Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(Cl)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:7]=1)=[O:4].N12CCCN=C1CCCCC2.[NH2:30][C:31]1[CH:47]=[CH:46][C:34]([O:35][C:36]2[CH:41]=[CH:40][N:39]=[C:38]([C:42]([NH:44][CH3:45])=[O:43])[CH:37]=2)=[CH:33][CH:32]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[NH:30][C:31]2[CH:47]=[CH:46][C:34]([O:35][C:36]3[CH:41]=[CH:40][N:39]=[C:38]([C:42]([NH:44][CH3:45])=[O:43])[CH:37]=3)=[CH:33][CH:32]=2)=[CH:7][C:8]=1[C:13]([F:16])([F:15])[F:14]
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)C(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
2,2,2-trichloro-N-(4-chloro-3-(trifluoromethyl)phenyl)acetamide (45 g, 0.1319 mol) was refluxed in N,N-dimethyl formamide (100 ml) with 1,8-diazabicyclo[5.4.0]undec-7-ene (24.67 ml, 0.1649 mol) and 4-(4-aminophenoxy)-N-methylpicolinamide (32.07 g, 0.1319 mol) for 24 hours and cooled to room temperature. The reaction mass was quenched in water (1000 ml). The quenched mass was extracted repeatedly with ethyl acetate and the combined ethyl acetate layer was then back washed with water to remove DMF traces. It was dried over sodium sulfate and evaporated under vacuum to obtain solid. The obtained solid was slurried in ethyl acetate (1000 ml) at ambient temperature and filtered to give 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl) ureido)phenoxy)-N-methylpicolinamide (sorafenib base) (52 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:25]4[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=4[CH3:23])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1cccc(B(O)O)c1C
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cccc(C)c4C)c3O2)cc1
Yield: 62.8 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with (2,3-dimethyl-phenyl)boronic acid (0.294 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.041 g, 0.052 mmol), and potassium carbonate (0.41 g, 3.25 mmol) generally according to the procedure described for Intermediate 37 provided 0.335 g (62%) of (±)-[7-(2,3-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. Treatment of (±)-[7-(2,3-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate with sodium azide (0.134 g, 2.06 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-7-(2,3-dichlorophenyl)-2,3-dihydro-1-benzofuran-7 amine. To a solution of (±)-2-(azidomethyl)-7-(2,3-dichlorophenyl)-2,3-dihydro-1-benzofuran-7 amine (0.135 g, 1.483 mmol) in tetrahydrofuran (5 mL) was added polymer supported triphenyl phosphine (0.152 g, 0.58 mmol) and the reaction mixture was allowed to stir at room temperature for 12 h. The reaction mixture was filtered (celite) and the solvent removed in vacuo to provide a colorless oil. The oil was re-dissolved in isopropanol (3 mL) and hydrogen chloride (1.0 N in diethyl ether, 10.0 mL) was added. The resulting precipitate was filtered, washed (diethyl ether), and dried to afford 0.075 g (54%) of (±)-1-[7-(2,3-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp >225° C.:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([C:19](=[N:21][OH:22])[NH2:20])=[CH:14][CH:15]=3)[N:10]=[C:9]2[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:4][CH:3]=1.CCN(CC)CC.Cl.[N:39]1[CH:44]=[CH:43][C:42]([C:45](Cl)=O)=[CH:41][CH:40]=1>CN(C=O)C.CCOCC.C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([C:19]4[N:20]=[C:45]([C:42]5[CH:43]=[CH:44][N:39]=[CH:40][CH:41]=5)[O:22][N:21]=4)=[CH:14][CH:15]=3)[N:10]=[C:9]2[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: COC(=O)CCCCc1nc2cc(C(N)=NO)ccc2c(=O)n1-c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCCCc1nc2cc(-c3noc(-c4ccncc4)n3)ccc2c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a microwave vial containing methyl 5-[3-(4-fluorophenyl)-7-(N′-hydroxycarbamimidoyl)-4-oxo-3,4-dihydroquinazolin-2-yl]pentanoate (14B) in DMF was added Et3N (4 eq) and 4-pyridinecarbonyl chloride-HCl (1.2 eq). The mixture was stirred at rt for 1 h, then at 100° C. overnight. The mixture was then cooled to rt, diluted with Et2O, and saturated NaHCO3. The organic layer was separated, washed with H2O, brine, and dried over MgSO4. Concentration and purification by flash chromatography (EtOAc/hexanes) to afford methyl 5-(3-(4-fluorophenyl)-4-oxo-7-(5-(pyridin-4-yl)-1,2,4-oxadiazol-3-yl)-3,4-dihydroquinazolin-2-yl)pentanoate.
