hz, 3H); MS (ESI): m/z 440.2 [M+1]+.
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([C:50]1([OH:53])[CH2:52][CH2:51]1)[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([C:50]4([OH:53])[CH2:51][CH2:52]4)([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C5(O)CC5)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Solvent: Clc1ccccc1Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C5(O)CC5)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.8 %

Procedure:
To a solution of 1-[(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]cyclopropanol 6a (75 mg, 0.1 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 5 mL) were added o-dichlorobenzene (74.97 mg, 0.51 mmol) and 10% Pd/C (15 mg, 0.01 mmol) in turn. The mixture was stirred at room temperature under H2 for 4 hours and filtered. The filter cake was washed with a methanol/tetrahydrofuran mixture (v/v=4/1, 10 mL×2). The combined filtrates were concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=1/4 to give the title compound 6 as colourless oil (24 mg, 50.0%, HPLC: 83.3%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 463.1[M+H]+; and 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.38 (m, 2H), 7.29 (m, 1H), 7.10 (m, 2H), 6.84 (m, 2H), 5.27 (s, 1H), 5.19 (d, 1H), 5.02 (d, 1H), 4.95 (d, 1H), 4.06 (m, 1H), 3.99 (m, 3H), 3.96 (m, 1H), 3.80 (t, 1H), 3.41 (m, 2H), 3.29 (m, 1H), 1.31 (t, 3H), 0.55 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[O:19])[NH:9]2)[CH:7]=1.C(N(CC)CC)C.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[CH:37])[CH:31]=1>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.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>[Cl:29][C:30]1[CH:31]=[C:32]([C:36]#[C:37][C:2]2[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]3([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[O:19])[NH:9]3)[CH:7]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: C#Cc1cccc(Cl)c1
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(Br)ccc2F)C1(F)F
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)OCC(=O)N[C@](C)(c2cc(C#Cc3cccc(Cl)c3)ccc2F)C1(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.6 %

Procedure:
A dried pressure tube was charged with (R)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepan-3-one (intermediate B6.1) (250 mg, 622 μmol) and dimethylformamide (2 ml). The solution was flushed with argon, thereafter, successively bis(triphenylphosphin)palladium(II)chloride (31.2 mg, 43.5 μmol), triphenylphoshine (3.26 mg, 12.4 μmol), triethylamine (126 mg, 1.24 mmol), 1-chloro-3-ethynylbenzene (175 mg, 1.24 mmol), and copper(i) iodide (3.6 mg, 18.7 μmol) were added. The tube was sealed and the reaction mixture stirred at room temperature for 10 minutes, then it was heated at 60° C. for 16 hours. For the workup, the reaction mixture was cooled and evaporated at reduced pressure. The residue was directly purified by chromatography on an amine-silica phase using a gradient of heptane/ethyl acetate=100:0 to 60:10 as the eluent. The (R)-5-[5-(3-chloro-phenylethynyl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one (235 mg, 90% yield) was obtained as a green foam. MS (ISP): m/z=422.1 [M+2+H]+ and 424.2 [M+H]+.
Reaction SMILES: [CH:1]1[CH:5]=[C:4]([CH:6]=O)[O:3][CH:2]=1.[NH2:8][CH2:9][CH2:10][OH:11].C[C@H](NC([C@H]1N(C([C@@H](NC([C@@H](N)CC2C=CC(O)=CC=2)=O)CC(O)=O)=O)CCC1)=O)C(N1[C@H](C(N2[C@H](C(N3[C@H](C(N4[C@H](C(N5[C@H](C(N6[C@H](C(O)=O)CCC6)=O)CCC5)=O)CCC4)=O)CCC3)=O)CCC2)=O)CCC1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[O:3]1[CH:2]=[CH:1][CH:5]=[C:4]1[CH2:6][NH:8][CH2:9][CH2:10][OH:11]
Reactant: NCCO
Reactant: O=Cc1ccco1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(=O)O)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Agent: [Na+]
Solvent: ClCCCl
Product: OCCNCc1ccco1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
An aldehyde, e.g., 2-furfuraldehyde (2 g, 20.82 mmol), and an amine, e.g., 2-aminoethanol, (1.65 g, 27.06 mmol) were poured together in a mixture 1:1 TMOF:DCE (50 ml) and the reaction mixture was cooled down to zero degree. The reducing agent NaBH(OAc)3 (6.18 g, 29.14 mmol) was added in 4 subsequent portions over a 5 min period, the reaction mixture was allowed to gradually warm to room temperature and stirred for 16 hours. The solvents was removed from the reaction in vacuo and the residue was partitioned between dichloromethane (150 ml) and saturated bicarbonate solution (50 ml). After separation, the organic layer was washed with saturated bicarbonate solution (50 ml) and brine (50 ml). The combined organic layers were then dried over sodium sulphate, filtered and the solvent removed in vacuo. The desired secondary amines, e.g., 2-[(2-furylmethyl)amino]ethanol, were obtained as a yellowish oil (1.82 g, 62%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][CH:41]([CH2:44][CH2:45][C:46]([OH:48])=[O:47])[CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:38]3[CH2:43][CH2:42][CH:41]([CH2:44][CH2:45][C:46]([OH:48])=[O:47])[CH2:40][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C(O)CCC1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CCC(=O)O)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 3-piperidin-4-yl-propionic acid (Astatech) to give the title compound. HR-MS (ES, m/z) calculated for C37H45Cl2N4O4 [(M+H)+] 679.2813, observed 679.2814.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>CN(C=O)C.O>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][C:13]([Br:18])=[C:12]([NH2:17])[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cccc2c1cnn2Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(Br)ccc2c1cnn2Cc1ccccc1
Reaction time: 4 h
Yield: 4.2 %

