Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:51])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][N:12]2[CH2:18][CH2:17][CH2:16][C@H:15]([N:19]([CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=3)[C:20]3[N:21]=[N:22][N:23]([CH3:25])[N:24]=3)[C:14]3[CH:41]=[C:42]([CH3:50])[C:43]([C:46]([F:49])([F:48])[F:47])=[C:44]([CH3:45])[C:13]2=3)[CH2:7][CH2:6]1>[OH-].[Na+].CO>[F:39][C:37]([F:38])([F:40])[C:29]1[CH:28]=[C:27]([CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=1)[CH2:26][N:19]([C:20]1[N:21]=[N:22][N:23]([CH3:25])[N:24]=1)[C@H:15]1[CH2:16][CH2:17][CH2:18][N:12]([CH2:11][CH:8]2[CH2:9][CH2:10][CH:5]([CH2:4][C:3]([OH:51])=[O:2])[CH2:6][CH2:7]2)[C:13]2[C:44]([CH3:45])=[C:43]([C:46]([F:47])([F:48])[F:49])[C:42]([CH3:50])=[CH:41][C:14]1=2
Reactant: COC(=O)CC1CCC(CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)c(C)c32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2c(c(C)c1C(F)(F)F)N(CC1CCC(CC(=O)O)CC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Yield: 66.7 %

Procedure:
Heat the mixture of (S)-(4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-cyclohexyl)-acetic acid methyl ester (0.0950 g, 0.129 mmol) in 5.0 N NaOH (1 mL) and methanol (2 mL) under reflux for 2 h. Evaporate the solvents and re-dissolve in water (10 mL). Adjust to pH=7 by adding 2.0 N HCl. Extract with ethyl acetate (2×10 mL). Combine organic layers, dry over anhydrous sodium sulfate and filter. Remove the solvent under reduced pressure. Chromatograph the residue over silica gel, eluting with ethyl acetate/hexanes (0-100%), to provide the title compound as a white foam (0.0620 g, 67%). MS (ES+): 721 (M+H); 719 (M−H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=O)[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([N:18]3[CH:22]=[CH:21]N=C3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:27]N(C)C=O.C(N)C#C>O>[Cl:1][C:2]1[C:7]2[CH2:8][N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH:18][CH2:22][C:21]#[CH:27])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Reactant: CN(C)C=O
Agent: C#CCN
Solvent: O
Product: C#CCNC(=O)c1ncn2c1[C@@H]1CCCN1Cc1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 54.7 g (148.7 mmol) of 1-[[(S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl]carbonyl]imidazole, 100 ml of N,N-dimethylformamide and 8.60 g (156.1 mmol) of propargylamine is stirred at room temperature overnight. The solution obtained is then poured into 500 ml of water, the resulting suspension is filtered under suction and the filter residue is dried. By recrystallization from methylene chloride and ethyl acetate there is obtained (S)-8-chloro-11,12,13,13a-tetrahydro-N-(2-propynyl)-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamide of melting point 233°-235°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]#[CH:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:21]=[CH:20][C:15]([CH2:16][N:17]=[N+:18]=[N-:19])=[CH:14][CH:13]=1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].O>CCOC(C)=O.O.O.O.O.O.[O-]S([O-])(=O)=O.[Cu+2].CC(O)(C)C>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[N:19]=[N:18][N:17]([CH2:16][C:15]3[CH:20]=[CH:21][C:12]([O:11][CH3:10])=[CH:13][CH:14]=3)[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN=[N+]=[N-])cc1
Reactant: C#Cc1ccnc(Br)c1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(Cn2cc(-c3ccnc(Br)c3)nn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
To a flask containing 2-bromo-4-ethynylpyridine (1 g, 5.49 mmol) was added 4-methoxybenzyl azide (896 mg, 5.49 mmol), CuSO4(H2O)5 (137 mg, 0.549 mmol), sodium ascorbate (544 mg, 2.75 mmol), water (13.7 mL) and tBuOH (13.7 mL) and the reaction was stirred for 16 h at rt. The reaction was diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO3 (1×20 mL) and brine (1×20 mL). The organic phase was dried (MgSO4), filtered, and purified by silica gel chromatography using a gradient solvent system of 30-70% EtOAc/Hexanes. Concentration of the product fractions yielded 2-bromo-4-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)pyridine (1.46 g, 77%) as a white powder. MS ESI calcd for C15H13BrN4O [M+H]+ 345, found 345.
Reaction SMILES: [F:1][C:2]([F:17])([S:13]([O-:16])(=[O:15])=[O:14])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].[OH:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([S+:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][C:20]=1[CH3:39].C(=O)([O-])[O-].[K+].[K+].CN(C)CCN(C)C.[CH:54]([O:56][CH2:57][CH2:58]Cl)=[CH2:55]>CS(C)=O>[F:17][C:2]([F:1])([S:13]([O-:16])(=[O:15])=[O:14])[C:3]([F:11])([F:12])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].[CH:54]([O:56][CH2:57][CH2:58][O:18][C:19]1[C:20]([CH3:39])=[CH:21][C:22]([S+:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:23][C:24]=1[CH3:25])=[CH2:55]
Reactant: C=COCCCl
Reactant: Cc1cc([S+](c2ccccc2)c2ccccc2)cc(C)c1O
Agent: CN(C)CCN(C)C
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CS(C)=O
Product: C=COCCOc1c(C)cc([S+](c2ccccc2)c2ccccc2)cc1C
Temperature: 80 °C
Reaction time: 47 h

