Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:7]1[CH2:12][CH:11]=[C:10]([C:13]2[N:14]=[C:15]([S:18][C:19]3[C@H:25]([CH3:26])[C@H:24]4[N:21]([C:22](=[O:34])[C@@H:23]4[C@H:27]([O:29][Si](C)(C)C)[CH3:28])[C:20]=3[C:35]([O:37]CC=C)=[O:36])[S:16][CH:17]=2)[CH2:9][C@H:8]1[CH2:41][Cl:42])=O)C=C.Cl.C(=O)([O-])O.[Na+].C([SnH](CCCC)CCCC)CCC.P([O-])([O-])([O-])=O>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.ClCCl.C(O)(=O)C.O>[OH:29][C@@H:27]([C@H:23]1[C:22](=[O:34])[N:21]2[C@@H:24]1[C@@H:25]([CH3:26])[C:19]([S:18][C:15]1[S:16][CH:17]=[C:13]([C:10]3[CH2:9][C@@H:8]([CH2:41][Cl:42])[NH:7][CH2:12][CH:11]=3)[N:14]=1)=[C:20]2[C:35]([OH:37])=[O:36])[CH3:28]
Reactant: C=CCOC(=O)C1=C(Sc2nc(C3=CCN(C(=O)OCC=C)[C@H](CCl)C3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(Sc3nc(C4=CCN[C@H](CCl)C4)cs3)[C@H](C)[C@H]12
Reaction time: 0.25 h
Yield: 59.5 %

Procedure:
To a solution of allyl (4R,5S,6S)-3-({4-[(2S)-1-[(allyloxy)carbonyl]-2-(chloromethyl)-1,2,3,6-tetrahydro-4-pyridinyl]-1,3-thiazol-2-yl}sulfanyl)-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (54 mg, 0.083 mmol) in THF (4 ml) was added at 0° C. water (7 ml) and then the solution was adjusted to pH about 2 with 1N hydrochloric acid and stirred for 15 minutes. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution. The solution was adjusted to pH 7.5 and extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the solvent in vacuo, the residue was dissolved in dichloromethane (2 ml). To the solution were added at 0° C. acetic acid (12 μl), tributyltin hydride (0.23 ml) and bis(triphenylphosphine)palladium chloride (5.8 mg, 0.014 mmol) and the mixture was stirred at the same temperature for 10 minutes. To the reaction mixture were added phosphate buffer (50 mM, pH7, 25 ml) and dichloromethane (20 ml). After separation of the aqueous layer, the dichloromethane layer was extracted with water and the aqueous layer was washed twice with dichloromethane (3 ml). The organic solvent in the aqueous layer was evaporated under reduced pressure, and the residue was purified by polymer chromatography (CHP-20P). The fractions eluted with an 1–3% aqueous THF solution were combined and lyophilized to give (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-3-({4-[(2S)-2-(chloromethyl)-1,2,3,6-tetrahydro-4-pyridinyl]-1,3-thiazol-2-yl}sulfanyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (22.5 mg, 46%) as a white amorphous.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=2[CH:26]=O)[CH:7]=1)[CH3:2].C(OC(=O)CC1C=C(C(F)(F)F)C=C(OC2C=CC([N+]([O-])=O)=CC=2CO)C=1)C.[F:57][C:58]([F:62])([F:61])[CH2:59][SH:60]>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[CH:9]=[C:8]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=2[CH2:26][S:60][CH2:59][C:58]([F:62])([F:61])[F:57])[CH:7]=1)[CH3:2]
Reactant: FC(F)(F)CS
Reactant: CCOC(=O)Cc1cc(Oc2ccc([N+](=O)[O-])cc2C=O)cc(C(F)(F)F)c1
Agent: CCOC(=O)Cc1cc(Oc2ccc([N+](=O)[O-])cc2CO)cc(C(F)(F)F)c1
Product: CCOC(=O)Cc1cc(Oc2ccc([N+](=O)[O-])cc2CSCC(F)(F)F)cc(C(F)(F)F)c1

