Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][C@@H:16]([CH3:20])[CH2:17][O:18][CH3:19])[CH:14]=1)[C:9]([OH:11])=O.[CH2:24]([O:26][C:27](=[O:36])[CH2:28][S:29][C:30]1[S:34][C:33]([NH2:35])=[N:32][CH:31]=1)[CH3:25]>>[CH2:24]([O:26][C:27](=[O:36])[CH2:28][S:29][C:30]1[S:34][C:33]([NH:35][C:9](=[O:11])[C:8]2[CH:12]=[C:13]([O:15][C@@H:16]([CH3:20])[CH2:17][O:18][CH3:19])[CH:14]=[C:6]([O:5][C:4]3[CH:21]=[CH:22][CH:23]=[C:2]([F:1])[CH:3]=3)[CH:7]=2)=[N:32][CH:31]=1)[CH3:25]
Reactant: COC[C@H](C)Oc1cc(Oc2cccc(F)c2)cc(C(=O)O)c1
Reactant: CCOC(=O)CSc1cnc(N)s1
Product: CCOC(=O)CSc1cnc(NC(=O)c2cc(Oc3cccc(F)c3)cc(O[C@@H](C)COC)c2)s1

Procedure:
The title compound was prepared from 3-(3-fluoro-phenoxy)-5-((S)-2-methoxy-1-methyl-ethoxy)-benzoic acid and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester following general procedure A
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[C:8]([CH3:24])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18][CH3:19])=[O:17])[C:10](=[O:12])[CH:11]=1.C1C(=O)N([Br:37])C(=O)C1>ClCCl>[Br:37][C:11]1[C:10](=[O:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18][CH3:19])=[O:17])[C:8]([CH3:24])=[N:7][C:6]=1[O:5][CH2:4][C:3]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:2]=1[F:1]
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3F)cc2=O)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.2 %

Procedure:
A mixture of methyl 3-[4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate (0.41 g, 0.001 mol, from Step 3) and NBS (0.2 g, 0.0011 mol) in dichloromethane (5.0 mL) is stirred at room temperature for 1.5 h under argon atmosphere. The reaction mixture is purified by flash chromatography using 30% EtOAc in hexanes to furnish the title compound (0.37 g, 75%) as a white amorphous powder: 1H NMR (CD3OD/400 MHz) δ 8.04 (d, 1H, J=1.6 Hz), 7.89 (d, 1H, J=1.6 Hz), 7.62 (m, 2H), 7.01 (m, 2H), 5.56 (s, 2H), 3.89 (s, 3H), 2.15 (s, 3H), and 2.133 (s, 3H); ES-HRMS m/z 479.0412 (M+H calcd for C21H18N2O4F2Br requires 479.0413). 19F NMR (CD3OD/400 MHz) −111.870 (m) and −115.95 (m).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:15])=O)[C:8](=[O:20])[C:7]3=[CH:21][NH:22][C:5]([C:6]=23)=[N:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C:26]#[N:27].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.CN(C=O)C>[Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([C:16]([CH3:17])([CH3:19])[CH3:18])[C:13]([NH:27][CH2:26][CH2:25][C:24]#[N:23])=[O:15])[C:8](=[O:20])[C:7]3=[CH:21][NH:22][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: CC(C)(C)[C@H](C(=O)O)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Reactant: N#CCCN
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[C@H](C(=O)NCCC#N)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Yield: 53.5 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3,3-dimethylbutanoic acid (5 mg, 0.016 mmol). DMF (0.5 mL), 3-aminopropanenitrile (1.089 mg, 0.016 mmol), HOBt (3.57 mg, 0.023 mmol), EDC (4.47 mg, 0.023 mmol) and N,N-dimethylpyridin-4-amine (1.898 mg, 0.016 mmol) were added and the solution was stirred at 25° C. for 4 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 20-50%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow oil (3.2 mg, 55.1%). 1H NMR (500 MHz, CD3OD) δ 1.19 (s, 9 H) 2.63-2.72 (m, 2 H) 3.38-3.53 (m, 2 H) 4.89 (br. s., 1 H) 5.29 (d, J=19.04 Hz, 1 H) 5.41 (d, J=19.00 Hz, 2 H) 7.85 (s, 1 H) 8.24 (s, 1 H) 8.55 (d, J=4.88 Hz, 1 H). [M+H] calc'd for C18H20ClN5O2, 374; found, 374.5.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[C:8]([CH:13]=1)[C:9]([O:11]C)=O)(=[O:3])[CH3:2].[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH2:25]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[C:8]([CH:13]=1)[C:9]([NH:25][CH2:24][CH2:23][N:22]([CH3:26])[CH3:21])=[O:11])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(C(C)=O)ccc1OCCCC(=O)O
Reactant: CN(C)CCN
Product: CC(=O)c1ccc(OCCCC(=O)O)c(C(=O)NCCN(C)C)c1
Yield: 14.9 %

