Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)COCCOCCO.NC(N)=[S:13].[CH3:15][O:16][CH:17]([O:28][CH3:29])[CH2:18][CH:19]([CH3:27])[CH2:20][CH2:21][CH2:22][C:23](Cl)([CH3:25])[CH3:24].NCCNCCNCCNCCN>>[CH3:15][O:16][CH:17]([O:28][CH3:29])[CH2:18][CH:19]([CH3:27])[CH2:20][CH2:21][CH2:22][C:23]([SH:13])([CH3:25])[CH3:24]
Reactant: COC(CC(C)CCCC(C)(C)Cl)OC
Reactant: NC(N)=S
Agent: NCCNCCNCCNCCN
Solvent: OCCOCCOCCO
Product: COC(CC(C)CCCC(C)(C)S)OC
Reaction time: 12 h

Procedure:
To a mixture of 100 ml. of triethylene glycol and 42 g. of thiourea, at 75°-80°, slowly added one equivalent of 1,1-dimethoxy-7-chloro-3,7-dimethyloctane, with stirring, keeping the temperature below 130°. When the reaction mixture is homogeneous, the reaction is continued 12 hours and then one equivalent of tetraethylenepentamine is added slowly. Then the reaction mixture is heated to reflux until the head temperature is constant. The mixture is then distilled to give crude 1,1-dimethoxy-7-mercapto-3,7-dimethyloctane which is purified by fractional distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[Br:10][CH2:11][CH2:12][CH2:13]Br.[OH-].[Na+]>O>[Br:10][CH2:11][CH2:12][CH2:13][O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:9])[CH:4]=1
Reactant: BrCCCBr
Reactant: Cc1cc(O)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(OCCCBr)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred and refluxing mixture of 122 parts of 4-chloro-3-methylphenol, 214.1 parts of 1,3-dibromopropane and 850 parts of water added dropwise, during a one hour-period, a solution of 34 parts of sodium hydroxide in 213 parts of water. Upon completion, stirring at reflux is continued overnight. The reaction mixture is cooled to room temperature and the product is extracted with 765 parts of benzene. The extract is washed with a sodium hydroxide solution 10%, dried, filtered and evaporated. The residue is distilled twice, yielding 114 parts of 4-(3-bromopropoxy)-1-chloro-2-methylbenzene; bp. 119° C. at 0.6 mm. pressure.
Reaction SMILES: [CH3:1][C:2](=[N:4][NH:5][C:6]([NH2:8])=[O:7])[CH3:3].[CH3:9][N:10]([CH3:15])[CH2:11][CH2:12][CH2:13]N>>[C:2](=[N:4][NH:5][C:6]([NH:8][CH2:13][CH2:12][CH2:11][N:10]([CH3:15])[CH3:9])=[O:7])([CH3:3])[CH3:1]
Reactant: CC(C)=NNC(N)=O
Reactant: CN(C)CCCN
Product: CC(C)=NNC(=O)NCCCN(C)C

Procedure:
Acetone semicarbazone (23 g) and 3-dimethylaminopropylamine (24.5 g) were heated to 175° C. over 40 minutes, then cooled and partitioned between t-butyl methyl ether and brine. The ether layer was concentrated to give 13.2 g waxy solid 2-isopropylidene-N-(3-dimethylaminopropyl)hydrazinecarboxamide (mp 49°-53° C.). Of this, 2.0 g was boiled 8 hr. in water maintained at a volume of 20 ml, then treated with 1.67 ml 12N HCl and concentrated in vacuo to give 2.5 g crude N-(3-dimethylaminopropyl)hydrazinecarboxamide dihydrochloride as a syrup. One fifth of the latter was reacted with 5-nitro-2-furaldehyde (0.282 g) in 6 ml 1:1 methanol-ethanol containing 0.16 ml pyridine at reflux for 30 minutes. The mixture was cooled and treated with 10 ml isopropanol to give 0.51 g of the title compound as a yellow solid, mp 200°-202° C. (dec.).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:14]=3[C:15]([NH2:17])=[O:16])[CH2:7][CH:6]3[CH2:23][O:24][CH2:25][CH2:26][N:5]3[C:4]=2[N:3]=1.[NH:27]1[C:35]2[C:30](=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28]1>O1CCOCC1.C([O-])(O)=O.[Na+].CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH:27]1[C:35]2[C:30](=[C:31]([C:2]3[N:11]=[CH:10][C:9]4[N:8]([CH2:12][C:13]5[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:14]=5[C:15]([NH2:17])=[O:16])[CH2:7][CH:6]5[CH2:23][O:24][CH2:25][CH2:26][N:5]5[C:4]=4[N:3]=3)[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28]1
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: Cc1ccc(C(N)=O)c(CN2CC3COCCN3c3nc(Cl)ncc32)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(N)=O)c(CN2CC3COCCN3c3nc(-c4cccc5[nH]ccc45)ncc32)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 33.3 %

