Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O/[C:2](/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:3](/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)\[CH:4]=O.CC1C=CC(S(O)(=O)=O)=CC=1.[CH3:29][NH:30][C:31]([NH2:33])=[O:32].C(OCC)C>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:29][N:30]1[C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:4]=[N:33][C:31]1=[O:32]
Reactant: CNC(N)=O
Reactant: O=C/C(=C(\O)c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cn1c(-c2ccccc2)c(-c2ccccc2)cnc1=O

Procedure:
A solution of (Z)-3-hydroxy-2,3-diphenyl-propenal (105, 423 mg, 1.89 mmol), pTSA (30 mg, 7.56 mmol) and methyl urea (118 mg, 0.62 mmol) in toluene was heated at 110° C. overnight. The reaction was quenched with water, and the products were extracted with ethyl acetate. The organic layer was separated and washed with brine, and dried over MgSO4, and concentrated in vacuo to produce a yellow oil. The crude product was dissolved in CH2Cl2 and titrated with diethyl ether to give the title compound as a white solid.
Reaction SMILES: [F-].[Cs+].Cl[C:4]1[CH:21]=[CH:20][C:19]2[C:6](=[CH:7][C:8]3[C:17]([CH:18]=2)=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=3)[CH:5]=1.C([Sn](CCCC)(CCCC)[C:27]1[S:31][C:30]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)=[CH:29][CH:28]=1)CCC.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>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>[CH:5]1[C:6]2[C:19](=[CH:18][C:17]3[C:8]([CH:7]=2)=[CH:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=3)[CH:20]=[CH:21][C:4]=1[C:27]1[S:31][C:30]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)=[CH:29][CH:28]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(-c2cccs2)s1
Reactant: Clc1ccc2cc3cc4ccccc4cc3cc2c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: c1csc(-c2ccc(-c3ccc4cc5cc6ccccc6cc5cc4c3)s2)c1
Temperature: 100 °C

Procedure:
Pd2(dba)3 (21 mg, 0.023 mmol, 1.5%), CsF (511 mg, 3.37 mmol, 2.2 eq), dioxane (25 mL), 2-chlorotetracene (403 mg, 1.53 mmol), 5-tri-n-butylstannyl-2,2′-bithiophene (766 mg, 1.68 mmol), P(t-Bu)3 (0.26 mL, 0.090 mmol, 6%) were mixed, bubbled with N2 via cannula for 30 min, and then heated at 100° C. for 16 h. An additional charge of 10 mg of Pd[P(t-Bu)3]2 and 140 mg 5-tri-n-butylstannyl-2,2′-bithiophene and heated at 100° C. for another 24 h. Cooled the mixture and poured on a glass filter frit (10-15 μm pores) and washed the reddish crude with Et2O, water, and air-dried. Gradient sublimation at a source temperature of 250-270° C. afforded 443 mg (74%, on 2-chlorotetracene) of bright orange-red product. DSC: 341° C. (mp, ΔH=87 Jg−1). EIMS: 392 ([M]+, 100%), 196 ([M]2+, 20%). Anal. Calcd. for C26H16S2: C, 79.6; H, 4.1. Found: C, 80.0; H, 4.34.
Reaction SMILES: I[C:2]1[CH:28]=[CH:27][C:5]2[N:6]([CH2:9][C:10]3[CH:26]=[CH:25][C:13]4[N:14]=[C:15]([NH:17][C@@H:18]5[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]5[OH:24])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[C:29]([O:33][CH2:34][CH3:35])(=[O:32])[CH:30]=[CH2:31].C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:24][C@@H:19]1[CH2:20][CH2:21][CH2:22][CH2:23][C@H:18]1[NH:17][C:15]1[S:16][C:12]2[CH:11]=[C:10]([CH2:9][N:6]3[C:5]4[CH:27]=[CH:28][C:2](/[CH:31]=[CH:30]/[C:29]([O:33][CH2:34][CH3:35])=[O:32])=[CH:3][C:4]=4[N:8]=[CH:7]3)[CH:26]=[CH:25][C:13]=2[N:14]=1
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(I)ccc43)cc2s1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 120 °C
Yield: 130.8 %