Procedure:
[3-(2-Formyl-4-nitro-phenoxy)-5-trifluoromethyl-phenyl]acetic acid ethyl ester was reduced to [3-(2-hydroxymethyl-4-nitro-phenoxy)-5-trifluoromethyl-phenyl]-acetic acid ethyl ester according to the procedure described in Example 21, Step 6 and then brominated as described in Example 21, Step 7 and then treated with 2,2,2-trifluoroethanethiol to give {3-[4-Nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-5-trifluoromethyl-phenyl}-acetic acid ethyl ester. The amine was reduced as described in Example 21, Step 9, and then treated with pivaloyl chloride as described in Example 21, Step 10 to provide {3-[4-(2,2-Dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-5-trifluoromethyl-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester as described in Example 21, Step 11 provided the acid.
Reaction SMILES: C1COC2C=CC(NC3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=CC=2O1.Cl[C:28]1[N:33]=[C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH:42]([CH3:44])[CH3:43])=[CH:37][CH:36]=2)[C:31]([F:45])=[CH:30][N:29]=1.[CH3:46][O:47][C:48]([C:50]1[O:51][C:52]2[CH:58]=[CH:57][C:56]([NH2:59])=[CH:55][C:53]=2[CH:54]=1)=[O:49]>>[F:45][C:31]1[C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH:42]([CH3:44])[CH3:43])=[CH:37][CH:36]=2)=[N:33][C:28]([NH:59][C:56]2[CH:57]=[CH:58][C:52]3[O:51][C:50]([C:48]([O:47][CH3:46])=[O:49])=[CH:54][C:53]=3[CH:55]=2)=[N:29][CH:30]=1
Reactant: COC(=O)c1cc2cc(N)ccc2o1
Reactant: CC(C)Oc1ccc(Nc2nc(Cl)ncc2F)cc1
Agent: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Product: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4ccc(OC(C)C)cc4)n3)ccc2o1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-[4-(isopropoxy)phenyl]-4-pyrimidineamine and 2-methoxycarbonyl-5-aminobenzofuran were reacted to yield 5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 8.04 (d, 1H, J=1.8 Hz), 7.49-7.41 (m, 4H), 7.35 (dd, 1H, J=2.4 and 8.7 Hz), 7.14 (bs, 1H), 6.90 (d, 2H, J=9.3 Hz), 6.70 (bs, 1H), 4.56 (2q, 1H, J=5.7 Hz), 3.98 (s, 3H), 1.37 (d, 6H, J=5.7 Hz); LCMS: ret. time: 25.52 min.; purity: 98%; MS (m/e): 437 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:14]2[C:5]([C:6]3[O:7][CH2:8][CH2:9][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:11]=3[CH:12]=[CH:13]2)=[N:4][C:3]=1[C:22](OCC)=[O:23].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[OH:23][CH2:22][C:3]1[N:4]=[C:5]2[N:14]([C:2]=1[CH3:1])[CH:13]=[CH:12][C:11]1[N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][CH2:8][O:7][C:6]2=1
Reactant: CCOC(=O)c1nc2c3c(ccn2c1C)N(C(=O)OC(C)(C)C)CCO3
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CO)nc2c3c(ccn12)N(C(=O)OC(C)(C)C)CCO3
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.4 %

Procedure:
To a solution of 10-tert-butyl 4-ethyl 5-methyl-13-oxa-3,6,10-triazatricyclo[7.4.0.0{2,6}]trideca-1(9),2,4,7-tetraene-4,10-dicarboxylate (757 mg, 2.09 mmol) in 50 mL of THF was added LAH (2.364 g, 6.27 mmol) at 0° C. The mixture was stirred for 3 h at room temperature. To the mixture was added sodium sulfate decahydrate (257 mg) and the mixture was stirred for 15 min at room temperature. The solid was removed by filtration and the filtrate was concentrated. The residue was purified by reverse phase column chromatography (eluting with 15% acetonitrile in water, with 0.1% NF3—H2O) to give tert-butyl 4-(hydroxymethyl)-5-methyl-13-oxa-3,6,10-triazatricyclo[7.4.0.0{2,6}]trideca-1(9),2,4,7-tetraene-10-carboxylate (630 mg, 94% yield) as a white solid. ESI MS: m/z 320 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]12[CH2:9][C:7]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=3)([CH2:8]1)[C:6](=[O:19])[N:5]([CH2:20][CH2:21][CH3:22])[C:4]2=[O:23])[CH3:2].CCOCC>C(OCC)(=O)C.[Pd]>[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]23[CH2:9][C:3]([CH2:1][CH3:2])([CH2:8]2)[C:4](=[O:23])[N:5]([CH2:20][CH2:21][CH3:22])[C:6]3=[O:19])=[CH:15][CH:14]=1
Reactant: CCCN1C(=O)C2(CC)CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Agent: [Pd]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCN1C(=O)C2(CC)CC(c3ccc(N)cc3)(C2)C1=O