Procedure:
To a 10 mL vial were added 2-((2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)methyl)-4-methylbenzamide (PREPARATION x84, 57 mg, 0.152 mmol), 1H-indol-4-ylboronic acid (49.1 mg, 0.305 mmol), and PdCl2(dppf) (11.16 mg, 0.015 mmol) in dioxane (2 mL) and saturated NaHCO3 (0.4 mL). The resulting orange suspension was heated to 100° C. and stirred overnight. The reaction mixture was subsequently diluted with EtOAc and washed with saturated NH4Cl (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated. The product was purified by preparative HPLC, using a 20-45% CH3CN gradient in H2O (with 0.05% TFA). The pure fractions were combined and lyophilized to give the title compound as a yellow solid (23 mg, 33%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.33 (s, 3 H), 3.06-3.19 (m, 1 H), 3.24-3.33 (m, 2 H), 3.56-3.64 (m, 1 H), 3.89-4.05 (m, 1 H), 4.06-4.18 (m, 1 H), 4.41-4.55 (m, 1 H), 4.67-4.81 (m, 2 H), 6.94-7.08 (m, 1 H), 7.21-7.33 (m, 2 H), 7.33-7.41 (m, 1 H), 7.44-7.54 (m, 1 H), 7.54-7.74 (m, 2 H), 7.79-7.91 (m, 1 H), 11.46-11.66 (m, 1H); ESI-MS m/z [M+H]′ calc'd for C26H26N6O2, 455.2; found 455.3.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH2:4][CH2:3]1.Br[C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([Br:22])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:22][C:20]1[CH:21]=[C:16]([NH:14][C:11]2[CH:10]=[CH:9][C:8]([CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:13][N:12]=2)[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CN1CCC(c2ccc(N)nc2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN1CCC(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
Temperature: 100 °C
Yield: 50.3 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 232c (1.5 g, 7.9 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (2.0 g, 7.9 mmol), cesium carbonate (5.0 g, 16 mmol), and 1,4-dioxane (50 mL). After bubbling nitrogen through the resulting suspension for 30 minutes, XantPhos (455 mg, 0.79 mmol) and tris(dibenzylideneacetone)dipalladium(0) (718 mg, 0.79 mmol) were added. The system was subject to three cycles of vacuum/argon flush and heated at 100° C. for 2 h. After this time the reaction was cooled to room temperature and filtered. The filtrate was partitioned between ethyl acetate (100 mL) and water (100 mL). The aqueous layer was separated and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine (3×20 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1:3 ethyl acetate/petroleum ether to afford 232d as a brown solid (1.5 g, 50%). MS-ESI: [M+H]+ 377.
Reaction SMILES: [CH2:1]([CH:3]1[CH:8]([CH3:9])[CH:7]([CH2:10][O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH2:6][C:5](=[O:16])[CH:4]1[C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)[CH3:2]>C1COCC1.[NH4+].[Cl-].C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:8]([CH3:9])[CH:7]([CH2:10][O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH2:6][C:5]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)([OH:16])[CH:4]1[C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:21][CH:22]=1)[CH3:2]
Reactant: CCC1C(c2ccc(Oc3ccccc3)cc2)C(=O)CC(CO[Si](C)(C)C)C1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC1C(C)C(CO[Si](C)(C)C)CC(O)(c2ccc(OC)cc2)C1c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-ethyl-4-methyl-2-(4-phenoxy-phenyl)-5-trimethylsilanyloxymethyl-cyclohexanone (1.8 g, 3.8 mmol) in THF (10 mL) at −10° C. was added Grinard reagent (1.0 M, 7.5 mL). The reaction mixture was stirred at 25° C. for 1 h and then refluxed for 30 min. The reaction mixture was then cooled and diluted with aqueous saturated NH4Cl (100 mL) and ethyl acetate (100 mL). The organic layer was separated, dried over MgSO4 and purified on SiO2 (100% ethyl acetate) to yield crude product 3-ethyl-1-(4-methoxy-phenyl)-4-methyl-2-(4-phenoxy-phenyl)-5-trimethylsilanyloxymethyl-cyclohexanol. NMR showed S: R product ratio or 2:1. Further purification provide pure 3-ethyl-1-(4-methoxy-phenyl)-4-methyl-2-(4-phenoxy-phenyl)-5-trimethylsilanyloxymethyl-cyclohexanol.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][C:12]1[O:13][C:14]([CH3:17])=[CH:15][N:16]=1)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:17][C:14]1[O:13][C:12]([CH2:11][CH2:10][CH2:9][OH:8])=[N:16][CH:15]=1
Reactant: Cc1cnc(CCCOCc2ccccc2)o1
Agent: [Pd]
Solvent: CCO
Product: Cc1cnc(CCCO)o1
Reaction time: 8 h
Yield: 58.7 %

