Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([NH2:14])[C:12]=3[N:11]=[CH:10]2)[O:8][C@H:5]([CH2:6][OH:7])[C@H:3]2[O:4][C@@H:2]12.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].O>N1C=CC=CC=1>[Si:19]([O:7][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([NH2:14])[C:12]=3[N:11]=[CH:10]2)[C@@H:2]2[O:4][C@H:3]12)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@H]2O[C@H]21
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2O[C@@H]21
Reaction time: 3.5 h
Yield: 96 %

Procedure:
To a stirred solution of 9.5 g (38.1 mmol) of 2',3'-anhydroadenosine (Robins, M. J.; Hansske, F.; Low, N. H.; Park, J. I. Tetrahedron Lett. 1984, 367-370) in 114 mL of pyridine was added 11.5 g (76.2 mmol) of t-butyldimethylsilyl chloride. After 3.5 h at room temperature, an additional 5.75 g (38.1 mmol) of t-butyldimethylsilyl chloride was added. After a total of 4.25 h, the reaction mixture was diluted into 2 L of water and extracted with 3×500 mL of dichloromethane. The combined dichloromethane extracts were washed with one liter of saturated aqueous sodium bicarbonate, with 3×500 mL of water, and then dried over magnesium sulfate. Concentration under reduced pressure afforded 13.3 g of 5'-O-(t-butyldimethylsilyl)-2',3'-anhydroadenosine. To a stirred solution of 2.0 g (5.50 mmol) of 5'-O-(t-butyldimethylsilyl)-2',3'-anhydroadenosine in 55 mL of THF at 0° C. was added 22 mL (22 mmol) of a 1M solution of lithium triethyl borohydride in THF. The reaction mixture was then allowed to warm to room temperature. After 3 hours, the reaction mixture was recooled to 0° C. and then carefully treated with 4.0 mL of 5% aqueous acetic acid. The resulting mixture was diluted with 150 mL of EtOAc, washed with 3×100 mL of saturated aqueous NaCl, dried over magnesium sulfate, concentrated under reduced pressure, and then coevaportated with three portions of chloroform. Chromatography of the residue on silica gel with a 100:0 to 97:3 chloroform/methanol gradient afforded 1.8 g (90%) of the title compound: colorless glass; Rf =0.10 (silica gel 60 F-254, 0.25 mm, E. Merck (SG), 95:5 CHCl3 :MeOH); [α]D23 -47.8° (c 2.47, CHCl3); IR (CDCl3) 3480, 3415, 3320, 3165, 3125, 2960, 2935, 2860, 1635, 1595, 1575, 1470, 1415, 1330, 1290, 1255, 1210, 1135, 1090, 995 cm-1 ; 1H NMR (300 MHz, CDCl3, TMS=0.00 ppm) δ 0.08, 0.09 (2s, 6H, (CH3)2Si), 0.88 (s, 9H, (CH3)3CSi), 2.10 (ddd, 1H, J=13.5 Hz, J'=6.5 Hz, J"=4.0 Hz, 3'-H), 2.34 (ddd, 1H, J=13.5 Hz, J'=7.5 Hz, J"=6.0 Hz, 3'-H), 3.74 (dd, 1H, J=12.0 Hz, J'=3.0 Hz, 5'-H), 4.05 (dd, 1H, J=12.0 Hz, J'=3.0 Hz), 4.62 (dddd, 1H, J=7.5 Hz, J'=6.5 Hz, J"=J"'=3.0 Hz, 4'-H), 4.70 (ddd, 1H, J=6.0 Hz, J'=4.0 Hz, J"=2.5 Hz, 2'-H), 5.88 (bs, 1H, OH), 6.01 (d, 1H, J=2.5 Hz, 1'-H), 6.15 (bs, 2H, NH2), 8.30, 8.33 (2 s, 2H, H-2, H-8); FAB MS, m/z 366 (M+H)+, 136.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]([OH:23])[CH2:14][CH2:15][CH:16]([CH2:20][CH2:21][CH3:22])[C:17]([O-:19])=O)[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:11])([F:10])[F:9].Cl.C(O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]2[O:23][C:17](=[O:19])[CH:16]([CH2:20][CH2:21][CH3:22])[CH2:15][CH2:14]2)[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: CCCC(CCC(O)c1cc(F)c(C(F)(F)F)c(Cl)c1)C(=O)[O-]
Agent: Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCC1CCC(c2cc(F)c(C(F)(F)F)c(Cl)c2)OC1=O
Reaction time: 3 h
Yield: 73.3 %