Procedure:
A sample of 0.140 g (0.50 mmol) of 5-acetyl-2-(3-carboxypropoxy)-benzoic acid, methyl ester (Example 19) is heated on a steam bath, under dry conditions with 5.49 mL (50.0 mmol) of N,N-dimethylethylenediamine for 5 hours. The mixture is allowed to cool for 20 hours to ambient temperature and evaporated under vacuum at 55° C. The brown gum produced is triturated with ether, and the remaining residue taken up in water and acidified with hydrochloric acid. This is then extracted with ethyl acetate, and the aqueous solution is evaporated under vacuum, leaving a gum. It is next triturated with hot chloroform and this solution is evaporated to give a brown glass. This is chromatographed on a preparatory silica gel plate which is eluted with a 9/1 mixture of chloroform to methanol. The product band is cut from the plate, triturated with the above solvent mixture, filtered, and evaporated leaving 0.025 g (15%) of 5-acetyl-2-(3-carboxypropoxy)-N-(2-dimethylaminoethyl)-benzamide as a light brown gum: MS (FAB) m/e 337.1753 Δ=+0.9 mmμ (M+ +H), 359 (M+ +Na). 1HNMR (CDCl3) is consistent with the desired product.
Reaction SMILES: Cl.[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1>>[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=2)=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3]
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(C)NCC(=O)c1ccc(O)c(O)c1
Agent: Cl
Product: CC(C)NCC(=O)c1ccc(OC(=O)c2cccnc2)c(O)c1

Procedure:
Following a procedure similar to that described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride, and nicotinoyl chloride instead of isovaleryl chloride, there is obtained 3-hydroxy-4-(nicotinoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-(nicotinoyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [CH:1]1([C:4](=[O:21])[CH:5](C(OC)=O)[C:6]([C:8]2[S:12][C:11]([CH3:13])=[C:10]([O:14][CH3:15])[C:9]=2[F:16])=[O:7])[CH2:3][CH2:2]1>C(#N)C.O.Cl>[CH:1]1([C:4](=[O:21])[CH2:5][C:6]([C:8]2[S:12][C:11]([CH3:13])=[C:10]([O:14][CH3:15])[C:9]=2[F:16])=[O:7])[CH2:3][CH2:2]1
Reactant: COC(=O)C(C(=O)c1sc(C)c(OC)c1F)C(=O)C1CC1
Agent: Cl
Solvent: CC#N
Solvent: O
Product: COc1c(C)sc(C(=O)CC(=O)C2CC2)c1F
Yield: 65.4 %

Procedure:
A solution of 3-cyclopropyl-1-(4-fluoro-3-methoxy-2-methylthiophenyl)-2-methoxycarbonyl-propane-1,3-dione (0.15 g) in a mixture of acetonitrile/water (95:5) containing 3 drops of hydrochloric acid (2M) was heated at reflux for 44 hours, cooled, dried (magnesium sulphate) and evaporated to give the title compound (0.08 g), NMR 0.9 (m, 2H), 1.1 (m, 2H), 1.65 (m, 1H), 2.37 (s, 3H), 3.96 (s, 3H), 4.15 (s, 1H), 5.9 (s, 1H), 6.95-7.15 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2O.C(=O)(O)[O-].[Na+].C(OCC)(=O)C.P(Cl)(Cl)([Cl:29])=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[Cl:29]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Temperature: 85 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
1-(6-Bromo-4-hydroxyquinolin-3-yl)ethanone (2.2 g, 8.27 mmol) was suspended in phosphoryl chloride (30 mL) and the reaction was heated to 85° C. and stirred for 3 h. After this time the reaction mixture was cooled to room temperature and slowly poured into a 2:1 solution of satd. aq. sodium bicarbonate/ethyl acetate that was cooled to 0° C. The organic layer was separated, washed with satd. aq. sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to afford the desired product (710 mg, 72%) as a light brown solid: ESI MS m/z 280 [C11H7BrClNO+H]+.
Reaction SMILES: C([C:3]1([C:15]([O:17]CC)=[O:16])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:12]([O-:14])=[O:13])[CH2:4]1)#N.C(O)(=O)C.Cl>O>[N+:12]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:11][CH:3]([C:15]([OH:17])=[O:16])[CH2:4]2)([O-:14])=[O:13]
Reactant: CCOC(=O)C1(C#N)Cc2cccc([N+](=O)[O-])c2C1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)C1Cc2cccc([N+](=O)[O-])c2C1
Yield: 107.3 %

