Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[C:10]([CH3:11])=[C:9]([S:12][CH2:13][CH2:14][CH2:15][CH2:16][SH:17])[CH:8]=[CH:7][N:6]=1.Cl[CH2:19][CH2:20][N:21]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][N:23]=[C:22]1[CH3:29]>CN(C=O)C.C(O)(=O)C>[OH:3][CH2:4][C:5]1[C:10]([CH3:11])=[C:9]([S:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17][CH2:19][CH2:20][N:21]2[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][N:23]=[C:22]2[CH3:29])[CH:8]=[CH:7][N:6]=1
Reactant: Cc1c(SCCCCS)ccnc1CO
Reactant: Cc1ncc([N+](=O)[O-])n1CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1c(SCCCCSCCn2c([N+](=O)[O-])cnc2C)ccnc1CO
Temperature: 0 °C

Procedure:
0.43 g (15 mmol) of sodium hydride are initially introduced in 25 ml of DMF with ice-cooling. 3.33 g (13.7 mmol) of 2-hydroxymethyl-4-(4-mercaptobutylthio)-3-methylpyridine are added. After the evolution of gas has ended, 2.62 g (13.7 mmol) of 1-(2-chloroethyl)-2-methyl-5-nitroimidazole in 10 ml of DMF are added dropwise. The mixture is stirred with ice- cooling for 1 h. It is then diluted with 200 ml of ice-water and neutralized with acetic acid. The mixture is extracted 3 times with dichloromethane. The combined organic phases are washed 4 times with water, dried over magnesium sulfate, filtered and concentrated. The crude product is chromatographed on silica gel using ethyl acetate/methanol/conc. ammonia=89/10/1. The title compound is obtained on concentrating as a yellow crystallizate which is washed by stirring with diethyl ether. M.p. 86°-87° C.; yield 4 g (75% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[N:9]=[CH:8][CH:7]=[CH:6]2.[Br:14]N1C(=O)CCC1=O.[OH-].[K+]>OS(O)(=O)=O>[Br:14][C:4]1[C:3]([O:2][CH3:1])=[C:12]([CH3:13])[CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc2cccnc2cc1C
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: COc1c(C)cc2ncccc2c1Br
Temperature: 15 °C
Reaction time: 3.5 h

Procedure:
To the solution of 6-methoxy-7-methylquinoline (4.28 g, 24.6 mmol) in 50 mL of concentrated H2SO4 was added N-bromosuccinimide (4.41 g, 14.6 mmol) at 15° C., and the reaction was stirred at 15° C. for 3.5 hours. The reaction mixture was poured into ice-water (600 mL). The aqueous mixture was adjusted with a 50% KOH solution to pH ˜10, and then extracted with DCM (3×). The combined extract was dried with sodium sulfate. Concentration under reduced pressure gave 5-bromo-6-methoxy-7-methylquinoline. LCMS-ESI+ (m/z): 252.1, 254.1 (M+H)+.
Reaction SMILES: C([O:4][C@H:5]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:28]2[C:27](=[O:33])[C@@H:26]([O:34]C(=O)C)[C@@:25]2([CH3:38])[C@H:11]3[CH2:12][C@@H:13]3[O:18][C@@:17]4([O:24][CH2:23][C@H:21]([CH3:22])[CH2:20][CH2:19]4)[C@@H:15]([CH3:16])[C@@H:14]32)[CH2:6]1)(=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:16][C@@H:15]1[C@:17]2([O:24][CH2:23][C@H:21]([CH3:22])[CH2:20][CH2:19]2)[O:18][C@H:13]2[CH2:12][C@@H:11]3[C@@:25]([CH3:38])([C@@H:14]12)[C@H:26]([OH:34])[C@H:27]([OH:33])[C@H:28]1[C@H:10]3[CH2:9][CH2:8][C@@H:7]2[C@:29]1([CH3:32])[CH2:30][CH2:31][C@H:5]([OH:4])[CH2:6]2
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=O)[C@@H](OC(C)=O)[C@]2(C)[C@@H]4[C@H](C[C@@H]32)O[C@]2(CC[C@@H](C)CO2)[C@H]4C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4[C@@H](O)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C