Procedure:
In a manner analogous to that described in Example 12a, 6.3 g of 5-ethyl-1-(4-nitrophenyl)-3-n-propyl-3-azabicyclo[3.1.1]-heptane-2,4-dione are dissolved in 120 ml of ethyl acetate, hydrogenated in the presence of 0.6 g of 5% palladium-on-carbon and worked up. Melting point 124.5°-125° (from ether).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:3]=1[C:4]([OH:6])=[O:5].[Cl-].[NH4+].BrC1C=CC=C([N+]([O-])=O)C=1C>[Fe].CO>[NH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1c(Br)cccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cc1c(Br)cccc1[N+](=O)[O-]
Agent: [Cl-]
Solvent: CO
Product: Nc1cccc(Br)c1C(=O)O

Procedure:
The target compound was obtained by reducing 2-bromo-6-nitrobenzoic acid with iron in a mixed solvent of methanol and ammonium chloride aqueous solution. 2-bromo-6-nitrobenzoic acid was manufactured by the method described in the literature (J. Chem. Soc. Perkin Trans. 1, 1991, p. 1565) using 2-bromo-6-nitrotoluene as starting material.
Reaction SMILES: Br[C:2]1[C:3]([S:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)[O:26]1.C1(P(C2CCCC2)C2CCCC2)CCCC1.[F-].[Cs+]>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=1[S:15][C:3]1[CH:4]=[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)[N:6]=[CH:7][C:2]=1[OH:26]
Reactant: Cc1csc(Nc2cc(Sc3c(Cl)cccc3Cl)c(Br)cn2)n1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCC2)C2CCCC2)C1
Agent: CC(=O)[O-]
Solvent: CC#N
Product: Cc1csc(Nc2cc(Sc3c(Cl)cccc3Cl)c(O)cn2)n1
Temperature: 90 °C

Procedure:
A degassed mixture of N-(5-bromo-4-(2,6-dichlorophenylthio)pyridin-2-yl)-4-methylthiazol-2-amine (1.18 g, 2.66 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.35 g, 5.32 mmol), Pd(OAc)2 (60 mg, 0.27 mmol), tricyclopentylphosphine (93 mg. 0.40 mmol) and cesium fluoride (3.64 g, 23.9 mmol) in acetonitrile is heated at 90° C. for 5 hours. The reaction mixture is cooled and partitioned between ether and water. The crude product is dissolved in THF. N-morpholine N-oxide (1.40 g, 12.0 mmol) is added and the reaction mixture is heated at reflux for 12 hours. The reaction mixture is cooled and partitioned between ether and water. The organic layer is washed with water and brine, dried and concentrated. The residue is purified by silica gel chromatography, eluting with 10-20% EtOAc in hexanes to afford 4-(2,6-dichlorophenylthio)-6-(4-methylthiazol-2-ylamino)pyridin-3-ol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]2[C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH:13]=1.[CH3:32][C:33]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH:45]=O)[CH2:41][CH2:40]1)=[O:38])([CH3:35])[CH3:34]>>[C:33]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45][NH:1][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[CH:4][C:3]=2[C:12]2[CH:13]=[C:14]([O:18][C:19]3[C:24]4[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=4[CH:22]=[CH:21][CH:20]=3)[N:15]=[CH:16][N:17]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:32])[CH3:34]
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4N)ncn3)cccc2s1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NCC4CCN(C(=O)OC(C)(C)C)CC4)ncn3)cccc2s1

