Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH2:10].C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)[C:13](=[O:14])C1.Cl.[Cl:30][C:31]1[CH:50]=[CH:49][C:34]([O:35][C:36]2[CH:37]=[C:38]([CH:46]=[CH:47][CH:48]=2)[CH2:39][N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:33][CH:32]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CCOC(C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:13]([N:43]1[CH2:44][CH2:45][N:40]([CH2:39][C:38]2[CH:46]=[CH:47][CH:48]=[C:36]([O:35][C:34]3[CH:49]=[CH:50][C:31]([Cl:30])=[CH:32][CH:33]=3)[CH:37]=2)[CH2:41][CH2:42]1)=[O:14]
Reactant: Clc1ccc(Oc2cccc(CN3CCNCC3)c2)cc1
Reactant: Nc1nc2ccccc2o1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc2ccccc2o1)N1CCN(Cc2cccc(Oc3ccc(Cl)cc3)c2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 63.1 %

Procedure:
To a solution of benzooxazole-2-ylamine (35.8 mg, 0.267 mmol) in CH2Cl2 (6.0 mL) was added N,N′-disuccinimidyl carbonate (68.4 mg, 0.267 mmol). The reaction mixture was stirred at rt for 6 h, then treated with 1-[3-(4-chloro-phenoxy)-benzyl]-piperazine hydrochloride (100 mg, 0.267 mmol) and diisopropylethylamine (92 μL, 0.536 mmol) and stirred for an additional 16 h at rt. The reaction mixture was diluted with EtOAc (100 mL) and extracted with H2O (100 mL) then saturated aqueous NaCl (50 mL). The organic layer was dried (MgSO4), and concentrated. The crude residue was purified (FCC, 2 N NH3 in MeOH/DCM) to give 4-[3-(4-chloro-phenoxy)-benzyl]-piperazine-1-carboxylic acid benzooxazol-2-ylamide (78.0 mg, 63%). MS (ESI+): calcd for C25H23ClN4O3 m/z 462.15, found 463.5 (M+H)+. 1H NMR (d6-DMSO): 12.13 (br s, 1H), 7.46-7.39 (m, 3H), 7.36 (t, J=7.9, 1H), 7.30 (br s, 1H), 7.22 (t, J=7.6, 1H), 7.18-7.11 (m, 2H), 7.04 (d, J=9.0, 2H), 7.00 (br s, 1H), 6.94-6.91 (m, 1H), 3.73-3.54 (br m, 4H), 3.50 (s, 2H), 2.40-2.31 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([O:15][CH:16]3[CH2:25][CH2:24][C:19]4(OCC[O:20]4)[CH2:18][CH2:17]3)=[CH:10][C:9]=2[F:26])[C:6](=[O:27])[CH:5]=[CH:4][C:3]=1[C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1.Cl>O1CCOCC1.O>[NH2:1][C:2]1[N:7]([C:8]2[C:9]([F:26])=[CH:10][C:11]([O:15][CH:16]3[CH2:25][CH2:24][C:19](=[O:20])[CH2:18][CH2:17]3)=[CH:12][C:13]=2[F:14])[C:6](=[O:27])[CH:5]=[CH:4][C:3]=1[C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1
Reactant: Nc1c(C(=O)c2ccc(F)cc2)ccc(=O)n1-c1c(F)cc(OC2CCC3(CC2)OCCO3)cc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Nc1c(C(=O)c2ccc(F)cc2)ccc(=O)n1-c1c(F)cc(OC2CCC(=O)CC2)cc1F
Reaction time: 18 h
Yield: 85.6 %