Procedure:
(3β,5α,12β,25R)-3,12-di(acetoxy)spirostan-11-one (purchased from Steraloids, Inc., or see preparationG13) was converted into the title compound via reduction with lithium aluminum hydride in THF at room temperature according to the procedure described in J. Am. Chem. Soc., 1951, 73, 1777.
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[NH:16][CH:15]([C:5]2=1)[CH2:14][CH2:13]3.[C:17]([C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[N:23][CH:24]=1)#[CH:18]>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](/[CH:18]=[CH:17]\[C:19]1[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][CH:20]=1)[C:6]1[CH2:11][C@@H:12]3[NH:16][C@H:15]([C:5]2=1)[CH2:14][CH2:13]3
Reactant: C#Cc1ccc(C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCC(C3)N1
Product: Cc1ccc2c(c1)c1c(n2/C=C\c2ccc(C)nc2)C[C@H]2CC[C@@H]1N2

Procedure:
The coupling of 2-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole (212 mg, 1.00 mmol; Example 4A) and 5-ethynyl-2-methylpyridine (586 mg, 5.00 mmol; International Publication No. WO2005090333) was performed as described in Example 20 to afford the racemate of the title compound. The individual enantiomers 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 peak: 1H NMR (300 MHz, methanol-d4) δ ppm 1.37-1.53 (m, 1H), 1.99-2.13 (m, 3H), 2.29-2.36 (m, 1H), 2.38 (s, 3H), 2.41 (s, 3H), 3.01 (dd, J=16, 5 Hz, 1H), 3.90 (t, J=6 Hz, 1H), 4.55 (d, J=4 Hz, 1H), 6.58 (d, J=8 Hz, 1H), 6.80-6.88 (m, 2H), 6.90 (d, J=9 Hz, 1H), 7.01-7.14 (m, 2H), 7.28 (s, 1H), 7.93 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 330 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[N:18]1([C:23]2[CH2:27][CH2:26][CH2:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([C:4]([C:24]2[CH2:25][CH2:26][CH2:27][C:23]=2[N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: C1=C(N2CCCC2)CCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(C1=C(N2CCCC2)CCC1)c1cccnc1Cl
Reaction time: 21 h

Procedure:
Dissolve 2-chloronicotinoyl chloride (0.10 mole) in CHCl3 (90 ml). Add the resulting solution to a 5° C. solution of triethylamine (0.10 mole) and an enamine, 1-(1-pyrrolidinyl)-1-cyclopentene (0.10 mole), dissolved in CHCl3 (90 ml). Allow C-acylation to proceed for 21 hrs., while the temperature of the reaction mixture rises to 25° after the second hour. Monitor the course of the reaction by thin-layer chromatography as needed. Wash the resulting solution with water, aqueous NaHCO3 solution, and with water. After drying, carefully evaporate solvent to obtain the enaminoketone, (2-chloro-3-pyridinyl)[2-(1-pyrrolidinyl)-1-cyclopenten-1-yl]methanone, m.p. 102.5°-104.0° C., after recrystallization from ethyl acetate. This compound is referred to in Examples 1 and 3 below as Compound 1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:53])=[C:6]([CH2:8][N:9]([CH3:52])[C:10]([CH:12]([NH:26][C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[C:33]([N:37]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[N:32][CH:31]=[CH:30]3)[C:13]2[CH:18]=[C:17]([CH3:19])[C:16]([C:20]([F:24])([F:23])[CH2:21][OH:22])=[C:15]([CH3:25])[CH:14]=2)=[O:11])[CH:7]=1.[C:54](Cl)(Cl)=[O:55]>ClCCl.C(#N)C>[Br:53][C:5]1[CH:4]=[CH:3][C:2]2=[CH:7][C:6]=1[CH2:8][N:9]([CH3:52])[C:10](=[O:11])[CH:12]([NH:26][C:27]1[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=1)[C:33]([N:37]([C:38]([O:39][C:40]([CH3:43])([CH3:41])[CH3:42])=[O:44])[C:45](=[O:46])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[N:32][CH:31]=[CH:30]3)[C:13]1[CH:14]=[C:15]([CH3:25])[C:16]([C:20]([F:23])([F:24])[CH2:21][O:22][C:54](=[O:55])[NH:1]2)=[C:17]([CH3:19])[CH:18]=1
Reactant: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)N(C)Cc2cc(N)ccc2Br)cc(C)c1C(F)(F)CO
Reactant: O=C(Cl)Cl
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cc2cc(C)c1C(F)(F)COC(=O)Nc1ccc(Br)c(c1)CN(C)C(=O)C2Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 59.4 %