Reaction SMILES: [N+:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:5]1)([O-])=O.[CH2:15](N(CC)CC)C.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[C:30]1[C:34]([C:35](Cl)=[O:36])=[C:33]([CH3:38])[O:32]N=1.C(Cl)(Cl)Cl>C(O)(=O)C.ClCCl.O=[Pt]=O>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[C:30]1[C:34]([C:35]([NH:1][CH:4]2[CH2:9][CH2:8][CH2:7][CH:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:5]2)=[O:36])=[C:33]([CH3:38])[O:32][CH:15]=1
Reactant: COC(=O)CC1CCCC([N+](=O)[O-])C1
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Reactant: CCN(CC)CC
Agent: O=[Pt]=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)CC1CCCC(NC(=O)c2c(-c3c(F)cccc3Cl)coc2C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
To a solution of methyl 2-(3-nitrocyclohexyl)acetate (13.8 g, 71.0 mmol) in 200 mL of acetic acid was added 6.9 g of PtO2. The mixture was hydrogenated overnight at ambient temperature and 60 psi, then was filtered through celite and concentrated to dryness. To a solution of the residue, 8.8 g (38.0 mmol) in 200 mL of dichloromethane was added 27 mL (190 mmol) of triethylamine and 10.4 g (38.0 mmol) of 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride. The mixture was stirred overnight at ambient temperature then chloroform was added. The organics were washed with 0.5N HCl, saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated to dryness. The resulting residue was chromatographed on silica gel using 5% acetone/dichloromethane to yield 4.43 g (29%) of the desired mixture of isomers as a colorless, viscous oil. 1H—NMR is consistent with structure. MS (ion spray) 409.2 (M+1).
Reaction SMILES: C([O-])([O-])[O:2][CH2:3][CH3:4].[CH3:7][O:8][N:9]=[C:10]([C:16](=[O:18])[CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH2:19](O)[CH3:20]>>[CH3:7][O:8][N:9]=[C:10]([C:16]([O:2][CH2:3][CH3:4])([O:18][CH2:19][CH3:20])[CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC([O-])[O-]
Reactant: CCO
Reactant: CCOC(=O)C(=NOC)C(C)=O
Product: CCOC(=O)C(=NOC)C(C)(OCC)OCC

Procedure:
Ethyl orthoformate (1.71 g), "Amberlist 15" (trademark) (200 mg) and ethyl 2-methoxyimino-3-oxobutyrate (syn isomer, 0.5 g) in dry ethanol (2 ml) were treated in a similar manner to that of Example 8 (1) to give ethyl 2-methoxyimino-3,3-diethoxybutyrate (syn isomer, 0.35 g).