Procedure:
A mixture of 2-cyano-2-ethoxycarbonyl-4-nitroindan (21 g, 81 mmol), acetic acid (290 mL), hydrochloric acid (37%, 130 mL) and water (140 mL) was stirred under reflux temperature over night. The acid was evaporated in vacuo and the residue was made alkaline with a 2 M sodium hydroxide solution. The mixture was stirred at room temperature, insoluble matter was filtered and the filtrate was acidified with hydrochloric acid. The obtained precipitate was filtered and washed with water to afford 18 gram of the crude acid: mp ˜140° C.; EIMS (70 eV) m/z (relative intensity) 207 (40, M+).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][O:10][C:9]3=[N:13][C:14]([NH2:16])=[N:15][N:8]23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]2)[CH:19]=1.C(Cl)Cl>C(Cl)Cl.CO>[CH3:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:29][CH2:28][CH:27]([NH:16][C:14]3[N:13]=[C:9]4[O:10][CH2:11][CH2:12][CH:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:8]4[N:15]=3)[CH2:26][CH2:25]2)[CH:19]=1
Reactant: Cc1cc(N2CCC(=O)CC2)ncn1
Reactant: Nc1nc2n(n1)C(c1ccccc1)CCO2
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(N2CCC(Nc3nc4n(n3)C(c3ccccc3)CCO4)CC2)ncn1

Procedure:
Prepared in analogy to example 1h, starting from 7-phenyl-6,7-dihydro-5H-[1,2,4]triazolo[5,1-b][1,3]oxazin-2-amine and 1-(6-methylpyrimidin-4-yl)piperidin-4-one (see example 93b). The title compound was obtained as a light yellow solid (yield: 17%) after column chromatography on silica gel using a gradient from methylene chloride to methylene chloride/methanol 19:1 (v/v) as eluent. MS ISP (m/e): 392.3 (100) [(M+H)+].
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18]C)=[O:17])[C:8](=[O:24])[CH:7]=1.[OH-].[Na+].Cl>C1COCC1.O>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([OH:18])=[O:17])[C:8](=[O:24])[CH:7]=1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)O)cc1-n1c(C)cc(OCc2ccc(F)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
Methyl 3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoate (14 g, 35.0 mmol) (from step 2) was taken up in THF (25 ml) and H2O. 2.5 N NaOH (aq.) was added and the reaction stirred for 30 minutes at room temperature. The reaction was made acidic via the addition of concentrated HCl. The product was extracted with ethyl acetate. The ethyl acetate extraction was dried over Na2SO4, filtered, and the solvent removed in vacuo. Upon vacuum removal of the solvent, the product crashed out of the ethyl acetate. This precipitate was collected on a filter pad and washed with a 50 ethyl acetate/hexanes to yield a white powder (9 g, 7%). 1H NMR (300 MHz, CDCl3) δ 8.01 (dd, J=, 1.61 Hz, 1H), 7.84 (d, J=1.61 Hz, 1H), 7.52-7.47 (app q, J=8.26, 1H), 7.43 (d, J=8.06 Hz, 1H), 7.00-6.88 (m, 2H), 6.19 (d, J=2.62 Hz, 1H), 6.05 (dd, J=2.62, 1.81 Hz, 1H), 5.17 (s, 2H), 2.19 (s, 3H), 1.90 (s, 3H); ES-HR/MS m/z 386.12 (M+H calcd for C21H18F2NO4 requires 386.1198).
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH:3]([CH3:5])[CH3:4].C([CH:9]([C:23]([O-:25])=O)[C:10]([C:20]([O-:22])=O)([OH:19])[C:11](CC)(CC)[C:12]([O-:14])=O)C>CO>[CH2:1]([NH:6][C:12](=[O:14])[CH2:11][C:10]([CH2:9][C:23]([NH:6][CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])=[O:25])([C:20]([NH:6][CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])=[O:22])[OH:19])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CCN
Reactant: CCC(C(=O)[O-])C(O)(C(=O)[O-])C(CC)(CC)C(=O)[O-]
Solvent: CO
Product: CC(C)CCNC(=O)CC(O)(CC(=O)NCCC(C)C)C(=O)NCCC(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 52.1 %

