Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH2:2]([O:9][C:10]1[C:15]([CH2:16][CH2:17][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:14]([F:37])[C:13]([F:38])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:39]([O:43][C@@H:44]([C:50]1[C:51]([CH3:93])=[N:52][C:53]2[N:54]([N:88]=[C:89]([CH:91]=O)[CH:90]=2)[C:55]=1[N:56]1[CH2:61][CH2:60][C:59]([O:63][CH2:64][CH2:65][CH2:66][CH2:67][C@H:68]([O:70][Si:71]([C:84]([CH3:87])([CH3:86])[CH3:85])([C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)[C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[CH3:69])([CH3:62])[CH2:58][CH2:57]1)[C:45]([O:47][CH2:48][CH3:49])=[O:46])([CH3:42])([CH3:41])[CH3:40]>C1COCC1>[CH2:2]([O:9][C:10]1[C:15]([CH2:16][CH:17]=[CH:91][C:89]2[CH:90]=[C:53]3[N:52]=[C:51]([CH3:93])[C:50]([C@H:44]([O:43][C:39]([CH3:42])([CH3:41])[CH3:40])[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[C:55]([N:56]4[CH2:61][CH2:60][C:59]([O:63][CH2:64][CH2:65][CH2:66][CH2:67][C@H:68]([O:70][Si:71]([C:84]([CH3:85])([CH3:86])[CH3:87])([C:72]5[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=5)[C:78]5[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=5)[CH3:69])([CH3:62])[CH2:58][CH2:57]4)[N:54]3[N:88]=2)=[C:14]([F:37])[C:13]([F:38])=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Fc1ccc(OCc2ccccc2)c(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1F
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=O)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: [I-]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=CCc3c(OCc4ccccc4)ccc(F)c3F)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 5 h
Yield: 50.2 %

Procedure:
To a suspension of (6-(benzyloxy)-2,3-difluorophenethyl)triphenylphosphonium, iodide salt (217 mg, 0.340 mmol) in THF (5 ml) at 0° C. was added n-Buli (0.213 ml, 0.340 mmol) and the resulting mixture was heated at 60° C. for 1 h. The mixture was then cooled to rt and (S)-ethyl 2-(tert-butoxy)-2-(7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-2-formyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (175 mg, 0.227 mmol) dissolved in THF (5 ml) was added dropwise and the mixture was stirred rt for 5 h. The reaction was quenched with water and the product was extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage; 0%-30% EtOAc/hexane) to afford (S)-ethyl 2-(2-(3-(6-(benzyloxy)-2,3-difluorophenyl)prop-1-en-1-yl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (114 mg, 0.114 mmol, 50% yield) as mixture of E and Z isomers. LCMS (M+H)=1001.8.
Reaction SMILES: CO[C:3](=[O:24])[C:4]([C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[CH:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[CH3:21])[C:14]([C:4]1[C:3](=[O:24])[C:12]2[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:23]
Reactant: COC(=O)C(=CNc1cccc(F)c1)C(=O)c1ccc(C)c(C)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1ccc(C(=O)c2c[nH]c3cc(F)ccc3c2=O)cc1C
Yield: 79.8 %

Procedure:
Compound 3k was prepared following the procedure described in Step 2 of Example 5 using 1.19 g (3.64 mmol) of 2-(3,4-Dimethyl-benzoyl)-3-(3-fluoro-phenylamino)-acrylic acid methyl ester 2h and 30 mL of diphenyl ether to yield 0.858 g of 3-(3,4-dimethyl-benzoyl)-7-fluoro-1H-quinolin-4-one 3k as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH:21]=[O:22].C[Li].[CH3:25]COCC>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH:21]([OH:22])[CH3:25]
Reactant: CSc1ccc(/C=C2/C(C)=C(C=O)c3cc(F)ccc32)cc1
Reactant: CCOCC
Agent: [Li]C
Solvent: C1CCOC1
Product: CSc1ccc(/C=C2/C(C)=C(C(C)O)c3cc(F)ccc32)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of aldehyde from Example 9, Step 2 (1.5 g, 4.8 mmol) in THF (25 mL) at 0° C. there was added methyl lithium (1.4 M) in ether (3.8 mL, 5.3 mmol) and the mixture stirred at 0° C. for 45 minutes; it was then quenched with saturated aqueous ammonium chloride and extracted with ether to afford crude material which was chromatographed on silica gel to provide the title compound as a reddish syrup.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([C:24]([OH:26])=[O:25])[CH2:18][C:19]1[N:23]=[CH:22][NH:21][CH:20]=1>>[C:24]([CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH2:18][C:19]1[N:23]=[CH:22][NH:21][CH:20]=1)([OH:26])=[O:25]
Reactant: NC(Cc1c[nH]cn1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)c1cc2ccccc2nc1NC(Cc1c[nH]cn1)C(=O)O
Yield: 33 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with DL-histidine to provide the title compound in 33% yield as yellow needles (recrystallization from DMF/water).