Procedure:
A solution of 12.0 g (31.2 mmol) of ethyl=5-(3-chloro-5-fluoro-4-trifluoromethylphenyl)-5-hydroxy-2-propylpentanoate [prepared by reacting 3-propyl-5-formylpentanoic acid with 3-chloro-5-fluoro-4-trifluromethylphenylmagnesium bromide], 25 ml of a concentrated hydrochloric acid, and 100 ml of ethanol was heated at 50° C. while being stirred for 3 hours. To the reaction solution was added 50 ml of toluene, and the organic layer thus obtained was washed with a diluted aqueous sodium bicarbonate solution thrice and water thrice, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure and the residue was subjected to silica gel chromatography (eluent: heptane/toluene=1/1) to obtain 7.7 g of a crude 6-(3-chloro-5-fluoro-4-trifluoromethylphenyl)-3-propyltetrahydro-2-pyrone. (Yield: 73.3%)
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([O:17]C)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:19]1[CH2:21][CH2:20]1.B(Br)(Br)Br.C(Cl)Cl>>[C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:19]1[CH2:21][CH2:20]1
Reactant: COc1cccc2c1cc(C1CC1)n2Cc1ccccc1-c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc2c1cc(C1CC1)n2Cc1ccccc1-c1ccccc1
Yield: 29.2 %

Procedure:
By the method used in Example 1, Part D, 1.25 g (3.7 mmol) of 1-([1,1′-biphenyl]-2-ylmethyl)-2-cyclopropyl-4-methoxyl-1H-indole was O-demethylated by treating it with 15 mL of 1M BBr3/CH2Cl2. The crude product was chromatographed on silica gel and eluted with 20% EtOAc/hexane to give 367 mg (29% yield) of 1-([1,1′-biphenyl]-2-ylmethyl)-2-cyclopropyl-4-hydroxy-1H-indole as an oil.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])[CH:15]=2)=[O:13])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C(C1C=CC(C(CCC)CCCCCCC(C2C3C(=CC=CC=3)N(CCCC(OCC)=O)C=2)=O)=CC=1)C(C)C>>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH:15]=2)=[O:13])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](C(=O)c2cn(CCCC(=O)OCC)c3ccccc23)CC1
Agent: CCCC(CCCCCCC(=O)c1cn(CCCC(=O)OCC)c2ccccc12)c1ccc(CC(C)C)cc1
Product: CCCCC[C@H]1CC[C@H](C(=O)c2cn(CCCC(=O)O)c3ccccc23)CC1

Procedure:
The procedure of Ex. 16 was repeated except that transethyl 4-[3-(4-pentylcyclohexylcarbonyl)-1-indolyl]butyrate obtained in Ex. 32 was used in place of ethyl 4-[3-[8-(4-isobutylphenyl) undecanoyl]-1-indolyl]butyrate to give trans-4-[3-(4-pentylcyclohexylcarbonyl)-1-indolyl]butyric acid.
Reaction SMILES: C([O:5][C:6](=[O:25])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][N:10]=1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[O:24]=[C:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH:16]=[CH:15][C:12]1[CH:13]=[CH:14][C:9]([CH:8]=[CH:7][C:6]([OH:25])=[O:5])=[N:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(C=CC(=O)c2ccccc2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C=Cc1ccc(C=CC(=O)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 155.5 %