Procedure:
N,N′,N″-tri-iso-amylcitramide was prepared by the reaction of iso-amylamine with triethylcitrate. To a round-bottomed flask were added triethylcitrate (30.001 g, 1 eq), iso-amylamine (28.399 g, 3.0 eq) and methanol (40 mL). The clear light yellow solution stirred for 2 days at room temperature and then additional amine (1.1 eq) was added. After stirring 1 week, a clear yellow solution was observed. Methanol was removed in vacuo and the resulting white solid was triturated using diethylether, collected via filtration and dried in vacuo to give a white powder with a very slight odor (22.52 g, 52.1% yield).
Reaction SMILES: [C:1]([C:4]1[C:8]([O:9][CH3:10])=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[N:5]=1)([OH:3])=O.C[Li].[CH:27]([Mg]Br)=[CH2:28].Cl>O1CCCC1.O>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:6]1[C:7]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[C:8]([O:9][CH3:10])[C:4]([C:1]([CH:27]=[CH2:28])=[O:3])=[N:5]1
Reactant: C=C[Mg]Br
Reactant: COc1c(C(=O)O)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Agent: Cl
Agent: [Li]C
Solvent: O
Solvent: C1CCOC1
Product: C=CC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of 3-carboxy-1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-1H-pyrazole (1.09 g) in tetrahydrofuran (30 mL) was added dropwise methyl lithium (2.9 mL, 1.04 M diethylether solution) at −78° C. under nitrogen-gas atmosphere and the mixture was stirred at the same temperature for 30 minutes After warming to room temperature, to the reaction mixture was added dropwise vinylmagnesium bromide (7.7 mL, 0.97 M tetrahydrofuran solution) and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added water and an aqueous 1N HCl solution. After stirring, the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=90/10 to 85/15) to obtain 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-vinylcarbonyl-1H-pyrazole (780 mg, yield: 70%) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH:12]2[C@:7]1([CH3:17])[CH2:8][CH2:9][CH2:10][CH:11]2[OH:16])([CH3:4])([CH3:3])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.C(OCC)C>[C:1]([O:5][C@H:6]1[CH2:15][CH2:14][CH2:13][C@@H:12]2[C@:7]1([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)O[C@H]1CCCC2C(O)CCC[C@@]21C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)O[C@H]1CCC[C@H]2C(=O)CCC[C@]12C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
To a solution of 3.4 g (14.1 mMol) of (1RS,4aS,5S,8aRS)-5-tert-butoxy-4a-methyl-decahydro-naphtalen-1-ol in 34 ml methylenechloride was added under stirring 3.66 g (17.0 mMol) of pyridiniumchlorochromate and the reaction mixture was kept under stirring overnight. Then the reaction was diluted with 33 ml diethylether, kept stirring for 15 minutes and filtered over florisil. The filtrate was evaporated to dryness in vacuo and the residue dissolved in 33 ml of tetrahydrofurane. Under stirring and argon atmosphere 1.65 ml of a one molar solution of potassium-tertio-butoxyde in tetrahydrofurane was added and the reaction was kept overnight. This equilibration is monitored by TLC (silicagel, hexane/ethylacetate 4/1), which shows the almost complete disappearance of one of the two epimers. The reaction mixture is evaporated in vacuo to dryness, the residue is taken up in water and extracted three times with diethylether. The combined organic phase is washed with water and brine, dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed over 120 g of silicagel with hexane/ethylacetate 9/1 to yield 2.39 g (71%) of pure (4aS,5S,8aR)-5-tert-butoxy-4a-methyl-octahydro-naphtalen-1-one.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9](=[O:16])[CH2:10][CH2:11]2)(=O)=O.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9](=[O:16])[CH2:10][CH2:11]2
Reactant: O=C1CCc2cccc(OS(=O)(=O)C(F)(F)F)c21
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1CCc2cccc(-c3ccc(Cl)cc3Cl)c21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.7 %

Procedure:
A solution containing 3-oxo-2,3-dihydro-1H-inden-4-yl trifluoromethanesulfonate (0.666 g, 2.38 mmol), 2,4-dichlorobenzeneboronic acid (0.907 g, 4.75 mmol), and potassium carbonate (0.657 g, 4.75 mmol) in toluene (10 mL) stirred at room temperature for 15 minutes. Pd(PPh3)4 (1.37 g, 1.19 mmol) was added and the mixture was stirred at 90° C. for 2 hours. The catalyst was removed by filtration and concentrated. Flash chromatography gave the desired product as a brown solid (0.572 g, 87%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][O:7][C:6]=1[CH3:10])=[O:4].C1C(=O)N([Br:18])C(=O)C1>C(Cl)(Cl)Cl.C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([Br:18])[O:7][C:6]=1[CH3:10])=[O:4]
Reactant: COC(=O)c1ccoc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)oc1C
Temperature: 25 °C
Reaction time: 19 h
Yield: 78.5 %