Procedure:
To a stirred solution of (1R,2R)-2-((6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (150 mg, 0.30 mmol) from Step 5 of Example 183 in DMF (2 mL) were added ethyl acrylate (0.036 mL, 0.33 mmol), palladium (II) acetate (7 mg 0.03 mmol), and triethylamine (0.088 mL, 0.63 mmol). The mixture was flushed with argon and heated in a sealed vessel at 120° C. for 3 h. The mixture was cooled to rt and partitioned between EtOAc and water. The separated aqueous layer was extracted twice with EtOAc and the combined organic phases were washed three times with a 1:1 mixture of water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure to afford (E)-ethyl 3-(1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)acrylate (187 mg) as a solid. The product was used directly in the next step. LCMS (ESI) m/z 477 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(S(Cl)(=O)=O)C=CC=CC=1.N.C([O:24][C:25](=[O:32])[C:26]([CH3:31])([CH3:30])[C:27](O)=[O:28])C.C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1.CN(C)C1C=CN=CC=1.ClCCCl>[CH3:30][C:26]([CH3:31])([C:27](=[O:28])[NH:10][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])[C:25]([OH:32])=[O:24]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: CCOC(=O)C(C)(C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: N
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CC(C)(C(=O)O)C(=O)NS(=O)(=O)c1ccccc1
Temperature: 40 °C

Procedure:
Benzenesulfonamide was made by adding benzenesulfonyl chloride to a solution of ammonia in tetrahydrofuran and evaporating to a solid. Benzenesulfonamide (87 mg, 0.50 mmole) was added to a shaken suspension of 3-ethoxy-2,2-dimethyl-3-oxopropanoic acid (100 mg, 0.62 mmole) reactivated on PS-DCC resin (1.62 g, 1.25 mmole) and 1.50 mmole of N,N-dimethylpyridin-4-amine in DCE. When reaction is complete the resin is filtered off and the organic layer washed with 1N HCl dried and evaporated. The resulting residue was dissolved in 6 ml of ethanol and 6 ml of 1N LiOH was added and heated to 40° C. The reaction was neutralized with 1N HCl and evaporated to afford 2,2-dimethyl-3-oxo-3-[(phenylsulfonyl)amino]propanoic acid as a crude product which was used with no further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.[CH3:12][O:13][CH2:14][CH2:15][NH2:16]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:16][CH2:15][CH2:14][O:13][CH3:12])(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1
Reactant: COCCN
Reactant: O=S(=O)(Cl)c1cncc(Br)c1
Solvent: C1CCOC1
Product: COCCNS(=O)(=O)c1cncc(Br)c1
Yield: 26.9 %

