Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1[C:7]([C:8]([N:10]([CH3:14])[CH2:11][C:12]#[CH:13])=[O:9])=[C:6]([Cl:15])[N:5]=[CH:4]N=1>[N+](C1C=CC=CC=1)([O-])=O>[Cl:15][C:6]1[C:7]2[C:8](=[O:9])[N:10]([CH3:14])[CH2:11][C:12]=2[CH:13]=[CH:4][N:5]=1
Reactant: C#CCN(C)C(=O)c1c(Cl)ncnc1Cl
Solvent: O=[N+]([O-])c1ccccc1
Product: CN1Cc2ccnc(Cl)c2C1=O
Yield: 55.8 %

Procedure:
A solution of 4,6-dichloro-N-methyl-N-(prop-2-yn-1-yl)pyrimidine-5-carboxamide (Compound 310F, 7.6 g, 31 mmol) in Nitrobenzene (76 mL) was evacuated and purged with argon (3×). The reaction mixture was irradiated in the microwave for 1.5 minutes at 250° C. The reaction mixture was filtered through a pad of celite. The nitrobenzene solution was passed through a silica gel plug and washed with DCM to remove the nitrobenzene. The silica was then washed with DCM/MeOH solution (90:10). The filtrated was concentrated under reduced pressure to yield a red solid. The crude material was purified by silica gel chromatography on a combi-flash Rf system using DCM/MeOH (100:0→95:5) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield an orange solid (3.1598 g, 56%). 1H NMR (DMSO-d6, 400 MHz): δ=8.53 (d, J=5.05 Hz, 1H), 7.70 (d, J=5.05 Hz, 1H), 4.53 (s, 2H), 3.05 (s, 3H). MS (ES+): m/z 183.02 [MH+] (TOF, polar).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[N:9].[S:10]([O-])([O-:12])=[O:11].[Na+:14].[Na+]>CCO.O>[Na+:14].[C:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:10]([O-:12])=[O:11])#[N:9]
Reactant: N#CCCCCCCBr
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCCCCCCS(=O)[O-]
Yield: 36 %

Procedure:
##STR13## In a three necked flask, fitted with a water condenser, a mechanical stirrer and a dropping funnel a solution of 1-bromo-6-cyanohexane (8.04 g, 42.3 mmol) was placed in 75 mL of 95% EtOH. The mixture was heated to reflux and to it was slowly added a solution of sodium sulfite (8.00 g, 63.5 mmol) in 50 mL of H2O over a period of 30 min. The mixture was heated for 2 h and then concentrated under reduced pressure. The residue was dissolved in 95% EtOH (200 ml), heated to boiling and filtered. The filtrate was concentrated and cooled in an ice bath. The precipitate was collected by filtration and dried to give 3.00 g of a white solid. The mother liquor on further concentration, produced another batch of 2.2 g of the product. 1H NMR (300 MHz, DMSO-d6) δ 2.50 (t, j=8 Hz, 2H), 2.40(t, 8 Hz, 2H), 1.55 (m, 4H), 1.3(m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[S:10][C:3]=12.CNC.N1CC[CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:15][CH2:21][CH2:20][CH2:14]3)=[O:12])[S:10][C:3]=12
Reactant: CN(C)C(=O)c1cc2nccc(Cl)c2s1
Reactant: C1CCNC1
Agent: CNC
Product: O=C(c1cc2nccc(Cl)c2s1)N1CCCC1

Procedure:
Following the procedures described above for the synthesis of compound 5 (scheme 1, example 1) but replacing dimethyl amine in the step 4 for pyrrolidine, title compound 139 was obtained. LRMS (M+1) 267.1 (100%).
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH:24][CH3:25])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>ClCCl>[CH:1]1([CH2:7][C@@H:8]([N:24]([CH3:25])[C:39]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:40])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:12][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CN[C@H](CC1CCCCC1)CN1CCN(c2ccccc2OC)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C[C@@H](CC2CCCCC2)N(C)C(=O)C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.4 %