Procedure:
4-Hydroxy-3,5-dimethylphenyldiphenylsulfonium perfluorobutanesulfonate salt (56.1 g), potassium carbonate (18.4 g), and N,N,N′,N′-tetramethylethylenediamine (1.07 g) were dissolved in dimethyl sulfoxide (118 g). Chloroethyl vinyl ether (14.2 g) was added to the solution, followed by heating to 80° C. The reaction mixture was stirred for 47 hours and cooled to 30° C. or lower. After removal of solid through filtration, water (280 g) was added to the filtrate, and the aqueous layer was washed three times with hexane (168 g). To the washed aqueous layer, dichloromethane (226 g) and water (50 g) were added under stirring, whereby the target substance was extracted to the dichloromethane layer. The organic layer was repeatedly washed with distilled water until the pH of the separated aqueous layer was shifted to 7. The solvent was removed by means of a rotary evaporator, to thereby yield 41.0 g of an oily substance. Through 1H-NMR and ion chromatography, the substance was identified to be 4-vinyloxyethoxy-3,5-dimethylphenyldiphenylsulfonium perfluorobutanesulfonate salt.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][NH:6][CH2:5][C@@H:4]1[C:9]([OH:11])=[O:10].[OH-].[Na+].N1CCNCC1C(O)=O.[C:23](Cl)([O:25][CH2:26][CH:27]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24].N1CCNCC1>O1CCOCC1.O1CCOCC1.O>[CH:38]1[C:39]2[CH:27]([CH2:26][O:25][C:23]([N:6]3[CH2:7][CH2:8][NH:3][C@@H:4]([C:9]([OH:11])=[O:10])[CH2:5]3)=[O:24])[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]=2[CH:35]=[CH:36][CH:37]=1
Reactant: O=C(O)[C@H]1CNCCN1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: C1CNCCN1
Agent: Cl
Agent: O=C(O)C1CNCCN1
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)[C@H]1CN(C(=O)OCC2c3ccccc3-c3ccccc32)CCN1
Temperature: 0 °C
Reaction time: 5.5 h
Yield: 73.4 %