Procedure:
To a solution of 6-amino-1-[4-(1,4-dioxa-spiro[4.5]dec-8-yloxy)-2,6-difluoro-phenyl]-5-(4-fluorobenzoyl)-1H-pyridin-2-one (0.55 g, 1.10 mmol) in 1,4-dioxane (10 ml) was added 2M aq HCl (5 ml) at room temperature. Stirring was continued for 18 h. Upon completion of reaction the reaction mixture was diluted with water (10 ml) before evaporation of dioxane under reduced pressure. The residual aqueous solution was extracted with EtOAc (2×10 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated to dryness under reduced pressure to give the desired ketone as a white solid (0.43 g, 86%). LCMS purity 98%, m/z 457 [M+H]+, 1H NMR (400 MHz, CDCl3), δ: 2.05-2.15 (2H, m), 2.25-2.45 (4H, m), 2.55-2.70 (2H, m), 4.65-4.75 (1H, m), 5.85 (1H, d), 6.70-6.75 (2H, m), 7.05-7.15 (2H, m), 7.50-7.65 (3H, m),
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C:9]1[C:10]([I:45])=[C:11]([C:31]([NH:33][CH2:34][CH:35]([O:41]C(=O)C)[CH2:36][O:37]C(=O)C)=[O:32])[C:12]([I:30])=[C:13]([C:28]=1[I:29])[C:14]([NH:16][CH2:17][CH:18]([O:24]C(=O)C)[CH2:19][O:20]C(=O)C)=[O:15])=[O:7])(=O)C.[C:46](OCCCC(ON(C1C(I)=C(C(N)=O)C(I)=C(C=1I)C(N(CC(OC(=O)C)COC(=O)C)CC(OC(=O)C)COC(=O)C)=O)C(=O)C)=O)(=[O:48])[CH3:47]>>[CH2:47]([N:8]([C:6]([CH2:5][OH:4])=[O:7])[C:9]1[C:28]([I:29])=[C:13]([C:14]([NH:16][CH2:17][CH:18]([OH:24])[CH2:19][OH:20])=[O:15])[C:12]([I:30])=[C:11]([C:31]([NH:33][CH2:34][CH:35]([OH:41])[CH2:36][OH:37])=[O:32])[C:10]=1[I:45])[CH2:46][OH:48].[OH:24][CH:18]([CH2:19][OH:20])[CH2:17][NH:16][C:14](=[O:15])[C:13]1[C:28]([I:29])=[C:9]([NH:8][C:6](=[O:7])[CH2:5][OH:4])[C:10]([I:45])=[C:11]([C:31]([NH:33][CH2:34][CH:35]([OH:41])[CH2:36][OH:37])=[O:32])[C:12]=1[I:30]
Reactant: CC(=O)OCCCC(=O)ON(C(C)=O)c1c(I)c(C(N)=O)c(I)c(C(=O)N(CC(COC(C)=O)OC(C)=O)CC(COC(C)=O)OC(C)=O)c1I
Reactant: CC(=O)OCC(=O)Nc1c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Product: O=C(CO)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Product: O=C(NCC(O)CO)c1c(I)c(C(=O)NCC(O)CO)c(I)c(N(CCO)C(=O)CO)c1I

Procedure:
) acid hydrolyzing said 5-acetoxyacetamido-N,N'-bis(2,3-diacetoxypropyl)2,4,6-triiodoisophthalamide and 5-[N-(2-acetoxyethyl)acetoxyacetamido]-N,N-bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalamide under acid hydrolyzing conditions to produce ioversol and N,N'-bis-(2,3-dihydroxypropyl)-5-glycolamido-2,4,6-triiodoisophthalamide; and
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:12])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:11])[CH2:9][CH3:10].[OH:13][C:14]1[CH:23]=[CH:22][C:17]2[CH:18]([CH3:21])[CH2:19][O:20][C:16]=2[CH:15]=1>>[CH3:12][C:4]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:11])[CH2:9][CH3:10])=[CH:3][CH2:2][O:13][C:14]1[CH:23]=[CH:22][C:17]2[CH:18]([CH3:21])[CH2:19][O:20][C:16]=2[CH:15]=1
Reactant: CCC(C)=CCCC(C)=CCBr
Reactant: CC1COc2cc(O)ccc21
Product: CCC(C)=CCCC(C)=CCOc1ccc2c(c1)OCC2C

Procedure:
1-bromo-3,7-dimethyl-2,6-nonadiene and 6-hydroxy-3-methyl-2,3-dihydrobenzofuran are reacted to form 6-[(3,7-dimethyl-2,6-nonadienyl)-oxy]-3-methyl-2,3-dihydrobenzofuran of boiling point 147° C./0.001 mmHg; nD20 = 1.5312; and
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[SH:9].[CH3:10][C:11]([O:14][C:15](=[O:26])[NH:16][CH2:17][CH2:18][C@H:19](O)[C:20]1[S:21][CH:22]=[CH:23][N:24]=1)([CH3:13])[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.CCCC(C)C.C(OCC)(=O)C>[CH3:13][C:11]([O:14][C:15](=[O:26])[NH:16][CH2:17][CH2:18][C@@H:19]([S:9][C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Cl:1])[C:20]1[S:21][CH:22]=[CH:23][N:24]=1)([CH3:10])[CH3:12]
Reactant: CC(C)(C)OC(=O)NCC[C@H](O)c1nccs1
Reactant: Sc1cc(Cl)ccc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCC(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC[C@@H](Sc1cc(Cl)ccc1Cl)c1nccs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.3 %