Procedure:
To a solution of 4A (289 mg, 0.362 mmol) in dichloromethane (5 mL) and acetonitrile (5.00 mL) at 0° C., was added phosgene (20% in toluene) (0.242 mL, 0.488 mmol). The reaction mixture was stirred at 0° C. for 15 min. Nitrogen was bubbled though the mixture for 0.5 h, then DMPU (˜0.4 mL) was added. The resulting solution was added dropwise via a syringe pump into a solution of TEA (0.353 mL, 2.53 mmol) in dichloromethane (90 mL) at rt over 4 h, stirred for an additional 15 min and then evaporated. The crude product was purified by flash chromatography to give 4B (177 mg, 0.215 mmol, 59.3% yield) as a white solid. MS and 1H NMR are consistent with the desired product.
Reaction SMILES: C([O:4][C@@H:5]1[NH:8][C:7](=O)[C@H:6]1[NH:10][C:11](=[O:20])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)C.[CH3:21][S:22]([O-:24])=[O:23].[Na+]>CO>[CH3:21][S:22]([C@@H:7]1[NH:8][C:5](=[O:4])[C@H:6]1[NH:10][C:11](=[O:20])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:24])=[O:23]
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(=O)COc1ccccc1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)[C@@H]1NC(=O)[C@H]1NC(=O)COc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.9 %

Procedure:
To a solution of 0.494 g of (3S,4S)-4-acetoxy-3-phenoxyacetamido-2-oxoazetidine in 14 ml of 50% methanol is added 0.51 g of sodium methylsulfinate and the mixture is stirred at room temperature for 18 hours. The methanol is distilled off under reduced pressure to give 222 mg of (3R,4S)-4-methylsulfonyl-3-phenoxyacetamido-2-oxoazetidine,
Reaction SMILES: [C:1]([OH:16])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:17](O)(=O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].P(=O)(O)(O)O.C(O)CCCCCCCCCCCCCCC>CCCCCC>[C:1]([O:16][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCCO
Agent: O=P(O)(O)O
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCC

Procedure:
Myristic acid/palmitic acid, 200 cc. of 85% phosphoric acid and 1800 ml. of hexane were mixed, heated to reflux and then 251 grams of cetyl alcohol added in 30 min. The mixture was refluxed further for 8 hours. Then the hot mixture consisted of a muddy acid layer and a opaque solvent layer which could not be separated by decantation or filtration. The mixture was further diluted with three volumes of hexane causing the slushy hexane layer to further soften enough to be separated from aqueous layer. The hexane layer was then cooled to bring about crystallization of fatty ester. The weight of cetyl myristate isolated was 294 grams which had a melting point of 54-59° C. The conversion, based on the cetyl alcohol used, was 63.71%.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[C:12][Si](C)(C)C)[CH:9]=2)[NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].CO>C1COCC1>[C:11]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[CH3:1])#[CH:12]
Reactant: Cc1n[nH]c2ccc(C#C[Si](C)(C)C)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1ccc2[nH]nc(C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
3-Methyl-5-(2-(trimethylsilyl)ethynyl)-1H-indazole (820 mg, 3.55 mmol) was dissolved in 20 mL THF and K2CO3 (4.9 g, 35.5 mmol) and 200 mL MeOH were added. The mixture was stirred for 1 hour at room temperature, filtered and evaporated. The mixture was purified via glass column chromatography (35% EtOAc in hexane) and the title compound (500 mg, 3.2 mmol) was obtained as a light yellow solid. LCMS (API-ES) m/z (%): 157.0 (100%, M++H).
Reaction SMILES: C([C:8]1[C:13]2=[C:14]3[C:19](=[CH:20][CH:21]=[C:12]2[O:11][C:10](=[O:27])[CH:9]=1)[N:18]([C:22](=[O:24])[CH3:23])[C@@H:17]([CH3:25])[CH2:16][C@H:15]3[NH2:26])C1C=CC=CC=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:22]([N:18]1[C:19]2[C:14](=[C:13]3[CH:8]=[CH:9][C:10](=[O:27])[O:11][C:12]3=[CH:21][CH:20]=2)[C@H:15]([NH:26][C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)[CH2:16][C@@H:17]1[CH3:25])(=[O:24])[CH3:23]
Reactant: CC(=O)N1c2ccc3oc(=O)cc(Cc4ccccc4)c3c2[C@H](N)C[C@@H]1C
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1c2ccc3oc(=O)ccc3c2[C@H](Nc2ccc(Cl)cc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.1 %