Procedure:
To a solution of 0.30 g (0.87 mmol) of {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl}-methyl-amine and 0.25 mL (1.74 mmol) of triethylamine in 10 mL of dichloromethane at 0° C. was added dropwise 0.19 g (1.31 mmol) of cyclohexanecarboxylic acid chloride in 4 mL of dichloromethane. The reaction mixture was allowed to stir under nitrogen overnight at ambient temperature, and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and then converted to the dihydrochloride salt with ethanolic HCl to yield 0.41 g (89%) of the title compound as a white solid; mp=222-224° C.; MS(+)ESI m/z=456 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[N:3]1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[F:44])[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C(=O)C>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:41]=[CH:42][C:43]([F:44])=[C:22]([NH:21][C:7]([C:4]5[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=5)=[O:9])[CH:23]=4)=[N:31][N:30]3[CH:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: Cn1ccc(C(=O)O)n1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1ccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
To a solution of 1-methyl-1H-pyrazole-3-carboxylic acid (115 mg, 0.92 mmol) in tetrahydrofuran (4.0 mL) were added N,N-dimethylformamide (20 μL, 0.26 mmol) and oxalyl chloride (80 μL, 0.92 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was added to a solution of N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol) in N,N-dimethylacetamide (4.0 mL), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure and ethanol (10 mL) was added to the residue. The mixture was stirred with heating at 75° C. and cooled to room temperature, and the precipitate was collected by filtration to give the title compound (144 mg, 54%) as a white powder.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][N:16]2[C:18]([CH2:21][CH2:22][OH:23])=[CH:19][N:20]=[C:15]2[C@H:14]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:13][CH2:12]1.I[CH3:33]>O1CCCC1>[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][N:16]2[C:18]([CH2:21][CH2:22][O:23][CH3:33])=[CH:19][N:20]=[C:15]2[C@H:14]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CCO)cnc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCc1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.3 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 4.0 mg, 0.112 mmol) was added to a solution of tert-butyl (6S,9R)-6-(2,3-difluorophenyl)-3-(2-hydroxyethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (19 mg, 0.047 mmol) and iodomethane (3.0 μL, 0.051 mmol) in tetrahydrofuran (0.5 mL) at 0° C., and the mixture was allowed to warm to ambient temperature. After 18 h, additional sodium hydride (2.0 mg, 0.056 mmol) and iodomethane (3.0 μL, 0.051 mmol) were added. After 1 h, the reaction was quenched with water. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (2×). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (100% dichloromethane→94% dichloromethane/methanol) gave the title compound (6 mg). MS 422.1 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[CH2:25]([O:32][C:33]1[CH:40]=[C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:38]=[CH:37][C:34]=1[CH:35]=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCCCC>ClCCl>[CH2:25]([O:32][C:33]1[CH:40]=[C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:38]=[CH:37][C:34]=1[CH:35]=[C:20]([Br:24])[Br:21])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Solvent: ClCCl
Product: BrC(Br)=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
A mixture of triphenylphosphine (15.7 g) and carbon tetrabromide (9.93 g) in dry dichloromethane (100 mL) is cooled to 0° C. and stirred for 30 minutes. A solution of 2,4-dibenzyloxybenzaldehyde (4.76 g) in dichloromethane (30 mL) is added and the solution stirred at 0° C. for 2 hours. The solution is treated with pentane to precipitate triphenylphosphine oxide. The filtrate is evaporated to give 1-(2,4-dibenzyloxyphenyl)-2,2-dibromoethylene as a yellow oil (4.85 g, 67%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([OH:13])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.Br[CH:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([O:13][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11]2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:20]
Reactant: COc1ccc2cccc(O)c2n1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Oc1cccc2ccc(OC)nc12)C(=O)OCC
Temperature: 80 °C
Yield: 75 %

Procedure:
To a solution of 2-methoxy-quinolin-8-ol (commercial; 1.75 g, 10 mmol) and diethyl bromomalonate (1.85 mL, 10 mmol) in DMF (35 mL) was added Cs2CO3 (6.52 g, 20 mmol). The reaction mixture was heated at 80° C. for 1.5 h then allowed to cool to rt. The reaction mixture was filtered and the filtrate concentrated to dryness. The residue was purified by CC (EA-Hept 1:3 to 1:1) to give the title compound as a yellowish oil (2.50 g, 75% yield).
Reaction SMILES: [CH3:1][C:2]([OH:11])([CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].[CH3:12][C:13]([CH3:15])=O>C1C=CC=CC=1>[CH3:12][C:13]1([CH3:15])[O:11][C:2]([CH3:1])([CH3:10])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:9]1
Reactant: CC(C)(O)c1ccccc1N
Reactant: CC(C)=O
Solvent: c1ccccc1
Product: CC1(C)Nc2ccccc2C(C)(C)O1
Yield: 27.2 %