Procedure:
A solution of 5-bromopyridine-3-sulfonyl chloride (1.5 g, 5.8 mmol)) and 2-methoxyethanamine (1.3 g, 18 mmol) in THF (40 mL) was stirred at room temperature for 16 h. After this time, the resulting reaction mixture was partitioned between saturated aqueous sodium chloride and ethyl acetate. The organic solution was dried and evaporated. The resulting residue was purified by flash column chromatography using ethyl acetate/hexanes to yield 5-bromo-N-(2-methoxyethyl)pyridine-3-sulfonamide (460 mg, 27%). LCMS Method T: Retention time 1.13 min; [M+1]=295, 297.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=3)[CH2:18][CH:17]([NH2:29])[CH2:16]2)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:30][C:31]1[S:32][C:33]([C:37](O)=[O:38])=[C:34]([CH3:36])[N:35]=1>>[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=3)[CH2:18][CH:17]([NH:29][C:37]([C:33]3[S:32][C:31]([CH3:30])=[N:35][C:34]=3[CH3:36])=[O:38])[CH2:16]2)=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CCc1ccc(C2CC(N)CN(C(=O)C3CCCC3)C2)cc1
Reactant: Cc1nc(C)c(C(=O)O)s1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)c3sc(C)nc3C)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
65 mg (0.15 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-amine trifluoroacetate (Example 8A) and 21 mg (0.13 mmol, 0.9 eq.) of 2,4-dimethyl-1,3-thiazole-5-carboxylic acid were reacted according to General Method 1. Yield: 43 mg (73% of theory)
Reaction SMILES: [NH2:1][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:7](=[O:15])[N:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]=2[S:4][C:3]=1[C:22]([O:24][CH3:25])=[O:23].P(Cl)(Cl)(Cl)=O.O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:5][N:6]([CH:16]=[N:1][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:7](=[O:15])[N:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]=2[S:4][C:3]=1[C:22]([O:24][CH3:25])=[O:23])[CH3:7]
Reactant: COC(=O)c1sc2c(c1N)c1ccccc1c(=O)n2-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1sc2c(c1N=CN(C)C)c1ccccc1c(=O)n2-c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution o 1.05 g of methyl 1-amino-4,5-dihydro-5-oxo-4-phenyl-thieno[2,3-c]isoquinoline-2-carboxylate in 20 ml of dimethylformamide was added 0.55 g of phosphorus oxychloride at room temperature, and the mixture was stirred for 30 minutes. The reaction mixture was poured into water, and neutralized with a saturated sodium bicarbonate aqueous solution, and precipitates were collected by a filtration. The precipitates were washed with water, and dried under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.09 g of the desired product as pale yellow crystals (eluent: n-hexane/chloroform=1/1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH:3]=1>[Pt]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(/C=C/c2cccc(Cl)c2)cc1
Agent: [Pt]
Product: Nc1ccc(CCc2cccc(Cl)c2)cc1

Procedure:
In an analogous manner to that described in Example 36b), the hydrogenation of (E)-1-chloro-3-[2-(4-nitrophenyl)ethenyl]-benzene using platinum on carbon (5%) as the catalyst but with a reaction time of 18 hours and simultaneous reduction of the double bond yields the 4-[2-(3-chloro-phenyl)-ethyl]-phenylamine as a dark brown oil; MS: m/e=232 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[CH:27]=[CH:26][C:9]([CH2:10][C:11]3[C:12]([CH:23]4[CH2:25][CH2:24]4)=[CH:13][C:14]([CH:21]=O)=[C:15]([CH:20]=3)[C:16](OC)=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.Cl.[NH2:29][C@@H:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[OH:35].C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[CH:23]1([C:12]2[CH:13]=[C:14]3[C:15](=[CH:20][C:11]=2[CH2:10][C:9]2[CH:26]=[CH:27][C:6]([N:1]4[CH:5]=[CH:4][CH:3]=[N:2]4)=[CH:7][CH:8]=2)[C:16](=[O:17])[N:29]([C@@H:30]2[CH2:34][CH2:33][CH2:32][C@H:31]2[OH:35])[CH2:21]3)[CH2:24][CH2:25]1
Reactant: N[C@@H]1CCC[C@H]1O
Reactant: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C2CC2)cc1C=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1c2cc(Cc3ccc(-n4cccn4)cc3)c(C3CC3)cc2CN1[C@@H]1CCC[C@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
A solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-4-cyclopropyl-2-formylbenzoate (0.11 g), trans-2-aminocyclopentanol hydrochloride (0.04 g), triethylamine (0.04 mL) and anhydrous magnesium sulfate (0.07 g) in THF (2.20 mL) was stirred at room temperature for 5 hr. The insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was diluted with methanol (2.20 mL) and THF (2.20 mL), sodium triacetoxyborohydride (0.13 g) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.06 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:53][C:54]2[CH:59]=[CH:58][C:57]([CH2:60][CH3:61])=[CH:56][CH:55]=2)=[CH:4][C:5]([C@:9]2([CH2:48][C:49]3([CH3:52])[CH2:51][O:50]3)[C@H:14]([O:15][CH2:16]C3C=CC=CC=3)[C@@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:12]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@@H:11]([CH2:39][O:40][CH2:41]C3C=CC=CC=3)[O:10]2)=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:16]([O:15][C@@H:14]1[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@H:12]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@@H:11]([CH2:39][O:40][CH2:41][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:10][C@:9]21[C:5]1[C:6](=[CH:7][C:2]([Cl:1])=[C:3]([CH2:53][C:54]3[CH:55]=[CH:56][C:57]([CH2:60][CH3:61])=[CH:58][CH:59]=3)[CH:4]=1)[O:8][C:49]([CH2:51][OH:50])([CH3:52])[CH2:48]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccc(Cc2cc([C@@]3(CC4(C)CO4)O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)cc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccc(Cc2cc3c(cc2Cl)OC(C)(CO)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Temperature: 70 °C
Yield: 137 %

