Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C:5]([O:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)([CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:35])[C:5]([O:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:27][CH:28]=1)([CH3:21])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(C2CCCCC2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C2CCCCC2)cc1
Reaction time: 20 h

Procedure:
2-(4-Cyclohexylphenoxy-3-(4-benzyloxyphenyl)-2-methyl-propionic acid ethyl ester (2.1 mmol) was dissolved in ethyl acetate (30 mL) and treated with 5% palladium on carbon (300 mg), and stirred under an atmosphere of hydrogen for 20 h. The suspension was filtered through celite and concentrated in vacuo to an oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:36])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]=[N+:22]=[N-:23])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:24])[C:12]=2[C@H:25]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH2:37]([O:40][CH:41]([CH:44]([CH3:46])[CH3:45])[C:42]#[CH:43])[CH:38]=[CH2:39].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CO>[CH2:37]([O:40][CH:41]([C:42]1[N:23]=[N:22][N:21]([CH2:20][C:18]2[CH:19]=[C:15]3[N:14]=[C:13]([CH3:24])[C:12]([C@H:25]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:11]([N:8]4[CH2:9][CH2:10][C:5]([O:4][CH2:1][CH:2]=[CH2:3])([CH3:36])[CH2:6][CH2:7]4)[N:16]3[N:17]=2)[CH:43]=1)[CH:44]([CH3:46])[CH3:45])[CH:38]=[CH2:39]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CN=[N+]=[N-])nn23)CC1
Reactant: C#CC(OCC=C)C(C)C
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CO
Product: C=CCOC(c1cn(Cc2cc3nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N4CCC(C)(OCC=C)CC4)n3n2)nn1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.7 %

Procedure:
A mixture of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(azidomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.15 g, 0.300 mmol), 3-(allyloxy)-4-methylpent-1-yne (0.083 g, 0.600 mmol), Cu(II)SO4.5H2O (7.50 mg, 0.030 mmol) and (+)-sodium L-ascorbate (0.059 g, 0.300 mmol) in MeOH (2 mL) was stirred for 1 h at rt. Then, purified by prep-HPLC to afford (2S)-ethyl 2-(2-((4-(1-(allyloxy)-2-methylpropyl)-1H-1,2,3-triazol-1-yl)methyl)-7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.0761 g, 0.119 mmol, 39.7% yield) as pale yellow paste. LCMS (M+H)=638.7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]=[CH:13][N:14]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:15]=2[NH:16][C:17](=O)[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.C[Si](Cl)(C)C>>[CH2:27]([N:14]1[CH:13]=[N:12][C:11]2[C:9](=[O:10])[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[N:16][C:15]1=2)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Nc1c(C(=O)Nc2ccc(Cl)cc2)ncn1Cc1ccccc1)c1ccc(Cl)cc1Cl
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Product: O=c1c2ncn(Cc3ccccc3)c2nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 70.9 %