Procedure:
A solution of 2-(3-Benzyloxy-propyl)-5-methyl-oxazole (675 mg, 2.92 mmol) in ethanol (15 ml) containing a suspension of 10% Pd on C (63.9 mg, 0.06 mmol) was hydrogenated overnight at room temperature. The catalyst was removed by filtration through Celite®, then the filtrate was concentrated and the residue was purified on silica gel using 1:1/heptane:ethyl acetate and then ethyl acetate as eluants. Fractions that contained product were combined and concentrated under reduced pressure to yield 3-(5-Methyl-oxazol-2-yl)-propan-1-ol (242 mg, 59%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]3[N:17]([CH3:18])[CH:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3.[C:19]([C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[N:25][CH:26]=1)#[CH:20]>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](/[CH:20]=[CH:19]\[C:21]1[CH:26]=[N:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:6]1[CH2:11][C@@H:12]3[N:17]([CH3:18])[C@H:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1C
Reactant: C#Cc1ccc(C)nc1
Product: Cc1ccc2c(c1)c1c(n2/C=C\c2ccc(C)nc2)C[C@H]2CCC[C@@H]1N2C

Procedure:
The coupling of 2,12-dimethyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (110 mg, 0.458 mmol; Example 114A) and 5-ethynyl-2-methylpyridine (107 mg, 0.915 mmol; prepared as described in International Publication No. WO2005090333) was performed according to the procedure described in Example 20 to give the racemic mixture of the title compound as the major of two alkene isomers. The individual enantiomers from the racemic mixture of the major alkene isomer were separated by preparative chiral supercritical fluid chromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50% gradient of CH3OH—CO2 containing 0.1% diethylamine) to afford the title compound as the first-eluting enantiomer: 1H NMR (300 MHz, methanol-d4) δ ppm 1.18-1.30 (m, 1H), 1.30-1.41 (m, 1H), 1.48 (dd, J=13, 2 Hz, 1H), 1.69 (dd, J=13, 2 Hz, 1H), 1.83-2.09 (m, 2H), 2.26 (d, J=17 Hz, 1H), 2.28 (s, 3H), 2.38 (s, 3H), 2.39 (s, 3H), 2.89 (dd, J=18, 7 Hz, 1H), 3.17 (t, J=5 Hz, 1H), 4.13 (s, 1H), 6.64 (d, J=9 Hz, 1H), 6.84-6.90 (m, 1H), 6.92-7.01 (m, 2H), 7.03-7.09 (m, 1H), 7.15-7.22 (m, 2H), 7.96 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 358 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:24][C:25](=[O:33])[CH:26]([NH:31][CH3:32])[CH2:27][CH:28]([CH3:30])[CH3:29])[C:17](=[O:23])[NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:43]([O:46][CH2:47][CH2:48]Br)(=[O:45])[CH3:44]>C1COCC1>[CH2:47]([O:46][C:43](=[O:45])[CH2:44][N:31]([CH:26]([C:25](=[O:33])[NH:24][CH:16]([C:17](=[O:23])[NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1)[CH2:27][CH:28]([CH3:30])[CH3:29])[CH3:32])[CH3:48]
Reactant: CNC(CC(C)C)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C
Reactant: CC(=O)OCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CN(C)C(CC(C)C)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 84 %