Procedure:
To a solution of 2,5-dichlorothiophenol (179 mg, 1 mmol), [(3S)-3-hydroxy-3-(2-thiazolyl)propyl]carbamic acid 1,1-dimethylethyl ester (258 mg, 1 mmol) and triphenylphosphine (315 mg, 1.2 mmol) in dry tetrahydrofuran (30 ml) at 0° C. under nitrogen, was added diisopropyl azodicarboxylate (243 mg, 0.24 ml, 1.2 mmol) dropwise over 5 minutes. The mixture was stirred at room temperature for 16 h, then concentrated in vacuo to leave a crude yellow gum. Flash chromatography (silica, 15% ethyl acetate in isohexane) afforded a clear oil (85 mg, 21%).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[C:33](Br)[CH:34]=[CH:35][CH:36]=4)[N:31]=3)[CH2:26][CH2:25]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[C:43]1(OB(O)O)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]([F:42])([F:41])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[C:33]([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)[CH:34]=[CH:35][CH:36]=4)[N:31]=3)[CH2:26][CH2:25]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: OB(O)Oc1ccccc1
Reactant: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc4cccc(Br)c4n3)CC2)c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc4cccc(-c5ccccc5)c4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
A reaction mixture of 0.2 g (0.314 mmol) of 9-{4-[4-(8-bromo-quinolin-2-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide, 0.033 g (0.267 mmol) of phenylboric acid, 0.018 g (0.016 mmol) of tetrakis triphenyl palladium and 0.2 ml of a 2 M sodium carbonate solution in 3 ml of toluene is refluxed for 20 hours under nitrogen. The solvent is distilled off. The residue is purified by column chromatography on silica gel (eluant: cyclohexane/ethyl acetate=3:2).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12](/[CH:16]=[CH:17]/[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:13][CH:14]=2)[C:9]([CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:8]1)=[O:4].C([O-])=O.[NH4+]>[Pd].CO.O1CCCC1>[CH3:1][O:2][C:3]([CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:13][CH:14]=2)[C:9]([CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:8]1)=[O:4]
Reactant: COC(=O)CCn1cc(Cc2cccnc2)c2cc(/C=C/C(=O)OC(C)(C)C)ccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CCn1cc(Cc2cccnc2)c2cc(CCC(=O)OC(C)(C)C)ccc21
Temperature: 60 °C
Yield: 98.8 %

Procedure:
A mixture of t-butyl (E)-3-[1-(2-methoxycarbonylethyl)-3-(3-pyridylmethyl)-1H-indol-5-yl]-2-propenoate (7.86 g), 10% palladium on carbon (0.70 g) and ammonium formate (5.60 g) in a mixture of methanol (40 ml) and tetrahydrofuran (40 ml) was heated at 60° C. for 3 hours and then cooled. The mixture was filtered and the residue was washed with methanol. The filtrate and washings were combined and evaporated, and the residue-was partitioned between water and ether. The organic layer was separated and the aqueous layer was extracted with ether. The organic layers were combined, washed with water and dried (MgSO4). Evaporation of the solvent gave the title compound as an oil (7.80 g). Found: C,70.51; H,6.98; N,6.54. C25H30N2O4 requires: C,71.06; H,7.16; N,6.63%.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:19]=3[C:20]([NH2:22])=[O:21])[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:28][C:29](OC(Cl)(Cl)Cl)=[O:30].C>O1CCOCC1>[ClH:28].[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3[C:18]4[C:19](=[C:23]([F:27])[CH:24]=[CH:25][CH:26]=4)[C:20](=[O:21])[NH:22][C:29]3=[O:30])[CH2:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)c1c(F)cccc1NCCCCN1CC=C(c2ccccc2)CC1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Cl
Product: O=c1[nH]c(=O)n(CCCCN2CC=C(c3ccccc3)CC2)c2cccc(F)c12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 2-[N-{4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butylamino-6-fluorobenzamide (900 mg), trichloromethyl chloroformate (1.5 ml) and active charcoal (catalytic amounts) in dioxane (20 ml) was stirred for 1 hour at 80° C. The solvent was removed in vacuo. The residue was dissolved in 10% hydrogen chloride-methanol, then the solution was filtered. After evaporation of the filtrate, the residue was crystallized from ethanol-ether. The crude crystals were collected, and washed with hot ethanol to afford 1-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-5-fluoro-2,4(1H,3H)-quinazolinedione hydrochloride (80 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH:6]([CH3:20])[C:7]([CH2:18][CH3:19])([CH2:13][CH2:14][C:15](=[O:17])[CH3:16])[C:8]2=O)=[CH:4][C:3]=1[O:21][CH2:22][C:23]([O:25]C)=[O:24]>C(O)(=O)C.Cl>[Cl:11][C:10]1[C:2]([Cl:1])=[C:3]([O:21][CH2:22][C:23]([OH:25])=[O:24])[CH:4]=[C:5]2[C:9]=1[C:8]1[C:7]([CH2:18][CH3:19])([CH:6]2[CH3:20])[CH2:13][CH2:14][C:15](=[O:17])[CH:16]=1
Reactant: CCC1(CCC(C)=O)C(=O)c2c(cc(OCC(=O)OC)c(Cl)c2Cl)C1C
Agent: Cl
Solvent: CC(=O)O
Product: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2C
Temperature: 0 °C