Procedure:
3-[5-(3-oxo-3-phenyl-propenyl)-pyridin-2-yl]-acrylic acid tert-butyl ester (130 mg, 0.38 mmol) was dissolved in DCM (4 ml) and TFA (1 ml). The resulting solution was stirred for 4 h at room temperature and then the solvent was removed under vacuo. The resulting oil was crystallized from Et2O to give 165 mg of 3-[5-(3-oxo-3-phenyl-propenyl)-pyridin-2-yl]-acrylic acid as the trifluoroacetate salt.
Reaction SMILES: Br[C:2]1[C:3]([O:10][CH3:11])=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:12][N:13]1[CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=[N:14]1.C([O-])(O)=O.[Na+]>COCCOC.O>[CH3:9][O:8][C:5]1[N:4]=[C:3]([O:10][CH3:11])[C:2]([C:16]2[CH:15]=[N:14][N:13]([CH3:12])[CH:17]=2)=[CH:7][N:6]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1ncc(Br)c(OC)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ncc(-c2cnn(C)c2)c(OC)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5-bromo-2,4-bis(methyloxy)pyrimidine (commercially available from Aldrich, 500 mg, 2.283 mmol) was dissolved in 1,2-Dimethoxyethane (DME) (5 ml). Pd(Ph3)4 (132 mg, 0.114 mmol) was added and the reaction mixture was stirred at room temperature for 15 min. 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (commercially available from Maybridge, 997 mg, 4.79 mmol) and 1M/H2O sol. of NaHCO3 (5 ml, 5.00 mmol) were added. After 2 h stirring at 90° C., the reaction mixture was cooled at room temperature, diluted with water (5 ml) and extracted with DCM (3×10 ml). The obtained residue was purified by flash chromatography first eluting with cyclohexane/EtOAc 4:1 then with 1:2 cyclohexane/EtOAc. 483.7 mg of the title compound were obtained.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Br[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18]>CN(C=O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:6][CH:5]=1
Reactant: COCCOCCBr
Reactant: Oc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCCOc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a cooled (0° C.) suspension of dry NaH (0.512 g, 21.4 mmol) in anhydrous DMF (10 mL) under an Argon atmosphere, a solution of 4-bromophenol (3.11 g, 17.8 mmol) in anhydrous DMF (20 mL) was added dropwise over 2-3 min. The mixture was stirred at 0° C. for 10 min and then allowed to warm to rt over 30 min. To the resulting white suspension was added 1-bromo-2-(2-methoxyethoxy)ethane (2.66 mL, 19.6 mmol) dropwise over 2 min and the mixture was stirred at rt for 30 min and then at 65° C. for 1.5 h. After cooling to rt, the mixture was concentrated under reduced pressure to an oily suspension, diluted with brine (80 mL), and the mixture was extracted with EtOAc (3×60 mL). The combined extracts were washed with brine (2×25 mL), dried over Na2SO4, filtered, and concentrated to give compound 85a as a mobile, pale amber-colored oil, used in the following reaction without further purification. Mass spectrum (LCMS, ESI pos.): Calcd. for C11H15BrO3, 275.0/277.0 (M+H). found 275.2/277.1
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][C:15]=2[O:24][CH3:25])=[C:4]([CH3:26])[N:3]=1.[CH3:27][S:28]([CH2:31][CH2:32][CH2:33]O)(=[O:30])=[O:29]>>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:33][CH2:32][CH2:31][S:28]([CH3:27])(=[O:30])=[O:29])=[O:22])=[CH:16][C:15]=2[O:24][CH3:25])=[C:4]([CH3:26])[N:3]=1
Reactant: CS(=O)(=O)CCCO
Reactant: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1OC
Product: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)OCCCS(C)(=O)=O)cc1OC

Procedure:
The title compound was prepared using the method of example 89 step (vii), using the product of example 89 step (vi) (150 mg) and 3-(methylsulfonyl)propan-1-ol (116 mg), to give the title compound as a gum, 6.3 mg.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9](/[CH:15]=[CH:16]/[CH:17]=[CH:18]/[C:19]([O:21][CH3:22])=[O:20])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd].CO>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)/C=C/C=C/c1ccc(OC)c(OC2CCCC2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCc1ccc(OC)c(OC2CCCC2)c1

