Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=O)[C@:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(C)[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.CO[CH2:23][CH2:24]O[AlH2-]OCCOC.[Na+]>C1(C)C=CC=CC=1>[CH:5]1([CH2:4][C@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH2:2][NH:1][CH2:23][CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@@](C)(CC1CCCCC1)C(N)=O
Reactant: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCNC[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-tert-butyl 1-amino-3-cyclohexyl-2-methyl-1-oxopropan-2-ylcarbamate To a solution of (S)-tert-butyl 1-amino-3-cyclohexyl-2-methyl-1-oxopropan-2-ylcarbamate (811 mg, 2.85 mmol) in anhydrous toluene (15 mL) at 0° C. was added Red-Al (65%, 2.66 g, 2.6 mL, 8.55 mmol) within 20 min. After the addition, the reaction was allowed to be stirred at room temperature overnight. The reaction was cooled to 0° C. and quenched with Na2SO4.10H2O. The resulting mixture was stirred for 2-3 h, filtered through Celite, and washed with THF (200 mL). The filtrate was dried and concentrated to give crude product (S)-tert-butyl 1-cyclohexyl-3-(ethylamino)propan-2-ylcarbamate (860 mg). MS ESI +ve m/z 271 (M+H).
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]2[CH:13]=[CH:12][CH:11]=[CH:10][N:5]2[C:6](=[O:9])[C:7]=1[CH3:8].[Si]([O:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1)(C(C)(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:8][C:7]1[C:6](=[O:9])[N:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]2=[N:3][C:2]=1[O:1][CH2:32][C:31]1[CH:30]=[CH:29][C:28]([C:26](=[O:27])[C:25]2[CH:36]=[CH:37][C:22]([OH:21])=[CH:23][CH:24]=2)=[CH:35][CH:34]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Reactant: Cc1c(O)nc2ccccn2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(OCc2ccc(C(=O)c3ccc(O)cc3)cc2)nc2ccccn2c1=O
Yield: 4.7 %

Procedure:
A solution of 2-hydroxy-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (3.158 g), 4-(4-t-butyldimethylsilyloxybenzoyl)benzyl bromide (12.24 g) and potassium carbonate (5.07 g) in DMF (50 ml) was stirred at room temperature for 24 hours. This reaction mixture was concentrated and the residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate =1:2) and recrystallized from chloroform-methanol-ethyl acetate to provide the title compound as colorless solid (325 mg).
Reaction SMILES: C[Mg]Cl.Br[C:5]1[S:6][C:7]2[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:8]=2[N:9]=1.Cl>O1CCCC1>[Cl:15][C:10]1[C:8]2[N:9]=[CH:5][S:6][C:7]=2[CH:13]=[C:12]([Cl:14])[CH:11]=1
Reactant: Clc1cc(Cl)c2nc(Br)sc2c1
Agent: C[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: Clc1cc(Cl)c2ncsc2c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of 98 mmol of methyl magnesium chloride in tetrahydrofruan was added dropwise to a solution of 14 g (49 mmol) of 2-bromo-4,6-dichlorobenzothiazole in 200 ml of tetrahydrofuran, which solution had been cooled to -78° C. After 2 hours, acidification was effected with 10% strength hydrochloric acid and the product was then extracted with diethyl ether. The organic phase was washed with water, saturated aqueous sodium bicarbonate solution and water, dried over sodium sulfate and finally evaporated down. Purification of the crude product was effected by means of silica gel chromatography (eluent: 5:1 petroleum ether/methyl tert-butyl ether). Yield: 5.2 g.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[Cl:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)=[CH:26][CH:25]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:27]3[CH:26]=[CH:25][C:24]([Cl:23])=[CH:36][CH:35]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: Clc1ccc(OCCCCCBr)cc1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCOc2ccc(Cl)cc2)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.3 g) as starting compound and 5-(4-chlorophenoxy)-pentyl bromide (1.0 g) were reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-N-((1-(5-(4-chlorophenoxy)pentyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[N:13]=[C:14]([CH2:17][N:18]([CH3:20])[CH3:19])[S:15][CH:16]=1)=[N:4][C:5]#[N:6].[ClH:21].C([OH:24])C>>[ClH:21].[ClH:21].[CH3:1][NH:2][C:3]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[N:13]=[C:14]([CH2:17][N:18]([CH3:19])[CH3:20])[S:15][CH:16]=1)=[N:4][C:5]([NH2:6])=[O:24]
Reactant: CCO
Reactant: CNC(=NC#N)NCCSCc1csc(CN(C)C)n1
Agent: Cl
Product: CNC(=NC(N)=O)NCCSCc1csc(CN(C)C)n1
Reaction time: 96 h