Procedure:
[Step 5] 22 mg of the cis-benzyl-7-acetyl-10-amino-8-methyl-7,8,9,10-tetrahydro-3H-pyrano[3,2-f]-quinolin-3-one and 19 mg of 4-chlorophenylboronic acid were dissolved in 10 mL of dichloromethane followed by adding 29 mg of divalent copper acetate and 34 μL of triethylamine and stirring for 18 hours at room temperature in the presence of air. Following completion of the reaction, the solution was filtered with celite and water was added followed by extracting three times with ethyl acetate. After washing with saturated brine and dehydrating with anhydrous sodium sulfate, the solution was concentrated under reduced pressure and the resulting residue was purified using silica gel chromatography (ethyl acetate:hexane=1:1) to obtain 7 mg of the target compound in the form of a yellow solid (23%).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:12]2[N:8]([C:9]([CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[C:11]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][C:6]1([CH3:35])[CH3:34])(=O)C.[OH-].[K+].O.Cl>CO>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([C:10]2[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:12]3[N:8]([CH2:7][C:6]([CH3:34])([CH3:35])[CH:5]3[O:4][CH3:1])[C:9]=2[CH2:26][C:27]([OH:29])=[O:28])=[CH:24][CH:23]=1
Reactant: CC(=O)OC1c2c(-c3ccccc3)c(-c3ccc(Cl)cc3)c(CC(=O)OC(C)(C)C)n2CC1(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC1c2c(-c3ccccc3)c(-c3ccc(Cl)cc3)c(CC(=O)O)n2CC1(C)C

Procedure:
tert-Butyl 1-acetoxy-6-(4-chlorophenyl)-2,3-dihydro-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-ylacetate (example 9c, 1.00 g, 2.0 mmol) is dissolved in 10 ml of MeOH. 0.5 g of KOH is added and the mixture is heated under reflux until the intermediately formed precipitate has dissolved. It is then allowed to cool and is stirred into 600 ml of water. The cloudy solution is brought to pH 3 using conc. HCl. It is extracted three times using 100 ml of diethyl ether each time. The ether extracts are washed twice with water and dried over Na2SO4, filtered and concentrated in a rotary evaporator. A mixture of 6-(4-chlorophenyl)-2,3-dihydro-1-hydroxy-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-ylacetic acid and 2-[6-(4-chlorophenyl)-2,3-dihydro-1-methoxy-2,2-dimethyl -7-phenyl-1H-pyrrolizin-5-yl]acetic acid is obtained (cf. example 16).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:38])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[O:41]=[S:42]1(=[O:54])[CH2:47][CH2:46][CH:45]([N:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[CH2:44][CH2:43]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:38])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:51]3[CH2:52][CH2:53][N:48]([CH:45]4[CH2:44][CH2:43][S:42](=[O:41])(=[O:54])[CH2:47][CH2:46]4)[CH2:49][CH2:50]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:31])([CH3:32])[C:33]#[N:34])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=S1(=O)CCC(N2CCNCC2)CC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C2CCS(=O)(=O)CC2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(1,1-dioxo-tetrahydro-2H-thiopyran-4-yl)-piperazine dihydrochloride to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). LR-MS: 749.63 [(M+H)+]
Reaction SMILES: [Na].[Cl-].[NH2:3][C:4]([NH2:6])=[NH2+:5].[F:7][C:8]([F:30])([F:29])[C:9]1[CH:17]=[C:16]2[C:12]([C:13](=[O:28])[N:14]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH:15]2[CH2:18][C:19](OCC)=[O:20])=[CH:11][CH:10]=1>C(O)C.C(OCC)C>[CH2:24]([N:14]1[C:13](=[O:28])[C:12]2[C:16](=[CH:17][C:9]([C:8]([F:7])([F:29])[F:30])=[CH:10][CH:11]=2)[CH:15]1[CH2:18][C:19]([NH:5][C:4]([NH2:6])=[NH:3])=[O:20])[CH:25]([CH3:27])[CH3:26]
Reactant: CCOC(=O)CC1c2cc(C(F)(F)F)ccc2C(=O)N1CC(C)C
Reactant: NC(N)=[NH2+]
Agent: [Cl-]
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: CC(C)CN1C(=O)c2ccc(C(F)(F)F)cc2C1CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 16 h
Yield: 7.6 %