Procedure:
Piperazine-2(R)-carboxylic acid dihydrochloride (5.95 g) was added to 50 mL dioxane/water (1:1). The solution was cooled in an ice bath and aqueous sodium hydroxide (10% w/v) solution was added drop-wise to adjust the pH to 9˜10. At this pH, piperazine-2-carboxylic acid dissolved completely. Then, Fmoc Chloride (2.46 g) in dioxane was added drop-wise to the ice-cooled solution of piperazine and the reaction mixture was stirred from 0° C. to RT over 5-6 hr. The mixture was poured into 800 ml of ice water and washed once with ether. Then the aqueous phase was acidified to pH 2-3 with 2N of HCl which precipitated a white solid. This solid was filtered and dried in vacuo to obtain 2.46 g of a white powder. MS (ESI pos.): 353 (M+H).
Reaction SMILES: [CH:1]12[CH2:11][CH:7]3[CH:8](C[CH2:10]1)[CH:3]([CH2:4][CH2:5][CH2:6]3)[CH2:2]2.F[C:13](F)(F)S(O)(=O)=O>>[CH3:13][C:5]12[CH2:4][CH:3]3[CH2:2][CH:1]([CH2:11][CH:7]([CH2:8]3)[CH2:6]1)[CH2:10]2
Reactant: C1CC2CC3CCC2C(C1)C3
Reactant: O=S(=O)(O)C(F)(F)F
Product: CC12CC3CC(CC(C3)C1)C2
Temperature: 80 °C
Yield: 90.5 %

Procedure:
A mixture of 7.5 g (0.05 mole) of tricyclo[5.3.1.03,8 ]-undecane (II) and 76 g (0.5 mole) of trifluoromethanesulfonic acid was heated at 80°C. for 30 hours under agitation. The reaction mixture was allowed to cool and then poured over 200 ml of ice water. The organic layer was separated and the water layer was extracted with methylene chloride. The methylene chloride extract was combined with the organic layer, and the mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with water, and dried over anhydrous sodium sulfate. Methylene chloride was distilled off and the residue was sublimed to obtain 6.8 g (yield: 90 wt.%) of 1-methyladamantane (II). All of the IR, NMR and MS spectra of the product were in agreement with those of the authentic sample.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:15]=[C:14]([CH3:16])[S:13][C:4]=2[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[CH3:17][N:18]1[CH2:23][CH2:22]N[CH2:20][CH2:19]1>CC(O)C>[CH3:16][C:14]1[S:13][C:4]2[NH:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=[C:2]([N:1]3[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]3)[C:3]=2[CH:15]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Solvent: CC(C)O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 80 %

Procedure:
4-Amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine (50 g, 0.19 mol), N-methylpiperazine (125 mL, 2.5 vol) and 2-propanol (150 mL, 3 vol) were charged into a three-necked round bottom flask, equipped with reflux condenser, overhead stirrer, and thermometer. The reaction mixture was heated to reflux (about 100° C.) slowly under a nitrogen atmosphere and then refluxed overnight. The reaction mixture was allowed to cool slowly to below 40° C. (about 1 h), whereupon solid precipitates out. This precipitate was then isolated by filtration and the resulting light yellow solid was twice washed with 2-propanol (100 mL). The light yellow solid was stirred with water (4 volumes) for 2.5 hours, filtered, and the resulting solid, was washed twice with water (2 volumes) and dried to furnish olanzapine (47 g, 80%).
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[O:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:9]=2[O:8][CH:7]=[CH:6]1.C(N(CC)CC)C.O>CN(C)C=O>[O:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([N:15]3[CH2:20][CH2:19][N:18]([CH2:2][C:3]#[N:4])[CH2:17][CH2:16]3)[C:9]=2[O:8][CH2:7][CH2:6]1
Reactant: C1=COc2c(cccc2N2CCNCC2)O1
Reactant: N#CCBr
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCN1CCN(c2cccc3c2OCCO3)CC1
Yield: 99 %