Procedure:
A solution of 15 g (0.1 mol) α,α-dimethyl-2-aminobenzyl alcohol and 5.7 g (0.1 mol) acetone in 120 ml of benzene was heated under reflux in a Dean-Stark trap for 3 hours. About 1.5 ml of water was separated from the reaction mixture. The benzene solution was then evaporated to give an oil which solidified on standing. Recrystallization from ethanol-water gave 5.2 g 2,2,4,4-tetramethyl-1,2-dihydro-4H-3,1-benzoxazine, as a white solid.
Reaction SMILES: CN(C)C=O.[CH3:6][N:7]([CH2:14][CH2:15][OH:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.F[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.CC(C)([O-])C.[K+]>O>[CH3:6][N:7]([CH2:14][CH2:15][O:16][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CN(CCO)c1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CCOc1ccc(C=O)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.9 %

Procedure:
In a 2l three necked, round bottom flask, 500 ml dimethylformamide is added, followed by addition of 100 g of 2-(N-methyl-N-(2-pyridyl)amino)ethanol (II) and 100 g of 4-fluorobenzaldehyde (III) was added to the reaction mixture and it was stirred for 10 minutes at room temperature and 80 g of potassium tertiary butoxide was added to the reaction mixture. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to 5-10° C. and under the cold conditions, 1.5 l of water was added and stirred for 15 min. The mixture was extracted with 4×500 ml of ethyl acetate. The combined organic layer was washed with 3×1 l water. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to give 148 g (88%) of 4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy)benzaldehyde (IV).
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[N:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4([OH:23])[CH2:22][CH2:21][CH2:20]4)[N:14]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH3:24][C:25]1[N:26]=[CH:27][S:28][CH:29]=1>>[CH3:24][C:25]1[N:26]=[C:27]([C:2]2[C:3]3[N:11]=[N:10][N:9]([CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([C:19]5([OH:23])[CH2:22][CH2:21][CH2:20]5)[N:14]=4)[C:4]=3[N:5]=[C:6]([NH2:8])[N:7]=2)[S:28][CH:29]=1
Reactant: Nc1nc(Cl)c2nnn(Cc3cccc(C4(O)CCC4)n3)c2n1
Reactant: Cc1cscn1
Product: Cc1csc(-c2nc(N)nc3c2nnn3Cc2cccc(C3(O)CCC3)n2)n1

Procedure:
This is prepared from 7-chloro-3-(6-[1-hydroxycyclobutyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine and 4-methylthiazole by the method of Example 38.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1.Cl[C:25]1[C:30]2[N:31]=[CH:32][N:33]([CH3:34])[C:29]=2[CH:28]=[CH:27][N:26]=1>>[CH3:34][N:33]1[C:29]2[CH:28]=[CH:27][N:26]=[C:25]([NH:2][C:3]3[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=3)[CH2:6][NH:7][C:8]3[C:17]4[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][N:9]=3)[C:30]=2[N:31]=[CH:32]1
Reactant: NC(=O)c1cccc2c(NCc3cccc(N)c3)ncnc12
Reactant: Cn1cnc2c(Cl)nccc21
Agent: Cl
Product: Cn1cnc2c(Nc3cccc(CNc4ncnc5c(C(N)=O)cccc45)c3)nccc21
Reaction time: 10 h

Procedure:
The title compound was prepared according to Example 549 starting 4-(3-Amino-benzylamino)-quinazoline-8-carboxylic acid amide hydrochloride and 4-Chloro-1-methyl-1H-imidazo[4,5-c]pyridine. Reaction conditions: 120° C. in the microwave for 10 h:
Reaction SMILES: [CH2:1]=[C:2]([C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1)[C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)=[O:4].O1CCOCC1>[Pd].C(OCC)C>[CH3:25][C:21]1([CH3:26])[CH2:20][CH2:19][C:18]([CH3:27])([CH3:28])[C:17]2[CH:16]=[C:15]([CH:2]([CH3:1])[C:3]([NH:5][C:6]3[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:13][CH:14]=3)=[O:4])[CH:24]=[CH:23][C:22]1=2
Reactant: C=C(C(=O)Nc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C(=O)Nc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
650 mg (1.7 mmol) of 4-(α-methylene-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylacetamido)benzoic acid, 100 mg of palladium on charcoal (10%) and 100 ml of dioxane are introduced into a reactor. The mixture is hydrogenated at room temperature and under a pressure of 7 bars for 2 h, the catalyst is filtered off and the filtrate is evaporated. The residue obtained is ground in the minimum amount of ethyl ether, filtered off and dried. 580 mg (89%) of acid, melting point 195°-6° C., is obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:32](OCC)(=[O:38])[C:33]([O:35][CH2:36][CH3:37])=[O:34].[Cl-].[NH4+]>O1CCCC1>[CH2:36]([O:35][C:33](=[O:34])[C:32]([C:15]1[C:16]([NH:20][C:21](=[O:26])[C:22]([CH3:23])([CH3:25])[CH3:24])=[CH:17][CH:18]=[CH:19][C:14]=1[N:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]1)=[O:38])[CH3:37]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(C)(C)C(=O)Nc1cccc(N2CCN(Cc3ccccc3)CC2)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1c(NC(=O)C(C)(C)C)cccc1N1CCN(Cc2ccccc2)CC1
Temperature: 15 °C
Reaction time: 3 h
Yield: 48.5 %