Procedure:
N-[2-(2-Isobutyl-3-oxo-6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl)-acetyl]-guanidine is prepared as described in Example 9, starting with 10 cm3 of absolute ethanol, 0.13 g of sodium, 0.52 g of guanidinium chloride and 1.25 g of ethyl (6-trifluoromethyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate in 10 cm3 of absolute ethanol. The reaction mixture is stirred at a temperature in the region of 20° C. for 16 hours and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is then taken up in a mixture of 5 cm3 of water and 15 cm3 of diethyl ether and then concentrated to dryness again under the same conditions. The residue is taken up in 100 cm3 of ethyl acetate and the organic phase is washed with twice 50 cm3 of aqueous 1N sodium hydroxide solution and then with 30 cm3 of aqueous 4N hydrochloric acid solution. The acidic aqueous phase is treated with aqueous 30% sodium hydroxide solution to pH 14, and then extracted with 3 times 50 cm3 of ethyl acetate. The organic extracts are combined and washed with saturated sodium chloride solution, dried over magnesium sulfate and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The white solid thus obtained is taken up in 20 cm3 of diethyl ether-and stirred at a temperature in the region of 20° C., and then filtered. The solid is dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20° C. 0.099 g of N-[2-(2-Isobutyl-3-oxo-6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl)-acetyl]-guanidine is thus obtained in the form of a pale yellow solid melting at 154° C. Mass spectrum: EI: m/e 356 (M+), m/e 269, m/e 200, m/e 86 (base peak).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:14][N:15]=3)[S:10][C:3]=12.[CH3:20][C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([NH2:30])=[CH:25][CH:24]=2.C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C.ClC(Cl)C>C(O)(C)(C)C>[CH3:20][C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([NH:30][C:2]1[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]4[S:12][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:14][N:15]=4)[S:10][C:3]=13)=[CH:25][CH:24]=2
Reactant: CC(C)(O)c1cnc(-c2cc3nccc(Cl)c3s2)s1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(Cl)Cl
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: Cc1cc2cc(Nc3ccnc4cc(-c5ncc(C(C)(C)O)s5)sc34)ccc2[nH]1
Yield: 94 %

Procedure:
2-[2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-thiazol-5-yl]-propan-2-ol (129 mg, 0.42 mmol), 2-methyl-5-aminoindole (72 mg, 0.50 mmol), potassium carbonate (138 mg. 8.84 mmol), and triethylamine (0.12 mL, 0.84 mmol) were dissolved in 2 mL of t-butyl alcohol and 2 mL of dichloroethane and the solution was heated to 85° C. After allowing the reaction to go dry overnight solvent was added along with an additional 36 mg of the indole an the solution was heated an additional 18 hours. Chromatography of the residue with 20% methanol:methylene chloride afforded 166 mg (40%) of 2-{2-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-thiazol-5-yl}-propan-2-ol. 1H NMR (400 MHz, CD3OD) δ8.13 (d, 1H), 7.71 (s, 1H), 7.62 (s, 1H), 7.35 (d, 1H), 7.30 (d, 1H), 6.99 (d, 1H), 6.64 (d, 1H), 6.13 (s, 1H), 2.43 (s, 3H), 1.65 (s, 6H). LC-MS: 421 (MH+); HPLC RT: 4.75 min.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[Li][C:13]([CH3:16])([CH3:15])[CH3:14].Cl[C:18]1[CH:31]=[CH:30][C:29]2[C:28](=O)[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=O)[C:20]=2[CH:19]=1>C1COCC1>[CH3:14][C:13]1[CH:16]=[CH:23][C:24]([C:18]2[CH:31]=[CH:30][C:29]3[C:20](=[C:21]([C:31]4[CH:18]=[CH:19][C:20]5[C:29](=[CH:28][CH:27]=[CH:22][CH:21]=5)[CH:30]=4)[C:22]4[C:27]([C:28]=3[C:2]3[CH:11]=[CH:10][C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[CH:3]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:19]=2)=[CH:25][CH:15]=1
Reactant: O=C1c2ccccc2C(=O)c2cc(Cl)ccc21
Reactant: [Li]C(C)(C)C
Reactant: Brc1ccc2ccccc2c1
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(-c4ccc5ccccc5c4)c4ccccc4c(-c4ccc5ccccc5c4)c3c2)cc1
Reaction time: 0.08 h