Procedure:
A mixture of [S-(R*,R*)]-4-methyl-2-methylamino-pentanoic acid [2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide (0.55 mmol), diisopropyl ethylamine (1.65 mmol), 2-bromoethyl acetate (0.8 mmol), and anhydrous THF (6 mL) was stirred at 25° C. for 6 hours. The precipitate was filtered off. The reaction mixture was concentrated and purified by column chromatography on silica gel eluting with 10% acetone/methylene chloride to give the titled compound (84% yield).
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]([C:10]1[C:11]([N:23]([S:32]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2/[CH:42]=[CH:43]\[CH2:44]O)(=[O:34])=[O:33])[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[CH:12][CH:13]=[C:14]2[C:19]=1[O:18][CH2:17][C:16]1[O:20][CH:21]=[CH:22][C:15]2=1)=[O:9].[CH:46]([N:49](C(C)C)CC)(C)[CH3:47].C(N)C>C(Cl)Cl>[CH2:46]([NH:49][CH2:44]/[CH:43]=[CH:42]\[C:36]1[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:35]=1[S:32]([N:23]([C:11]1[C:10]([C:8]([O:7][CH3:6])=[O:9])=[C:19]2[C:14]([C:15]3[CH:22]=[CH:21][O:20][C:16]=3[CH2:17][O:18]2)=[CH:13][CH:12]=1)[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])(=[O:33])=[O:34])[CH3:47]
Reactant: COC(=O)c1c(N(COCC[Si](C)(C)C)S(=O)(=O)c2ccc(F)cc2/C=C\CO)ccc2c1OCc1occc1-2
Reactant: CCN(C(C)C)C(C)C
Agent: CCN
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCNC/C=C\c1cc(F)ccc1S(=O)(=O)N(COCC[Si](C)(C)C)c1ccc2c(c1C(=O)OC)OCc1occc1-2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
Methanesulfonyl chloride (0.100 g) was added to an ice-cooled, stirred solution of methyl-7-{N-[4-fluoro-2-((Z)-3-hydroxyprop-1-enyl)benzenesulfonyl]-N-(2-trimethylsilanylethoxymethyl)amino]-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 48, 0.413 g) and diisopropylethylamine (0.226 g) in DCM (7 mL). The reaction mixture was stirred with ice cooling for 30 minutes. Ethylamine (2M in THF, 2 mL) was added and the reaction mixture was stirred at room temperature for 5 hours. It was diluted with DCM and washed with water. The organic layer was dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with DMAW 350, followed by DMAW 240 and then DMAW 120. The resultant product was azeotroped with toluene and ethanol to give methyl 7-{N-[2-((Z)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonyl]-N-(2-trimethylsilanylethoxymethyl)amino}-4H-furo[2,3-c]chromene-6-carboxylate (0.401 g) as a dark yellow gum.
Reaction SMILES: CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[NH2:17][CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])[CH2:23][CH2:22]1)=[O:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:61]1([N:67]2[CH2:72][CH2:71][CH:70]([C:73](O)=[O:74])[CH2:69][CH2:68]2)[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>CN(C=O)C.O>[O:20]=[C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:35])[F:36])[CH2:25][CH2:26]1)[CH2:18][NH:17][C:73]([CH:70]1[CH2:69][CH2:68][N:67]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH2:72][CH2:71]1)=[O:74]
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)C1CCN(c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)C1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 29.3 %

