Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH3:13].[CH3:14][N:15]([CH3:29])[CH2:16][CH2:17][O:18][C:19]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=O.[O-]CC.[Na+]>C(O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1/[CH:13]=[CH:21]/[C:20]1[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:19]=1[O:18][CH2:17][CH2:16][N:15]([CH3:29])[CH3:14]
Reactant: COc1cccc(C=O)c1OCCN(C)C
Reactant: Cc1nc2ccccn2c(=O)c1Br
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3ccccn3c(=O)c2Br)c1OCCN(C)C

Procedure:
The title compound was prepared from 3-bromo-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (1.021 g, 4.18 mmol) and 2-[2-(dimethylamino)ethoxy]-3-methoxybenzaldehyde (0.969 g, 5.011 mmol) in the presence of sodium ethoxide (0.426 g, 6.27 mmol) in absolute ethanol (25 ml) as described in Intermediate 1 to give 649 mg of the product as a light yellow solid; 1H NMR (300 MHz, CDCl3) δ 2.39 (s, 6H), 2.82 (s, 2H), 3.87 (s, 3H), 4.12 (s, 2H), 6.91 (d, J=7.5 Hz, 1H), 7.04-7.10 (m, 2H), 7.28-7.34 (m, 1H), 7.66-7.71 (m, 3H), 8.40 (d, J=15.0 Hz, 1H), 8.95 (d, J=7.2 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C([Li])(C)(C)C.CCCCC.C([Sn](Cl)(CCCC)CCCC)CCC.[CH3:37][Si:38]([CH3:54])([CH3:53])[CH2:39][CH2:40][O:41][C:42](=[O:52])[NH:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50]Cl)=[CH:46][CH:45]=1>O1CCCC1.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.CN(C)P(N(C)C)(N(C)C)=O>[CH3:53][Si:38]([CH3:37])([CH3:54])[CH2:39][CH2:40][O:41][C:42](=[O:52])[NH:43][C:44]1[CH:45]=[CH:46][C:47]([CH2:50][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=2)=[CH:48][CH:49]=1
Reactant: C[Si](C)(C)CCOC(=O)Nc1ccc(CCl)cc1
Reactant: CC(C)OCc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCC
Product: CC(C)OCc1ccc(Cc2ccc(NC(=O)OCC[Si](C)(C)C)cc2)cc1
Temperature: 65 °C
Reaction time: 0.33 h
Yield: 3.9 %

Procedure:
To a stirred solution of 1-bromo-4-isopropoxymethyl-benzene (300 mg, 13.1 mmol) (prepared as described in Preparation 1) in dry tetrahydrofuran (1.4 mL) at −78° C. under argon atmosphere was added dropwise 1.7M tert-butyllithium in pentane (1.62 mL, 2.75 mmol). After the mixture was stirred for about 20 minutes, tri-n-butyltin chloride (0.35 mL, 1.31 mmol) was added. The mixture was allowed to reach 0° to 5° C. and stirred for about 1 hour. A mixture of (4-chloromethylphenyl) carbamic acid 2-trimethylsilanyl-ethyl ester (374 mg, 13.1 mmol) (prepared as described in Preparation 2), hexamethylphosphoramide (4.4 mL), tetrakis(triphenylphosphine)palladium(0) (29.3 mg, 0.025 mmol) was added at 0° to 5° C., and then heated to about 65° C. for 20 hours. The solution was partitioned between water (15 mL) and diethyl ether (15 mL). The aqueous phase was extracted with diethyl ether, and the combined organic layers were washed with water and brine, dried (Na2SO4), and evaporated in vacuo. The residue was dissolved in acetonitrile, washed with hexane (2×20 mL), dried (Na2SO4), concentrated in vacuo, and purified by flash chromatography to give pure 4-(4-isopropoxymethylbenzyl)phenyl carbamic acid 2-trimethylsilanyl-ethyl ester (204 mg, 26%) as clear oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:13][C:12]([C:22](=[O:24])[CH3:23])=[CH:11][C:10]=1[C:25]([CH3:28])([CH3:27])[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1)([OH:31])=[O:30].[OH-].[K+].Cl>CO>[CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)=[CH:13][C:12]([C:22](=[O:24])/[CH:23]=[CH:36]/[C:35]2[CH:38]=[CH:39][C:32]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=2)=[CH:11][C:10]=1[C:25]([CH3:28])([CH3:27])[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1cc(-c2ccc(C)cc2)c(OCc2ccccc2)c(C(C)(C)C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2cc(C(=O)/C=C/c3ccc(C(=O)O)cc3)cc(C(C)(C)C)c2OCc2ccccc2)cc1
Reaction time: 36 h
Yield: 38 %

