Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[F:27][C:28]1[CH:29]=[C:30]2[C:35](=[C:36]([O:38][CH:39]([CH3:41])[CH3:40])[CH:37]=1)[N:34]=[C:33]([CH:42]=O)[CH:32]=[CH:31]2>C(O)C>[F:26][C:2]([F:25])([F:1])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10]/[N:11]=[CH:42]/[C:33]2[CH:32]=[CH:31][C:30]3[C:35](=[C:36]([O:38][CH:39]([CH3:41])[CH3:40])[CH:37]=[C:28]([F:27])[CH:29]=3)[N:34]=2)=[CH:8][CH:9]=1
Reactant: CC(C)Oc1cc(F)cc2ccc(C=O)nc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Solvent: CCO
Product: CC(C)Oc1cc(F)cc2ccc(/C=N/Nc3ccc([C@@H](N4CC[C@H](NC(=O)OC(C)(C)C)C4)C(F)(F)F)cn3)nc12
Yield: 99.9 %

Procedure:
tert-Butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (100 mg, 0.266 mmol) and 6-fluoro-8-isopropoxyquinoline-2-carbaldehyde (62.1 mg, 0.266 mmol) were stirred in ethanol (5 mL) for 72 hours at ambient temperature. The reaction was concentrated under reduced pressure to yield tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-((E)-2-((6-fluoro-8-isopropoxyquinolin-2-yl)methylene)hydrazinyl)pyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (157 mg, 99.8% yield) as a yellow paste.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[N+:11]([O-])([OH:13])=[O:12]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1ccc(F)cc1
Product: CC(=O)c1ccc(F)c([N+](=O)[O-])c1

Procedure:
1-fluoro-4-acetyl-benzene was reacted with nitric acid to obtain 2-fluoro-5-acetyl-nitro benzene with a melting point of 56°-58° C. which was reacted as in Example 1 to obtain 0-(4-acetyl-2-nitro-phenyl)-hydroxylamine melting at 132° C.
Reaction SMILES: ClC(Cl)(Cl)C[CH:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.S(=O)(=O)(O)O.Cl.[C:20]([OH:23])(=[O:22])[CH3:21]>S(=O)(=O)(O)O.O>[C:20]([OH:23])(=[O:22])[CH:21]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: ClC(CC(Cl)(Cl)Cl)c1ccccc1
Reactant: CC(=O)O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)C=Cc1ccccc1