Procedure:
About 0.6 g. of N-methyl-N'-2-([2-(dimethylaminomethyl)-4-thiazolyl]methylthio)ethyl-N"-cyanoguanidine were dissolved in 8 ml. of 1.5 N aqueous hydrochloric acid. The resulting solution was allowed to remain at ambient temperature for about four days. Volatile constituents were then removed by evaporation in vacuo. The resulting residue, comprising N-methyl-N'-2-([2-(dimethylaminomethyl)-4-thiazolyl]methylthio)ethyl-N"-aminocarbonylguanidine dihydrochloride formed in the above reaction, was dissolved in ethanol and the ethanol removed by evaporation. The residue obtained thereby was recrystallized from isopropanol. The crystalline product was collected and digested with ethyl acetate. The ethyl acetate was removed by evaporation and the product obtained was crystallized from isopropanol to yield N-methyl-N'-2-([2-(dimethylaminomethyl)-4-thiazolyl]methylthio)ethyl-N"-aminocarbonylguanidine dihydrochloride melting at 156.5°-159.5° C.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([CH2:12][CH:13]3[NH:19][C:18](=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:9]([C:21]([F:24])([F:23])[F:22])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[CH3:30][O+](C)C>>[CH3:30][O:20][C:18]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]([CH2:12][C:10]2[C:9]([C:21]([F:23])([F:22])[F:24])=[N:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:11]=2)[N:19]=1
Reactant: C[O+](C)C
Reactant: O=C1CCCCC(Cc2cn(-c3ccccc3)nc2C(F)(F)F)N1
Agent: F[B-](F)(F)F
Product: COC1=NC(Cc2cn(-c3ccccc3)nc2C(F)(F)F)CCCC1

Procedure:
The title material of Example 140 is reacted with trimethyloxonium tetrafluoroborate by the method of Example 3 to generate the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].C(O[CH:13](O)[CH:14]([F:16])[F:15])C.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:5]([O:4][CH:3]([O:7][CH2:8][CH3:9])[CH2:2][NH:1][CH2:13][CH:14]([F:16])[F:15])[CH3:6]
Reactant: CCOC(O)C(F)F
Reactant: CCOC(CN)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCOC(CNCC(F)F)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
A solution of 3 g (22.5 mM) of 1-amino-2,2-diethoxyethane, 3.1 g (24.8 mM) of difluoroacetaldehyde ethyl hemiacetal and 1 pellet of solid NaOH in 44 ml of toluene was heated at 120° C. with a Dean-Stark trap for 1.5 hours. The mixture is left to stand until it has cooled to room temperature and is concentrated in vacuo. The residue is diluted with 80 ml of methanol, and 3.4 g (90 mM) of sodium borohydride were added in small quantities. The reaction mixture is then stirred overnight, concentrated in vacuo and partitioned between ethyl acetate and water. The organic phase is isolated, dried (MgSO4) and concentrated in vacuo. 3.7 g of crude substance are obtained as a colorless oil. The residue is subjected to a flash chromatography on 40 g of SiO2 (elution with DCM/MeOH, gradient 1-8%). 3.1 g of the desired amine were obtained as a colorless oil.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:4][C@@H:3]1[C:17]([O:19]CC)=[O:18].O.[OH-].[Na+]>C(O)C>[CH2:10]([O:9][C:7]([N:5]1[CH2:6][C@H:2]([OH:1])[C@@H:3]([C:17]([OH:19])=[O:18])[CH2:4]1)=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Temperature: 0 °C
Yield: 226.9 %