Procedure:
970 mg (2.6 mmol) of 1-(6-benzyloxy-5-tert-butyl-4′-methyl-3-biphenylyl)ethanone are dissolved in 40 mL of methanol. 350 mg (2.3 mmol) of 4-carboxybenzaldehyde are added, followed by 1.23 mL (10 mmol) of 47% KOH. The reaction medium is stirred for 36 hours and then acidified with concentrated hydrochloric acid. The medium is extracted with ethyl acetate, and the residue obtained is purified by chromatography on a column of silica. The solid obtained is recrystallized from an ethyl ether/heptane mixture. A yellow powder is obtained (m=500 mg; yield=38%; m.p.=208° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](OS(C(F)(F)F)(=O)=O)[C:10]=1/[CH:23]=[CH:24]/[C:25]([O:27][CH3:28])=[O:26].[O:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[O:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]#[CH:42].C(N(CC)CC)C.C#C>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.C(OCC)(=O)C.O.CN(C)C=O>[CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:42]#[C:41][CH2:40][CH2:39][CH2:38][CH2:37][O:36][CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][O:30]2)[C:10]=1/[CH:23]=[CH:24]/[C:25]([O:27][CH3:28])=[O:26]
Reactant: C#CCCCCOC1CCCCO1
Reactant: COC(=O)/C=C/c1c(OCCCCC(=O)OC)cccc1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C#C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)/C=C/c1c(C#CCCCCOC2CCCCO2)cccc1OCCCCC(=O)OC
Temperature: 100 °C
Reaction time: 24 h
Yield: 38.1 %

Procedure:
A mixture of 2.27 g (5 mmol) of (E)-5-[3-[[(trifluoromethyl)sulfonyl]oxy]-2-(3-methoxy-3-oxo-1-propenyl)phenoxy]pentanoic acid methyl ester, 1.0 g (5.5 mmol) of rac-6-[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexyne, 0.3 g (0.428 mmol) of dichlorobis(triphenylphosphine)palladium (II), 0.075 g of cuprous iodide, 7.5 mL of dry triethylamine, and 35 mL of dry N,N-dimethylforamide was stirred and heated at 100° C. for 3.5 hr. An additional 0.25 g of the acetylene was added and heating was continued for 24 hr at which point 0.75 g of the acetylene was added and heating was continued for 6 hr. The resulting mixture was cooled, poured into water and worked-up with ethyl acetate in the usual manner. The crude, oily product was chromatographed on silica gel. Elution with 10:1 toluene-ethyl acetate afforded 0.9 g (38%) of rac-(E)-5-[2-(3-methoxy-3-oxo-1-propenyl)-3-[ 6-[(tetrahydro-2H-pyran-2-yl)oxy]-1hexynyl]phenoxy]pentanoic acid methyl ester as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:31](=[CH:32][CH:33]=1)[O:30][C:29]([CH3:35])([CH3:34])[C:25]1([CH2:28][O:27][CH2:26]1)[C:5]12[CH2:9][O:8][C:7]([N:10](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:6]1.[Cl:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[C:41]([F:43])[CH:42]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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:36][C:37]1[CH:38]=[C:39]([C:2]2[CH:3]=[C:4]3[C:31](=[CH:32][CH:33]=2)[O:30][C:29]([CH3:35])([CH3:34])[C:25]2([CH2:28][O:27][CH2:26]2)[C:5]23[CH2:9][O:8][C:7]([NH2:10])=[N:6]2)[CH:40]=[C:41]([F:43])[CH:42]=1
Reactant: OB(O)c1cc(F)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(Br)ccc1OC(C)(C)C21COC1
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: [Na+]
Solvent: C1COCCO1
Product: CC1(C)Oc2ccc(-c3cc(F)cc(Cl)c3)cc2C2(COC(N)=N2)C12COC2
Temperature: 100 °C
Reaction time: 12 h
Yield: 45.8 %