Procedure:
The title compound was prepared from N-{4-[6-(2-amino-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide (Example 151) and N-Boc-4-piperidinylcarboxaldehyde according the procedure described in Example 159. MS(ESI, pos. ion) m/z: 643 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16]([F:26])=[C:17]3[C:22](=[CH:23][C:24]=2[F:25])[CH:21]=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=O)(C)(C)C>CO>[F:26][C:16]1[C:15]([O:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[C:24]([F:25])[CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][N:20]=[CH:21]2
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(F)cc3cnccc3c2F)CC1
Solvent: CO
Product: Fc1cc2cnccc2c(F)c1OC1CCNCC1

Procedure:
4-(5,7-Difluoro-isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (374) is deprotected in Methanol/2 N HCl by the general procedure described in AAV2 to yield the title compound as HCl-salt. Rt=0.43 min (Method #TOP). Detected mass: 265.1 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[N:10]([CH2:16][CH:17]=[CH2:18])[CH2:11][CH2:12][CH2:13]C=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.C1CCC([P+](C([P+](C2CCCCC2)(C2CCCCC2)C2CCCCC2)C2C=CC=CC=2)(C2CCCCC2)C2CCCCC2)CC1.Cl[Ru]Cl>[CH2:1]([O:8][C:9]([N:10]1[CH2:16][CH:17]=[CH:18][CH2:13][CH2:12][CH2:11]1)=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCCCN(CC=C)C(=O)OCc1ccccc1
Agent: Cl[Ru]Cl
Agent: c1ccc(C([P+](C2CCCCC2)(C2CCCCC2)C2CCCCC2)[P+](C2CCCCC2)(C2CCCCC2)C2CCCCC2)cc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC=CCCC1
Yield: 56.4 %

Procedure:
Allyl-pent-4-enyl-carbamic acid benzyl ester (15.5 g, 59.8 mmol) was dissolved in dichloromethane and bis(tricyclohexylphosphine)benzylidene ruthenium(IV) dichloride (1 g) was added. The mixture was refluxed under a nitrogen atmosphere until TLC analysis showed complete reaction. The solvent was evaporated under vacuum and the residue was purified by flash chromatography (ethyl acetate/hexane 1:9) to give 2,3,4,7-Tetrahydro-azepine-1-carboxylic acid benzyl ester (7.8 g).
Reaction SMILES: F[C:2]1[C:3]([C:12]#[C:13][Si](C)(C)C)=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7].C([O-])([O-])=O.[K+].[K+].[C:24]1([C@H:30]([NH2:32])[CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN1C(=O)CCC1>[C:24]1([C@H:30]([N:32]2[C:2]3[C:3](=[C:4]([C:10]#[N:11])[C:5]([C:6]#[N:7])=[CH:8][CH:9]=3)[CH:12]=[CH:13]2)[CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C[Si](C)(C)C#Cc1c(F)ccc(C#N)c1C#N
Reactant: C[C@@H](N)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: C[C@H](c1ccccc1)n1ccc2c(C#N)c(C#N)ccc21
Temperature: 60 °C
Reaction time: 15 h
Yield: 51.2 %

Procedure:
An oven-dried vial was charged with 4-fluoro-3-((trimethylsilyl)ethynyl)phthalonitrile (Example 40C) (0.100 g, 0.413 mmol) and K2CO3 (0.057 g, 0.413 mmol) and sealed with a rubber septum. Anhyd NMP (2 mL) and (R)-1-phenylethanamine (0.053 mL, 0.413 mmol) were added via syringe and the mixture was stirred in a heating block at 60° C. under N2. After 15 h, the mixture was cooled, quenched by addition of satd NH4Cl, poured into water and extracted with EtOAc (×3). Combined organics were washed (water ×2, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) affording (R)-1-(1-phenylethyl)-1H-indole-4,5-dicarbonitrile (0.0574 g, 51% yield) as a pale yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J=3.3 Hz, 1H), 7.48 (dd, J=8.6, 0.7 Hz, 1H), 7.43 (d, J=8.7 Hz, 1H), 7.37-7.27 (m, 3H), 7.12-7.06 (m, 2H), 6.88 (dd, J=3.3, 0.7 Hz, 1H), 5.72 (q, J=7.1 Hz, 1H), 1.98 (d, J=7.0 Hz, 3H); MS (LCMS ES+) m/z 272 ([M+H]+, 5%), 289 (100%), 313 ({[M+H]+MeCN}, 23%), 335 ({[M+Na]+MeCN}, 22%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)[N:13]=1.C(Cl)(=O)C([Cl:22])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12](/[CH:14]=[CH:15]/[C:16]([Cl:22])=[O:18])[N:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)/C=C/c1csc(-c2c(F)cccc2Cl)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)/C=C/c1csc(-c2c(F)cccc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a suspension of (E)-3-(2-(2-chloro-6-fluorophenyl)thiazol-4-yl)acrylic acid (5.4 g, 19 mmol) in DCM (20 mL) was added oxalyl chloride (4.8 g, 38 mmol) and 2 drops of DMF. The resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give the crude product (5.7 g, 100% yield), which was used in the next step without purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:8]=[C:9](C(C)(C)C)[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].Cl>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(O)c(C(C)(C)C)c1
Yield: 71.8 %