Procedure:
A solution of bromoacetonitrile (2.38 g, 19.86 mmol), benzodioxin-5-ylpiperazine (5.1 g, 19.86 mmol) and triethylamine (11.05 mL, 79.4 mmol) in dimethylformamide (50 mL) was stirred under a nitrogen atmosphere at 70° C. for 3 days. Water (300 mL) was added and the product extracted into ethyl acetate (6×50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL) and dried over anhydrous sodium sulfate. Filtration and concentration on a rotary evaporator gave the desired compound as a light yellow oil which solidified on standing (5.1 g, 99% yield). The compound was isolated as its hydrochloride salt by treatment in ethyl acetate with ethereal HCl to yield a light yellow solid, mp=193-194° C.; MS (+) ESI m/z=260 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[O:8][C:9]3[C:14]([C:15]4([CH:19]([CH2:20][O:21][CH3:22])[S:18][C:17]([NH2:23])=[N:16]4)[C:4]=2[CH:3]=1)=[CH:13][C:12]([C:24]1[C:25]([F:30])=[N:26][CH:27]=[CH:28][CH:29]=1)=[CH:11][CH:10]=3.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:39][C:40]1[CH:45]=[C:44](B(O)O)[CH:43]=[CH:42][N:41]=1.O1CCOCC1>CCOC(C)=O.O.C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1N(C)C)(C)(C)C.C(Cl)Cl>[F:30][C:25]1[C:24]([C:12]2[CH:13]=[C:14]3[C@@:15]4([C@@H:19]([CH2:20][O:21][CH3:22])[S:18][C:17]([NH2:23])=[N:16]4)[C:4]4[CH:3]=[C:2]([C:44]5[CH:43]=[CH:42][N:41]=[C:40]([F:39])[CH:45]=5)[N:7]=[CH:6][C:5]=4[O:8][C:9]3=[CH:10][CH:11]=2)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: COCC1SC(N)=NC12c1cc(-c3cccnc3F)ccc1Oc1cnc(Cl)cc12
Reactant: OB(O)c1ccnc(F)c1
Agent: CN(C)c1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC[C@H]1SC(N)=N[C@]12c1cc(-c3cccnc3F)ccc1Oc1cnc(-c3ccnc(F)c3)cc12
Temperature: 135 °C
Yield: 64.6 %

Procedure:
To a vial was added 3-chloro-7-(2-fluoropyridin-3-yl)-5′-(methoxymethyl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-thiazol]-2′-amine (715 mg, 1.61 mmol), potassium phosphate (1.20 g, 5.65 mmol), (2-fluoropyridin-4-yl)boronic acid (910 mg, 6.46 mmol), and then dioxane (8.1 mL) and water (2.7 mL) were added. The mixture was purged with N2 and finally 1,1-bis[(di-t-butyl-p-dimethylaminophenyl]palladium(II) chloride (114 mg, 0.16 mmol) was added. The resulting mixture was then heated 135° C. in a microwave for 15 min. The reaction mixture were diluted with EtOAc and water. The organic extract was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the crude material as a orange solid. Small amount of DCM was added and light brown precipitate formed. After filtration through Buchner funnel gave (4′S,5′S)-7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-5′-(methoxymethyl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-thiazol]-2′-amine (523 mg, 1.04 mmol, 64% yield) as light brown solid.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:11][C:10]=2[F:24])[C:6]2[S:25][C:26]([CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:27][C:5]=2[C:4](=[O:33])[NH:3]1.Br[CH2:35][C:36]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)=[O:37].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[F:24][C:10]1[CH:11]=[C:12]([C:16]2[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:13]=[C:14]([F:15])[C:9]=1[CH2:8][N:7]1[C:6]2[S:25][C:26]([CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:27][C:5]=2[C:4](=[O:33])[N:3]([CH2:35][C:36]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)=[O:37])[C:2]1=[O:1]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: N#Cc1ccccc1-c1cc(F)c(Cn2c(=O)[nH]c(=O)c3cc(CC(F)(F)F)sc32)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Cn2c(=O)c3cc(CC(F)(F)F)sc3n(Cc3c(F)cc(-c4ccccc4C#N)cc3F)c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
To a mixture of 4′-{[2,4-dioxo-6-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}-3′,5′-difluorobiphenyl-2-carbonitrile (0.65 g), 2-bromo-1-(4-methoxyphenyl)ethanone (0.34 g) and N,N-dimethylformamide (15 mL) was added 60% sodium hydride (0.082 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.5 g, 59%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:19][N:20]([CH3:26])[CH:21]1[CH2:25][CH2:24][NH:23][CH2:22]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:23]2[CH2:24][CH2:25][CH:21]([N:20]([CH3:26])[CH3:19])[CH2:22]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Reactant: CN(C)C1CCNC1
Product: CN(C)C1CCN(c2nc(Cl)nc3c2CCC3c2ccc(F)cc2)C1
Yield: 85.6 %