Procedure:
A solution of methyl [(6,7-dichloro-2-ethyl-2,3-dihydro-3-methyl-1-oxo-2-(3-oxobutyl)-1H-inden-5-yl)oxy]acetate (0.40 g) in acetic acid (6 ml) and 6N hydrochloric acid (6 ml) was heated at reflux for 90 hours, poured into ice water, extracted into ether, washed with water, brine, dried over MgSO4 and evaporated in vacuo. Crystallization from butyl chloride gave [(5,6-dichloro-9a-ethyl-9-methyl-3-oxo-2,3,9,9a-tetrahydro-1H-fluoren-7-yl)oxy]acetic acid which melted at 212°-214° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[O:10].[F:15][C:16]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:17]=1[O:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[N:30]=[C:29]3[CH2:31][NH:32][CH2:33][CH2:34][C:28]3=[N:27][C:26]=2[NH:35][CH:36]([CH3:38])[CH3:37])[CH2:21][CH2:20]1.N1C=CC=CC=1>C(Cl)Cl>[F:15][C:16]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:17]=1[O:18][CH:19]1[CH2:20][CH2:21][N:22]([C:25]2[N:30]=[C:29]3[CH2:31][N:32]([C:1](=[O:3])[CH3:2])[CH2:33][CH2:34][C:28]3=[N:27][C:26]=2[NH:35][CH:36]([CH3:38])[CH3:37])[CH2:23][CH2:24]1.[C:9]([OH:10])([C:11]([F:14])([F:13])[F:12])=[O:8]
Reactant: COc1ccc(OC2CCN(c3nc4c(nc3NC(C)C)CCNC4)CC2)c(F)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC(C)C)CCN(C(C)=O)C4)CC2)c(F)c1
Reaction time: 1 h