Procedure:
A mixture of 50 g of methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate, 2.5 g of conc. hydrochloric acid and 30 ml of toluene was refluxed for 2 hours while stirring. After the completion of the reaction, the reaction mixture was washed with water and the solvent wa distilled off. Hexane was added to the residue and the mixture was icecooled. The resulting crystals were collected by filtration and recrystallized from hexane to give 29 g of methyl 3-(3-tert-butyl-4-hydroxyphenyl)propionate as white crystals, m.p. 59°-61° C.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][C@@H:6]1[CH2:20][C@H:19]2[C@@H:9]([CH2:10][C:11]3[C:21]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]2=4)[NH:13][CH:12]=3)[N:8]([CH3:22])[CH2:7]1)(=O)=O.[CH3:30][N:31]1[CH2:35][C:34](=[O:36])[NH:33][C:32]1=[O:37].C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>CN(C)C=O>[CH3:30][N:31]1[CH2:35][C:34](=[O:36])[N:33]([CH2:5][C@@H:6]2[CH2:20][C@H:19]3[C@@H:9]([CH2:10][C:11]4[C:21]5[C:14](=[CH:15][CH:16]=[CH:17][C:18]3=5)[NH:13][CH:12]=4)[N:8]([CH3:22])[CH2:7]2)[C:32]1=[O:37]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Reactant: CN1CC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: CN1CC(=O)N(C[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)C1=O
Yield: 69.9 %

Procedure:
A mixture of 0.5 g of 6-methylergolin-8β-ylmethyl tosylate, 1.0 g of 1-methylimidazolidin-2,4-dione, 1.0 g of potassium carbonate, 10 ml of methyl ethyl ketone and 10 ml of dimethylformamide was refluxed for 4 hours with stirring, and the solvent was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, and the solvent was distilled off. The residue (which was dissolved in dichloromethane and adsorbed on silica gel) was purified by silica gel column chromatography (eluted with ethyl acetate and then with ethyl acetate:isopropyl alcohol=1:1 by volume). The product was recrystallized from dichloromethane-hexane to obtain 0.3 g of the titled product as colorless needles having a melting point higher than 210° (with decomposition).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH:18]=[CH2:19])=[CH:4][CH:3]=1.[CH2:21]([O:23][C:24]([C:26]1([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)[CH2:28][CH2:27]1)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24]([C:26]1([C:29]2[CH:34]=[CH:33][C:32]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH:18]=[CH2:19])=[CH:4][CH:3]=3)=[CH:31][CH:30]=2)[CH2:27][CH2:28]1)=[O:25])[CH3:22]
Reactant: C=CCCC(C)Nc1c(C)noc1-c1ccc(Br)cc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: C=CCCC(C)Nc1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(1-methyl-pent-4-enyl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1]I.[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][OH:11])[C:5]=1[OH:12]>>[F:3][C:4]1[C:5]([O:12][CH3:1])=[C:6]([CH2:10][OH:11])[CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: OCc1cccc(F)c1O
Product: COc1c(F)cccc1CO