Procedure:
A mixture of 50 (19 mg, 22.6 μmol) and potassium carbonate (30 mg, 226 μmol) in DMF (2 mL) was heated to 70° C. for 2 h in a closed vial. LCMS indicated a complete conversion to a less polar product. The mixture was evaporated, and the residue was separated between water and DCM. The organic phase was dried (Na2SO4), filtered, and evaporated. The residue was purified by preparatory TLC, developed with 15% EtOAc in petroleum ether to give 51 (13 mg, 68% yield). 1H NMR (300 MHz, CDCl3) δ 7.09-7.31 (m, 19H), 6.93-7.01 (m, 4H), 6.90 (s, 1H), 6.80-6.84 (m, 2H), 4.73-4.86 (m, 3H), 4.29-4.55 (m, 3H), 4.28 (d, J=10.8 Hz, 1H), 4.09 (d, J=15.0 Hz, 1H), 4.02 (d, J=8.7 Hz, 1H), 3.69-3.93 (m, 7H), 3.17-3.38 (m, 3H), 2.49-2.59 (m, 3H), 2.20 (d, J=15.6 Hz, 1H), 1.46 (s, 3H), 1.14 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:8][CH:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][Cl:11].S(=O)(=O)(O)O>C(Cl)(Cl)Cl>[CH2:1]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH:9]([CH3:8])[CH2:10][Cl:11])=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: C=CCCCCC
Reactant: CC(CCl)Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CCCCCCCc1ccc(CC(C)CCl)cc1
Reaction time: 14 h
Yield: 75 %

Procedure:
25 parts by weight of hept-1-ene are added dropwise at 10° C. to a mixture of 42 parts by weight of 2-methyl-3-phenylpropyl chloride and 20 parts by weight of 96% strength sulfuric acid. Stirring is continued at room temperature for 14 hours. The crude product is dissolved in CHCl3, and the solution is washed with ice water, dried over Na2CO3 and distilled. 50 parts by weight of 3-(4-heptylphenyl)-2-methyl-propyl chloride are obtained; boiling point 114°-7° C./0.1 mm Hg, yield 75% (based on 2-methyl-3-phenylpropyl chloride).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([SH:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=1>CN(C=O)C>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([S:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][N:2]=[CH:1]3)=[N:20][CH:21]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Sc1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Sc2cccc3cnccc23)nc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
According to the method in Example 10, a mixture of 5-isoquinolinethiol 1.12 g (6.9 mmol), DMF 20 ml, potassium carbonate 1.92 g (13.9 mmol) and 2-chloro-5-nitropyridine 1.00 g (6.3 mmol) was stirred at 100° C. for 2 hours, and 5-[(5-nitro-2-pyridyl)-sulfanyl)isoquinoline 1.40 g (78.4%) was obtained.
Reaction SMILES: O=O.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[C:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1>CO.[Ru]>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C@H:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1
Reactant: CC(C)=C(C(=O)O)c1ccc(F)cc1
Agent: [Ru]
Agent: O=O
Solvent: CO
Product: CC(C)[C@H](C(=O)O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.5 %