Reaction SMILES: C(NC(C)C)(C)C.C(O[B:12]([O:17][CH:18]([CH3:20])[CH3:19])[O:13][CH:14]([CH3:16])[CH3:15])(C)C.C([Li])CCC.[Cl:26][C:27]1[S:28][CH:29]=[CH:30][N:31]=1.OC(C(O)(C)C)(C)C.C(O)(=O)C>C(OCC)C>[Cl:26][C:27]1[S:28][C:29]([B:12]2[O:13][C:14]([CH3:15])([CH3:16])[C:18]([CH3:19])([CH3:20])[O:17]2)=[CH:30][N:31]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Clc1nccs1
Agent: CC(C)(O)C(C)(C)O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CC(C)NC(C)C
Product: CC1(C)OB(c2cnc(Cl)s2)OC1(C)C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
Diisopropylamine (0.66 mL, 4.6 mmol) and triisopropylborate (1.26 mL, 5.44 mmol) were dissolved in 52 mL of anhydrous diethyl ether and then cooled to −90° C. n-Butyllithium (2.6 M in toluene, 1.77 mL, 4.6 mmol) was added slowly to the reaction and the mixture was stirred for 30 min. 2-Chlorothiazole (0.5 g, 4.18 mmol) was added and the reaction was allowed to gradually reach room temperature over 3 h. A solution of pinacol (0.69 g, 5.85 mmol) in 5 mL of diethyl ether was added. After 15 min, acetic acid (0.26 mL, 4.6 mmol) was added and the mixture was then filtered through Celite, rinsing with more diethyl ether. The filtrate was evaporated and the residue was distilled using a Kugelrohr apparatus at a temperature of 120-130° C. to give 0.84 g (82%) of 2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiazole.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[C:17]([C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1)[C:18]([O:20][CH3:21])=[O:19])=[N-]>CCCCCCCCCCCCC1C=CC(S(N2[C@@H](C(O)=O)CCC2)(=O)=O)=CC=1.CCCCCCCCCCCCC1C=CC(S(N2[C@@H](C(O)=O)CCC2)(=O)=O)=CC=1.CCCCCCCCCCCCC1C=CC(S(N2[C@@H](C(O)=O)CCC2)(=O)=O)=CC=1.CCCCCCCCCCCCC1C=CC(S(N2[C@@H](C(O)=O)CCC2)(=O)=O)=CC=1.[Rh].[Rh]>[CH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[C@:17]1([C:18]([O:20][CH3:21])=[O:19])[CH2:8][C:7]1([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=C(c1ccccc1)c1ccccc1
Reactant: COC(=O)C(=[N+]=[N-])c1ccc2ccccc2c1
Agent: [Rh]
Agent: CCCCCCCCCCCCc1ccc(S(=O)(=O)N2CCC[C@@H]2C(=O)O)cc1
Product: COC(=O)[C@@]1(c2ccc3ccccc3c2)CC1(c1ccccc1)c1ccccc1
Yield: 74 %

Procedure:
To a flame-dried round bottom flask kept under a dry atmosphere of argon, was added Rh2(R-DOSP)4 (0.01 equiv., 474 mg), 1,1-diphenylethlyene (2.32 equiv., 10.5 g, 58 mmol), and dry degassed pentane (100 mL). A solution of freshly prepared methyl 2-diazo-2-(naphthalen-2-yl)acetate (1.0 equiv., 5.65 g, 25 mmol) in dry, degassed pentane (250 mL) was added to the former solution drop-wise over 3 hours at −40° C. The mixture was allowed to stir overnight to room temperature, and then concentrated in vacuo. The crude material was purified using flash column chromatography eluting with a 40:1 mixture of hexanes/ethyl acetate to provide the desired product as a white solid (7.0 g, 74% yield, >99% ee). mp: 138-139° C.; [α]20D −347.9° (c=1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.74-7.71 (m, 1H), 7.50-7.36 (m, 4H), 7.24-7.22 (m, 1H), 7.06-7.04 (m, 2H), 6.96-6.86 (m, 3H), 3.38 (s, 3H), 2.79 (d, J=5.6 Hz, 1H), 2.57 (d, J=5.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 171.4, 141.9, 139.4, 133.6, 132.8, 132.3, 130.4, 130.2, 129.9, 128.7, 128.3, 127.7, 127.6, 127.5, 126.9, 126.7, 126.1, 125.8, 125.6, 141.9, 139.4, 133.6, 132.8, 132.2, 130.4, 130.2, 129.9, 128.7, 128.3, 127.7, 127.6, 127.5, 126.9, 126.7, 126.1, 125.8, 125.6, 52.2, 44.5, 43.2, 23.1; IR (neat): 3057, 3024, 2947, 1724, 1433, 1215; HRMS (APCI) calcd for C27H23O2 (M+H)+ 379.16926. found 379.16952; HPLC (ODH, 0.5% isopropanol in hexane, 1.0 mL/min, 1 mg/mL, 30 min, UV 254 nm) retention times of 8.6 min (major) and 9.6 min (minor), >99% ee.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:18])=[C:13]([CH:17]=1)[C:14](O)=[O:15])=[O:7].CN1CCOCC1.[NH2:31][C:32]1[N:37]=[CH:36][C:35]([NH2:38])=[CH:34][N:33]=1>C(Cl)Cl>[NH2:31][C:32]1[N:37]=[CH:36][C:35]([NH:38][C:14](=[O:15])[C:13]2[CH:17]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:19]=[CH:20][CH:21]=[C:3]([C:2]([F:22])([F:23])[F:1])[CH:4]=3)[CH:10]=[CH:11][C:12]=2[Cl:18])=[CH:34][N:33]=1
Reactant: Nc1cnc(N)nc1
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Nc1ncc(NC(=O)c2cc(NC(=O)c3cccc(C(F)(F)F)c3)ccc2Cl)cn1
Reaction time: 1 h
Yield: 73 %

Procedure:
A solution of intermediate 1 (Example 2) (380 mg, 1.11 mmol) in DCM was charged with CDMT (233 mg, 1.33 mmol), and NMM (0.3 mL, 2.73 mmol). After 1 hr of stirring, 2,5-diaminopyrimidine (121 mg, 1.10 mmol) was added and the solution was allowed to stir for 48 h. The mixture was concentrated and purified by HPLC to afford the title compound as a white solid (350 mg, 73%).