Procedure:
A mixture of di-tert-butyl (6′-bromo-2′,2′-dimethyldispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl)imidodicarbonate (13.8 mg), 3-chloro-5-fluorophenylboronic acid (8.7 mg), Pd(PPh3)4 (2.9 mg) and 1M aqueous Na2CO3 (0.063 mL) in dioxane (0.25 mL) was stirred for 12 hours at 100° C. The mixture was filtered by using Chem Elut cartridges and washed with CHCl3. The filtrate was evaporated. The residue was purified with HPLC (Column: Waters SunFire™ Prep C18 OBD™ 5 micrometer, 19×100 mm; MeOH/0.1% aqueous HCOOH 11/89 to 95/5(v/v)) and afforded 6′-(3-chloro-5-fluorophenyl)-2′,2′-dimethyldispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-amine (4.6 mg).
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1>[Pt].O>[ClH:1].[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:4][CH2:3]1
Reactant: O=C(O)CCCc1ccncc1
Agent: [Pt]
Agent: Cl
Solvent: O
Product: O=C(O)CCCC1CCNCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To the 30% aqueous solution of 4-(4-pyridyl)butanoic acid hydrochloride prepared in step 2 (208.9 kg) and water (145 kg) is added platinum on charcoal (50% wet, 5%, 2.52 kg). The mixture is hydrogenated at about 70° C. under atmospheric pressure over 15 hours and then allowed to cool to ambient temperature. The catalyst is filtered and washed with water (20 kg). The resulting aqueous 16% solution of 4-piperidinebutanoic acid hydrochloride (388.5 kg) is used as is in step 4.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][C@:22](/[CH:27]=[CH:28]\[CH2:29]O)([OH:26])[C@@H:21]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][C@:22]2([O:26][CH2:29][CH:28]=[CH:27]2)[C@@H:21]1[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@](O)(/C=C\CO)[C@@H]1c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@]2(C=CCO2)[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
Diethyl azodicarboxylate (18.2 ml, 115 mmol) in THF (100 ml) was added dropwise to a solution of Z-(2S,3R)-1-tert-butoxycarbonyl-3-(3-hydroxyprop-1-en-1-yl)-2-phenylpiperidin-3-ol (Description 20; 32 g, 96 mmol) and triphenylphosphine (30.2 g, 115 mmol) in THF (700 ml). The mixture was stirred at 0° C. for 30 minutes then at room temperature for 1.5 hours. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with hexane/ethyl acetate (95:5 increasing to 80:20) to give the title compound as a colorless solid (23.4 g, 77%). MS (ES+) m/z 316 (M+ +1, 100%). 1H NMR (CDCl3) δ 7.45 (2H, d, J 7.4 Hz), 7.27 (2H, t, J 7.4 Hz), 7.20 (1H, t, J 7.4 Hz), 6.03 (1H, dt, J 6.1, 2.0 Hz), 5.68 (1H, dt, J 6.1, 2.0 Hz), 5.06 (1H, s), 4.61 (1H, dt, J 13.1, 2.0 Hz), 4.32 (1H, dt, J 13.1, 2.0 Hz), 4.08 (1H, m), 3.05 (1H, m), 2.05 (1H, m), 1.75 (3H, m), and 1.37 (9H, s).
Reaction SMILES: O=[C:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][CH2:4][CH:5]([C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:6]([O:8]CC)=[O:7].C([O-])(=O)C.[NH4+].C1(C2C(C(OCC)=O)=CC=C(C3C=CC=CC=3)[N:39]=2)C=CC=CC=1.C(C(CCC(=O)C1C=CC=CC=1)C(OCC)=O)(=O)C1C=CC=CC=1>C(O)(=O)C>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=[C:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:39]=1
Reactant: CCOC(=O)c1ccc(-c2ccccc2)nc1-c1ccccc1
Reactant: CCCCCCCC(=O)CCC(C(=O)OCC)C(=O)c1ccccc1Cl
Agent: CC(=O)[O-]
Agent: CCOC(=O)C(CCC(=O)c1ccccc1)C(=O)c1ccccc1
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCCCCCCc1ccc(C(=O)O)c(-c2ccccc2Cl)n1
Yield: 70.6 %

