Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:16]=1)[C:11]([OH:13])=[O:12].C1(N=C=NC2CCCCC2)CCCCC1.O[N:40]1[C:44](=[O:45])[CH2:43][CH2:42][C:41]1=[O:46].CCOCC>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:16]=1)[C:11]([O:13][N:40]1[C:44](=[O:45])[CH2:43][CH2:42][C:41]1=[O:46])=[O:12]
Reactant: O=C(O)c1cc(OC2CCCCO2)cc(OC2CCCCO2)c1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(ON1C(=O)CCC1=O)c1cc(OC2CCCCO2)cc(OC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 40 h
Yield: 89.8 %

Procedure:
A mixture of 3,5-bis[(tetrahydro-2H-pyran-2-yl)oxy]benzoic acid (5.00 g, 15.5 mmol), 1,3-dicyclohexylcarbodiimide (3.72 g, 18.1 mmol) and N-hydroxysuccinimide (2.08 g, 18.0 mmol) in tetrahydrofuran (100 Ml) was stirred at room temperature for 40 h. Ether (100 Ml) was added and the mixture was stirred for 20 min. The white solid was filtered off and discarded. The solvent was evaporated from the filtrate, and the residue was coated onto silica gel and chromatographed (50–75% ethyl acetate/hexanes) to give 1-[[3,5-bis[(tetrahydro-2H-pyran-2-yl)oxy]benzoyl]oxy]-2,5-pyrrolidinedione (5.84 g, 90%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([OH:12])[CH3:11].Br[C:14]1[C:15]([NH2:21])=[N:16][CH:17]=[C:18]([Br:20])[N:19]=1>>[Br:20][C:18]1[N:19]=[C:14]([O:12][CH:10]([C:3]2[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[Cl:1])[CH3:11])[C:15]([NH2:21])=[N:16][CH:17]=1
Reactant: CC(O)c1c(Cl)ccc(F)c1Cl
Reactant: Nc1ncc(Br)nc1Br
Product: CC(Oc1nc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl

Procedure:
5-Bromo-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-ylamine was prepared following procedure 2 below, from 1-(2,6-dichloro-3-fluoro-phenyl)-ethanol and 3,5-dibromo-pyrazin-2-ylamine. 1H NMR (400 MHz, DMSO-d6) δ 1.74 (d, 3H), 6.40 (m, 1H), 6.52 (br s, 2H), 7.30 (m, 1H), 7.48 (m, 1H), 7.56 (s, 1H); MS m/z 382 (M+1).
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].N1C=CC=CC=1.[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1)([O-:13])=[O:12]>O1CCCC1>[C:1]([O:4][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=1)(=[S:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: CC(O)=S
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=S)OCc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Yield: 77.3 %

Procedure:
Thioacetic acid (20 cm3, 0.28 mol) and anhydrous pyridine (15.2 cm3, 0.188 mol) were added to a solution of 4-nitrobenzyl chloride (12.0 g, 70 mmol) in anhydrous tetrahydrofuran (200 cm3). The stirred reactants were heated at 50° C. for 24 h. The cooled products were filtered and the flltrate was evaporated under reduced pressure. The residue was dissolved in dichloromethane (300 cm3) and the resulting solution was washed with saturated aqueous sodium hydrogen carbonate (2×250 cm3), dried (MgSO4) and concentrated under reduced pressure. The residue was crystallized from ethyl acetate--petroleum ether (bp 60°-80° C.) to give 4-nitrobenzyl thioacetate 16a (11.43 g, 77%) as pale yellow needles, m.p. 55.5°-57.5° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([C:8]([F:11])([F:10])[F:9])[CH:4]([NH2:7])[CH2:5][OH:6].C(N(CC)CC)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)Cl>[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:7][CH:4]([CH2:5][OH:6])[CH:3]([C:8]([F:9])([F:10])[F:11])[C:2]([F:12])([F:13])[F:1])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: NC(CO)C(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NC(CO)C(C(F)(F)F)C(F)(F)F)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 1.8 %