Procedure:
639 g of 1-benzyl 3-ethyl (3S,4R)-4-hydroxypyrrolidine-1,3-dicarboxylate (equivalent to 1.03 mol) was dissolved in 3.02 L of ethanol and 3.02 L of water was added to the solution. While the mixture was stirred and cooled in an ice bath, a sodium hydroxide solution (formed by dissolving 124 g of sodium hydroxide (3.09 mol) in 3.02 L of water) was added dropwise at an internal temperature of 6.0 to 9.8° C. and the mixture was subsequently stirred at an internal temperature of 6 to 10° C. for 1 hour. This was followed by addition of 60.4 g of active carbon. The mixture was then taken out of the ice bath and stirred at room temperature for 30 minutes. The insoluble material was separated by filtration and washed with 1.21 L of water. The filtrate and the wash were combined and concentrated under reduced pressure. To the resulting residue, 3.02 L of diisopropyl ether was added and the mixture was stirred for 5 minutes. Subsequently, the mixture was allowed to stand and the aqueous layer (bottom layer) was collected. To the aqueous layer, 3.02 L of diisopropyl ether was added and the mixture was stirred for 5 minutes. The mixture was allowed to stand again and the aqueous layer (bottom layer) was collected. While the aqueous layer was stirred, 0.54 L of 6 mol/L hydrochloric acid was added dropwise (pH changed from 12.8 to 1.5). To the resulting mixture, 4.83 L of ethyl acetate and 1.21 kg of sodium chloride were added and the mixture was stirred for 5 minutes. The mixture was then allowed to stand and the organic layer (top layer) was collected. To the organic layer, 3.02 L of 28% brine was added and the mixture was stirred for 5 minutes. The mixture was then allowed to stand again and the organic layer (top layer) was collected. To the organic layer, 302 g of anhydrous sodium sulfate was added and the mixture was stirred for 1 hour. The resulting solid was separated by filtration and washed with 0.90 L of ethyl acetate. The filtrate and the wash were combined and concentrated under reduced pressure to give 620 g of a crude product of the title compound as a pale brown solid. This product was used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[N:18][N:17]=1.C(N(C(C)C)CC)(C)C.CCOC(C)=O>CS(C)=O.O>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:16]([N:6]3[CH2:5][CH2:4][N:3]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[C@@H:2]([CH3:1])[CH2:7]3)=[N:17][N:18]=2)=[CH:31][CH:30]=1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: Fc1ccc(-c2nnc(Cl)c3ccccc23)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: C[C@H]1CN(c2nnc(-c3ccc(F)cc3)c3ccccc23)CCN1C(=O)OC(C)(C)C
Temperature: 102 °C
Reaction time: 48 h
Yield: 97.1 %

Procedure:
Add (S)-tert-butyl 2-methylpiperazine-1-carboxylate (276 g, 1.38 mol) to a slurry of 1-chloro-4-(4-fluorophenyl)phthalazine (275 g, 1.06 mol) and diisopropylethylamine (346 mL, 1.99 mol) in DMSO (2.56 L) at 25° C. Heat the mixture to 102° C. for 9 h. Cool the reaction to 25° C. and stir for 48 h. Add the mixture to EtOAc (2.5 L) and water (3.5 L). Extract the aqueous phase with ethyl acetate (2×2.0 L). Combine the organic layers, wash with water (2.5 L) and concentrate to a brown foam. Dissolve the foam in acetonitrile (1.0 L) and cool to 1° C. for 30 min. Filter the precipitate to obtain a tan solid. Concentrate the mother liquor and slurry the residue in acetonitrile (500 mL) for 30 min. Filter the mixture to obtain a tan solid. Combine the solid precipitates and dry in a vacuum oven (14 torr, 25° C.) for 25 h to obtain the title compound as a tan solid (435 g, 96%). ES/MS m/z 423.0 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH2:39][CH:38]([NH2:42])[CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH2:39][CH:38]([NH:42][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:14][C:15]4[S:16][C:17]5[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=5[N:19]=4)=[N:4][C:5]=3[CH:10]=2)=[O:12])[CH2:37]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NC3CCCN(C(=O)OC(C)(C)C)C3)ccc21
Yield: 74.2 %