Procedure:
A mixture of 77.4 g of 1,1,1,3-tetrachloro-3-phenylpropane, 7.7 g of 98% acetic acid and 1.8 g of 98% sulphuric acid is stirred and refluxed at 130° to 138° C. while a mixture of 15.5 g of water, 4 ml of acetic acid and 0.5 ml of sulphuric acid is gradually added over the period of 2.5 h, after which time the hydrogen chloride evolution ceases. The work-up of the reaction mixture as described in Example 1 gives 33.6 g of cinnamic acid in 75.6% total yield (melting point 132° to 133° C., min. 99% purity).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:32][CH:33]([C:38]#[N:39])[C:34]([NH:36][CH3:37])=[O:35].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:38]([CH:33]([NH:32][C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:29])([F:31])[F:30])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:34]([NH:36][CH3:37])=[O:35])#[N:39]
Reactant: CNC(=O)C(N)C#N
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CNC(=O)C(C#N)NC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 26.1 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 20 mg, 0.046 mmol), (R/S)-2-amino-2-cyano-N-methylacetamide (7.87 mg, 0.070 mmol), 4-methylmorpholine (18.76 mg, 0.185 mmol), and HATU (22.92 mg, 0.060 mmol) were added to DMF (2 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.5 min) to provide (R/S)-2-cyano-2-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)-N-methylacetamide (8 mg, 0.012 mmol, 26.5% yield) as a mixture of diastereomers. LCMS=527.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.12-8.28 (2 H, m), 7.48-7.78 (7 H, m), 5.40-5.58 (1 H, m), 5.27 (1 H, s), 2.80 (3 H, s); HPLC peak RT=9.4 min (Method A).
Reaction SMILES: [C:1]1([C:7]2[C:12]3[S:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[B:25](OC)([O:28]C)[O:26]C.Cl>C1COCC1.CCCCCC>[C:1]1([C:7]2[C:12]3[S:13][C:14]4[C:19]([B:25]([OH:28])[OH:26])=[CH:18][CH:17]=[CH:16][C:15]=4[C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cccc3c2sc2ccccc23)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1cccc2c1sc1c(-c3ccccc3)cccc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
3.5 g (13.4 mmol) 4-phenyldibenzothiophene was dissolved in ˜30 mL anhydrous THF in a three necked 250 mL flask and cooled down to −78° C. To the mixture, 17 mL (27 mmol) 1.6 M BuLi in hexane was added and stirred for 30 minutes. The cooling batch was removed and let reaction kept stirring for overnight. The reaction mixture was cooled down again to −78° C. and 4.5 mL (40 mmol) trimethyl borate was added and stirred at room temperature for 4 hours. ˜100 1M HCl was added and kept stirring for 1 hour. The mixture was extracted by ethyl acetate and the organic extracts were combined. The solvent was evaporated to dryness. The solid was added with ˜100 mL 20% ethyl acetate in hexane was stirred for few hours and then filtered. The filtered solid washed by hexane few times. ˜2.5 g white solid was obtained as product which was confirmed by proton NMR.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:11](=[O:13])[CH3:12])(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccccc1N
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccccc1C(C)=O
Temperature: 4 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To 1-(2-amino-phenyl)-ethanone 2 (90.37 g, 0.67 moles) was added acetic anhydride (68.25 g, 0.67 moles) and stirred for 2 h at 4° C. The reaction mixture was poured into crushed ice and the precipitate was filtered, washed with ice water, and air-dried to afford N-(2-acetyl-phenyl)-acetamide 3 (104.70 g, 88% yield). 1HNMR (400 MHz, DMSO-d6) δ2.10 (s, 3H), 2.60 (s, 3H), 7.17-7.21 (m, 1H), 7.55-7.59 (m, 1H), 7.95 (d, 1H, J=8.0 Hz), 8.26 (d, 1H, J=8.0 Hz), 11.16 (s 1H); MS m/z 17 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:31][CH3:32])[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([O:36][C:37](=[O:54])[CH2:38][C:39]1[CH:44]=[C:43](OS(C(F)(F)F)(=O)=O)[CH:42]=[C:41]([F:53])[CH:40]=1)[CH3:35]>>[CH2:34]([O:36][C:37](=[O:54])[CH2:38][C:39]1[CH:44]=[C:43]([C:13]2[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:19])[F:20])=[CH:17][C:12]=2[CH2:11][N:10]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:33])[CH2:31][CH3:32])[CH:42]=[C:41]([F:53])[CH:40]=1)[CH3:35]
Reactant: CCOC(=O)Cc1cc(F)cc(OS(=O)(=O)C(F)(F)F)c1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccccc1
Product: CCOC(=O)Cc1cc(F)cc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid benzyl ester and (3-fluoro-5-trifluoromethanesulfonyloxy-phenyl)-acetic acid ethyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.C([CH2:15][S:16]([CH2:19][S:20]([CH2:23][C:24](O)=O)(=[O:22])=[O:21])(=[O:18])=[O:17])(O)=O>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])/[CH:5]=[CH:15]/[S:16]([CH2:19][S:20](/[CH:23]=[CH:24]/[C:4]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([OH:1])[CH:3]=1)(=[O:21])=[O:22])(=[O:17])=[O:18]
Reactant: COc1ccc(C=O)cc1O
Reactant: O=C(O)CS(=O)(=O)CS(=O)(=O)CC(=O)O
Solvent: CC(=O)O
Product: COc1ccc(/C=C/S(=O)(=O)CS(=O)(=O)/C=C/c2ccc(OC)c(O)c2)cc1O
Yield: 62 %