Procedure:
To a solution of 3,3,3-trifluoro-2-(trifluoromethyl)-1-(hydroxymethyl)propyl amine (79 mg, 0.374 mmol) in CH2Cl2 (1 mL) was added triethylamine (0.1 mL, 0.749 mmol) and 4-fluorobenzenesulfonyl chloride (80.5 mg, 0.4 mmol) in CH2Cl2 (1 mL). The solution was stirred for 20 hours at 25° C. and then concentrated. EtOAc (5 mL) was added and the solution was washed with 1M HCl (1 mL), brine (1 mL), dried over Na2SO4 and concentrated. The crude solid was purified by Biotage Flash™ chromatography, eluting with EtOAc/hexanes (1:4), to give 4-fluoro-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzene sulfonamide (2.5 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[OH-].[Na+].[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O.C(O)C>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:5][N:6]=1
Reactant: Nc1nnc(S)s1
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1nnc(SCc2ccccc2)s1
Temperature: 50 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
In a mixture of 40 ml of water and 45 ml of ethanol, 21.1 g of 2-amino-5-mercapto-1,3,4-thiadiazole and 6.9 g of sodium hydroxide were dissolved. To this solution, 19.6 g of benzyl chloride was added, and the mixture was stirred at 50° C. for 1 hour. After cooling, water was added to the reaction mixture, the formed precipitate was separated by filtration and washed with water and an ethanol/n-hexane (1:1) mixture respectively. The thus treated precipitate was dried under reduced pressure, and thus 32.5 g of 2-amino-5-benzylthio-1,3,4-thiadiazole was obtained. m.p. 159°-161° C. Yield 94%.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][O:9][C:10]2=[O:11])=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][O:9][C:10]2=[O:11])=[CH:6][CH:5]=1
Reactant: O=C1OCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1ccc2c(c1)C(=O)OC2

Procedure:
6-Nitrophthalide (14.0 g; J A Houbion, J A Miles and J A Paton, Organic Preparations and Procedures International, 11 (1), 27, 1979) in solution in acetic acid was hydrogenated over a palladium on carbon catalyst to give 6-aminophthalide (12.0 g; W R Vaughan and S L Baird, J. Amer. Chem. Soc. 68, 1314, 1946). 6-Aminophthalide (10.0 g) was converted, via the diazonium salt intermediate, to 6-chlorophthalide (8.5 g; J Tirouflet, Bull. soc. sci. Bretagne Spec. No 26, 7, 1951).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[NH2:12][C:13]1[N:21]=[C:20]2[C:16]([NH:17][CH:18]=[N:19]2)=[C:15]([Cl:22])[N:14]=1.[CH:23]([O:26][C:27]([O:36][CH:37]([CH3:39])[CH3:38])([P:32]([OH:35])([OH:34])=[O:33])[O:28][CH2:29][CH2:30]Cl)([CH3:25])[CH3:24]>CN(C=O)C>[NH2:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[CH2:30][CH2:29][O:28][C:27]([O:26][CH:23]([CH3:24])[CH3:25])([O:36][CH:37]([CH3:38])[CH3:39])[P:32]([OH:35])([OH:34])=[O:33])=[C:15]([Cl:22])[N:14]=1
Reactant: CC(C)OC(OCCCl)(OC(C)C)P(=O)(O)O
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)OC(OCCn1cnc2c(Cl)nc(N)nc21)(OC(C)C)P(=O)(O)O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
In 120 ml DMF, 29.3 g of DBU, 32.45 g (0.191 mol) of 2-amino-6-chloropurine were added, stirred at 80° C. for 30 min, then 50 g (0.193 mol) of 2-(diisopropyloxy-phosphonomethoxy)-ethyl chloride was added, the reaction was performed at 100° C. for 8 h, cooled, distilled at a reduced pressure to remove DMF, added with water and ethyl acetate, layered, the water phase was extracted twice with ethyl acetate, the organic phases were combined, dried, separated by silica gel column chromatography, eluted with MeOH:CH2Cl2=1:30, yield 46 g of II1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C@@H:5]1[CH2:9][CH:8]([OH:10])[CH2:7][N:6]1[CH2:11][CH3:12])[CH3:2].C(N(CC)CC)C.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:13])[C@@H:5]1[CH2:9][CH:8]([O:10][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:7][N:6]1[CH2:11][CH3:12])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)[C@@H]1CC(O)CN1CC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@H]1CC(OS(C)(=O)=O)CN1CC
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.7 %