Procedure:
DIPEA (66 mg, 0.51 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone TFA salt (125 mg, 0.29 mmol) in DMF (1.5 mL). HOBT (27 mg, 0.20 mmol) and EDCI.HCl (39 mg, 0.20 mmol) were then added at room temperature. After 2 minutes, 1-phenyl-piperidine-4-carboxylic acid (35 mg, 0.17 mmol) was added and the resulting mixture was stirred at room temperature for 4 hrs. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 25 mg (29% yield) of 1-phenyl-piperidine-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity %: 87.4%, 1H NMR (DMSO-d6): δ 7.8-7.7 (m, 3H), 7.4-7.3 (d, 1H), 7.3-7.2 (t, 1H), 7.0-6.9 (d, 1H), 6.8 (t, 1H), 6.6 (m, 1H), 4.2-3.8 (m, 4H), 3.8-3.6 (m, 4H), 3.5 (m, 2H), 3.4-3.3 (t, 1H), 3.2 (m, 2H), 2.7 (m, 2H), 2.3 (m, 1H), 2.0-1.8 (m, 4H).
Reaction SMILES: Br[C:2]1[C:3]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:9]([C:17]3[C:18]([NH2:22])=[N:19][O:20][N:21]=3)=[N:8][C:4]=2[CH:5]=[N:6][CH:7]=1.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1B(O)O.C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:11]1([N:10]2[C:3]3[C:2]([C:24]4[S:23][CH:27]=[CH:26][CH:25]=4)=[CH:7][N:6]=[CH:5][C:4]=3[N:8]=[C:9]2[C:17]2[C:18]([NH2:22])=[N:19][O:20][N:21]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1nonc1-c1nc2cncc(Br)c2n1-c1ccccc1
Reactant: OB(O)c1cccs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1nonc1-c1nc2cncc(-c3cccs3)c2n1-c1ccccc1
Temperature: 110 °C
Yield: 17.8 %

Procedure:
A stirred mixture of the product from Example 180 (50 mg, 0.14 mmol), thiophene-2-boronic acid (27 mg, 0.21 mmol) and Pd(dppf)2Cl2.CH2Cl2 (11 mg, 0.014 mmol) in 3.5 ml of 2.5:1 Dioxane/2 M K2CO3 contained in a 20 ml pressure tube was heated to 110° C. for 18 h. The resulting biphase mixture was cooled to room temperature. The organic layer (top) was removed with pipet, filtered to remove the Pd. The aqueous layer was extracted once with EtOAc. EtOAc was combined with the organic filtrate, washed with sat'd NaHCO3, water, brine, dried (Na2SO4) and reduced in vacuo. the residue was purified by silica gel chromatography eluting with 10% MeOH in CHCl3, to afford the title compound, (9 mg, 18%); MS (ES+) m/e 361 [M+H]+.
Reaction SMILES: C(OCC)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:12][CH:13]([CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[C:14]([NH2:16])=O.[OH-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH3:12][CH:13]([CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH2:14][NH2:16]
Reactant: CC(Cc1ccncc1)C(N)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCOCC
Product: CC(CN)Cc1ccncc1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
Next, anhydrous diethyl ether (20 ml) was added to lithium aluminum hydride (0.45 g, 12 mmol) under a nitrogen atmosphere, and the mixture was stirred under ice-cooling. A solution of 2-methyl-3-(4-pyridyl)propionamide (0.68 g, 4.1 mmol) in anhydrous methylene chloride (20 ml) was added dropwise to the mixture over five minutes, the temperature was raised to room temperature, and the whole was stirred overnight. The reaction mixture was cooled with ice again, ethyl acetate (5 ml) was added slowly to the reaction mixture, and then a 1 N aqueous sodium hydroxide solution was added thereto first slowly (total 100 ml). The whole was extracted with chloroform (100 ml), and the organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 0.56 g (90%) of the titled compound as a pale yellow oily matter.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][CH:19]=[C:18]([F:23])[C:17]=2[F:24])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[C:18]([F:23])[C:17]=1[F:24]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1n[nH]c(=O)c(-c2c(F)ccc(F)c2F)c1-c1ccc(Cl)cc1
Product: Cc1nnc(Cl)c(-c2c(F)ccc(F)c2F)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
3.50 g of 5-(4-chlorophenyl)-6-methyl-4-(2,3,6-trifluorophenyl)-2H-pyridazin-3-one and 15 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. The reaction mixture was cooled down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 3.68 g of 3-chloro-5-(4-chlorophenyl)-6-methyl-4-(2,3,6-trifluorophenyl)pyridazine (hereinafter, referred to as compound (iv) of the present invention).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].I[CH:13]([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN(C=O)C>[CH:13]([O:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])([CH3:15])[CH3:14]
Reactant: CC(C)I
Reactant: COc1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C=O)c(OC(C)C)c1
Temperature: 45 °C
Reaction time: 18 h