Procedure:
A mixture of 0.90 g of compound I, 2.73 g of ammonium acetate and 2.80 g of ferric chloride hexahydrate in 20 cc of acetic acid was heated under reflux for 8 hours. Thereafter, 0.60 g of compound J was obtained in the same manner as in the production of compound H from compound G, Yield: 70.6%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N:7]1([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][C:14]=2[C:22]([F:25])([F:24])[F:23])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.O[N:27]=[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37])[NH2:29].CCN(C(C)C)C(C)C>>[CH3:37][O:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:28]1[N:27]=[C:17]([C:16]2[CH:20]=[CH:21][C:13]([N:7]3[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]3)=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:15]=2)[O:19][N:29]=1
Reactant: COc1ccccc1C(N)=NO
Reactant: O=C(O)c1ccc(N2CCCCC2)c(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1noc(-c2ccc(N3CCCCC3)c(C(F)(F)F)c2)n1

Procedure:
Oxalyl chloride (190 mg; 1.5 mmol; 3 eq.), Intermediate 42 (137 mg; 0.5 mmol; 1 eq.), Intermediate 1 (83 mg; 0.5 mmol, 1 eq.) and DIEA (194 mg; 1.5 mmol; 3 eq.) were reacted according to general procedure 2. Purification by crystallisation from n-pentane afforded the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[O:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:32][CH:29]3[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NC1CCOCC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC3CCOCC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and tetrahydro-2H-pyran-4-ylamine. MS obsd. (ESI+) [(M+H)+] 438, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.89 (dd, J=6.95, 3.41 Hz, 2 H), 7.78 (s, 1 H), 7.59 (t, J=7.07 Hz, 1 H), 7.47 (t, J=7.58 Hz, 1 H), 7.31 (d, J=8.59 Hz, 1 H), 7.23 (d, J=8.59 Hz, 1 H), 6.33 (d, J=8.08 Hz, 1 H), 6.09 (s, 1 H), 5.09 (brs, 2 H), 4.44 (brs, 1 H), 3.99 (d, J=9.85 Hz, 2 H), 3.94-3.82 (m, 1 H), 3.69-3.52 (m, 4 H), 2.36 (s, 3 H), 1.85 (d, J=11.87 Hz, 2 H), 1.69-1.44 (m, 2 H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:65][C:66]([F:80])([F:79])[C:67]1[CH:68]=[C:69]([CH:72]=[C:73]([C:75]([F:78])([F:77])[F:76])[CH:74]=1)[CH2:70][NH2:71].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(OCC)(=O)C>[F:65][C:66]([F:79])([F:80])[C:67]1[CH:68]=[C:69]([CH:72]=[C:73]([C:75]([F:78])([F:76])[F:77])[CH:74]=1)[CH2:70][NH:71][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][N:3]=1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)CCCOc1cnc(Cl)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCCOc1cnc(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
Tert-butyl 4-(2-chloropyrimidin-5-yloxy)-butyrate (5.0 g) is dissolved in toluene (100 ml) and thereto are added palladium acetate (412 mg) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.26 g), and the mixture is stirred under nitrogen atmosphere at 50° C. for 1 hour. The reaction solution is cooled to room temperature, and thereto are added 3,5-bis-trifluoromethyl-benzylamine (5.35 g) and sodium tert-butoxide (3.88 g) and the mixture is stirred at 35° C. for 2 hours. Thereto are added ethyl acetate and water, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→2:1) and NH-silica gel column chromatography (hexane:ethyl acetate=4:1→2:1) to give tert-butyl 4-[2-(3,5-bis-trifluoromethyl-benzylamino)-pyrimidin-5-yloxy]-butyrate (5.59 g). MS (m/z): 480 [M+H]+
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH:29]([O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)[CH3:30])=[CH:23][CH:22]=1)[C:17]([O:19][CH3:20])=[O:18]>>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH:16]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH:29]([O:31][C:32]3[CH:33]=[CH:34][C:35]([C:38]([F:39])([F:41])[F:40])=[CH:36][CH:37]=3)[CH3:30])=[CH:25][CH:26]=2)[C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)C(Br)c1ccc(OCC(C)Oc2ccc(C(F)(F)F)cc2)cc1
Product: COC(=O)C(Oc1ccc(Oc2ccccc2)cc1)c1ccc(OCC(C)Oc2ccc(C(F)(F)F)cc2)cc1