Procedure:
To a mixture of 2.50 g of N-ethyl-4-hydroxy-L-proline ethylester, 1.76 g of triethylamine and 10 ml of chloroform were dropwise added 1.84 g of mesyl chloride while cooling with ice-water and the combined was stirred at room temperature for 2 hours and then poured into ice-water. The mixture was extracted with chloroform and the extract was washed with an aqueous sodium bicarbonate solution and then with water, dried over magnesium sulfate and concentrated under reduced pressure to obtain 3.64 g of N-ethyl-4-mesyloxy-L-proline ethylester.
Reaction SMILES: [CH3:1][CH:2]([NH2:11])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Br[CH:13]([CH3:24])[C:14]([C:16]1[S:20][CH:19]=[C:18]([C:21]([NH2:23])=[O:22])[CH:17]=1)=[O:15].CC(=O)CC>CCOC(C)=O>[CH3:1][CH:2]([N:11]=[C:13]([CH3:24])[C:14]([C:16]1[S:20][CH:19]=[C:18]([C:21]([NH2:23])=[O:22])[CH:17]=1)=[O:15])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(N)CCc1ccccc1
Reactant: CC(Br)C(=O)c1cc(C(N)=O)cs1
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: CC(=NC(C)CCc1ccccc1)C(=O)c1cc(C(N)=O)cs1
Reaction time: 48 h

Procedure:
A solution of 1-methyl-3-phenylpropylamine (9.0 g) and 5-(2-bromo-1-oxopropyl)thiophene-3-carboxamide (7.6 g) was stirred for 2 h; butanone (75 ml) was added and stirring continued for 48 h. The resulting mixture was filtered and the filtrate evaporated to small volume (ca. 30 ml) and added to vigorously stirred light petroleum (b.p. 60°-80°: 500 ml) to precipitate a yellow gum (ca. 9 g) which was separated on a short path silica (7736H; 300 g) column eluted with ethyl acetate/2% isopropanol/20% triethylamine to give three products. TLC SiO2 (EtOAc/20% i-PrOH/2% Et3N) Rf 0.26, 0.39 and 0.5 respectively.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[Cl:29][C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][C:36]=1[F:37])[NH2:33]>O1CCOCC1.C(#N)C>[ClH:2].[Cl:29][C:30]1[CH:31]=[C:32]([NH:33][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]4)=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][N:4]=2)[CH:34]=[CH:35][C:36]=1[F:37]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: COc1cc2c(Cl)ncnc2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: COc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OC1CCNCC1
Temperature: 70 °C
Yield: 153.4 %

Procedure:
4.0M HCl in Dioxane (1 ml) was added to a suspension of tert-butyl 4-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carboxylate (331 mg, 0.84 mmol) and 3-chloro-4-fluoroaniline (134.5 mg) in acetonitrile (10 ml). The reaction mixture was stirred and heated at 70° C. for 4 hours. The resulting precipitate was filtered hot, washed with acetonitrile and dried under vacuum to give N-(3-chloro-4-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride (566 mg); Mass Spectrum: (M+H)+ 403.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[CH:15][C:14]3[C:9](=[CH:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:26]1([N:30]2[C:34]3[N:35]=[CH:36][N:37]=[C:38]([NH2:39])[C:33]=3[C:32](I)=[CH:31]2)[CH2:29][CH2:28][CH2:27]1.C([O-])([O-])=O.[Na+].[Na+]>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>[CH:26]1([N:30]2[C:34]3[N:35]=[CH:36][N:37]=[C:38]([NH2:39])[C:33]=3[C:32]([C:11]3[CH:10]=[C:9]4[C:14]([CH:15]=[N:16][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[N:8]4)=[CH:13][CH:12]=3)=[CH:31]2)[CH2:27][CH2:28][CH2:29]1
Reactant: CC1(C)OB(c2ccc3cnc(-c4ccccc4)nc3c2)OC1(C)C
Reactant: Nc1ncnc2c1c(I)cn2C1CCC1
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+]
Product: Nc1ncnc2c1c(-c1ccc3cnc(-c4ccccc4)nc3c1)cn2C1CCC1
Temperature: 80 °C