Procedure:
A solution of 1-benzyl-1H-indazol-4-amine (0.087 g, 0.39 mmol) in DMF (2 mL) was treated with N-bromosuccinimide (0.069 g, 0.39 mmol) at ambient temperature and stirred for 4 hours. The mixture was diluted with water, extracted with EtOAc, dried (phase separator silicone treated filter paper), concentrated and purified on silica gel (10-50% EtOAc in hexanes) to provide 1-benzyl-5-bromo-1H-indazol-4-amine (0.005 g, 4% yield).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][SH:5].[C:6]1([C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.B(F)(F)F>C(O)(=O)C>[CH:23]1[CH:24]=[CH:25][C:20]([C:12]([S:5][CH2:4][CH2:3][NH2:2])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:21][CH:22]=1.[ClH:1]
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCS
Agent: Cl
Agent: FB(F)F
Solvent: CC(=O)O
Product: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
1 equivalent of cysteamine hydrochloride and 1 equivalent of triphenylmethanol are dissolved in glacial acetic acid at 60° and treated with stirring with 1.1 equivalents of BF3 etherate. The mixture is stirred for one hour and worked up in the customary manner and Trt-cysteamine hydrochloride (“C”) is obtained.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:31]O.Cl>CO.O.C(Cl)Cl>[CH3:27][S:24]([C:21]1[CH:22]=[CH:23][C:18]([C@H:10]2[CH2:9][C@@H:8]([C:6]3[O:7][NH:31][C:4](=[O:3])[CH:5]=3)[CH2:13][CH2:12][N:11]2[C:14]([O:16][CH3:17])=[O:15])=[CH:19][CH:20]=1)(=[O:26])=[O:25]
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccc(S(C)(=O)=O)cc2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(S(C)(=O)=O)cc1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 49.9 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(methylsulfonyl)phenyl)piperidine-1-carboxylate (2.6 g, 6.32 mmol) was suspended in MeOH (100 mL). DCM (40 mL) was added and the reaction cooled to −40° C. 3.8 M sodium hydroxide (1.663 mL, 6.32 mmol) in water (10.00 mL) was added and the reaction stirred at −40° C. for 20 min. Hydroxylamine (50% in water, 0.387 mL, 6.32 mmol) was added and the reaction stirred at −40° C. for 3 h. The reaction mixture was then added to a prewarmed 80° C. solution of 6 M hydrogen chloride (63.2 mL, 379.13 mmol) and the reaction stirred for 30 min. The solvent was evaporated in vacuo. DCM (250 mL) and water (250 mL) were added, shaken and the phases separated. The organic phase was dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 15-45% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(4-(methylsulfonyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.200 g, 49.9%) was isolated as a white solid. 1H NMR (600 MHz, cdcl3) δ 1.85-1.91 (m, 1H), 2.18-2.29 (m, 2H), 2.35-2.41 (m, 1H), 2.98 (s, 3H), 3.00-3.13 (m, 1H), 3.38-3.44 (m, 1H), 3.67 (s, 3H), 4.13-4.19 (m, 1H), 5.20 (t, 1H), 5.47 (s, 1H), 7.34 (d, 2H), 7.83 (d, 2H). MS m/z 381 (M+H)+
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][CH:17]([CH3:19])[CH3:18])(=O)=O.[Cl:20]C1C=C2C(=CC=1)NC=C2CC(N)(C)C.[CH3:35][S:36]([C:39]1[NH:40][C:41]2[C:46]([C:47]=1[CH2:48][C:49]([NH2:52])([CH3:51])[CH3:50])=[CH:45][CH:44]=[CH:43][CH:42]=2)(=[O:38])=[O:37]>>[ClH:20].[CH3:35][S:36]([C:39]1[NH:40][C:41]2[C:46]([C:47]=1[CH2:48][C:49]([NH:52][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][CH:17]([CH3:18])[CH3:19])([CH3:50])[CH3:51])=[CH:45][CH:44]=[CH:43][CH:42]=2)(=[O:38])=[O:37]
Reactant: CC(C)(N)Cc1c[nH]c2ccc(Cl)cc12
Reactant: CC(C)(N)Cc1c(S(C)(=O)=O)[nH]c2ccccc12
Reactant: CC(C)COc1ccccc1OCCOS(C)(=O)=O
Product: CC(C)COc1ccccc1OCCNC(C)(C)Cc1c(S(C)(=O)=O)[nH]c2ccccc12
Product: Cl