Procedure:
To a solution of 0.20 g (0.66 mmol) of methyl 5-(3-cyclopentoxy-4-methoxyphenyl)-2,4-E,E-pentadienoate 75 mL of methanol is added 0.05 g of 5% palladium on carbon black. The suspension is shaken under a 50 psi atmosphere of hydrogen for 52 minutes after which time the excess gas is dissociated and the solution is filtered over Celite 545. The mixture is concentrated to dryness followed by liquid chromatography of the crude product over 100 g of silica gel eluting with 7.5% ethyl acetate in hexane. The final product is dried in vacuo and is found to be as analytically pure as an oil.
Reaction SMILES: Cl.[NH2:2][O:3][CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([OH:7])=[O:6].[CH:14]1[C:23]2[N:24]3[C:28]([C:29](=O)[C:21]4[C:22]=2[C:17]([CH:18]=[CH:19][N:20]=4)=[CH:16][CH:15]=1)=[CH:27][CH:26]=[CH:25]3>O.C(O)C.N1C=CC=CC=1>[C:5]([CH:4]([O:3][N:2]=[C:29]1[C:21]2[C:22]3[C:17]([CH:18]=[CH:19][N:20]=2)=[CH:16][CH:15]=[CH:14][C:23]=3[N:24]2[C:28]1=[CH:27][CH:26]=[CH:25]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:7])=[O:6]
Reactant: NOC(C(=O)O)c1ccccc1
Reactant: O=c1c2nccc3cccc(c32)n2cccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCO
Product: O=C(O)C(ON=c1c2nccc3cccc(c32)n2cccc12)c1ccccc1
Yield: 70.4 %

Procedure:
A solution of α-aminooxyphenylacetic acid hydrochloride (15.0 g.) in water (6.6 cc.) is added to a stirred boiling solution of 7H-indolizino[5,6,7-ij]isoquinoline-7-one (15.0 g.) in ethanol (450 cc.) and pyridine (583 g.). Boiling is maintained for 2 hours 30 minutes. After cooling, the yellow crystals obtained are filtered off and then washed with 90% ethanol, then with absolute ethanol and finally with diethyl ether. After drying, 7-(α-carboxybenzyloxyimino)-7H-indolizino[5,6,7-ij]isoquinoline (17.7 g.), melting at 200° C. with decomposition, is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[C:12]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH:28]1([S:31](Cl)(=[O:33])=[O:32])[CH2:30][CH2:29]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[C:12]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][S:31]([CH:28]4[CH2:30][CH2:29]4)(=[O:33])=[O:32])[CH3:20])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[C@H](N)[C@H](Oc1cccc2c1cnn2-c1ccc(F)cc1)c1ccccc1
Reactant: O=S(=O)(Cl)C1CC1
Product: C[C@H](NS(=O)(=O)C1CC1)[C@H](Oc1cccc2c1cnn2-c1ccc(F)cc1)c1ccccc1

Procedure:
Prepared according the protocol described for Example 1 using (1R,2S)-1-[1-(4-fluorophenyl)indazol-4-yl]oxy-1-phenyl-propan-2-amine (3a, 30 mg, 0.08 mmol) and cyclopropylsulphonyl chloride (22 μl, 0.21 mmol). Yield: 20 mg (53%).
Reaction SMILES: [C:1]([N:5]1[CH2:43][CH2:42][CH2:41][CH2:40][C:8]2[C:9]([C:35]3[S:36][CH:37]=[CH:38][CH:39]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([N:20]5[CH:24]=[C:23]([CH2:25][C@H:26]6[CH2:30][O:29]C(C)(C)[O:27]6)[N:22]=[N:21]5)[C:16]([O:33][CH3:34])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:44])([CH3:4])([CH3:3])[CH3:2].[NH4+].[OH-]>C(O)(=O)C>[C:1]([N:5]1[CH2:43][CH2:42][CH2:41][CH2:40][C:8]2[C:9]([C:35]3[S:36][CH:37]=[CH:38][CH:39]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([N:20]5[CH:24]=[C:23]([CH2:25][C@H:26]([OH:27])[CH2:30][OH:29])[N:22]=[N:21]5)[C:16]([O:33][CH3:34])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:44])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(cc1-n1cc(C[C@H]3COC(C)(C)O3)nn1)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1cc2c(cc1-n1cc(C[C@H](O)CO)nn1)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Temperature: 25 °C
Reaction time: 48 h
Yield: 42.8 %