Procedure:
Under a nitrogen atmosphere, a solution of N-[3-(4-benzyl-piperazin-1-yl)-phenyl]-2,2-dimethyl-propionamide (2.4 g, 6.8 mmol) and N,N,N′N′-tetramethylethylenediamine (3.2 g, 27.4 mmol) in tetrahydrofuran (24 mL) was stirred for 15 minutes at 0° C., n-butyllithium (2.5M in hexane) (11 mL, 27.5 mmol) was added dropwise, and the mixture stirred for 3 hours at 15° C. The mixture was then cooled to −78° C., and diethyl oxalate (4.0 g, 27.4 mmol) was added. The mixture was stirred at −20° C. for 30 minutes, poured into a saturated aqueous solution of ammonium chloride (50 mL), and the product extracted into ethyl acetate (3×30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum to yield 4.5 g of crude product as a light brown oil. Purification by chromatography (150 g silica gel, 2% methanol in chloroform) afforded the title compound (1.5 g, 3.3 mmol, 49% yield) as a straw colored oil; this compound was confirmed by the following mass spectrometry results: EI M+ @ m/z 451 and (+)FAB [M+H]+ @ m/z 452, [M+Na]+ @ m/z 474.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([SH:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:12]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:10]2[O:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Sc1nc2cccc(Br)c2o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1nc2cccc(Br)c2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 6 g (26.1 mmol) 7-bromo-benzooxazole-2-thiol, 7.28 g (52.2 mmol) K2CO3, 4.1 g (28.7 mmol) MeI in 80 ml DMF is stirred at room temperature for 1 h. The reaction mixture is then poured on water and extracted 2× with EtOAc. The combined organic layers are washed with water and saturated NaCl solution, dried over MgSO4, filtered and the filtrate is concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:24]=[CH:23][C:22]2[C@H:12]3[CH2:13][CH2:14][C@@:15]4([CH3:21])[C@H:19]([C@@H:11]3[CH2:10][CH2:9][C:8]=2[CH:7]=1)[CH2:18][CH2:17][C:16]4=[O:20])[CH:2]([CH3:4])[CH3:3].C(OC1C=CC2[C@H]3CC[C@@]4(C)[C@H]([C@@H]3CCC=2C=1)CCC4=O)CC>>[CH2:1]([O:5][C:6]1[CH:24]=[CH:23][C:22]2[C:12]3=[CH:13][CH2:14][C@@:15]4([CH3:21])[C@H:19]([C@@H:11]3[CH2:10][CH2:9][C:8]=2[CH:7]=1)[CH2:18][CH2:17][C:16]4=[O:20])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: CCCOc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: CC(C)COc1ccc2c(c1)CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 80.5 %