Procedure:
A solution of 3-hydroxy-4-methoxybenzaldehyde (2 mmol) and carboxymethane-sulfonylmethanesulfonyl-acetic acid (1 mmol) in acetic acid (10 mL) was subjected to General Procedure 1, to yield the title compound in 62% yield. m.p. 148-150° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[CH:28]=[CH:27][CH:26]=[CH:25][C:12]=2[CH2:13][CH:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:4][CH:3]=1.[C:29](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:30].[Na+].C(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)(=O)C>[CH2:29]([N:10]([CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[C:11]1[CH:28]=[CH:27][CH:26]=[CH:25][C:12]=1[CH2:13][CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:30]
Reactant: Oc1ccc(CCNc2ccccc2CC2CCc3cc(O)ccc3C2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCN(CCc1ccc(O)cc1)c1ccccc1CC1CCc2cc(O)ccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To a solution of 6-{2-[2-(4-hydroxyphenyl)ethylamino]benzyl}-5,6,7,8-tetrahydronaphthalen-2-ol (1.0 g) in tetrahydrofuran (15 ml) were sequentially added acetic acid (in catalytic amounts), sodium triacetoxyborohydride (2.8 g) and acetaldehyde (572 mg), and the solution was stirred overnight at room temperature. To the reaction solution was added a saturated aqueous solution of sodium bicarbonate, the solution was extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (730 mg).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:34]=[CH:33][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[O:24])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:52][C:53]1[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH:61]2[CH2:63][O:62]2)=[CH:55][CH:54]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[F:32][C:29]1[CH:28]=[CH:27][C:26]([NH:25][C:23]([CH2:22][CH2:21][NH:20][C:18]([N:15]2[CH2:14][CH2:13][CH:12]([NH:11][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:63][C@H:61]([OH:62])[CH2:60][O:59][C:56]4[CH:57]=[CH:58][C:53]([OH:52])=[CH:54][CH:55]=4)=[CH:34][CH:33]=3)[CH2:17][CH2:16]2)=[O:19])=[O:24])=[CH:31][CH:30]=1
Reactant: NCCc1ccc(NC2CCN(C(=O)NCCC(=O)Nc3ccc(F)cc3)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Product: O=C(CCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1)Nc1ccc(F)cc1

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-[3-(4-fluoroanilino)-3-oxopropyl]-1-piperidinecarboxamide formate (0.28 g, 0.6 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane according to Procedure G to give the title compound (0.11 g, 0.13 mmol).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:6](=[O:21])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:12]=2[CH3:20])[CH:8]=[CH:9][CH:10]=1.[H][H]>C1COCC1.[Pd]>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([N:7]2[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][CH2:3][CH2:2][OH:1])[C:6]2=[O:21])=[C:12]([CH3:20])[CH:13]=1
Reactant: [H][H]
Reactant: Cc1cc([N+](=O)[O-])ccc1-n1cccc(CCCO)c1=O
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(N)ccc1-n1cccc(CCCO)c1=O

Procedure:
475 mg (1.65 mmol) of the compound from Example 49A are dissolved in 48 ml of THF. 50 mg (0.05 mmol) of palladium on carbon are then added, and the mixture is hydrogenated at RT in a hydrogen atmosphere under atmospheric pressure. The mixture is then filtered, the filter cake is washed three times with THF and the filtrate is freed from the solvent. The reaction product is reacted further without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH2:15][C:16]3=[O:19])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH2:15][CH:16]3[OH:19])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1
Reactant: O=C1CCCc2ccc(OCc3ccncc3)cc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OC1CCCc2ccc(OCc3ccncc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a solution of Compound 1 (16.41 g, 64.9 mmol) in tetrahydrofuran (75 mL) at 0° C. was added dropwise a 1M solution of diisobutylaluminum hydride in toluene (97.3 mL). After 1 hr, the reaction was quenched with aqueous potassium sodium tartrate and diluted with ethyl acetate followed by warming to room temperature. After stirring for an additional hour, the layers were separated and the aqueous phase was re-extracted with ethyl acetate (2×). The extracts were combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Chromatography of the residue on silica gel (elution with ethyl acetate) provided 12.96 g of Compound 2 as an oil which crystallized upon standing.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[C:5]([NH2:6])=[C:4]([Cl:14])[CH:3]=1.C(N(CC)CC)C.[C:22]([CH2:26][C:27](Cl)=[O:28])([CH3:25])([CH3:24])[CH3:23]>ClCCl>[Br:1][C:2]1[CH:8]=[C:7]([O:9][C:10]([F:12])([F:11])[F:13])[C:5]([NH:6][C:27](=[O:28])[CH2:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[C:4]([Cl:14])[CH:3]=1
Reactant: Nc1c(Cl)cc(Br)cc1OC(F)(F)F
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CC(=O)Nc1c(Cl)cc(Br)cc1OC(F)(F)F
Temperature: 25 °C
Yield: 92.6 %