Procedure:
As described in Example 35, 4.66 of p-phenoxyphenol is reacted with methyl bromo{p-[2-(α,α,α-trifluoro-p-tolyloxy)propoxy]phenyl}acetate (0.02 mole) in refluxing methanol-benzene for 24 hrs to give the product as a gum.
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].Cl[C:29]1[CH:69]=[CH:68][C:32]([CH2:33][O:34][CH:35]2[CH:40]([C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][CH2:50][O:51][CH2:52][C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=4[O:59][CH3:60])=[CH:43][CH:42]=3)[CH2:39][CH2:38][N:37]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:36]2)=[CH:31][C:30]=1[O:70][CH2:71][CH2:72][CH2:73][O:74][CH3:75].[NH:76]1[CH2:81][CH2:80][O:79][CH2:78][CH2:77]1>C1(C)C=CC=CC=1>[CH3:60][O:59][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=1[CH2:52][O:51][CH2:50][CH2:49][CH2:48][O:47][C:44]1[CH:45]=[CH:46][C:41]([CH:40]2[CH2:39][CH2:38][N:37]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:36][CH:35]2[O:34][CH2:33][C:32]2[CH:68]=[CH:69][C:29]([N:76]3[CH2:81][CH2:80][O:79][CH2:78][CH2:77]3)=[C:30]([O:70][CH2:71][CH2:72][CH2:73][O:74][CH3:75])[CH:31]=2)=[CH:42][CH:43]=1
Reactant: C1COCCN1
Reactant: COCCCOc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1Cl
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCCCOc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1N1CCOCC1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
The mixture of 0.0074 g of 2-(di-t-butylphosphino)biphenyl, 0.017 g of dipalladiumtris (dibenzylidenacetone)-chloroform complex and 0.055 g of sodium tert-butoxide is admixed under argon with the solution of 0.280 g of tert-butyl 3-[4-chloro-3-(3-methoxypropoxy)benzyloxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 31a) and 0.043 ml of morpholine in 2.0 ml of toluene. The reaction mixture is stirred at 110° C. over 16 hours, subsequently cooled, poured onto water (20 ml) and extracted with ethyl acetate (2×20 ml). The organic phases are washed with brine (20 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a white foam from the residue by means of flash chromatography (SiO2 60F). Rf=0.23 (2:1 EtOAc-heptane); Rt=5.46.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6]1[S:7][CH2:8][C:9](=[O:11])[N:10]=1.[N:17]1[C:26]2[C:21](=[N:22][C:23]([CH:27]=O)=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6]1[S:7][C:8](=[CH:27][C:23]2[CH:24]=[CH:25][C:26]3[C:21](=[CH:20][CH:19]=[CH:18][N:17]=3)[N:22]=2)[C:9](=[O:11])[N:10]=1
Reactant: O=Cc1ccc2ncccc2n1
Reactant: O=C1CSC(NCc2ccc(F)cc2Cl)=N1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: O=C1N=C(NCc2ccc(F)cc2Cl)SC1=Cc1ccc2ncccc2n1
Temperature: 130 °C
Yield: 47.8 %