Procedure:
A flask equipped with a reflux condenser was charged with 2-phenyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (67 mg, 0.20 mmol), 7-cyclobutyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (64 mg, 0.20 mmol) and Na2CO3 (56 mg, 0.51 mmol). The reaction setup was evacuated and refilled with Ar (3×). Pd(PPh3)4 (24 mg, 0.021 mmol) was added swiftly minimizing exposure to air and the system was evacuated and refilled with Ar (3×) again. Degassed solvent mixture H2O-DMF (1:5 v/v, 5 mL) was added and the reaction mixture was heated at 80° C. for 42 h. The resulting orange-light brown solution was partitioned between DCM (−80 mL) and H2O (10 mL). The aqueous layer was extracted with DCM (3×). Combined organics were washed with brine, dried (Na2SO4) and concentrated under reduced pressure (125 mg). Purification by flash chromatography (silica gel, 25 g, 0-2% MeOH in DCM) provided the title compound as a pale yellow solid; The material was also later triturated (hexane 2×, Et2O 1×); 1H NMR (400 MHz, CDCl3) δ 9.46 (d, J=0.8 Hz, 1H), 8.65-8.58 (m, 2H), 8.35 (s, 1H), 8.16 (s, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.75 (dd, J=2.0 Hz, 8.4 Hz, 1H), 7.56-7.46 (m, 3H), 7.39 (s, 1H), 5.44 (br, 2H), 5.33 (quintet, J=8.2 Hz, 1H), 2.67-2.40 (m, 4H), 2.17-1.89 (m, 2H). MS (ES+): m/z 393.1 (100) [MH+]; HPLC: tR=2.91 min (OpenLynx, polar—5 min).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([C@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH2:12])=[CH:3][CH:2]=1.C1CCN2C(=NCCC2)CC1.[CH:25]([S:28](Cl)(=[O:30])=[O:29])([CH3:27])[CH3:26]>C(Cl)Cl>[C:1]1([CH3:13])[CH:2]=[CH:3][C:4]([C@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH:12][S:28]([CH:25]([CH3:27])[CH3:26])(=[O:30])=[O:29])=[CH:5][CH:6]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Cc1ccc([C@H]2CCC[C@H]2N)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: Cc1ccc([C@H]2CCC[C@H]2NS(=O)(=O)C(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 100 mL round bottom flask equipped with a magnetic stirrer is charged with (+,−) cis-2-p-tolyl-cyclopentylamine (313 mg, 1.79 mmol, from preparation 9), methylene chloride (5.0 mL) and the solution cooled to 0° C. DBU (0.32 mL, 2.14 mmol) and isopropylsulfonyl chloride (0.24 mL, 2.14 mmol) were added. The reaction was then stirred at 0° C. for 60.0 minutes and brought to room temperature with stirring overnight. The reaction was diluted with methylene chloride and washed with aqueous ammonium chloride, brine and the organic layer dried over sodium sulfate. The title compound was purified by radial chromatography eluting with methylene chloride to give 250 mg (50%) of the purified title compound.
Reaction SMILES: O[C@H:2]([C:22]1[CH:23]=[CH:24][C:25]2[O:30][C@H:29]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:34][CH:33]=3)C=C[C:26]=2[CH:46]=1)[C@H:3]([O:19][CH2:20][CH3:21])C(N1[C@@H](CC2C=CC=CC=2)COC1=O)=O.C([SiH](CC)CC)C.FC(F)(F)[C:56]([OH:58])=[O:57]>>[CH2:39]([O:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][CH2:29][O:30][C:25]2[CH:24]=[CH:23][C:22]([CH2:2][C@H:3]([O:19][CH2:20][CH3:21])[C:56]([OH:58])=[O:57])=[CH:46][CH:26]=2)=[CH:33][CH:34]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc2c(c1)C=C[C@@H](Cc1ccc(OCc3ccccc3)cc1)O2
Reactant: O=C(O)C(F)(F)F
Agent: CC[SiH](CC)CC
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(OCc3ccccc3)cc2)cc1)C(=O)O

Procedure:
(R) -6-{(1R, 2S)-1-Hydroxy-2-ethoxy-3-[(S)-4-benzyl-2-oxo-3-oxazolidinyl ]-3 -oxopropyl}-2-(4-benzyloxybenzyl)-2H-benzopyran (18.8 g, 31 mmol) was dissolved in trifluoroacetic acid (200 ml) and triethylsilane (49 ml, 0.31 mmol) was added. After 45 minutes the volatile components were evaporated and the oily residue was triturated with isopropyl alcohol. The product was purified by flash-chromatography (hexanes/ethyl acetate, 2:) and obtained as a thick oil (8.9 g).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH:9]=[CH:10][C:11]#[N:12])[CH2:4]1.Cl[C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][N:17]=[C:16]2[CH:23]=[CH:24][S:25][C:15]=12.C(N(CC)CC)C>C(O)(C)C>[N+:20]([C:19]1[C:14]([NH:2][CH:3]2[CH2:8][CH2:7][CH2:6][CH:5]([CH:9]=[CH:10][C:11]#[N:12])[CH2:4]2)=[C:15]2[S:25][CH:24]=[CH:23][C:16]2=[N:17][CH:18]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Reactant: N#CC=CC1CCCC(N)C1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: N#CC=CC1CCCC(Nc2c([N+](=O)[O-])cnc3ccsc23)C1
Temperature: 90 °C