Procedure:
The reaction mixture of 1-benzyl-5-(2,4-dichloro-benzoylamino)-1H-imidazole-4-carboxylic acid (4-chloro-phenyl)-amide (60 mg, 0.12 mmol), triethylamine (670 μL, 4.8 mmol) and trimethylsilyl chloride (303 μL, 2.4 mmol) is heated at 100° C. for 2 days. After cooled to room temperature, the resulting mixture is quenched with 1 N HQ and dichloromethane. The aqueous phase is extracted with dichloromethane. The organic phases is combined, ished with brine and dried over magnesium sulfate. Concentration followed by purification with chromatography gives the desired product (41 mg, 71% yield).
Reaction SMILES: C([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:11]([Cl:22])[CH:10]=[N:9]1)C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].O>C1(C)C=CC=CC=1>[Cl:22][C:11]1[CH:10]=[N:9][NH:8][C:13](=[O:14])[C:12]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1
Reactant: O=c1c(-c2ccc(Cl)cc2)c(Cl)cnn1Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1[nH]ncc(Cl)c1-c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To a solution of 2-benzyl-5-chloro-4-(4-chlorophenyl)pyridazin-3(2H)-one (10.2 gm, 30.8 mmol) in toluene (154 mL) was added aluminum chloride (10.3 g, 77 mmol). The mixture was stirred at 50° C. for 1 h. After this time, the solution was cooled to RT, and the reaction mixture was poured into water (200 mL). The reaction mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with saturated NaCl. The organic layer was dried (Na2SO4), filtered and concentrated. The resulting residue was triturated with EtOAc-hexane to give the title compound, 5-chloro-4-(4-chlorophenyl)pyridazin-3(2H)-one as an off-white solid (6.8 g, 92%). LC/MS (method A): RT=2.91 min, (M+H)+=241;
Reaction SMILES: C([O-])(=O)CC([O-])=O.C(C(CC)(O[Mg+2])C)C.[O-]CC.[Mg+2].[O-]CC.[C:23]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].[F:34][CH:35]([F:49])[O:36][C:37]1[C:38]([F:48])=[C:39]([CH:43]=[C:44]([F:47])[C:45]=1[F:46])[C:40](Cl)=[O:41].Cl>C(OCC)C>[F:49][CH:35]([F:34])[O:36][C:37]1[C:38]([F:48])=[C:39]([CH:43]=[C:44]([F:47])[C:45]=1[F:46])[C:40]([CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:23]([O:31][CH2:32][CH3:33])=[O:30])=[O:41]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(Cl)c1cc(F)c(F)c(OC(F)F)c1F
Agent: CCC(C)(CC)O[Mg+2]
Agent: CC[O-]
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)c(OC(F)F)c1F

Procedure:
Meanwhile, a suspension of diethyl ethoxymagnesium malonate in diethyl ether was prepared from a mixture of 2.80 g (0.0238 moles) of magnesium ethoxide and 3.81 g (0.0238 moles) of diethyl malonate in 60 ml of anhydrous diethyl ether by heating under reflux for 1 hour, whilst stirring. A solution of the 3-difluoromethoxy-2,4,5-trifluorobenzoyl chloride prepared as described above in 50 ml of anhydrous diethyl ether was then added dropwise to the suspension, whilst stirring at room temperature, and the mixture was then stirred at room temperature for an additional 2 hours. 35 ml of 1N aqueous hydrochloric acid were added to the reaction mixture, and the mixture was vigorously stirred. The organic layer was then separated, washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure to give 7.07 g of diethyl 3-difluoromethoxy-2,4,5-trifluorobenzoylmalonate [(XIV), R1 =--OCHF2, R3' =H, R17 =C2H5, X=X'=F] as a brown liquid.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13]C)=[CH:9][CH:8]=2)[O:4][N:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[O:4][N:3]=1
Reactant: COc1ccc(-c2cc(O)no2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Oc1ccc(-c2cc(O)no2)cc1
Yield: 82 %

Procedure:
3-Hydroxy-5-(4-methoxyphenyl)isoxazole (5.0 g) was suspended in dichloromethane (50 ml), and aluminum chloride (7.0 g) was added thereto, followed by reflux of the resulting mixture for 66 hours. At the end of this time, the reaction mixture was poured into ice-cold water, and 6N hydrochloric acid was added thereto, followed by extraction with ethyl acetate. After the extract was washed with a saturated aqueous NaCl solution, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: cyclohexane/ethyl acetate=2/1) to obtain the title compound (3.8 g, 83%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:4][N:3]1[P:5](Br)([N:7]1[CH2:9][C:8]1([CH3:11])[CH3:10])=[S:6].[CH3:14][NH2:15]>C1COCC1>[CH3:1][C:2]1([CH3:13])[CH2:4][N:3]1[P:5]([N:7]1[CH2:9][C:8]1([CH3:11])[CH3:10])(=[S:6])[NH:15][CH3:14]
Reactant: CN
Reactant: CC1(C)CN1P(=S)(Br)N1CC1(C)C
Solvent: C1CCOC1
Product: CNP(=S)(N1CC1(C)C)N1CC1(C)C
Temperature: 4 °C
Yield: 65 %