Procedure:
2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) (100 mg, 0.353 mmol) and N,N-dimethylpyrrolidin-3-amine (44.3 μL, 0.353 mmol) were combined and purified as per Preparation Hb to give 1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N,N-dimethylpyrrolidin-3-amine (109 mg, 86% yield). LC-MS (M+H)+=361.2.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C@H:5]([NH2:10])[C:6]([O:8][CH3:9])=[O:7])[CH3:3].Cl.C(N(CC)CC)C.[NH:19]([C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[C@H:20]([C:24](O)=[O:25])[CH:21]([CH3:23])[CH3:22].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[NH:19]([C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[C@H:20]([C:24]([NH:10][C@H:5]([C:6]([O:8][CH3:9])=[O:7])[CH2:4][CH:2]([CH3:3])[CH3:1])=[O:25])[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
19.9 g (110 mmols) of H-Leu-OMe. HCl are dissolved in 120 ml of dimethylformamide and 14.6 ml (105 mmols) of triethylamine are added at 0°C. The precipitated triethylamine hydrochloride is filtered off, the filtrate is added to a solution of 25.1 g (100 mmols) of Z-Val-OH in 200 ml of dimethylformamide (0°C), and 22.6 g (110 mmols) of dry dicyclohexylcarbodiimide are then added. After 1 hour's stirring at 0°C and standing overnight in the refrigerator the mixture is filtered and the solution evaporated in a high vacuum at 40°C. The oily residue is taken up in 30 ml of ethyl acetate, and the solution is cooled to 0°C and freed of precipitated dicyclohexylurea. After adding n-hexane the product crystallises out from the filtrate overnight. Melting point 102°-105°C; [α]D : -41° (c = 2.88 in methanol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][OH:11].N1C=CN=C1.[CH:17]([Si:20](Cl)([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])([CH3:19])[CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][O:11][Si:20]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COc1ccc(Br)c(CO)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc(Br)c(CO[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
(2-Bromo-5-methoxyphenyl)methanol (1 eq.) was dissolved in anhydrous DMF (1.1M solution) and imidazole (1.05 eq.) was added. To the stirred solution triisopropylsilyl chloride (1.1 eq.) was added and the resulting mixture was left stirring at RT for 8 h. All volatiles were evaporated in vacuo and the residual material was filtered with PE/EtOAc (9:1) over a pad of silica gel. After evaporation in vacuo the product was obtained as a colorless oil (94%), which was used without further characterization in the next reaction.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.CCCCCCC.[CH3:16][O:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][CH2:23][C:24]2=O)=[CH:20][CH:19]=1.Cl>C1COCC1>[CH3:16][O:17][C:18]1[CH:26]=[C:25]2[C:21](=[CH:20][CH:19]=1)[CH2:22][CH:23]=[C:24]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: Brc1cccc(I)c1
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: COc1ccc2c(c1)C(c1cccc(Br)c1)=CC2
Reaction time: 24 h