Procedure:
To the solution of 2-hydroxy-4-methoxybenzaldehyde 10 (6.6 mmol, 1 equiv.) and 2-iodopropane (7.23 mmol, 1.1 equiv.) in 7 mL of DMF was added K2CO3 (26.3 mmol, 4 equiv.). The reaction was stirred at 45° C. for 18 h. Next day, added DCM 5 mL, filtered off solid, and washed solid with DCM twice. The filtrate was washed by water. And then organic layer was dried over MgSO4, and concentrated. The remaining residues was purified by Biotage SP1:0-20% EtOAc in hexane over 7 CV, 20% EtOAc in hexane over 5 CV.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:14][C@@H:13]([S:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][N:11]1[S:35]([C:38]1[CH:49]=[CH:48][C:41]2[NH:42][C:43](=O)[O:44][C:45](=[O:46])[C:40]=2[CH:39]=1)(=[O:37])=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH3:43][O:44][C:45](=[O:46])[C:40]1[CH:39]=[C:38]([S:35]([N:11]2[CH2:12][C@H:13]([S:15][C:16]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][C@H:10]2[CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:37])=[O:36])[CH:49]=[CH:48][C:41]=1[NH2:42]
Reactant: O=c1[nH]c2ccc(S(=O)(=O)N3C[C@H](SC(c4ccccc4)(c4ccccc4)c4ccccc4)C[C@H]3COCc3ccccc3)cc2c(=O)o1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: COC(=O)c1cc(S(=O)(=O)N2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2COCc2ccccc2)ccc1N
Reaction time: 6 h

Procedure:
A solution of 0.72 g (1.05 mmol) (2S,4R)-6-(2-benzyloxymethyl-4-tritylsulfanyl-pyrrolidine-1-sulfonyl)-1H-benzo[d][1,3]oxazine-2,4-dione in 40 ml CH2Cl2 was treated at room temperature with 0.42 ml (10.5 mmol) MeOH and 0.31 ml (2.09 mmol) DBU and stirred for 6 h. Flash chromatography on silica gel (Hexane/EtOAc 9:1) gave (2S,4R)-2-amino-5-[2-benzyloxymethyl-4-tritylsulfanyl-pyrrolidine-1-sulfonyl]-benzoic acid methyl ester which was deprotected (following Method 3) to give (2S,4R)-2-amino-5-[2-benzyloxymethyl-4-mercapto-pyrrolidine-1-sulfonyl]-benzoic acid methyl ester, MS: 437 (M+H+).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][CH:5]=1)=[O:3].ClCC(OC(C1C=CC(I)=CC=1)C)=O>>[I:10][C:7]1[CH:8]=[CH:9][C:4]([C@@H:2]([OH:3])[CH3:1])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(I)cc1
Agent: CC(OC(=O)CCl)c1ccc(I)cc1
Product: C[C@H](O)c1ccc(I)cc1

Procedure:
Starting from 4-iodophenyl methyl ketone, which is reduced to the racemic alcohol and converted to (±)-1-(4-iodophenyl)ethyl chloroacetate, the racemic ester is subjected to stereoselective enzyme hydrolysis. The remaining (S)-isomer of the ester is separated from the (R)-alcohol and transesterified to give (S)-1-(4-iodophenyl)ethanol (ee >98%) III.