Reaction SMILES: [C:1]([C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=1)#[CH:2].C([Li])CCC.[CH2:14]=[O:15]>>[C:3]1([C:1]#[C:2][CH2:14][OH:15])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=1
Reactant: C#CC1=CCCCC1
Reactant: C=O
Agent: [Li]CCCC
Product: OCC#CC1=CCCCC1
Yield: 82 %

Procedure:
First, the appropriate alkynyl alcohols are synthesized. To produce the particular compositions disclosed herein, 1-Ethynylcyclohexene, for example, is deprotonated with butyl lithium and then condensed with paraformaldehyde (Brandsma and Verkruijsse). By this process, 3-Cyclohexenyl-2-propyn-1-ol was produced in 82% yield (Baudouy, et al.). This compound had been reported previously without complete spectroscopic data (Baudouy). 1-Ethynylcyclohexene (3.00 g, 28.6 mmol) was dissolved in diethyl ether (125 mL) and cooled to −78° C. 2.5 M n-butyllithium in hexane (12.4 mL, 31.1 mmol) was added dropwise. The solution was allowed to stir at −78° C. for 1.5 h and then paraformaldehyde (1.70 g, 56.5 mmol) was added. The reaction mixture was allowed to warm to 25° C. overnight. The mixture was poured into sat. NH4Cl solution (125 mL) and then extracted with diethyl ether (3×50 mL). The ether extracts were dried with MgSO4 and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel using 1:1 diethyl ether/pentane to yield a light yellow oil (3.17g, 23.3 mmol, 82.4%). 1H NMR (CDCl3): 6.09 (m, 1 H), 4.35 (s, 2 H), 2.07 (m, 4 H), 1.62-1.57 (m, 5 H). EI HRMS (m/e) called for (M+)(C9H12O) 136.0888, found 136.0894.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:4]=1[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([F:42])=[C:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH:17]3[CH2:21][NH:22][C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:14]=2)[C:9](=[O:43])[C:8]([C:44]([O:46]CC)=[O:45])=[CH:7]1.[OH-].[Li+].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:4]=1[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([F:42])=[C:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH:17]3[CH2:21][NH:22][C:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:14]=2)[C:9](=[O:43])[C:8]([C:44]([OH:46])=[O:45])=[CH:7]1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(N3CCCC3CNC(c3ccccc3)(c3ccccc3)c3ccccc3)c(F)cc2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(Cn2cc(C(=O)O)c(=O)c3cc(F)c(N4CCCC4CNC(c4ccccc4)(c4ccccc4)c4ccccc4)nc32)c(OC)c1

Procedure:
A mixture of EXAMPLE 7B (1.7 g) and 0.1M lithium hydroxide (40 mL) in ethanol (80 mL) was stirred for 18 hours, adjusted to pH 5 with 1M hydrochloric acid, and filtered.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([Sn](C)(C)C)=[N:14][N:13](COCC[Si](C)(C)C)[C:10]3=[CH:11][N:12]=2)[CH:2]=1.Br[C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][N:37]=1)[C:32]([NH2:34])=[O:33]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([C:29]4[CH:30]=[C:31]([CH:35]=[CH:36][N:37]=4)[C:32]([NH2:34])=[O:33])=[N:14][NH:13][C:10]3=[CH:11][N:12]=2)[CH:2]=1
Reactant: NC(=O)c1ccnc(Br)c1
Reactant: C[Si](C)(C)CCOCn1nc([Sn](C)(C)C)c2cc(-c3cccnc3)ncc21
Product: NC(=O)c1ccnc(-c2n[nH]c3cnc(-c4cccnc4)cc23)c1
Yield: 21 %

Procedure:
Following the Stille coupling procedure of Example 299, 5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(trimethylstannyl)-1H-pyrazolo[3,4-c]pyridine and 2-bromoisonicotinamide were reacted. The product was deprotected by the procedure of Example 225 and purified via silica gel chromatography using a gradient of methanol in dichloromethane to afford 10 mg (21%) of 302 over two steps. ESI MS m/z 317.1 (M+1). 1H NMR (400 MHz, DMSO): 14.16 (s, 1H), 9.28 (d, J=12.0 Hz, 2H), 8.96 (s, 1H), 8.94 (d, J=5.1 Hz, 1H), 8.62 (d, J=5.3 Hz, 2H), 8.45 (d, J=8.0 Hz, 1H), 8.40 (s, 1H), 7.80 (d, J=5.1 Hz, 1H), 7.76 (s, 1H), 7.55 (dd, J=8.0, 4.7 Hz, 1H)
Reaction SMILES: [C:1]([NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:20])[C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Cl[C:22]1C=CC=CC=1.[OH-].[K+].COS(=O)(=O)OC>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:1]([N:4]([CH3:22])[C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:20])[C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Clc1ccccc1
Reactant: CC(=O)Nc1cccc2c1C(=O)c1ccccc1C2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CC(=O)N(C)c1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A mixture of 1-acetylaminoanthraquinone (purity 99.9%, 26.5 g), monochlorobenzene (320 g), tetra-n-butyl ammonium bromide (0.3 g) and 96% potassium hydroxide (12.0 g) was stirred for 30 minutes while being maintained at 50° C. Then, dimethylsulfuric acid (25.2 g) was dropped at 50° C. over 2 hours. The solution was stirred at 50° C. for 30 minutes, 60° C. for 2 hours and 70° C. for 4 hours, successively. After water (150 g) was added, the solution was stirred for 1 hour while being maintained at 50° C. Then, the same procedure as in Example 3 was carried out to obtain N-acetyl-1-methylaminoanthraquinone (27.9 g, purity 93.6%, yield 93.6%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].Cl[C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=2)[C:10]([C:24]([C:26]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=2)=[O:25])=[CH:9][N:8]=1.O>CN(C)C=O>[CH3:1][N:2]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=2)[C:10]([C:24]([C:26]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=2)=[O:25])=[CH:9][N:8]=1)[CH2:3][CH2:4][OH:5]
Reactant: COc1ccc(CNc2nc(Cl)ncc2C(=O)c2cc(OC)c(OC)c(OC)c2)cc1Cl
Reactant: CNCCO
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CNc2nc(N(C)CCO)ncc2C(=O)c2cc(OC)c(OC)c(OC)c2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
A solution of 2-methylaminoethanol 100 mg in dimethylformamide 1 ml is added at room temperature to a solution of 2-chloro-5-(3,4,5-trimethoxyphenylcarbonyl)-4-(3-chloro-4-methoxybenzylamino) pyrimidine (120 mg) prepared in above Example 1-(3) in dimethylformamide (1 ml). The mixture is stirred at room temperature for 1 hour and thereto is added water 50 ml. The mixture is extracted with ethyl acetate-chloroform and the extract is subjected to silica gel chromatography (solvent:chloroform-methanol 5%) to give 2-(N-methyl-N-(2-hydroxyethyl)amino)-5-(3,4,5-trimethoxyphenylcarbonyl)-4-(3-chloro-4-methoxybenzylamino)pyrimidine 110 mg as white crystals. mp 166.5-168° C.