Procedure:
The procedure described in Example 10 hereinbefore was repeated except that 1 gram of 3-isobutoxy-13β-methylgona-1,3,5(10)-trien-17-one was substituted for the 3-n-propoxy-13β-methylgona-1,3,5(10)-trien-17-one that was used in that example. In this manner, 0.8 gram of 3-isobutoxy-13β-methylgona-1,3,5(10),9(11)-tetraen-17-one was obtained after distillation of the dichloromethane from the electrolyzed solution and precipitation by adding a small amount of water to the remaining solution. This compound, after recrystallization from a mixture of dichloromethane and methanol, had a melting point of 107°-108° C. and a specific optical rotation of +257.5° at a temperature of 25° C. for the sodium D line.
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.FC(F)(F)S(O)(=O)=O.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[C:27]([F:34])[CH:26]=1.C(=O)([O-])O.[Na+].[C:40](#[N:42])[CH3:41]>>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[O:33][C:40]([CH3:41])=[N:42][CH:32]=2)=[C:27]([F:34])[CH:26]=1
Reactant: CC#N
Reactant: CC(=O)c1ccc(Br)cc1F
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Product: Cc1ncc(-c2ccc(Br)cc2F)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of iodobenzene diacetate (6.7 g) in acetonitrile (100 mL) was added dropwise trifluoromethanesulfonic acid (3.7 mL), and the mixture was stirred at room temperature for 30 min. A mixture of 1-(4-bromo-2-fluorophenyl)ethanone (6.7 g) in acetonitrile (20 mL) was added to the reaction mixture, and the mixture was heated under reflux for 2 hr. The reaction mixture was allowed to cool to room temperature, and neutralized with saturated aqueous sodium hydrogen carbonate solution, and the solvent was evaporated under reduced pressure. The residue was extracted with ethyl acetate, the extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.6 g).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:7]([CH2:15][CH3:16])=[N:8][N:9]([CH2:13][CH3:14])[C:10]=1[CH2:11][CH3:12])C.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[CH2:13]([N:9]1[C:10]([CH2:11][CH3:12])=[C:6]([CH2:5][CH:4]=[O:3])[C:7]([CH2:15][CH3:16])=[N:8]1)[CH3:14]
Reactant: CCOC(=O)Cc1c(CC)nn(CC)c1CC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CCc1nn(CC)c(CC)c1CC=O
Reaction time: 5 h

Procedure:
Cool a solution of (1,3,5-triethyl-1H-pyrazol-4-yl)-acetic acid ethyl ester (0.92 g, 3.86 mmol) in tetrahydrofuran (50 mL) to −78° C. and add diisobutylaluminum hydride (16.2 mL, 16.2 mmol, 1 M in toluene) dropwise. Stir the resulting mixture for 5 hr. at −78° C. Quench the reaction mixture with saturated aqueous potassium sodium tartrate solution (30 mL) and ethyl acetate (100 mL) and stir at room temperature for 16 hr. Separate the organic layer; dry (sodium sulfate), filter and concentrate to give the title preparation as an oil (0.65 g, 87%). 1H-NMR (400 MHz, CDCl3) δ 9.57 (t, 1H), 4.01 (q, 2H), 3.38 (d, 2H), 2.57 (q, 4H), 1.39 (t, 3H), 1.20 (t, 3H), 1.15 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].[H][H]>[Pd].C(OCC)(=O)C>[NH2:8][C:7]1[C:2]([CH3:1])=[C:3]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1c(N)cccc1NS(C)(=O)=O
Yield: 84 %

Procedure:
The crude product from Example 1A and 10% palladium on carbon (1.4 g) were stirred vigorously in ethyl acetate (70 mL) for 24 hours under one atmosphere of hydrogen. The reaction was placed under a nitrogen atmosphere, filtered through a 1 inch pad of 1:1 Celite:silica gel eluting with ethyl acetate and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, ethyl acetate) to provide the title compound as a brown solid (11.06 g, 84%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[CH:6][O:7]2.C([O-])([O-])=O.[K+].[K+].[CH2:28](Br)[C:29]#[CH:30]>CC(C)=O>[C:28]([O:12][C:10]1[CH:9]=[C:8]2[C:3]([C:4](=[O:21])[C:5]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[CH:6][O:7]2)=[C:2]([OH:1])[CH:11]=1)#[C:29][CH3:30]
Reactant: C#CCBr
Reactant: COc1ccc(-c2coc3cc(O)cc(O)c3c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC#COc1cc(O)c2c(=O)c(-c3ccc(OC)cc3)coc2c1

Procedure:
A mixture of 5,7-dihydroxy-4′-methoxyisoflavone (2.84 g, 0.01 mol), K2CO3 (2.8 g, 0.02 mol), Kl (0.166 g, 0.001 mol), propargyl bromide (1.78 g 0.015 mol) and acetone (100 mL) was refluxed 10 h and hot filtered. The solvent was evaporated and the residue was crystallized by toluene. This yields 2.25 g of a product with the following characteristics: m.p. 174-176° C.; 1H NMR (CDCl3) δ: 2.6 (m, 1H), 3.86 (s, 3H), 4.8 (s, 2H), 647-7.91 (m, 7H), 12.90 (s, 1H).