Procedure:
A mixture of 3-(3-aminocyclohexyl)acrylonitrile hydrochloride (0.090 g, 0.48 mmol), 7-chloro-6-nitrothieno[3,2-b]pyridine (0.085 g, 0.40 mmol) and triethylamine (0.22 mL, 1.6 mmol) in isopropyl alcohol (0.9 mL) was heated at 90° C. for 1 h. The mixture was concentrated to give the desired product to be used in the next step directly. LCMS calculated for C16H17N4O2 (M+H)+: m/z=329.1. Found: 329.1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2.[CH3:26][O:27][C:28]1[CH:48]=[CH:47][C:31]([CH2:32][N:33]2[CH2:38][CH2:37][N:36]([CH2:39][C:40]3[CH:41]=[CH:42][C:43]([NH2:46])=[N:44][CH:45]=3)[CH2:35][CH2:34]2)=[CH:30][CH:29]=1>C(Cl)Cl.CO>[CH3:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[CH2:38][CH2:37][N:36]([CH2:39][C:40]3[CH:41]=[CH:42][C:43]([NH:46][C:23]([C:20]4[CH:21]=[CH:22][C:13]([C:3]5[C:4]([Cl:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=5[Cl:1])=[C:14]5[C:19]=4[N:18]=[CH:17][CH:16]=[CH:15]5)=[O:25])=[N:44][CH:45]=3)[CH2:35][CH2:34]2)=[CH:47][CH:48]=1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3ncccc23)c1Cl
Reactant: COc1ccc(CN2CCN(Cc3ccc(N)nc3)CC2)cc1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(CN2CCN(Cc3ccc(NC(=O)c4ccc(-c5c(Cl)c(OC)cc(OC)c5Cl)c5cccnc45)nc3)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (Step 159.1), 5-[4-(4-methoxy-benzyl)-piperazin-1-ylmethyl]-pyridin-2-ylamine (Step 105.1) and stirring the reaction mixture for 20 h at rt. Title compound: ESI-MS: 672.0 [M+H]+; TLC: Rf=0.25 (DCM/MeOH, 9:1).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][C:10]=1[CH2:21][CH2:22][CH3:23].N1C=CC=CC=1>CN(C1C=CN=CC=1)C>[C:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][C:10]=1[CH2:21][CH2:22][CH3:23])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCCc1cc(-c2ccccc2)ccc1O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCc1cc(-c2ccccc2)ccc1OC(C)=O
Temperature: 55 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
6.1 g (60 mmol) of acetic anhydride are added dropwise to a solution of 10.6 g (50 mmol) of 4-hydroxy-3-propyl-biphenyl, 4.3 g (55 mmol) of pyridine and 0.1 g of 4-(N,N-dimethylamino)pyridine, and the mixture is heated at 50 to 60° C. for 2 hours. The reaction solution is left standing overnight at 20° C. and washed with water and dilute hydrochloric acid, and the organic phase is dried and concentrated. 11.4 g (yield: 89.8% of theory) of 4-acetoxy-3-propyl-biphenyl are obtained as a pale oil of log p=4.32 (pH=2.3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][N:15]([CH3:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH:5]=[CH:6][CH:7]=O.[O:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][CH2:7][N:25]2[C:26](=[O:28])[CH2:27][O:23][C:24]2=[O:29])[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][N:15]([CH3:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CN(CCOc1ccc(C=CC=O)cc1F)c1ccccn1
Reactant: O=C1COC(=O)N1
Product: CN(CCOc1ccc(CCCN2C(=O)COC2=O)cc1F)c1ccccn1