Procedure:
In a similar manner 0.025 moles of P,P-bis(2,2-dimethyl-1-aziridinyl)thiophosphinic bromide in about 170 milliliters of THF, prepared in accordance with Example 1, is saturated with an excess of gaseous methylamine, stirred over night at 4° C., filtered, concentrated on a rotary evaporator at room temperature, and vacuum distilled to provide about 65% yield of P,P-bis(2,2-dimethyl-1-aziridinyl)-N methylthiophosphinic amide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13](O)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[NH:9][C:13]([C:12]3[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:11]=3[Cl:10])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Product: O=[N+]([O-])c1ccc(Cl)c(-c2nc3ncc(Br)cc3[nH]2)c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 127.6 %

Procedure:
A mixture of 5-bromopyridine-2,3-diamine (15 g, 79.78 mmol, 1.00 equiv), 2-chloro-5-nitrobenzoic acid (17.7 g, 87.81 mmol, 1.10 equiv) in PPA (200 mL) was stirred overnight at 130° C. and then quenched by the addition of 300 mL of H2O/ice. The pH value of the mixture was adjusted to 8 with sodium carbonate and the solids were collected by filtration, washed with water and dried in an oven under reduced pressure to give 36 g (crude) of 6-bromo-2-(2-chloro-5-nitrophenyl)-1H-imidazo[4,5-b]pyridine I-2a as a brown solid.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:22]([N:26]=[C:27]=[O:28])[CH2:23][CH2:24][CH3:25].Cl>ClC1C=CC=CC=1.O>[I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([S:12]([NH:15][C:27]([NH:26][CH2:22][CH2:23][CH2:24][CH3:25])=[O:28])(=[O:13])=[O:14])[CH:3]=1
Reactant: CCCCN=C=O
Reactant: COC(=O)c1ccc(I)cc1S(N)(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1
Solvent: O
Product: CCCCNC(=O)NS(=O)(=O)c1cc(I)ccc1C(=O)OC
Temperature: 90 °C
Reaction time: 2 h

Procedure:
34.1 g (0.1 mol) of the sulfonamide of the formula (IV) from Example 1 and 14.7 g of K2CO3 (0.105 mol) are admixed with 10.6 g of n-butyl isocyanate (98% pure) (0.105 mol) in 250 ml of chlorobenzene, and the mixture is kept at 55 to 60° C. for 2 hours. The mixture is then stirred at 90° C. for 8.5 h. The mixture is cooled to room temperature and initially 200 ml of water and then 2n of hydrochloric acid are added until the pH has reached 1-2. The organic phase is separated off and washed free of acid using four times 50 ml of water. The solvent is removed under reduced pressure, and 43.8 g of the desired compound of the formula (I) (99.3% of theory) of melting point 128 to 130° C. remain.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.Cl[CH2:27][CH2:28][O:29][CH2:30][CH2:31][OH:32].Cl>>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:20][CH2:21][N:22]([CH2:27][CH2:28][O:29][CH2:30][CH2:31][OH:32])[CH2:23][CH2:24]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCNCC4)n3)ccc21
Reactant: OCCOCCCl
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCN(CCOCCO)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described starting from 100 mg (0.28 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperazine and 36 μl (0.33 mmol) of 2-(2-chloroethoxy)ethanol. The product is in the form of the hydrochloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@H:12]([O:14][CH2:15][C:16]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:35]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)#[N:36].CO>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:35]([C:37]1[CH:42]=[CH:41][C:40]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C@H:12]([O:14][CH2:15][C:16]3([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:20][CH2:21]3)[CH3:13])[CH:3]=2)=[CH:39][CH:38]=1)#[N:36]
Reactant: C[C@@H](OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Br)cc(C(F)(F)F)c1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(-c2ccc(C#N)cc2)cc(C(F)(F)F)c1
Temperature: 120 °C