Procedure:
To a solution of 4-bromo-2-chloro-6-trifluoromethoxy-aniline (2.9 g, 10 mmol) and triethylamine (1.5 g, 15 mmol) in anhydrous dichloromethane (50 mL) was added dropwise tert-butylacetyl chloride (1.6 g, 12 mmol) with stirring at room temperature. The reaction mixture was stirred for 3 hours at room temperature, than the reaction mixture was diluted with dichloromethane and washed with water and dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column (ISCO, hexane/EtOAc, 0-40%, 40 min) to give a white solid (3.6 g, 93%).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[N:4]=[C:5](SC)[NH:6][CH:7]=1.[Cl:11][C:12]1[CH:27]=[CH:26][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH2:25])=[CH:19][CH:18]=2)=[CH:14][C:13]=1[C:28]([F:31])([F:30])[F:29]>C(O)C>[Cl:11][C:12]1[CH:27]=[CH:26][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH:25][C:5]3[NH:6][CH:7]=[C:2]([CH3:1])[C:3](=[O:10])[N:4]=3)=[CH:19][CH:18]=2)=[CH:14][C:13]=1[C:28]([F:29])([F:30])[F:31]
Reactant: CSc1nc(=O)c(C)c[nH]1
Reactant: NCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Solvent: CCO
Product: Cc1c[nH]c(NCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc1=O
Yield: 35.4 %

Procedure:
5-Methyl-2-methylsulfanyl-1H-pyrimidin-4-one (25 mg, 0.16 mmol, 1 eq) and 2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamine (60 mg, 0.192 mmol, 1.2 eq) were stirred in 300 μl of absolute ethanol for 50 hours. Solvent was then evaporated and the resulting crude was purified by chromatography on BIOTAGE SP1 purification device using 11 g normal phase silica KP—NH column and DCM/MeOH solvent system (gradient 0-7% of MeOH in 20 column volumes). Solvent from the gathered fractions of appropriate composition was evaporated and the crude was triturated with cyclohexane to obtain 2-{2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamino}-5-methyl-1H-pyrimidin-4-one (24 mg, yield=33.9%, purity=96%) in form of white powder. MS: [M+H]+=424.31. 1H NMR (300 MHz; CDCl3) δ/ppm 1.79 (s, 3H), 2.90 (t, J=6.24 Hz, 2H), 3.52 (s, 2H), 3.56-3.67 (m, 2H), 6.23 (br.s., 1H), 6.92 (d, J=7.56 Hz, 2H), 7.00 (d, J=7.95 Hz, 1H), 7.21 (d, J=7.56 Hz, 2H), 7.28 (s, 1H) 7.38 (d, J=8.32 Hz, 1H), 7.63 (s, 1H), 11.62 (br.s., 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C@@:15]4([C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[C:19](=[O:26])[O:18]4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O:27]1[CH2:32][CH2:31][CH:30](O)[CH2:29][CH2:28]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>>[O:27]1[CH2:32][CH2:31][CH:30]([O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:11]([N:13]4[CH2:17][CH2:16][C@@:15]5([C:25]6[CH:24]=[CH:23][N:22]=[CH:21][C:20]=6[C:19](=[O:26])[O:18]5)[CH2:14]4)=[O:12])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:29][CH2:28]1
Reactant: OC1CCOCC1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(O)cc4)CC3)C2)c2ccncc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(OC5CCOCC5)cc4)CC3)C2)c2ccncc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.6 %

Procedure:
A mixture of (1R)-1′-{[1-(4-hydroxyphenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one (10 mg, 0.00003 mol), tetrahydro-4H-pyran-4-ol (6.5 μL, 0.000068 mol), diisopropyl azodicarboxylate (13 μL, 0.000068 mol), and triphenylphosphine (18 mg, 0.000068 mol) in tetrahydrofuran (200 μL, 0.002 mol) was stirred at room temperature overnight. It was purified with prep-HPLC to afford 2.3 mg of product. LCMS: m/z 435.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([NH2:12])=[S:11])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH3:13][C:14]([C:17]([CH2:19]Br)=O)([CH3:16])[CH3:15]>C(O)C>[CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][CH:19]=[C:17]([C:14]([CH3:16])([CH3:15])[CH3:13])[N:12]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCN(C(N)=S)CC1
Reactant: CC(C)(C)C(=O)CBr
Solvent: CCO
Product: C=CCN1CCN(c2nc(C(C)(C)C)cs2)CC1