Procedure:
Ruthenium-catalyzed hydrogenation. -- A catalyst solution was prepared in a glove box (O2 content <1 ppm) by dissolving 0.418 g (0.544 mmol) of Ru(OAc)2 [(R)-BlPHEMP] in 100 ml of methanol and stirring at RT for 10 minutes. Then, 211.2 g (1.0875 mol) of 2-(p-fluorophenyl)-3-methylcrotonic acid and 700 ml of methanol were placed in a 2 l autoclave and the catalyst solution prepared above was added. The autoclave was sealed and the hydrogenation was carried out while stirring at 10° and under a pressure of 150-180 bar. The conversion was 100% after 24 hours. The hydrogenation solution was evaporated at 50°/200 mbar and the residue was distilled at 108-110°/ 0.01 mbar. There were obtained 208.1 g (97.5%) of (S)-2-(p-fluorophenyl)-3-methylbutyric acid as a colorless oil which solidified at RT; m.p. 53-56°; 96.6% ee.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:25][CH2:24][N:23]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)[C:22]3=[O:34])[CH2:17][CH:16]2O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(S(F)(F)[F:42])CC>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:25][CH2:24][N:23]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)[C:22]3=[O:34])[CH2:17][C@@H:16]2[F:42])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1ccc(CN2CCC(N3CCC(c4ccc(OCc5ccccc5)cc4)C(O)C3)C2=O)cc1
Solvent: ClCCl
Product: Cc1ccc(CN2CCC(N3CC[C@H](c4ccc(OCc5ccccc5)cc4)[C@@H](F)C3)C2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
A solution of 3-(-4-(4-(benzyloxy)phenyl)-3-hydroxypiperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (382 mg, 0.81 mmol) in DCM (5 mL) cooled to 0° C. was treated dropwise with DAST (0.32 mL, 2.4 mmol) over 3 min. The reaction mixture was then allowed to warm to rt and was stirred for 2 h. The reaction was then quenched with 50 mL of 10% aqueous sodium bicarbonate solution and extracted 4 times with 40 mL of DCM. The combined organic layers were washed with 50 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to yield 382 mg of 3-((3R,4R)-4-(4-(benzyloxy)phenyl)-3-fluoropiperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one as a mixture of two diastereomers and rearrangement products which was used without further purification. LCMS (method J) (main component of a mixture) RT 0.9 min, m/z 473 (M+H+).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=1.[NH2:20][C:21]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:24][NH:23][N:22]=1>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:22]3[N:23]=[CH:24][C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[C:21]3[N:20]=2)=[CH:5][CH:4]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)cc1
Reactant: Nc1n[nH]cc1-c1ccccn1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(-c4ccccn4)c3n2)cc1
Yield: 71 %

Procedure:
Reaction of 1-(4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (142 mg, 0.5 mmol), prepared from commercially available 3,4-dichloro-acetophenone according to general procedure A, and 3-amino-4-(2-pyridinyl)-pyrazole [CAS No. 493038-87-2; prepared from 2-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (145 mg, 71%). MS (ISP) 409.2 [(M+H)+]; mp 202° C.
Reaction SMILES: CC1(C)[O:7][C:6]2[CH:8]=[CH:9][C:10]([CH:12]([OH:32])[CH2:13][NH:14][C@H:15]3[CH2:24][CH2:23][C:22]4[C:17](=[CH:18][C:19]([O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:20][CH:21]=4)[CH2:16]3)=[CH:11][C:5]=2[CH2:4][O:3]1.Cl.C(=O)(O)[O-].[Na+]>COCCOC>[OH:32][CH:12]([C:10]1[CH:9]=[CH:8][C:6]([OH:7])=[C:5]([CH2:4][OH:3])[CH:11]=1)[CH2:13][NH:14][C@H:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:20][CH:21]=2)[CH2:16]1
Reactant: CCOC(=O)COc1ccc2c(c1)C[C@@H](NCC(O)c1ccc3c(c1)COC(C)(C)O3)CC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)COc1ccc2c(c1)C[C@@H](NCC(O)c1ccc(O)c(CO)c1)CC2
Temperature: 0 °C
Yield: 68.6 %