Procedure:
Acetic anhydride (9 μL, 0.095 mmol) was added to a solution of 3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (25.2 mg, 0.048 mmol) and pyridine (11.5 μL, 0.143 mmol) in DCM (500 μL) at rt. After 1 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (25.2 mg, 93%) as a yellow film. 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.32 (d, J=6.6 Hz, 6H), 1.89-2.00 (m, 2H), 2.06-2.15 (m, 2H), 2.19 (s, 1.4H), 2.21 (s, 1.6H), 2.77-2.83 (m, 0.9H), 2.87-2.93 (m, 1.1H), 3.04-3.14 (m, 2H), 3.42-3.50 (m, 2H), 3.75 (s, 3H), 3.80-3.85 (m, 1.1H), 3.85-3.90 (m, 0.9H), 4.09-4.19 (m, 1H), 4.35-4.42 (m, 1H), 4.55 (br s, 2H), 6.67 (dt, J=9.0, 1.4 Hz, 1H), 6.74 (dd, J=12.8, 2.9 Hz, 1H), 7.08 (t, J=9.2 Hz, 1H); ESI-MS m/z [M+H]+ 458.4.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6]/[C:7](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)/[CH2:8][OH:9].BrCBr.C([Mg]Cl)(C)(C)C.[Cl-].[NH4+]>C(OCC)C>[CH3:6][C:7]1([CH2:8][OH:9])[CH2:1][CH:10]1[C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1
Reactant: C/C(=C\c1ccc(C)cc1)CO
Reactant: [Li]CCCC
Agent: CC(C)(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: BrCBr
Solvent: CCOCC
Product: Cc1ccc(C2CC2(C)CO)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
n-Butyllithium (1.6 molar in hexanes; 33.2 ml; 53 1 mmol) was added dropwise to (2E)-2-methyl-3-(4-methylphenyl)-2-propen-1-ol (8.61 g, 53 1 mmol) in dry diethyl ether (120 ml) at 0° C. under nitrogen. After 10 minutes, dibromomethane (46.6 g; 265 mmol) was added dropwise, followed, after 15 minutes, by t-butyl magnesium chloride (2 molar in diethyl ether; 133 ml; 265 mmol). The reaction was then slowly warmed up to room temperature and stirred overnight. It was then cooled into an ice-water bath and a saturated aqueous ammonium chloride solution (300 ml) was added (initially dropwise, exothermic). After warming to room temperature, diethyl ether (200 ml) was added and the mixture shaken vigorously. The organic phase was washed with water (600 ml) and brine (300 ml). Each aqueous phase was re-extracted with diethyl ether (300 ml). Combined extracts were dried over solid anhydrous sodium sulfate. The product was purified by column chromatography on silica gel (heptane/ethyl acetate 5:1 to 2:1) followed by bulb-to-bulb distillation (120° C./1 mbar). 2.21 g of 90% pure material was obtained as a colorless liquid (11.3 mmol; 21%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:7][CH:6]([CH2:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5](=[O:15])[CH:4]=1.[Br:16]N1C(=O)CCC1=O>ClCCCl>[Br:16][C:4]1[C:5](=[O:15])[CH:6]([CH2:8][CH:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[CH2:7][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC1=CC(=O)C(CC2CCOCC2)C1
Solvent: ClCCCl
Product: COC1=C(Br)C(=O)C(CC2CCOCC2)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 80.9 %

Procedure:
To a stirred solution of 3-methoxy-5-(tetrahydro-pyran-4-ylmethyl)-cyclopent-2-enone (906 mg, 4.7 mmol) in 1,2-dichloroethane (15 ml) at 0° C. in an amber flask was added portion wise over one hour N-bromosuccinimide (890 mg, 5 mmol). The reaction was stirred at 0° C. for a further 90 minutes and then any remaining solid was removed by filtration. The filtrate was evaporated to dryness under reduced pressure, the resultant solid dissolved in warm toluene (50 ml) and washed quickly with ice-cold water (2×20 ml). The organic phase was dried over magnesium sulfate and the solvent evaporated in vacuo. The residue was purified using column chromatography (40% to 80% EtOAc in hexane) to give 2-bromo-3-methoxy-5-(tetrahydro-pyran-4-ylmethyl)-cyclopent-2-enone (1.1 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O.[H][H].[CH3:15][NH2:16]>CO.[Pt].[C]>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][NH:16][CH3:15]
Reactant: COCOc1cccc(C=O)c1
Reactant: CN
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Product: CNCc1cccc(OCOC)c1

Procedure:
5% platinum-carbon was suspended in 10 ml of methanol and a solution of 3.00 g of 3-(methoxymethoxy)benzaldehyde in 10 ml of methanol and 2.1 ml of 40% methylamine (methanol solution) were added. After heating to 30° C. under 2 atm, hydrogen was added for 22 hours. A catalyst was removed by filtering the reaction solution and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain 2.51 g of the desired compound as a yellowish oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][C:11](=[O:13])[NH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([N:26]1[CH2:27][CH2:28][N:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:24][CH2:25]1)=[O:16])[CH2:10][C:11](=[O:13])[NH2:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)N1CCN(c2ccccc2)CC1
Yield: 136.3 %

Procedure:
In the same manner as in Reference Example 2, N-tert-butoxycarbonyl-L-asparagine (4.3 g) and 1-phenylpiperazine (4.3 g) were condensed to obtain colorless powder 1-(N-tert-butoxycarbonyl-L-asparaginyl)-4-phenylpiperazine (9.5 g).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C@:5]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:6]1[C@@H:7]1[C@@:20]([CH3:23])([CH2:21][CH2:22]2)[C@@:19]2([CH3:24])[C@@H:10]([C@:11]3([CH3:37])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1.[C@@H:44]12[NH:52][C@@H:48]([CH2:49][CH2:50][CH2:51]1)[CH2:47][O:46][CH2:45]2.CCN(C(C)C)C(C)C>CS(C)=O>[C@@H:48]12[N:52]([CH2:2][CH2:3][NH:4][C@:5]34[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:6]3[C@@H:7]3[C@@:20]([CH3:23])([CH2:21][CH2:22]4)[C@@:19]4([CH3:24])[C@@H:10]([C@:11]5([CH3:37])[C@@H:16]([CH2:17][CH2:18]4)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]4[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=4)=[CH:13][CH2:12]5)[CH2:9][CH2:8]3)[C@@H:44]([CH2:51][CH2:50][CH2:49]1)[CH2:45][O:46][CH2:47]2
Reactant: C1C[C@@H]2COC[C@H](C1)N2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCCl)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3[C@@H]4CCC[C@H]3COC4)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 120 °C