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[OH:14][C@@H:15]1[C@@H:34]([N:35]2[CH2:40][CH2:39][O:38][C:37]([CH3:42])([CH3:41])[CH2:36]2)[CH2:33][C@@:32]2([CH3:43])[C@@H:17]([CH2:18][CH2:19][C@@H:20]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:44])[C@H:21]3[CH2:22][CH2:23][C@@H:24]2[C:25](=[O:27])[CH3:26])[CH2:16]1>CO>[OH:14][C@@H:15]1[C@@H:34]([N:35]2[CH2:40][CH2:39][O:38][C:37]([CH3:42])([CH3:41])[CH2:36]2)[CH2:33][C@@:32]2([CH3:43])[C@@H:17]([CH2:18][CH2:19][C@@H:20]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:44])[C@H:21]3[CH2:22][CH2:23][C@@H:24]2[C:25](=[O:27])[CH3:26])[CH2:16]1.[OH:4][C:3]([C:5]([O-:7])=[O:6])([CH2:8][C:9]([O-:11])=[O:10])[CH2:2][C:1]([O-:13])=[O:12]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](N5CCOC(C)(C)C5)C[C@]4(C)[C@H]3CC[C@]12C
Solvent: CO
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
A solution of citric acid (141 mg) in methanol (20 ml) was added to a solution of the 2-(2,2-dimethyl-4-morpholinyl) compound of Example 12 (290 mg) in methanol (20 ml). The solvent was removed under reduced pressure to afford (2β,3α,5α)-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)-pregnan-20-one 2-hydroxy-1,2,3-propanetricarboxylate (1:1) salt (430 mg). [α]D +99.5° (c 1.0).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[N:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH:15]3[CH2:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[C:22]1[CH:23]=[CH:24][C:25]([Cl:30])=[C:26]([O:28][CH3:29])[CH:27]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:30][C:25]1[CH:24]=[CH:23][C:22]([N:19]2[CH2:18][CH2:17][N:16]3[CH:11]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH2:12][CH2:13][CH2:14][CH:15]3[CH2:20]2)=[CH:27][C:26]=1[O:28][CH3:29]
Reactant: COc1ccc(C2CCCC3CNCCN32)cc1OC
Reactant: COc1cc(Br)ccc1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc(N2CCN3C(CCCC3c3ccc(OC)c(OC)c3)C2)ccc1Cl
Temperature: 80 °C

Procedure:
A quantity of 0.85 g (3.0 mmoles, 1 eq) of 6-(3,4-dimethoxy-phenyl)-octahydro pyrido[1,2-a]pyrazine and 0.76 g (3.4 mmoles, 1.1 eq) of 5-bromo-2-chloro-anisole is dissolved in 25 mL of anhydrous toluene, and the solution is purged with N2 for 20 min. To the solution is added 0.18 g (0.30 mmoles, 0.10 eq) of rac-2,2′-Bis(diphenyl-phosphino)-1,1′-binapphtyl, 0.14 g (0.15 mmole, 0.05 eq) of Tris(dibenzylideneacetone)-dipalladium(0) and 0.52 g (4.6 mmoles, 1.5 eq) of Potassium tert-butoxide in order. The mixture is heated at 80° C. under N2 overnight. After it is cooled down, the reaction is filtered through Celite. The organic solution is washed with 1N NaOH and brine, dried over Na2SO4 and concentrated. The residue is purified by flash chromatography on silica gel eluted with 50:1 dichloromethane:methanol to afford 2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxyphenyl)-octahydro-pyrido[1,2-a]pyrazine (compound 5) as a brownish stick solid (0.85 g, 68%). Analysis: 1H NMR (300 MHz, CDCl3): 7.16 (1H, d), 6.80 (3H, m), 6.40 (2H, m), 3.88 (3H, s), 3.86 (3H, s), 3.85 (3H, s), 3.40 (2H, m), 2.95 (1H, m), 2.70 (3H, m), 2.30 (1H, m), 2.00 (1H, m), 1.82-1.40 (6H, m). MS (LC-MS): Calculated for C23H29ClN2O3 416.94, found 417.23 (M+1). X. (6R,9S) 2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-octahydro-pyrrolo[1,2-a]pyrazin via Scheme J