Procedure:
3-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (44 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (41 mg), 3-amino-piperidine-1-carboxylic acid tert-butyl ester (67 mg), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 592. 1H NMR (DMSO-d6, 400 MHz): δ 8.22 (m, 1H), 8.06 (s, 1H), 7.87 (s, 1H), 7.73 (br, 1H), 7.53 (br, 1H), 7.43 (d, 1H), 7.32 (d, 1H), 3.82 (br, 1H), 3.65 (s, 3H), 3.20 (m, 2H), 2.80 (m, 2H), 1.81 (m, 1H), and 1.39 (s, 9H) and 1.03 (d, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[N:16]1)[CH2:7][CH2:6]2>CO.O=[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([NH2:20])[CH:17]=[N:16]1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCN2CCCn1cc([N+](=O)[O-])cn1
Agent: O=[Pt]=O
Solvent: CO
Product: COc1ccc2c(c1)CCN2CCCn1cc(N)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-methoxy-1-(3-(4-nitro-1H-pyrazol-1-yl)propyl)indoline (1.18 mmol), in MeOH (6.0 mL, degassed), PtO2 (12 mg, 0.05 mmol) was added and the reaction mixture was stirred at rt under a H2-atmosphere for 18 h. The mixture was diluted with MeOH, filtered over celite and the filter cake was rinsed with MeOH. The filtrate was concentrated to obtain the title compound as a brown oil, which was used in the next step without further purification. LC-MS conditions B: tR=0.32 min, [M+H]+=273.1.
Reaction SMILES: N1C=CC(CNCCN)=N1.C(N=C=S)C.[CH2:16]([NH:18][C:19]([NH:21][CH2:22][CH2:23][NH:24][CH2:25][C:26]1[CH:30]=[CH:29][NH:28][N:27]=1)=S)[CH3:17].[N:31]#[C:32][NH2:33].[Pb]>>[C:32]([NH:33][C:19]([NH:18][CH2:16][CH3:17])=[N:21][CH2:22][CH2:23][NH:24][CH2:25][C:26]1[CH:30]=[CH:29][NH:28][N:27]=1)#[N:31]
Reactant: N#CN
Reactant: CCNC(=S)NCCNCc1cc[nH]n1
Agent: NCCNCc1cc[nH]n1
Agent: [Pb]
Solvent: CCN=C=S
Product: CCNC(=NCCNCc1cc[nH]n1)NC#N