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-chloroethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (20 mg, 0.033 mmol), (1R,5S)-3-oxa-9-azabicyclo[3.3.1]nonane (16.78 mg, 0.132 mmol) and Hunig's Base (0.029 mL, 0.165 mmol) in DMSO (1 mL) was heated to 120° C. for 1 h. The reaction mixture was quenched with distilled water (2 mL), extracted with dichloromethane (2×2 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to provide methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1R,5S)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate as a brown solid which was taken to the next step without further purification.
Reaction SMILES: [CH2:1]([S:6][CH2:7][CH2:8][CH2:9][Cl:10])[CH2:2][CH:3]([CH3:5])[CH3:4].[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.Cl>C(OCC)C>[ClH:10].[CH2:1]([S:6][CH2:7][CH2:8][CH2:9][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: C1CCNCC1
Reactant: CC(C)CCSCCCCl
Agent: Cl
Solvent: CCOCC
Product: CC(C)CCSCCCN1CCCCC1
Temperature: 125 °C
Yield: 49.4 %

Procedure:
Mix 3-chloropropyl isopentyl sulfide (1.0 g, 5.5 mmol) and piperidine (3.3 mL, 33 mmol) and heat at 125° C. for 2 hours. Cool to room temperature and partition between 50% sodium hydroxide and ethyl ether. Separate the organic phase, wash the aqueous phase with ethyl ether (2×30 mL), combine the organic phases and dry (MgSO4). Evaporate the solvent in vacuo to yield 1.12 g (89%). Dissolve the product (1.0 g) in ethyl ether (100 mL) and treat with anhydrous hydrochloric acid. Collect the resulting yellow solid by vacuum filtration, recrystallize (ethyl acetate) and dry to yield 0.723 g of the title compound as white crystals; mp 155°-8° C. 438E-83
Reaction SMILES: C[O-].[Na+].C(O[C:7](=[O:19])[CH:8]([O:16][CH2:17][CH3:18])[C:9](=O)[C:10]([O:12][CH2:13]C)=[O:11])C.Cl.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[NH:27])=[C:24]([F:31])[C:23]=1[O:32][CH3:33].Cl>CO>[CH3:13][O:12][C:10]([C:9]1[C:8]([O:16][CH2:17][CH3:18])=[C:7]([OH:19])[N:27]=[C:26]([C:25]2[CH:29]=[CH:30][C:22]([Cl:21])=[C:23]([O:32][CH3:33])[C:24]=2[F:31])[N:28]=1)=[O:11]
Reactant: COc1c(Cl)ccc(C(=N)N)c1F
Reactant: CCOC(=O)C(=O)C(OCC)C(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCOc1c(O)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 0 %

Procedure:
Sodium methoxide (12 mL, 62.74 mmol) was added dropwise to a solution of 2-ethoxy-3-oxo-succinic acid diethyl ester (9.7 g of 75% purity, 31.37 mol), 4-chloro-2-fluoro-3-methoxybenzamidine hydrochloride (5 g, 20.91 mol) and MeOH (24 mL). The reaction was allowed to stir for 1 hour. The reaction was cooled to 0° C. and 1 N HCl was added to acidify the reaction. The reaction was extracted with ethyl acetate thrice. The organic extracts were combined, washed with brine, dried, filtered and concentrated. The product was purified by flash chromatography on silica gel (0-50% EtOAc/hexane) the recrystallized from dichloromethane/hexane to give a white solid (623 mg, 8% yield): mp 173-175° C.: 1H NMR (CDCl3) δ 11.28 (br s, 1H), 7.78 (dd, 1H), 7.31 (dd, 1H), 4.35 (q, 2H), 4.02 (s, 3H), 3.98 (s, 3H), 1.38 (t, 3H).