Reaction SMILES: [F:1][C:2]([F:11])([CH:5]([F:10])[C:6]([F:9])([F:8])[F:7])[CH2:3][OH:4].[F:12][C:13]([F:28])([S:24](F)(=[O:26])=[O:25])[C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17].[OH-].[K+]>O>[F:28][C:13]([F:12])([S:24]([O:4][CH2:3][C:2]([F:11])([F:1])[CH:5]([F:10])[C:6]([F:9])([F:7])[F:8])(=[O:26])=[O:25])[C:14]([F:22])([F:23])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: OCC(F)(F)C(F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(OCC(F)(F)C(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,2,3,4,4,4-hexafluorobutan-1-ol (202 g, 1.1 mol, obtained from Sinochem Corp., Beijing, China), 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (332 g, 1.1 mol, obtained from 3M Company of Saint Paul, Minn.) and water (300 g) were combined in a 3-L, 3-necked round bottom flask. The flask was equipped with a magnetic stirrer, cold water condenser, thermocouple and a 250-mL addition funnel Aqueous potassium hydroxide (149.3 g, 45 weight percent, 1.22 equivalents) was added dropwise via an addition funnel at such a rate that the temperature did not exceed 35° C. Once the addition of the base was complete the mixture was stirred for 16 hours at room temperature. The precipitated salts were then filtered from the mixture and the lower liquid fluorochemical product phase was separated from the upper aqueous phase. Unreacted 2,2,3,4,4,4-hexafluorobutan-1-ol and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride were removed by atmospheric distillation.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[C:23]([CH2:25][CH2:26][CH3:27])[CH:22]=[C:21]([CH2:28][CH2:29][CH3:30])[CH:20]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>O=[Pt]=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:20]=[C:21]([CH2:28][CH2:29][CH3:30])[CH:22]=[C:23]([CH2:25][CH2:26][CH3:27])[CH:24]=3)[CH2:17][CH2:18]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: CCCc1cc(CCC)cc(N2CCN(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)CC2)c1
Reactant: [H][H]
Agent: O=[Pt]=O
Product: CCCc1cc(CCC)cc(N2CCN(S(=O)(=O)c3ccc(N)cc3)CC2)c1

Procedure:
In the manner given in Example 1B, 1-[(p-nitrophenyl)sulfonyl]-4-(3,5-dipropylphenyl)piperazine is reduced with hydrogen over PtO2 to give 1-[(p-amino-phenyl)sulfonyl]-4-(3,5-dipropylphenyl)piperazine.