Procedure:
Compound 20e (30 mg) was dissolved in 2 ml of 80% acetic acid and stirred for 2 days at RT. The mixture was diluted with ice-water and neutralized by addition of conc. NH4OH. The product was extracted with ethyl acetate. The organic extract was washed with water, dried and concentrated, and the remainder purified by chromatography over silica gel, (using a gradient of heptane/acetone as eluent), to provide 12 mg of 20f.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([O:16][CH3:17])=[O:15])[N:2]=1.OC[CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>CN(C)C1C=CN=CC=1.C1(C)C(C)=CC=CC=1>[CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([O:16][CH2:17][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:15])[N:2]=1
Reactant: OCCN1CCOCC1
Reactant: COC(=O)c1cc2c(cn1)[nH]c1ccccc12
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1C
Product: O=C(OCCN1CCOCC1)c1cc2c(cn1)[nH]c1ccccc12
Temperature: 25 °C
Yield: 63 %

Procedure:
A suspension of β-carboline-3-carboxylic acid, methyl ester (5.3 g, 23.4 mmol), 4-(2-hydroxyethyl) morpholine (4.62 g, 35 mmol), 4-dimethylaminopyridine (1.2 g, 9.8 mmol), 4 Å molecular sieves (5 g) and xylene (250 mL) was heated at reflux for 48 hours. The reaction mixture was cooled to room temperature, concentrated under vacuum, and the resulting slurry was partitioned with CH2Cl2 (250 mL). The mixture was filtered under vacuum and the residue was washed with CH2Cl2 (2×25 mL). Combined organic layers were washed several times with water, dried over Na2SO4, and concentrated. Purification of crude product by column chromatography on silica with 8% 2M NH3—CH3OH in CH2Cl2 as eluent furnished the desired product (4.8 g, 64%) as a pale yellow solid. 1H NMR (CDCl3) δ9.09 (s, 1H), 8.88 (s, 1H), 8.21 (d,J=7.9 Hz, 1H), 7.63 (d,J=8.1 Hz, 1H), 7.63 (d,J=8.1 Hz, 1H), 7.62 (t,J=7.38 (t, J=7.4 Hz, 2H), 4.63 (t, J=6.1 Hz, 2H), 3.73 (t, J=4.6 Hz, 4H), 6.1 Hz, 2H), 2.59 (t, J=4.6 Hz, 4H); MS (APCI; (M+H)+) m/z 326.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]([O:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[CH3:24])([CH3:14])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=[O:6].Cl>[OH-].[Na+].CO>[CH3:14][C:4]([O:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[CH3:24])([CH3:3])[CH:5]([C:7]1[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=1)[OH:6]
Reactant: Cc1ccc(C(=O)C(C)(C)Oc2cc(C)cc(C)c2C)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(C(O)C(C)(C)Oc2cc(C)cc(C)c2C)cc1
Temperature: 35 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A solution of sodium borohydride (25.7 g) in 0.1N NaOH (202 mL) was added dropwise to a suspension of 2-methyl-1-(4-methylphenyl)-2-(2,3,5-trimethylphenoxy)-1-propanone (251.9 g) in methanol (2519 mL). The mixture was stirred at 35° C. for 3 hours. After the mixture was adjusted to pH 7 by addition of 1N HCl under ice-cooling, methanol was distilled off, followed by extraction with toluene (2015 mL). The extract was washed, and the solvent was distilled off to quantitatively obtain the title compound as an oil (253.7 g).
Reaction SMILES: [H-].[Na+].C1COCC1.[F:8][C:9]([F:41])([F:40])[C:10]1[CH:11]=[C:12]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:13][N:14]([CH2:30][CH2:31][OH:32])[C:15]([C:17]1[C:18](Cl)=[N:19][CH:20]=[CH:21][C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:16]>C(OCC)(=O)C>[F:8][C:9]([F:41])([F:40])[C:10]1[CH:11]=[C:12]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:13][N:14]1[C:15](=[O:16])[C:17]2[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:21][CH:20]=[N:19][C:18]=2[O:32][CH2:31][CH2:30]1
Reactant: O=C(c1c(-c2ccccc2)ccnc1Cl)N(CCO)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1c2c(-c3ccccc3)ccnc2OCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 86.1 %