Procedure:
Proceeding as an Example 3, but replacing 2-[2-(cyclopropylmethyloxy)phenoxy]ethyl methanesulfonate with 2-[2-(2-methylprop-1-yloxy)phenoxy]ethyl methanesulfonate and [2-(5-chloro-1H-indol-3-yl)-1,1-dimethylethyl]amine with [2-(2-methylsulfonyl-1H-indol-3-yl)-1,1-dimethylethyl]amine, gave [2-(2-methylsulfonyl -1H-indol-3-yl)-1,1-dimethylethyl]{2-[2-(2-methylprop-1-yloxy)phenoxy]ethyl}amine hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]#N)=[N:4][CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].CC1C(CN)=NC=C(C)C=1[O:20]C.N([O-])=O.[Na+]>>[CH3:1][C:2]1[C:3]([CH2:11][OH:20])=[N:4][CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9]
Reactant: COc1c(C)cnc(CN)c1C
Reactant: COc1c(C)cnc(C#N)c1C
Agent: O=N[O-]
Agent: [Na+]
Product: COc1c(C)cnc(CO)c1C

Procedure:
The invention accordingly relates to a process for the preparation of compounds of formula I ##STR2## in which X is the radical OH or Cl , comprising catalytical hydrogenation of 3,5-dimethyl-4-methoxy-2-cyanopyridine of formula II in the presence of an inert diluent, the resulting 3,5-dimethyl-4-methoxy-2-aminomethylpyridine of formula III ##STR3## being then reacted with sodium nitrite in aqueous-acidic solution to give 3,5-dimethyl-4-methoxy-2-hydroxymethylpyridine and, if desired, the latter being then reacted with thionyl chloride to give 3,5-dimethyl-4-methoxy-2-chlormethylpyridine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1[CH2:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17].N1C=CN=C1>ClCCl>[Si:20]([O:15][CH2:14][C@@H:9]1[CH2:10][O:11][CH2:12][CH2:13][N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC[C@@H]1COCCN1Cc1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1COCCN1Cc1ccccc1
Yield: 95.2 %