Procedure:
(R)-tert-Butyl 4-((1-(3-bromo-5-(trifluoromethyl)phenyl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate (0.35 g, 0.65 mmol), 4-cyanophenylboronic acid (284 mg, 1.93 mmol), and tetrakis(triphenylphosphine) palladium(0) (75 mg, 0.07 mmol) were combined in dry tetrahydrofuran (5 mL) in a microwave tube and sealed. After flushing with nitrogen, 2.3 mL of a 1 N potassium hydroxide aqueous solution was introduced. The mixture was heated at 120° C. for 1 h via microwave. After cooling to room temperature, the reaction mixture was concentrated and purified by flash chromatography on silica gel (15% ethyl acetate/hexanes) to afford 300 mg (82%) as an oil. LC/MS: tR=3.51 min, 565.23 (MH)+. (Phenomenex C18 4.6×50 mm, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA, Gradient time=4 min., Flow rate=4 mL/min.).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[NH:18][C:17]=2[CH3:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Na].[CH3:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35]>CN(C=O)C>[CH3:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([N:18]1[C:19]2[C:24](=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:16]([CH2:15][CH2:14][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]2[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:17]1[CH3:27])=[O:35]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: COc1ccc2[nH]c(C)c(CCN3CCCCC3CC3CCCCC3)c2c1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CCN1CCCCC1CC1CCCCC1)c(C)n2C(=O)c1ccccc1C