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[N:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O-:14])=O>[Pt]=O.C(O)C>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1=[O:14]
Reactant: O=C([O-])CCCCN=Cc1ccc[nH]1
Agent: O=[Pt]
Solvent: CCO
Product: O=C1CCCCN1Cc1ccc[nH]1
Yield: 139.5 %

Procedure:
A mixture of 150 g of 5-[[(1H-pyrrol-2-yl)methylen]amino]pentanoate and 120 g of ethanol was hydrogenated at 3.105Pa and at ambient temperature with 3.3 g of platinum oxide. After the calculated amount of hydrogen was consumed, the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in dichloromethane and the organic phase was washed three times with a sodium hydroxide 3N solution. The product was distilled at 13.30 Pa (bp. 100-130° C. The residue was crystallized from cyclohexane and hexane. The product was filtered off and dried, yielding 193 g (100%) of 1-(1H-pyrrol-2-ylmethyl)-2-piperidone; mp. 105.8° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:4]=1[C:5](=[O:15])[C:6](=[O:14])[NH:7]2.O1C2=CC3C(=O)C(=O)NC=3C=C2OCC1.Br[CH:32]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.BrCC1OC(C(F)(F)F)=CC=1>>[C:33]1([CH:32]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:7]2[C:8]3[C:4](=[C:3]([O:2][CH3:1])[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=3)[C:5](=[O:15])[C:6]2=[O:14])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: COc1cc2c(c(OC)c1)C(=O)C(=O)N2
Agent: FC(F)(F)c1ccc(CBr)o1
Agent: O=C1Nc2cc3c(cc2C1=O)OCCO3
Product: COc1cc(OC)c2c(c1)N(C(c1ccccc1)c1ccccc1)C(=O)C2=O

Procedure:
Following the procedure as described in PREPARATION 26A and making non-critical variations using 4,6-dimethoxy-1H-indole-2,3-dione to replace 2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione, and bromodiphenylmethane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 1-(diphenylmethyl)-4,6-dimethoxy-1H-indole-2,3-dione was obtained (90%): 1H NMR (300 MHz, DMSO-d6) δ7.49-7.19 (m, 10H), 6.72 (s, 1H), 6.21 (d, J=1.5 Hz, 1H), 5.87 (d, J=1.5 Hz, 1H), 3.86 (s, 3H), 3.70 (s, 3H).
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].[I-:10].[Na+].[OH-].[Na+].Cl[O-].[Na+].Cl.S([O-])([O-])=O.[Na+].[Na+]>CO>[I:10][C:6]1[CH:5]=[CH:4][C:2]([OH:3])=[C:1]([O:8][CH3:9])[CH:7]=1
Reactant: [I-]
Reactant: COc1ccccc1O
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(I)ccc1O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
4-Iodo-2-methoxyphenol was prepared according to the method described by K. J. Edgar and N. Falling, J. Org. Chem. 55, 5287 (1990). Guaiacol (50.0 g, 402 mmol), sodium iodide (60.5 g, 402 mmol) was dissolved in methanol (800 ml) and cooled to 0° C., and sodium hydroxide (16.0 g, 402 mmol) was added at such a rate that the temperature did not exceed 5° C. An aqueous solution of sodium hypochlorite (750 ml, 7.2% solution, 402 mmol) was added during 45 min. The temperature was not allowed to exceed 0° C. After completed addition it was stirred for another 10 minutes at 0° C. First aqueous hydrochloric acid (100 ml, 4 M solution) and then sodium sulfite (200 ml saturated aqueous solution) was added. The product was extracted with ether was followed by drying over magnesium sulfate. Evaporation of the solvent was followed by distillation and the fraction at 105-106° C. at 0.1 mm Hg was collected. Yield 55 g, 54%.