Procedure:
(3R)-4-Benzylmorpholine-3-methanol (1.04 g, 5.0 mmol), t-butyldimethylchlorosilane (0.83 g, 5.5 mol), and imidazole (0.41 g, 6.0 mmol) were allowed to react in 5 mL of dichloromethane at room temperature overnight. The reaction product was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain (3S)-3-(t-butyldimethylsilyloxy)methyl-4-benzylmorpholine (1.53 g, 95%) as a colorless oil.
Reaction SMILES: [C:1]1([C:6]([C:8]2[CH:18]=[CH:17][C:11]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:20](O)[CH3:21]>>[C:1]1([C:6]([C:8]2[CH:18]=[CH:17][C:11]([CH:12]([CH3:16])[C:13]([O:15][CH2:20][CH3:21])=[O:14])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C(=O)O)c1ccc(C(=O)c2cccs2)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(C)c1ccc(C(=O)c2cccs2)cc1

Procedure:
A mixture of 5.2 parts of p-(2-thenoyl)hydratropic acid, 40 parts of absolute denatured ethanol and 0.5 parts of hydrochloric acid solution is stirred and refluxed for 24 hours. The reaction mixture is evaporated and the residue is taken up in ether. The ethereal solution is shaken with alkaline water, separated and shaken twice with water. The ether phase is dried, filtered and evaporated, yielding ethyl p-(2-thenoyl)hydratropate, also named ethyl p-(2-thenoyl)-α-methyl-phenylacetate, as a residue.
Reaction SMILES: [Br:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:11]C(O)=O>CCOCC.C1COCC1>[Br:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:11])=[O:5]
Reactant: O=C(O)c1cccnc1Br
Reactant: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1cccnc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A solution of CH2N2 (4 eq.) in Et2O (1 M) was added dropwise to a solution of 2-bromonicotinic acid in THF (0.5 M) at RT. The reaction mixture was stirred at room temperature overnight, then quenched by dropwise addition of AcOH (4 eq.). The organic phase was washed with water and brine and dried (MgSO4). Evaporation of the solvent yielded (75%) the title compound which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3, 300K) δ 8.47 (1H, dd, J=4.8 Hz, 2.1 Hz), 8.07 (1H, dd, J=7.8 Hz, 2.1 Hz), 7.35 (1H, dd, J=7.5 Hz, 4.5 Hz), 3.93 (3H, s).
Reaction SMILES: [CH2:1]([NH:7][C:8]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.[C:25](=O)([O:27]CC)[NH2:26]>C(Cl)(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[CH2:1]([N:7]1[C:8]2[C:9](=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:26][C:25]1=[O:27])[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCOC(N)=O
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1NCC1CCCO1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Product: O=c1nc(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1CC1CCCO1
Temperature: 190 °C

Procedure:
A mixture of 1.63 g of 2-tetrahydrofurfurylamino-5-nitrobenzophenone, 3.0 g of ethyl carbamate and 0.2 g of zinc chloride was heated at 190° C. (oil bath temperature) for 2 hours. After cooling, the reaction mixture was dissolved in chloroform and the insoluble material was filtered off. The chloroform solution was washed successively with dilute hydrochloric acid and water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was washed with ether. The insoluble product was collected by filtration and dried to give 1-tetrahydrofurfuryl-4-phenyl-6-nitro-2(1H)-quinazolinone, m.p. 150°-152° C.
Reaction SMILES: I[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:4]([CH3:17])[C:3]=1[C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1)=[O:19].[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][N:34]=1>>[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36]([C:2]2[N:6]=[C:5]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)[N:4]([CH3:17])[C:3]=2[C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[O:19])=[CH:35][N:34]=1
Reactant: Cn1c(-c2ccc(C(F)(F)F)cc2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: COc1ncc(B(O)O)cn1
Product: COc1ncc(-c2nc(-c3ccc(C(F)(F)F)cc3)n(C)c2C(=O)N2CCC(N3CCCC3)CC2)cn1