Procedure:
Inv-A46, 2-(4-methylphenyl)-9,10-di-2-naphthalenylanthracene was prepared according to equation 1-equation 3. 2-Bromonaphthalene (9.2 g, 44.4 mmol) was dissolved in dry THF (118 ml) and cooled to −78° C. t-BuLi (1.7 M, 52.3 g, 89 mmol) was added in dropwise manner over 5 min, then the reaction was stirred at this temperature for another 5 min. Upon the addition of 2-chloroanthraquinone (4.3 g, 17.8 mmol), the reaction was removed from the acetone-dry ice bath and stirred at room temperature overnight. The reaction mixture was added to aqueous ammonium chloride solution and the product was extracted with methylene chloride. The organic phase was dried with magnesium sulfate, filtered, and concentrated. Purification by crystallization (85% ether/heptane) gave Int-1 (eq. 1).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH3:13].[CH3:14][N:15]([CH3:29])[CH2:16][CH2:17][O:18][C:19]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=O.[O-]CC.[Na+]>C(O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1/[CH:13]=[CH:21]/[C:20]1[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:19]=1[O:18][CH2:17][CH2:16][N:15]([CH3:29])[CH3:14]
Reactant: Cc1nc2ccccn2c(=O)c1Br
Reactant: COc1cccc(C=O)c1OCCN(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3ccccn3c(=O)c2Br)c1OCCN(C)C

Procedure:
The title compound was prepared from 3-bromo-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (1.021 g, 4.18 mmol) and 2-[2-(dimethylamino)ethoxy]-3-methoxybenzaldehyde (0.969 g, 5.011 mmol) in the presence of sodium ethoxide (0.426 g, 6.27 mmol) in absolute ethanol (25 ml) as described in Intermediate 1 to give 649 mg of the product as a light yellow solid; 1H NMR (300 MHz, CDCl3) δ 2.39 (s, 6H), 2.82 (s, 2H), 3.87 (s, 3H), 4.12 (s, 2H), 6.91 (d, J=7.5 Hz, 1H), 7.04-7.10 (m, 2H), 7.28-7.34 (m, 1H), 7.66-7.71 (m, 3H), 8.40 (d, J=15.0 Hz, 1H), 8.95 (d, J=7.2 Hz, 1H).
Reaction SMILES: C(OP(OCC)(O[CH:7]([CH3:16])/[CH:8]=[C:9](\[CH3:15])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)C.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1.CCCCCCC>C(Cl)Cl.[Pd]>[C:10]([O:12][CH:13]([CH3:14])[CH3:20])([CH3:9])=[O:11].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28]/[C:8](/[CH2:7][CH3:16])=[C:9](\[CH3:15])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:24][CH:23]=1
Reactant: COc1ccc(N)cc1
Reactant: CCOC(=O)/C(C)=C/C(C)OP(=O)(OCC)OCC
Agent: [Pd]
Solvent: ClCCl
Solvent: CCCCCCC
Product: CC(=O)OC(C)C
Product: CCOC(=O)/C(C)=C(\CC)Nc1ccc(OC)cc1
Yield: 182.3 %

Procedure:
Reaction of 17 (rac-Ethyl (2E)-4-(diethoxyphosphinyloxy)-2-methylpent-2-enoate) (188 mg, 0.60 mmol) with p-anisidine (148 mg, 1.2 mmol) and 5 mol % [Pd] in CH2Cl2 (3.5 ml) at room temperature. Flash chromatography (AcOiPr:heptane fraction 15:85 to 20:80) yields 19 (rac-Ethyl (2E)-N-(4-methoxyphenyl)-4-amino-2-methylpent-2-enoate) (144 mg, 91) as a yellow oil.