Procedure:
Sodium hydride (60% oily) (60 mg) was added to a THF (15 ml) solution of N-[3,5-bis (trifluoromethyl)benzyl]-2-chloro-N-(2-hydroxyethyl)-4-phenyl-3-pyridinecarboxamide (Reference Example 12) (348 mg) and the mixture was stirred for 2 hours while heating under reflux. Ethyl acetate was added to the reaction mixture, which was then washed with water and dried. After the solvent was removed by distillation, the entitled compound was obtained as colorless crystals (278 mg).
Reaction SMILES: [CH3:1][NH:2][N:3]=[C:4]([CH3:6])[CH3:5].C(N(CC)CC)C.[CH2:14]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH2:23][CH3:24])[C:17]=1[C:25](=[O:29])[C:26](Cl)=[O:27])[CH3:15]>C(#N)C>[CH2:14]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH2:23][CH3:24])[C:17]=1[C:25](=[O:29])[C:26]([N:2]([CH3:1])[N:3]=[C:4]([CH3:6])[CH3:5])=[O:27])[CH3:15]
Reactant: CNN=C(C)C
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)C
Temperature: 1 °C

Procedure:
To a 1000 ml volume four-necked flask, 1-methyl-2-(2-propylidene)hydrazine (17-a) (9.61 g), acetonitrile (280 ml), and triethylamine (17 ml) were added under a nitrogen atmosphere and cooled to about 1° C. To the mixture, 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl chloride (6-a) (27.12 g) dissolved in acetonitrile (77 ml) was added dropwise over 30 minutes.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]1([C:15]([F:18])([F:17])[F:16])[CH2:14][CH2:13]1)=[N:7][N:6]=[CH:5]2.[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)[CH2:21][CH2:20]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.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]>[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([C:12]3([C:15]([F:18])([F:17])[F:16])[CH2:14][CH2:13]3)=[N:7][N:6]=[CH:5]4)[CH:25]=2)[CH2:20][CH2:21]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: FC(F)(F)C1(c2nncc3cc(Cl)ccc23)CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(C3(C(F)(F)F)CC3)nncc2c1
Temperature: 135 °C

Procedure:
A mixture of 6-chloro-1-(1-(trifluoromethyl)cyclopropyl)phthalazine (20 mg, 73 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (27 mg, 88 μmol), Pd2(dba)3 (2.0 mg, 2.2 μmol), potassium phosphate (47 mg, 220 μmol) and X-Phos (2.0 mg) in 1.0 mL of dioxane and 0.5 mL water in a sealed glass tube was heated in a microwave for 20 min at 135° C. The mixture was partitioned between 1.0 N NaOH (1.0 mL) and EtOAc (5.0 mL). The organic layer was separated, dried and concentrated. Purification on an ISCO (4.0 g column, 60-100% EtOAc:Hexanes) provided the title compound as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 412.1 (M+1).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li]CCCC.Br[CH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH:24]([CH3:32])[CH:25]2[O:30][CH3:31].O>CCOCC>[CH3:31][O:30][CH:25]1[C:26]2[C:22](=[C:21]([CH2:20][CH:12]3[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[C:5]4[C:13]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[CH:29]=[CH:28][CH:27]=2)[CH2:23][CH:24]1[CH3:32]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: COC1c2cccc(CBr)c2CC1C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: COC1c2cccc(CC3c4ccccc4-c4ccccc43)c2CC1C
Temperature: -80 °C
Reaction time: 12 h

Procedure:
To a solution of 3.32 g (0.20 mol) of 9H-fluorene in 500 ml of ether 80 ml of 2.5 M (0.20 mol) n-BuLi in hexanes was added at 0° C. This mixture was stirred for 12 h, cooled to −80° C., and then a solution of 5.10 g (0.20 mol) of 4-(bromomethyl)-1-methoxy-2-methylindane in 150 ml of ether was added dropwise by vigorous stirring for 30 min at this temperature. The resulting mixture was stirred for 24 h at room temperature, and then 500 ml of water was added. The organic layer was separated, and the aqueous layer was extracted with 3×200 ml of dichloromethane. The combined organic extract was dried over Na2SO4 and evaporated to dryness. The product was isolated by flash chromatography on Silica Gel 60 (40-63 um, d 60 mm, l 150 mm; eluent: hexanes/ether=20/1). Yield 5.31 g (78%) of a mixture of the diastereomers A and B.