Procedure:
1-(2-Methylbenzoyl)-3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole is prepared by reaction of 3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole with sodium hydride in DMF and reaction of the resulting sodium salt with 2-methylbenzoyl chloride following the procedure described above in Example 1.
Reaction SMILES: OCC[C:4](=[O:32])[C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C@H:9]3[C@H:19]([C:20](=[O:24])[CH2:21]2)[C@:17]2([CH3:18])[C@H:12]([CH2:13][C@H:14]([O:25]C4CCCCO4)[CH2:15][CH2:16]2)[CH2:11][CH2:10]3)[CH2:7][CH2:6]1.[C:33]([O:36][C:37](=[O:39])[CH3:38])(=O)[CH3:34]>N1C=CC=CC=1>[C:37]([O:36][CH2:33][CH2:34][C:4](=[O:32])[C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C@H:9]3[C@H:19]([C:20](=[O:24])[CH2:21]2)[C@:17]2([CH3:18])[C@H:12]([CH2:13][C@H:14]([OH:25])[CH2:15][CH2:16]2)[CH2:11][CH2:10]3)[CH2:7][CH2:6]1)(=[O:39])[CH3:38]
Reactant: C[C@]12CC[C@@H](OC3CCCCO3)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CCO)[C@@]3(C)CC(=O)[C@@H]12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
21Hydroxymethyl-3α-tetrahydropyranyloxy-5α-pregnane-11,20- dione (600 mg) in anhydrous pyridine (12 ml) was treated with acetic anhydride (1.0 ml), and the solution was stirred at room temperature for 21/2 hours. The solution was partitioned between hydrochloric acid (2N, 100 ml) and ether/ethyl acetate 1/1, and the organic phase was washed with water, dried over sodium sulphate and evaporated to an oil (640 mg). The crude product (630 mg) was dissolved in I.M.S. (25 ml) and dilute hydrochloric acid (2N; 2.5 ml) was added. The solution was stirred at room temperature for 2 hours. The solution was neutralised with 10% potassium bicarbonate solution (5 ml) and concentrated by evaporation until an oily solid began to separate. The mixture was then diluted with water and extracted twice with ether/ethyl acetate 1/1. The combined organic extract was washed with water, dried over sodium sulphate and evaporated to a pale yellow oil (500 mg) which as purified by preparative t.l.c. in ethyl acetate/petrol 1/1. The main band, Rf 0.3 was separated to give 242 mg of solid which was recrystallized from ethyl acetate/petrol to give title compound (187 mg) as colourless plates, m.p. 113°-115°, [α]D + 103° (c 1.32).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1/[CH:21]=[CH:22]/[C:23](=[O:36])[CH2:24][C:25](=[O:35])/[CH:26]=[CH:27]/[C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1.[ClH:37]>C(OCC)(=O)C>[ClH:37].[ClH:37].[Br:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:5]=[CH:4][C:3]=1/[CH:21]=[CH:22]/[C:23](=[O:36])[CH2:24][C:25](=[O:35])/[CH:26]=[CH:27]/[C:28]1[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(/C=C/C(=O)CC(=O)/C=C/c3ccc(O)cc3)c(Br)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(/C=C/c1ccc(O)cc1)CC(=O)/C=C/c1ccc(N2CCNCC2)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of (1E,6E)-1-[2-bromo-4-(4-tert-butoxycarbonylpiperazin-1-yl)phenyl]-7-(4-hydroxyphenyl)hepta-1,6-diene-3,5-dione (35 mg, 0.063 mmol, synthesized in Example 126) in 1.0 mL of ethyl acetate was added 3M HCl (1.0 mL) at room temperature. After being stirred at room temperature overnight, the reaction mixture was concentrated in vacuo. The residue was treated with diethyl ether, and the resulting solid was collected by filtration. The solid was rinsed with ether, and dried under reduced pressure to obtain the title compound as a solid (28.0 mg, 84%).
Reaction SMILES: [CH2:1]([C:3]1[C:8]2[CH:9]3[CH:13]([CH2:14][CH2:15][C:7]=2[C:6]([O:18][CH3:19])=[C:5]([O:20][CH3:21])[CH:4]=1)[C:12](=[O:16])[NH:11][C:10]3=[O:17])[CH3:2].[CH2:22](I)[CH3:23]>>[CH2:22]([N:11]1[C:10](=[O:17])[CH:9]2[CH:13]([CH2:14][CH2:15][C:7]3[C:6]([O:18][CH3:19])=[C:5]([O:20][CH3:21])[CH:4]=[C:3]([CH2:1][CH3:2])[C:8]=32)[C:12]1=[O:16])[CH3:23]
Reactant: CCc1cc(OC)c(OC)c2c1C1C(=O)NC(=O)C1CC2
Reactant: CCI
Product: CCc1cc(OC)c(OC)c2c1C1C(=O)N(CC)C(=O)C1CC2

Procedure:
Using the procedure as in example 64, but starting with 9-ethyl-3a,4,5,9b-tetrahydro-6,7-dimethoxy-1H-benz[e]isoindole-1,3-(2H)-dione, and ethyl iodide in place of methyl iodide afforded the desired compound.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][C:3]=2[O:2]1.CC(C)=O.[I-:16].[Na+]>CCOCC>[CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][I:16])=[CH:4][C:3]=2[O:2]1
Reactant: [I-]
Reactant: ClCc1ccc2c(c1)OCO2
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: ICc1ccc2c(c1)OCO2
Reaction time: 2.5 h

Procedure:
11.65 g 3,4-methylenedioxybenzyl chloride in 128 ml of abs. acetone are treated with 49.7 g of sodium iodide, and this mixture is stirrred at RT for 2.5 h under argon and while excluding light. The reaction mixture is diluted with 1.5 l of ether, and this mixture is washed with 10% sodium thiosulfate solution (600 ml) and saline. The title compound is obtained after drying over sodium sulfate and removing the solvent. It is recrystallized from ether/hexane. m.p.: 51° C. TLC Rf (hexane:ethyl acetate, 4:1)=0.43. 1H-NMR (360 MHz, CDCl3): 6.93-6.77(m, 2H), 6.77-6.64(m,1H), 5.95(s, 2H), 4.44 (s,2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](I)[CH3:18]>CN(C=O)C>[CH2:17]([O:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1)=[O:10])[CH3:18]
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.1 %