Procedure:
To a solution of 1-bromo-3-iodobenzene (339 mmol) in 600 ml of anhydrous THF at −40° C. is added dropwise a 1 M n-dibutylmagnesium solution in heptane (185 mmol). 6-Methoxyindanone (154 mmol) is then added by small portions at −40° C. Stirring continues for 24 hours as the mixture returns to room temperature. After hydrolysis with 300 ml of 1 N HCl, the aqueous phase is extracted 2 times with ethyl acetate. The organic phases are combined, dried on sodium sulfate, concentrated and given form in isopropyl ether to obtain the expected product.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O[C:15](=[O:31])[C:16](=[CH:22][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[I:30])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:20]([O:19][C:17]([C:16]1[C:15](=[O:31])[C:29]2[C:24](=[C:25]([I:30])[CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)C(=CNc1ccccc1I)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2c(I)cccc2c1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46 %

Procedure:
In a 2-neck round bottomed flask (250 mL), phenylether (60 mL) was put to reflux on a heating mantel. When it started boiling, p-toluenesulfonic acid (0.140 g) was added. 2-[(2-iodo-phenylamino)-methylene]-malonic acid diethyl ester was dissolved in phenylether (20 mL) and the mixture was poured into the boiling solvent. The mixture was refluxed for 3 h. The crude was transferred to a bequer and cooled to room temperature. Hexanes (600 mL) were added and a precipitate was observed. The mixture was stirred for 5 min, followed by filtration of the solid and thorough wash with hexanes to afford 8-iodo-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester as a grayish solid (2 g, 46%). 1H NMR (DMSO-d6, 400 MHz) δ 1.43 (t, 3H), 4.39 (q, 2H), 7.36 (t, 1H), 8.32 (d, 1H), 8.37 (d, 1H), 8.63 (s, 1H), 11.4 (s, 1H). Exact mass calculated for C12H10INO3 342.97, found 343.9 (MH+).
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:17]O.[CH2:24]([N:26](CC)CC)C.[C-]#N.[Na+].C1OCCOCCOCCOCCOC1>C(Cl)Cl.O>[CH3:6][O:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:17][C:24]#[N:26]
Reactant: CCN(CC)CC
Reactant: CCCCCC(CO)c1ccc(OC)cc1OC
Agent: C1COCCOCCOCCOCCO1
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Solvent: ClCCl
Solvent: O
Product: CCCCCC(CC#N)c1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.9 %

Procedure:
0.68 ml (8.79 mmol) of methanesulfonyl chloride was added to a solution of 2.01 g (7.97 mmol) of (-)-2-(2,4-dimethoxyphenyl)heptanol [prepared as described in step (i) above] in 20 ml of methylene chloride, and then 1.3 ml (9.33 mmol) of triethylamine were added dropwise to the resulting mixture over a period of 2 minutes, whilst ice-cooling. The resulting mixture was then stirred at the same temperature for 15 minutes, after which it was mixed with water and then extracted with diethyl ether. The extract was washed with 2 N aqueous hydrochloric acid, with water, with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was dissolved in 10 ml of dimethylformamide, and to the resulting solution were added 611 mg (12.4 mmol) of sodium cyanide and 0.80 ml (4.0 mmol) of 15-crown-5. The resulting mixture was then stirred at 50° C. for 1 hour and then at 100° C. for 1 hour. At the end of this time, the reaction mixture was cooled to room temperature, after which it was mixed with water and then extracted with diethyl ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 150 g of silica gel using a gradient elution method, with mixtures of ethyl acetate and hexane ranging from 1:10 to 1:5 by volume as the eluent, to give fractions containing a pure compound. Fractions containing impure products were repeatedly subjected to column chromatography under the same conditions as above. A total of 1.58 g (yield 75%) of the title nitrile derivative was obtained as an oily substance.