Procedure:
By the procedure of Example 3(b), reacting N-(3-pyrazolylmethyl)ethylenediamine with ethyl isothiocyanate, then reacting the resulting N-ethyl-N'-[2-(3-pyrazolylmethylamino)ethyl]thiourea with lead cyanamide gives N-cyano-N'-ethyl-N"-[2-(3-pyrazolylmethylamino)ethyl]guanidine. By the same procedure, using propyl isothiocyanate the corresponding N'-propyl compound is prepared. Also, by the same procedure, using 2-dimethylaminoethyl isothiocyanate, the product is N-cyano-N'-(2-dimethylaminoethyl)-N"-[2-(3-pyrazolylmethylamino)ethyl]-guanidine.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:16]([O:18]CC)=[O:17])[C:11]([O:13]CC)=[O:12])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>>[F:1][C:2]([F:21])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:16]([OH:18])=[O:17])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(C(=O)O)c1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of diethyl 2-(4-(trifluoromethoxy)phenyl)malonate (5.6 g, 17.486 mmol, Intermediate 58, step a) and an aqueous 3 M NaOH solution were stirred in a 100° C. oil bath for 1 hour, cooled to RT, poured into ice water and acidified with 6N HCl. The aqueous mixture was extracted with EtOAc. The EtOAc extract was dried over Na2SO4, filtered, and evaporated in vacuo to provide the title compound.
Reaction SMILES: [CH:1]([N-:4]C(C)C)(C)C.[Li+].[CH2:9]([CH:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20][C:21]2([C:36]#[CH:37])[CH2:26][CH2:25][CH:24]([CH:27]3[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34][CH3:35])[CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[O:19])[CH2:14][CH2:13]1)[CH2:10][CH3:11].C1(C)C=CC(S(C#N)(=O)=O)=CC=1>C1COCC1>[CH2:9]([CH:12]1[CH2:13][CH2:14][CH:15]([C:18]([O:20][C:21]2([C:36]#[C:37][C:1]#[N:4])[CH2:26][CH2:25][CH:24]([CH:27]3[CH2:28][CH2:29][CH:30]([CH2:33][CH2:34][CH3:35])[CH2:31][CH2:32]3)[CH2:23][CH2:22]2)=[O:19])[CH2:16][CH2:17]1)[CH2:10][CH3:11]
Reactant: C#CC1(OC(=O)C2CCC(CCC)CC2)CCC(C2CCC(CCC)CC2)CC1
Reactant: CC(C)[N-]C(C)C
Agent: Cc1ccc(S(=O)(=O)C#N)cc1
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC1CCC(C(=O)OC2(C#CC#N)CCC(C3CCC(CCC)CC3)CC2)CC1
Reaction time: 0.25 h

Procedure:
5.10 ml of a 26% solution of lithium diisopropylamide in THF are added dropwise at −70° C. to 4.00 g of 4-ethynyl-4′-propylbicyclohexyl-4-yl 4-propylcyclohexanecarboxylate in 30 ml of THF, and the mixture is stirred for 15 minutes. A solution of 1.89 g of p-toluenesulfonyl cyanide in 10 ml of THF is subsequently added dropwise to the reaction solution at this temperature, and the cooling is removed. Conventional work-up gives 4-cyanoethynyl-4′-propylbicyclohexyl-4-yl 4-propylcyclohexanecarboxylate (C 89 N (58) I, Δε−10.18, Δn 0.02).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:22]=[CH:21][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([O:18]CC)=O)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[NH2:25][NH2:26]>C(O)C>[F:1][C:2]([F:23])([F:24])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]([NH:25][NH2:26])=[O:18])[CH2:13][CH2:14]2)=[CH:21][CH:22]=1
Reactant: NN
Reactant: CCOC(=O)CN1CCN(Cc2ccc(OC(F)(F)F)cc2)CC1
Solvent: CCO
Product: NNC(=O)CN1CCN(Cc2ccc(OC(F)(F)F)cc2)CC1

Procedure:
Synthesized according to General Procedure C: 6{17} (5.57 g, 16.1 mmol, 1 equiv.), anhydrous hydrazine (1.5 mL, 48.3 mmol, 3 equiv.), ethanol (32.4 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{17} (4.67 g, 87%) as a beige solid. 1H-NMR (500 MHz, CDCl3): δ 8.15 (br s, 1H), 7.28 (d, 2H, J=8.0 Hz), 7.11 (d, 2H, J=8.0 Hz), 3.83 (br s, 2H), 3.45 (s, 2H), 3.03 (s, 2H), 2.49 (br s, 4H), 2.41 (br s, 4H). 13C-NMR (125 MHz, CDCl3): δ 170.3, 148.1, 136.7, 130.1, 120.5, 120.3 (q, JC-F=255.5 Hz), 61.8, 60.4, 53.5, 52.9. 19F-NMR (470 MHz, CDCl3): −58.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH2:14][O:15][CH3:16])=[N:8][NH:9][C:10]2=O)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[C:7]([CH2:14][O:15][CH3:16])=[N:8][N:9]=1
Reactant: COCc1n[nH]c(=O)c2cc(OC)ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: COCc1nnc(Cl)c2cc(OC)ccc12