Reaction SMILES: [BH4-].[Na+].[CH2:3](COC)[O:4]C.[F:9][C:10]1[C:18]([F:19])=[C:17](C(O)=O)[C:16]([F:23])=[C:15]([F:24])[C:11]=1[C:12]([OH:14])=O.Cl>O.C1(C)C=CC=CC=1>[F:24][C:15]1([CH2:3][OH:4])[C:16]([F:23])=[CH:17][C:18]([F:19])=[C:10]([F:9])[CH:11]1[CH2:12][OH:14]
Reactant: COCCOC
Reactant: O=C(O)c1c(F)c(F)c(C(=O)O)c(F)c1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: OCC1C(F)=C(F)C=C(F)C1(F)CO
Temperature: 50 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Into a 200 mL flask equipped with a reflux condenser, 2.58 g of sodium borohydride and 25 g of dimethoxyethane were charged. The obtained mixture was adjusted to 50° C. and then, a solution obtained by mixing 6.10 g of 2,3,5,6-tetrafluoroterephthalic acid with 20 g of dimethoxyethane was added dropwise thereto over 1 hour while stirring. The obtained mixture was stirred for 7 hours at 60° C. To the obtained reaction mixture, 20 g of toluene was added followed by cooling to 50° C. Eight point five grams of 35% by weight hydrochloric acid was added dropwise thereto over 1 hour to stir at 60° C. for 6 hours. To the obtained mixture, 30 g of water was added followed by separating to an organic layer and an aqueous layer. The aqueous layer was extracted twice with 30 g of ethyl acetate. The obtained organic layers were mixed and washed with 10 g of a saturated aqueous potassium carbonate solution and then with 10 g of water. The organic layer was concentrated and the obtained solids were recrystallized with toluene and hexane to obtain white powder crystals of 2,3,5,6-tetrafluorobenzenedimethanol. The crystals were analyzed by liquid chromatography absolute calibration curve method to find out that the purity thereof was 95.1%. Yield: 95%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([SH:20])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.CN(C)C=O.[H-].[Na+].Br[CH:29]([CH3:31])[CH3:30]>O>[CH3:30][CH:29]([S:20][C:11]1[NH:12][C:13]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:10]=1)[CH3:31]
Reactant: COc1ccc(-c2nc(S)[nH]c2-c2ccncc2)cc1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(SC(C)C)[nH]c2-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(4-Methoxyphenyl)-5-(4-pyridyl)-2-mercaptoimidazole (2.2 g, 8 mm) was covered with 25 ml of dimethylformamide and sodium hydride (13 mm) was added. 2-Bromopropane (1.10 g, 9.5 mm) was added in a dimethylformamide solution (20 ml) and the reaction was allowed to stir at room temperature overnight. Pouring the solution into water precipitated the product which was taken up in chloroform, dried and evaporated to an oil which crystallized by the addition of ether. Yield of the title product was 1.5 g, m.p. 206°-210°.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[CH2:24][CH2:25][CH2:26][CH:27]([OH:29])[CH3:28])=[CH:18][CH:17]=2)=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:30](I)[CH3:31]>[Ag]=O.C(Cl)(Cl)Cl>[CH2:1]([O:9][C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:17]=[CH:18][C:19](/[CH:22]=[CH:23]/[CH2:24][CH2:25][CH2:26][CH:27]([O:29][CH2:30][CH3:31])[CH3:28])=[CH:20][CH:21]=2)=[N:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1cnc(-c2ccc(/C=C/CCCC(C)O)cc2)nc1
Reactant: CCI
Agent: O=[Ag]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCOc1cnc(-c2ccc(/C=C/CCCC(C)OCC)cc2)nc1
Yield: 43 %

Procedure:
At room temperature, 1.6 g (4 mmol) of the (-)-5-octyloxy-2-{4-(6-hydroxy-1-trans-heptenyl)-phenyl}-pyrimidine obtained in Example 9, 20 ml of ethyl iodide and 2.8 g (12 mmol) of silver oxide were stirred for 60 hours, washed successively with 1N hydrochloric acid and saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The reaction mixture thus obtained was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.76 g (yield 43%) of (-)-5-octyloxy-2-{4-(6-ethoxy-1-trans-heptenyl)-phenyl}-pyrimidine, [α]D20 =-1.2 (c=0.95, CHCl3).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[O:19][CH2:18][C@:13]2([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])[NH:14][O:15][C@@H:16]([CH3:17])[C@@H:12]2[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C@@]1(C2C=CC(F)=CC=2F)CO[C@@H](COCC2C=CC=CC=2)C[C@H]1CO>>[NH2:14][C@@:13]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[CH2:18][O:19][C@@H:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:11][C@H:12]1[C@@H:16]([OH:15])[CH3:17]
Reactant: C[C@@H]1ON[C@@]2(c3ccc(F)cc3F)CO[C@@H](COCc3ccccc3)C[C@@H]12
Agent: N[C@@]1(c2ccc(F)cc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO
Product: C[C@H](O)[C@@H]1C[C@H](COCc2ccccc2)OC[C@@]1(N)c1ccc(F)cc1F

Procedure:
The product, obtained as a yellow oil, was prepared from (3S,3aR,5R,7aS)-5-[(benzyloxy)methyl]-7a-(2,4-difluorophenyl)-3-methylhexahydro-1H-pyrano[3,4-c][1,2]oxazole (C15) according to the general procedure for the synthesis of [(2R,4R,5S)-5-amino-2-[(benzyloxy)methyl]-5-(2,4-difluorophenyl)tetrahydro-2H-pyran-4-yl]methanol (C6) in Preparation P1. Yield: 13.96 g, 37.00 mmol, 98%. LCMS m/z 378.2 [M+H+]. 1H NMR (400 MHz, CDCl3), characteristic peaks: δ 7.65-7.78 (br m, 1H), 7.27-7.40 (m, 5H), 6.93-7.02 (br m, 1H), 6.80 (ddd, J=12.6, 8.5, 2.6 Hz, 1H), 4.06 (dd, J=11.7, 2.2 Hz, 1H), 3.53 (dd, J=10.2, 3.7 Hz, 1H), 2.50-2.61 (br m, 1H), 1.62 (ddd, J=14, 4, 2.5 Hz, 1H), 0.89 (d, J=6.6 Hz, 3H).
Reaction SMILES: C[C:2]1[CH:7]=[CH:6]N=[C:4]([CH2:8]CCCC)[CH:3]=1.C([Mg]Br)CCCCC.Cl[C:22]1[CH:27]=[C:26]([CH2:28][CH3:29])[CH:25]=[CH:24][N:23]=1>>[CH2:28]([C:26]1[CH:25]=[CH:24][N:23]=[C:22]([CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH3:8])[CH:27]=1)[CH3:29]
Reactant: CCc1ccnc(Cl)c1
Reactant: CCCCCc1cc(C)ccn1
Agent: CCCCCC[Mg]Br
Product: CCCCCCc1cc(CC)ccn1

Procedure:
This compound was obtained using the same experimental procedure as per 4-methyl-2-pentyl-pyridine (see above), using hexyl magnesium bromide instead of pentyl magnesium bromide and 2-chloro-4-ethyl pyridine instead of 2-bromo-4-methylpyridine. The product was obtained with similar yield and purified in the same way.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[F:59][C:60]1[CH:68]=[CH:67][C:63]([C:64](Cl)=[O:65])=[CH:62][C:61]=1[C:69]([F:72])([F:71])[F:70]>>[F:59][C:60]1[CH:68]=[CH:67][C:63]([C:64]([NH:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3[CH:49]=[C:48]4[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]4=[O:50])=[CH:43][CH:42]=3)=[CH:39][CH:40]=2)=[O:65])=[CH:62][C:61]=1[C:69]([F:70])([F:71])[F:72]
Reactant: O=C(Cl)c1ccc(F)c(C(F)(F)F)c1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(F)c(C(F)(F)F)c4)cc3)cc2C1=O
Yield: 74 %

Procedure:
The compound of example 205 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 4-fluoro-3-trifluoromethyl benzoyl chloride.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])[CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>C1COCC1>[N:39]1([C:36]2[CH:35]=[CH:34][C:33]([NH:32][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])[CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:38][CH:37]=2)[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)C(=CO)C(=O)N3)c1
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)C(=CNc2ccc(N4CCOCC4)cc2)C(=O)N3)c1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-amide (prepared below, 30 mg, 0.072 mmol) and THF (1 mL). To the resulting solution was added N-(4-aminophenyl)morpholine (19.3 mg, 0.1082 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature, concentrated in vacuo and redissolved in EtOAc. Hexanes were added to the reaction mixture. The solid precipitate that formed was filtered and washed with ˜1 mL of ice cold THF yielding 36% (15 mg, 0.026 mmol) of the title compound.