Procedure:
In substantially the same manner as in Working Example 11, 3-fluoro-4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]cinnamaldehyde was condensed with 2,4-oxazolidinedione. The condensate was subjected to catalytic hydrogenation to yield 5-[3-[3-fluoro-4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]phenyl]propyl-2,4-oxazolidinedione, which was recrystallized from ethyl acetate-hexane to give colorless prisms, m.p.124-125° C.
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[C:14]1[C:22]2[C:17](=[C:18]([O:23][CH3:24])[N:19]=[CH:20][CH:21]=2)[N:16]([CH3:25])[CH:15]=1.[H][H]>[Pd].C(OCC)(=O)C>[F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[C:14]1[C:22]2[C:17](=[C:18]([O:23][CH3:24])[N:19]=[CH:20][CH:21]=2)[N:16]([CH3:25])[CH:15]=1
Reactant: COc1nccc2c(-c3cc([N+](=O)[O-])ccc3Oc3ccc(F)cc3F)cn(C)c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1nccc2c(-c3cc(N)ccc3Oc3ccc(F)cc3F)cn(C)c12
Temperature: 25 °C
Reaction time: 10 h
Yield: 99.5 %

Procedure:
A mixture of Example 2C (0.165 g, 0.401 mmol) and 10% palladium on carbon (0.043 g, 0.040 mmol) in ethyl acetate (10 mL) was treated with a balloon of hydrogen gas. The reaction mixture was stirred for 10 hours at ambient temperature. The solid was removed by filtration, and the filtrate was concentrated to give the title compound (0.152 g, 0.399 mmol, 99% yield).
Reaction SMILES: [CH3:1][C:2]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)([O:4]COCC[Si](C)(C)C)[CH3:3].[Br:18]Br.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Br:18][C:15]1[S:14][C:13]([C:2]([OH:4])([CH3:3])[CH3:1])=[N:17][CH:16]=1
Reactant: BrBr
Reactant: CC(C)(OCOCC[Si](C)(C)C)c1nccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(O)c1ncc(Br)s1
Reaction time: 1 h

Procedure:
To a solution of 2-(1-methyl-1-{[2-(trimethylsilyl)ethoxy]methoxy}ethyl)thiazole from Step 2 in chloroform (2 mL mmol) at room temperature was added bromine (2 molar eq) and the resulting mixture was stirred for 1 hour. Solid sodium bicarbonate (0.55 eq) was added and the mixture was stirred for 5 hours. More sodium bicarbonate was added (0.55 eq) and stirring was continued for 18 hours. After a final addition of sodium bicarbonate (0.55 eq) the mixture was stirred for a further 5 hours, diluted with chloroform and the organic phase was washed with saturated aqueous sodium bicarbonate, then with water, dried and evaporated. The crude material was chromatographed, eluting with a 3:7 mixture of ethyl acetate and hexane to afford the desired product.
Reaction SMILES: N[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:9][C:10]([C:13]#[N:14])=[CH:11][N:12]=2)=[CH:6][N:7]=1.N(OCCC(C)C)=O.C(Br)(Br)[Br:24]>>[Br:24][C:2]1[N:3]=[N:4][C:5]([C:8]2[S:9][C:10]([C:13]#[N:14])=[CH:11][N:12]=2)=[CH:6][N:7]=1
Reactant: N#Cc1cnc(-c2cnc(N)nn2)s1
Reactant: BrC(Br)Br
Agent: CC(C)CCON=O
Product: N#Cc1cnc(-c2cnc(Br)nn2)s1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
2-(3-Amino-1,2,4-triazin-6-yl)thiazole-5-carbonitrile (30 mg, 0.15 mmol) was dissolved in 1 mL of bromoform and heated to 90° C. Isoamyl nitrite (88 mg, 0.75 mmol) was added and stirred at 90° C. for 2 h. The reaction mixture was then concentrated and used directly in the next reaction.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][CH2:12][C:13]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([NH2:16])=[O:15])C)C1C=CC=CC=1>C(O)C.[Pd]>[C:17]1([C:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH2:12][CH2:11][CH2:10][NH:8][CH3:1])[C:14]([NH2:16])=[O:15])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Reaction time: 87 h

Procedure:
A mixture of 5-(N-benzyl-N-methylamino)-2,2-diphenylpentanamide (11 g-see Example 1) and 10% palladium-on-carbon (1.1 g) in ethanol (150 ml) was hydrogenated at room temperature and 50 p.s.i. (344.7 kPa) pressure for 87 hours. The mixture was filtered and the filtrate concentrated in vacuo to give an oil. The oil was triturated with ether to give the title compound as a colourless powder, yield 4.5 g.