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 7-methoxy-4-methoxymethyl-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [CH3:1][Si:2]([C:5]1[CH2:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C([Li])CCC.Cl[Si:16]([CH3:19])([CH3:18])[CH3:17]>>[CH3:1][Si:2]([CH3:4])([CH3:3])[C:5]1[CH2:9][CH:8]=[C:7]([Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1
Reactant: C[Si](C)(C)Cl
Reactant: C[Si](C)(C)C1=CC=CC1
Agent: [Li]CCCC
Product: C[Si](C)(C)C1=CCC([Si](C)(C)C)=C1
Temperature: 40 °C

Procedure:
Freshly distilled trimethylsilylcyclopentadiene (1.6 g, 11.5 mmole) is dissolved in 10 ml of absolute ligroin. To this solution is added a solution of butyllithium (1.9N, 6.35 ml, 12.0 mmole) in ligroin dropwise with stirring. The mixture is stirred for one hour at room temperature. Chlorotrimethylsilane (2.6 g, 24 mmole) is added to the mixture under an argon sweep, and the resulting mixture heated for 3 hours at 40° C. The ligroin solution is filtered, the solvent evaporated, and the residue distilled under a vacuum to give 1,3-bis(trimethylsilyl)cyclopentadiene, b.p. 45° C./3 mm Hg.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:20]([O:22][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:21])[CH2:10][CH2:11][O:12][Si](C(C)(C)C)(C)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C>C(O)(=O)C.C1COCC1.O>[OH:12][CH2:11][CH2:10][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:20]([O:22][CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27]1)=[O:21]
Reactant: CC(C)(C)OC(=O)N[C@H](CCO[Si](C)(C)C(C)(C)C)C(=O)OC1CCCC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CCO)C(=O)OC1CCCC1
Temperature: 30 °C
Reaction time: 16 h

Procedure:
Cyclopentyl N-(tert-butoxycarbonyl)-O-[tert-butyl(dimethyl)silyl]-D-homoserinate (1.57 g, 3.9 mmol) was dissolved in acetic acid:THF:water (3:1:1, 100 ml). The reaction mixture was stirred at 30° C. for 16 hours for complete reaction. Ethyl acetate (200 ml) was added and washed with 1M Na2CO3, 1M HCl and brine. The ethyl acetate extracts were dried over magnesium sulphate and evaporated under reduced pressure to give the product as a clear oil which crystallised on standing (1.0 g, 95%).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: CC1(C)C=CC(=O)CC1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CCC(=O)CC1
Yield: 98.7 %

Procedure:
To a solution of 4,4-dimethyl-2-cyclohexen-1-one (10 g) in ethanol (100 ml) was added 10% palladium on carbon (1 g), and hydrogen gas at atmosphere pressure for 4 hours. To the reaction mixture was filtered. The filtrate was concentrated by evaporation under reduced pressure to give 4,4-dimethylcyclohexanone (10.03 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[C:18]([NH2:21])([CH3:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](=[O:25])([O-])[O-:23].[K+].[K+]>>[C:2]([O:23][C:22](=[O:25])[NH:21][C:18]([C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:19])[CH3:20])([CH3:7])([CH3:3])[CH3:1]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(N)c1cc([N+](=O)[O-])ccc1OCc1ccccc1
Agent: [K+]
Product: CC(C)(C)OC(=O)NC(C)(C)c1cc([N+](=O)[O-])ccc1OCc1ccccc1
Yield: 94 %

Procedure:
Using the compound obtained in Example 564 as a starting material and also using potassium carbonate as a base, the same procedure of Example 63 gave 828 mg of the titled compound (yield, 94%).