Procedure:
In analogy to the procedure described for example 7, [5-iodo-3-methyl-2-(4-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 104) was reacted with 2-methoxy-pyrimidin-5-yl-boronic acid to give the title compound as light yellow solid. MS: 515.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@H:21]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH2:22][CH3:23])[C:11](=[O:30])[C@:10]([CH2:32][CH:33]([OH:36])CO)([CH3:31])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.I([O-])(=O)(=O)=O.[Na+].CO>O.C1COCC1.[Na+].[Cl-]>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@H:21]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH2:22][CH3:23])[C:11](=[O:30])[C@:10]([CH2:32][CH:33]=[O:36])([CH3:31])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](C1CCCCO1)N1C(=O)[C@@](C)(CC(O)CO)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC[C@@H](C1CCCCO1)N1C(=O)[C@@](C)(CC=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-3-methyl-1-((1S)-1-(tetrahydro-2H-pyran-2-yl)propyl)piperidin-2-one (3 mg, 5.61 μmol; Example 224, Step D) in water (20.0 μL) and THF (40.0 μL) was treated with sodium periodate (3.60 mg, 0.02 mmol). After a precipitate formed, methanol (40 μL) was added to form an emulsion which was stirred at ambient temperature for 1 hour. The reaction was diluted with sat. aq. NaCl solution and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and the filtrate was concentrated to provide a mixture of two diastereomers which was used in the next step. Mass Spectrum (ESI) m/z=502.1 (M+1)
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=1[SH:12].[H-].[Na+].[CH2:15]([Sn:19](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18].[H][H]>O1CCCC1.O>[CH2:15]([Sn:19]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[O:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=1[S:12][Sn:19]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][CH2:16][CH2:17][CH3:18])[CH2:16][CH2:17][CH3:18]
Reactant: [H][H]
Reactant: COc1cc(C)cc(CO)c1S
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)OCc1cc(C)cc(OC)c1S[Sn](CCCC)(CCCC)CCCC

Procedure:
10 g (54.3 mmol) of the compound from Example 15 are stirred at 0° to 25° C. with 4 g (163 mmol) of sodium hydride and 31 ml (114 mmol) of tributyltin chloride in 300 ml of tetrahydrofuran until evolution of hydrogen is complete and the mixture is then heated under reflux overnight. It is cautiously hydrolysed with water and washed with ether, and the combined organic phases are dried using sodium sulphate and concentrated in vacuo.
Reaction SMILES: [C:1]([NH:22][C@H:23]([C:36]([OH:38])=[O:37])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][P:32]([OH:35])([OH:34])=[O:33])=[CH:27][CH:26]=1)(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18]CC.C(O)(=O)CCCCCCC/C=C\CC=CCC=CCC>>[C:1]([NH:22][C@H:23]([C:36]([OH:38])=[O:37])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][P:32]([OH:35])([OH:34])=[O:33])=[CH:27][CH:26]=1)(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH:12]=[CH:13][CH2:14][CH:15]=[CH:16][CH2:17][CH3:18]
Reactant: CCCCCC=CCC=CCC=CC/C=C\CCCC(=O)N[C@@H](Cc1ccc(OP(=O)(O)O)cc1)C(=O)O
Agent: CCC=CCC=CC/C=C\CCCCCCCC(=O)O
Product: CCC=CCC=CC/C=C\CCCCCCCC(=O)N[C@@H](Cc1ccc(OP(=O)(O)O)cc1)C(=O)O

Procedure:
This compound was prepared as described above for (8), using 0.5 mmol (139 mg) of cis-9,12,15-octadecatrienoic acid; yield 52 mg (20%); Rf 0.05-0.10 (system B); 1H-NMR (CD3SOCD3, 200 MHz) δ0.9-1.0 (t, 3H, ω-CH3); 1.3(s, 8H, 4CH2); 1.4-1.5 (br, s, 2H, CH2CH2CO); 2.0-2.2 (m, 6H, CH2CO and 2CH2CH═CH); 2.7-2.9 (br s, 4H, 2HC═CH—CH2—CH═CH );2.9-3.1(m, 2H, CH2Ar); 4.3-4.4 (m, 1H, NHCHCO); 5.2-5.4 (br s, 6H, 3HC═CH); 7,0 (s, 4H, Ar); 8.2-8.4 (m, 3H, NH and 2POH).