Procedure:
In an analogous manner to that described in (α) 2-fluoro-6-hydroxymethyl-phenol was alkylated with methyliodide to yield (3-fluoro-2-methoxy-phenyl)-methanol as a white solid; MS: 142 (M)+.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]3[CH2:25][C@@H:24]([CH2:26][C:27]([O:29]C(C)C)=[O:28])[C:23]4[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=4[CH2:21][C:20]=3[CH:37]=2)[CH:6]=1)[CH3:3].CC1C=CN=C(NCCCOC2C=CC3C[C@@H](CC(OCC)=O)C4C=CC=CC=4CC=3C=2)C=1>>[CH3:3][CH:2]([O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]3[CH2:25][C@@H:24]([CH2:26][C:27]([OH:29])=[O:28])[C:23]4[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=4[CH2:21][C:20]=3[CH:37]=2)[CH:6]=1)[CH3:1]
Reactant: CC(C)OC(=O)C[C@@H]1Cc2ccc(OCCCNc3cc(OC(C)C)ccn3)cc2Cc2ccccc21
Agent: CCOC(=O)C[C@@H]1Cc2ccc(OCCCNc3cc(C)ccn3)cc2Cc2ccccc21
Product: CC(C)Oc1ccnc(NCCCOc2ccc3c(c2)Cc2ccccc2[C@H](CC(=O)O)C3)c1

Procedure:
According to the procedure of Example 13 (c), except substituting isopropyl (S)-10,11-dihydro-3-[3-[4-(2-propyloxy)pyridin-2-ylamino]-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate for the ethyl (S)-10,11-dihydro-3-[3-(4-methylpyridin-2-ylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate, the title compound was obtained as white powder: MS (ES) 461.3 (M+H)+. Anal. Calcd for C28H32N2O4.0.96 HCl: C, 67.86; H, 6.70; N, 5.65. Found: C, 68.26; H, 6.86; N, 5.25.
Reaction SMILES: C(OC(=O)C1C=CC(N[C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=CC=1)C.ClC1C=CC(C2N(C(C3CCCCC3)C(O)=O)C3C=C(F)C(F)=CC=3N=2)=CC=1.[CH3:68][O:69][C:70]([C:72]1([O:75][C:76]2[CH:81]=[CH:80][C:79]([NH2:82])=[C:78]([F:83])[CH:77]=2)[CH2:74][CH2:73]1)=[O:71]>CN(C)C1C=CN=CC=1>[CH3:68][O:69][C:70]([C:72]1([O:75][C:76]2[CH:81]=[CH:80][C:79]([NH:82][C:12](=[O:38])[CH:13]([N:20]3[C:24]4[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=4[N:22]=[C:21]3[C:31]3[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=3)[CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)=[C:78]([F:83])[CH:77]=2)[CH2:74][CH2:73]1)=[O:71]
Reactant: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Reactant: COC(=O)C1(Oc2ccc(N)c(F)c2)CC1
Agent: CN(C)c1ccncc1
Agent: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Product: COC(=O)C1(Oc2ccc(NC(=O)C(C3CCCCC3)n3c(-c4ccc(Cl)cc4)nc4cc(F)c(F)cc43)c(F)c2)CC1

Procedure:
This compound was prepared in analogy to example 22, intermediate d, from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid, 1-(4-amino-3-fluoro-phenoxy)-cyclopropanecarboxylic acid methyl ester and using 4-(dimethylamino)pyridine as base.
Reaction SMILES: ClC(Cl)(Cl)C(OC(=O)C(Cl)(Cl)Cl)=O.[NH2:14][C:15](=O)[C@@H:16]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[C:15]([C@@H:16]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:23]=1)#[N:14]
Reactant: CC(C)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(N)=O)cc1
Agent: O=C(OC(=O)C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccc(C[C@@H](C#N)NC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
Trichloroacetic acid anhydride (120 mg, 0.39 mmol) was added slowly to a solution of (S)-tert-butyl 1-amino-3-(4-isopropoxyphenyl)-1-oxopropan-2-ylcarbamate (50 mg, 0.2 mmol) in methylene chloride (3 mL) and triethylamine (86 uL, 0.62 mmol) at 0° C. The reaction was stirred for 1 h. at 0° C. The reaction was quenched with saturated NaHCO3 and was extracted with ethyl acetate. The organic phase was washed with water, saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was purified by Flash chromatography on a silica gel column (EtOAc:Hexane, 1:3 to 1:1) to obtain the (S)-tert-butyl 1-cyano-2-(4-isopropoxyphenyl)ethylcarbamate (40 mg, 80%) as clear oil. Analytical LCMS (M+Na)+: m/z=327.0.