Procedure:
3.7 g of 4-allyl-1-piperazinyl-thiocarboxamide are added to a solution of 3.6 g of bromopinacoline in 40 cc of ethanol, and the reaction mixture is subsequently heated to the boil at reflux for 2 hours. The mixture is subsequently concentrated by evaporation in a vacuum, the residue is dissolved in a small amount of water and divided between ether and a concentrated aqueous sodium hydroxide solution. The ether phase is washed with water, dried over sodium sulphate and saturated with hydrogen chloride gas after filtration. The monohydrochloride of 2-(4-allyl-1-piperazinyl)-4-tert.butyl-thiazole crystallizes and has an M.P. of 212°-214° after recrystallization from ethanol/diisopropyl ether.
Reaction SMILES: C(O[C:4](=[O:17])[CH2:5][NH:6][CH2:7][C:8]1[C:13]([Cl:14])=[C:12]([Cl:15])[CH:11]=[CH:10][C:9]=1[NH2:16])C.[N+]([O-])(O)=O.C[C:23]1C=C(C)N(C(N)=N)[N:24]=1>C(O)C>[Cl:14][C:13]1[C:12]([Cl:15])=[CH:11][CH:10]=[C:9]2[C:8]=1[CH2:7][N:6]1[CH2:5][C:4](=[O:17])[NH:24][C:23]1=[N:16]2
Reactant: CCOC(=O)CNCc1c(N)ccc(Cl)c1Cl
Reactant: Cc1cc(C)n(C(=N)N)n1
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: O=C1CN2Cc3c(ccc(Cl)c3Cl)N=C2N1
Yield: 39.8 %

Procedure:
A mixture of N-(2-amino-5,6-dichlorobenzyl)glycine ethyl ester (2.77 g, 0.01 mole) and 3,5-dimethylpyrazole-1-carboxamidine nitrate (2.01 g, 0.01 mole) in absolute ethanol (30 ml) was heated at reflux for 24 hours. The mixture was filtered and the product was washed successively with ethanol, acetone and ether to yield the title compound (1.02 g, 40%); identical (ir, nmr) with authentic material prepared by a prior art procedure.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C)C(C)=CC=CC=1>O>[CH:15](=[N:9][C:8]1[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=1[S:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: CN(C)CCCSc1ccccc1N
Solvent: Cc1ccccc1C
Solvent: O
Product: CN(C)CCCSc1ccccc1N=Cc1ccccc1

Procedure:
A mixture of 51g of 2-(3-dimethylaminopropylthio)aniline, 26g of freshly distilled benzaldehyde and 200 ml of xylene is refluxed under an atmosphere of nitrogen. The water formed in the reaction is collected in a Dean-Stark tube; the theoretical quantity is collected after 4 hours of refluxing. The xylene and any unchanged benzaldehyde are removed on the steam bath at 30 mm of Hg, finally at 2 mm of Hg. Fractionation of the residue yields 56g of the title compound, boiling point 182°-189° C. at 0.4 mm of Hg.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>C1COCC1>[CH2:1]([O:8][C:9](=[O:18])[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([O:17][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(N[C@H]1CC[C@H](O)CC1)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Combine trans-(4-hydroxy-cyclohexyl)-carbamic acid benzyl ester (16.0 g, 0.064 mol), imidazole (13.9 g, 0.10 mol), and anhydrous THF (300 mL), add tert-butyldimethylsilyl chloride (14.5 g, 0.10 mol) and stir at room temperature for 18 hours. Wash the reaction mixture with water (250 mL), saturated aqueous NaHCO3 (250 mL) and dry the organic layer over anhydrous Na2SO4. Remove the solvent and purify the residue by chromatography over silica gel (eluting with 0 to 30% EtOAc in hexane) to obtain the desired intermediate as clear oil (23.0 g, 98%).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]([O:29][CH2:30][CH3:31])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:9][C:8]=1[CH3:28])C.[Li+].[OH-]>>[CH2:30]([O:29][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:9][C:8]=1[CH3:28])[C:4]([OH:32])=[O:3])[CH3:31]
Reactant: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccc(F)cc3)oc2C)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCc2nc(-c3ccc(F)cc3)oc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], [rac]-2-ethoxy-3-{4-[2-(4-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid ethyl ester was treated with LiOH to obtain [rac]-2-ethoxy-3-{4-[2-(4-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid as colorless liquid, which can be separated into its antipodes by methods known in the art, such as separation of the antipodes via diastereomeric salts by crystallization with optically pure amines such as e.g. (R) or (S)-1-phenyl-ethylamine, (R) or (S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbens or a chiral eluent to give the title compound.