Procedure:
Ethyl 2-[(2S)-2-[[(2RS)-2-(2,2-dimethylbenzo[1,2-d]-1,3-dioxan-6-yl)-2-hydroxyethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy]acetate (11.5 g) was suspended in 75 ml of 1,2-dimethoxyethane, 252 ml of 1 N hydrochloric acid was added dropwise to the suspension while keeping the temperature at 20° C. or lower, and the resulting mixture was subjected to 30 minutes of reaction at room temperature. Then, 23.3 g of sodium bicarbonate was added with stirring at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous saturated sodium bicarbonate solution and brine and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel medium pressure liquid column chromatography (eluent: ethyl acetate/ethanol=5/1) to give 7.2 g of amorphous ethyl 2-[(2S)-2-[[(2RS)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl]-amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy]acetate.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[CH2:5]([O:7][C:8]([CH3:18])([CH3:17])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:16])[CH2:13][CH:14]=O)[CH3:6]>CN(C)C=O>[CH2:5]([O:7][C:8]([CH3:18])([CH3:17])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:16])[CH2:13][CH:14]=[CH:9][C:8]([CH3:17])=[CH:3][C:2]([O:7][CH2:5][CH3:6])=[O:1])[CH3:6]
Reactant: CC[O-]
Reactant: CCOC(C)(C)CCCC(C)CC=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(C)C=CCC(C)CCCC(C)(C)OCC
Reaction time: 1.5 h

Procedure:
Sodium ethoxide (prepared from 0.2 g. of sodium and 12 ml. of ethanol) is slowly added to a mixture of 1.1 g. of 7-ethoxy-3,7-dimethyloctan-1-al, diethyl 3-ethoxycarbonyl-2-methylprop-2-enyl phosphonate and 50 ml. of dimethylformamide, with stirring, under nitrogen, at 0°. The reaction is stirred for 1.5 hours after addition is complete and then worked up by extraction with ether to yield ethyl 11-ethoxy-3,7,11-trimethyldodeca-2,4-dienoate, mostly trans(2), trans(4), which can be further purified by chromatography and distillation.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:35])[C:16]([N:18]2[CH2:23][CH2:22][N:21]3[C:24](=[O:27])[CH2:25][CH2:26][C@H:20]3[C@@H:19]2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:48](Cl)(=[O:51])[O:49][CH3:50]>C1COCC1>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:35])[C:16]([N:18]2[CH2:23][CH2:22][N:21]3[C:24](=[O:27])[C:25]([C:48]([O:49][CH3:50])=[O:51])([C:48]([O:49][CH3:50])=[O:51])[CH2:26][C@H:20]3[C@@H:19]2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Cc1ccccc1[C@H]1[C@@H]2CCC(=O)N2CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(C(=O)OC)C[C@H]2[C@H](c3ccccc3C)N(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCN2C1=O
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
To a solution of (1S,8aS)-N-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethyl)-N-methyl-6-oxo-1-o-tolylhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxamide (300 mg, 0.57 mmol) in anhydrous THF (20 mL) under N2 atmosphere was added LiHMDS (2.3 mL, 1 M in THF, 2.3 mmol) at −60° C. The reaction was stirred for 30 min followed by addition of methyl carbonochloridate (134 mg, 1.43 mmol). After stirring for another 3 h at room temperature. The reaction was quenched with water at 0° C. and then extracted with EA (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4 and then concentrated in high vacuum. The residue was purified by silica gel chromatography (DCM/MeOH=20/1 to 10/1) to give the title compound (166 mg, yield: 45.3%); m/z (ES+): 644 [M+H]+.