Procedure:
To a suspension of 2-(2-chloro-4-fluoro-benzylamino)-thiazol-4-one (41.4 mg, 0.16 mmol), and 1,5-naphthyridine-6-carboxaldehyde (31.6 mg, 0.2 mmol) in toluene (1 mL) in a microwave tube were added benzoic acid (2.0 mg, 0.02 mmol) and piperidine (1.7 uM, 0.02 mmol). The reaction mixture was heated to 130° C. with microwave for 15 min., then cooled to r.t. and diluted with toluene. The solid was collected by filtration and washed with toluene, MeOH and ether to give 2-(2-chloro-4-fluoro-benzylamino)-5-[1,5]naphthyridin-2-ylmethylene-thiazol-4-one as a brown solid (30.5 mg, 47.8%). HR-ES (+) m/e calcd. for C19H12FClN4OS: (M+H)+ 399.0477. Found: 399.0476.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[NH:34][C@H:35]([CH2:38][OH:39])[CH2:36][CH3:37])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1.C(N(CC)CC)C.Cl[C:57](Cl)([O:59]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.[Cl-].[Na+].O>[F:48][C:2]([F:1])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:42]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]1[C@@H:35]([CH2:36][CH3:37])[CH2:38][O:39][C:57]1=[O:59])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][N:13]=1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2N[C@@H](CC)CO)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2N2C(=O)OC[C@@H]2CC)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 227.1 %

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-((S)-1-hydroxymethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (102 mg) is dissolved in methylene chloride (1.5 ml) and thereto is added triethylamine (31 μl), followed by an addition of triphosgene (17 mg) under water-cooling, and the mixture is stirred at room temperature overnight. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (hexane:ethyl acetate=9:1→7:3) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-((S)-4-ethyl-2-oxo-oxazolidin-3-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (94 mg). MS (m/z): 723 [M+H]+
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][N:12](C(OCC2C=CC=CC=2)=O)[C@H:11]([C:24]([CH3:26])=[CH2:25])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH2:1]([O:8][C@H:9]1[CH2:13][NH:12][C@H:11]([CH:24]([CH3:26])[CH3:25])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)[C@@H]1C[C@@H](OCc2ccccc2)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)[C@@H]1C[C@@H](OCc2ccccc2)CN1
Reaction time: 17 h

Procedure:
Benzyl (2S,4R)-4-(benzyloxy)-2-isopropenylpyrrolidine-1-carboxylate (1.00 g, 2.84 mmol) was dissolved in ethanol (40 mL) and then 5% Pd—C (100 mg) was added to the solution. The flask was purged with hydrogen and then shaken on a Parr under 53 psi atmosphere of hydrogen for 17 hours. The reaction was then flushed with nitrogen and filtered through Celite on a glass frit and washed with methanol. The filtrate was concentrated and chromatographed on silica gel (1% triethylamine/10% methanol/89% ethyl acetate) to furnish the amine as a pale yellow oil, 0.53 g (85%).