Procedure:
To 2-amino-5-pyridine carboxylic acid (10.1 g, 73.0 mmol) in DMF (100 ml) at room temperature under argon was added potassium carbonate (10.1 g, 73.0 mmol) followed by ethyl iodide (8.8 ml, 110.0 mmol) 15 minutes later. The reaction mixture was heated on a steam bath for 2 hours, then additional potassium carbonate (2.0 g) and ethyl iodide (4.4 ml) were added. The reaction mixture was heated on a steam bath for 60 hours, cooled to room temperature and stirred for 24 hours. The reaction mixture was warmed on a steam bath for 20 minutes, the solution was filtered and the filtrate was concentrated in vacuo. The residue was taken up in water (350 ml), the solution was chilled and the precipitate that was obtained was collected by filtration and air dried. The filtrate was extracted with chloroform (3×200 ml), the organic layers were combined, dried over anhydrous MgSO4 and the solvents were removed in vacuo. Ether was added to the residue and the solution was chilled for 24 hours. The resulting white precipitate was collected by filtration, air-dried dried and combined with the previously collected precipitate to afford 6.2 g (51%) of 2-amino-5-pyridinecarboxylic acid ethyl ester as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.[Li]CCCC.[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:25]3[N:29]([CH3:30])[CH:28]=[N:27][CH:26]=3)=[O:24])[CH:21]=2)[N:16]=[C:15]([O:31][CH3:32])[C:14]=1[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=1>C1COCC1>[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:6]3[N:2]([CH3:1])[N:3]=[N:4][CH:5]=3)([C:25]3[N:29]([CH3:30])[CH:28]=[N:27][CH:26]=3)[OH:24])[CH:21]=2)[N:16]=[C:15]([O:31][CH3:32])[C:14]=1[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([C:40]([F:42])([F:41])[F:43])=[CH:38][CH:39]=1
Reactant: COc1nc2ccc(C(=O)c3cncn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: Cn1ccnn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3cncn3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -43 °C
Reaction time: 0.5 h

Procedure:
To a flask containing 1-methyl-1H-1,2,3-triazole (100 mg, 1.2 mmol) was added THF (10 mL) and the colorless solution was cooled to −43° C. using a CH3CN—CO2 bath. Then, n-BuLi (2.5 M in hexanes, 490 μL, 1.23 mmol) was added dropwise which afforded an opaque mixture. The mixture was stirred at −40° C. for 30 minutes, then a homogeneous solution of (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone (255 mg, 0.54 mmol, Intermediate 80: step b) in 2 mL THF was introduced. After 5 minutes, the reaction mixture was then placed in an ice-water bath. The reaction was quenched after 20 minutes with aqueous NH4Cl solution and the aqueous portion was extracted with EtOAc (3×30 mL) and EtOAc:THF (1:1, 30 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The solid was triturated with MeOH and filtered to give a yellow filtrate which was concentrated and chromatographed on silica gel (3% MeOH-DCM increasing to 10% MeOH) to afford the title compound. 1H NMR (500 MHz, CDCl3) δ 8.22 (d, J=2.1 Hz, 1H), 7.76 (d, J=8.7 Hz, 2H), 7.49 (d, J=8.1 Hz, 2H), 7.41-7.35 (m, 3H), 7.10 (s, 1H), 6.99 (s, 1H), 6.22 (s, 1H), 4.29 (s, 2H), 4.07 (s, 3H), 3.89 (s, 3H), 3.41 (s, 3H). MS (ESI): mass calcd. for Chemical Formula: C26H22ClF3N6O2; Exact Mass: 542.14. m/z found 542.9 [M+H]+.