Procedure:
DK001 (The following reaction is carried out under exclusion of light.) Dissolve 2-Methyl-furan-3-carboxylic acid methyl ester (52) (3.60 mL, 28.5 mmol) in chloroform (20 mL) and glacial acetic acid (20 mL) and add NBS (6.90 g, 38.8 mmol) portionwise in between a period of 95 min. Stir the reaction suspension for additional 19 h at rt. Add water to the reaction mixture and extract the aqu. layer with dichloromethane (2 times), wash the combined organic layer with 2M aqu. NaOH, water (3 times) and brine and dry it with Na2SO4 to obtain 5-Bromo-2-methyl-furan-3-carboxylic acid methyl ester (53) (4.90 g, 78%) as a red brown oil. No further purification. 1H NMR (400 MHz, CDCl3): 2.54 (s, 3H); 3.80 (s, 3H); 6.53 (s, 1H).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:30]2[CH2:31][CH2:32][N:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)n1nc(CCCN2CCN(c3ccccc3)CC2)cc1-c1ccc(F)cc1

Procedure:
134 mg (80%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propanal (100 mg, 0.365 mmol), 1-phenylpiperazine (0.055 mL, 0.365 mmol), DIPEA (0.1 mL, 0.548 mmol) and NaBH(OAc)3 (232 mg, 1.095 mmol).
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[CH:25]=[CH:24][C:3]=1[O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[C:6]1=[O:23].[ClH:32].C(O)(C)C>CCOC(C)=O>[ClH:32].[F:1][C:2]1[CH:27]=[C:26]([CH:25]=[CH:24][C:3]=1[O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[C:6]1=[O:23])[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)c1ccc(O[C@H]2CCN(C3CCN(C(=O)OC(C)(C)C)CC3)C2=O)c(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: COC(=O)c1ccc(O[C@H]2CCN(C3CCNCC3)C2=O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of (S)-tert-butyl 4-(3-(2-fluoro-4-(methoxycarbonyl)phenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (2 g, 4.6 mmol) in EtOAc (20 mL) was added hydrogen chloride in isopropanol (5-6 M) (9.2 mL, 46 mmol) and the reaction was stirred overnight at ambient temperature. The reaction was concentrated under vacuum to give (S)-methyl 3-fluoro-4-(2-oxo-1-(piperidin-4-yl)pyrrolidin-3-yloxy)benzoate hydrochloride (1.5 g, 100%), which was used crude in the next reaction
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(N(CC)CC)C.[F:12][C:13]([F:47])([F:46])[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[N:17]=[C:16]([C:30]2[CH:31]=[C:32]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([S:42](Cl)(=[O:44])=[O:43])[CH:37]=3)[CH:33]=[CH:34][CH:35]=2)[N:15]=1>C1COCC1>[OH:2][CH2:1][CH2:3][NH:4][S:42]([C:38]1[CH:37]=[C:36]([C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([C:16]3[N:15]=[C:14]([C:13]([F:12])([F:46])[F:47])[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=4)[N:17]=3)[CH:31]=2)[CH:41]=[CH:40][CH:39]=1)(=[O:43])=[O:44]
Reactant: O=S(=O)(Cl)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Reactant: NCCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(NCCO)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Temperature: 0 °C
Yield: 67.8 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of ethanolamine (0.071 g, 1.16 mmol), triethylamine (0.06 ml, 0.42 mmol) and THF (2 ml) was added drop wise a solution of 3′-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-biphenyl-3-sulfonyl chloride (example 1.3) (0.21 g, 0.39 mmol) in THF (3 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound as a white solid (0.15 g, 69%). MS (ISP) 567.7 [(M+H)+]; mp 153° C.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[OH:12])=O.[CH3:13][N:14]([CH3:18])[C:15]([NH2:17])=[S:16]>>[CH3:13][N:14]([CH3:18])[C:15]1[S:16][CH:2]=[C:3]([C:5]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=2[OH:12])[N:17]=1
Reactant: Cc1ccc(O)c(C(=O)CCl)c1
Reactant: CN(C)C(N)=S
Product: Cc1ccc(O)c(-c2csc(N(C)C)n2)c1
Yield: 96 %

Procedure:
17.5 g or 2-chloroacetyl-4-methylphenol and 10.9 g of N,N-dimethyl thiourea are heated for 20 minutes to 110° C. After cooling, the solidified mass is recrystallised from aqueous methanol, affording 14.2 g (96% of theory) of 2-dimethylamino-4-(2'-hydroxy-5'-methylphenyl)-thiazole of the formula (101) ##STR13## with a melting point of 108°-110° C.