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[OH:24][C:25]([C:36]([O:38][CH2:39][CH3:40])=[O:37])([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26][C:27](O)=[O:28].C(Cl)CCl.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl.C(OCC)(=O)C>[OH:1][C:2]1([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)=[CH:12][CH:13]=2)[CH2:7][CH2:6][CH2:5][N:4]([C:27]([CH2:26][C:25]([OH:24])([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:28])[CH2:3]1
Reactant: OC1(c2ccc(-c3ccc4ccccc4c3)cc2)CCCNC1
Reactant: CCOC(=O)CC(O)(CC(=O)O)C(=O)OCC
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(O)(CC(=O)N1CCCC(O)(c2ccc(-c3ccc4ccccc4c3)cc2)C1)C(=O)OCC
Yield: 74.7 %

Procedure:
3-Hydroxy-3-(4-naphth-2-ylphenyl)piperidine (Preparation 7, 1.24 g, 4.09 mmol), 3-hydroxy-3, 4-bis(ethoxycarbonyl)butanoic acid (Preparation 1, 1.01 g, 4.09 mmol), EDC, (0.785 g, 4.09 mmol), 1-hydroxybenzotriazole (HOBT, 0.055 g, 2.05 mmol) and triethylamine (570 μL, 8.18 mmol) in THF or methylene chloride (150 mL) is stirred under argon overnight. The reaction mixture is diluted with CH2Cl2 or ethyl acetate and washed with water or 5% aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and brine. The organic layer is then dried over MgSO4 or Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography (using 60% ethyl acetate in hexane in this instance) to yield the diester intermediate, ethyl 4-[3-hydroxy-3-(4-naphth-2-yl-phenyl)piperidin-1-ylcarbonyl]-3-hydroxy-3-ethoxycarbonylbutanoate (1.63 g, 75%) as a foam solid.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([CH:21]=O)[C@@H:17]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[CH2:33]([O:35][C:36]([C@@H:38]1[CH2:43][CH2:42][CH2:41][NH:40][CH2:39]1)=[O:37])[CH3:34].CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([CH2:21][N:40]3[CH2:41][CH2:42][CH2:43][C@@H:38]([C:36]([O:35][CH2:33][CH3:34])=[O:37])[CH2:39]3)[C@@H:17]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: C[C@@H](O[C@H]1CC[C@@H](C=O)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H]1CCCN(C[C@@H]2CC[C@H](O[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H]2c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81 %

Procedure:
To a solution of 9.8 g (22 mmole) of 1-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(formyl)cyclopentane from Step A in 100 mL of 1,2-dichloroethane was added 8.7 g (28 mmole) of (R)-3-ethoxycarbonylpiperidine hydrochloride and 4.9 mL (28 mmole) of DIPEA. After stirring at room temperature for 10 minutes, 9.2 g (44 mmole) of sodium triacetoxyborohydride was added. The reaction was stirred for 16 hours. The reaction was quenched with sat'd sodium bicarbonate and was extracted twice with methylene chloride. The organic layers were each washed with a portion of brine, dried over sodium sulfate, combined and evaporated. The residue was purified by prep LC (20-30% ethyl acetate/hexanes) to give 10.5 g of title compound.