Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([NH:16][CH:17]3[CH2:22][C:21]([CH3:24])([CH3:23])[N:20]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[C:19]([CH3:33])([CH3:32])[CH2:18]3)[CH2:10][C:9]2([CH3:35])[CH3:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[P:37]1[O:42][CH2:41][C:40]2([CH2:47][O:46][P:45](Cl)[O:44][CH2:43]2)[CH2:39][O:38]1>>[CH:1]1([O:7][N:8]2[C:9]([CH3:35])([CH3:34])[CH2:10][CH:11]([N:16]([CH:17]3[CH2:18][C:19]([CH3:33])([CH3:32])[N:20]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[C:21]([CH3:23])([CH3:24])[CH2:22]3)[P:37]3[O:42][CH2:41][C:40]4([CH2:47][O:46][P:45]([N:16]([CH:17]5[CH2:22][C:21]([CH3:23])([CH3:24])[N:20]([O:25][CH:26]6[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]6)[C:19]([CH3:33])([CH3:32])[CH2:18]5)[CH:11]5[CH2:10][C:9]([CH3:35])([CH3:34])[N:8]([O:7][CH:1]6[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]6)[C:13]([CH3:15])([CH3:14])[CH2:12]5)[O:44][CH2:43]4)[CH2:39][O:38]3)[CH2:12][C:13]2([CH3:14])[CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: ClP1OCC2(CO1)COP(Cl)OC2
Reactant: CC1(C)CC(NC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)CC(C)(C)N1OC1CCCCC1
Product: CC1(C)CC(N(C2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)P2OCC3(CO2)COP(N(C2CC(C)(C)N(OC4CCCCC4)C(C)(C)C2)C2CC(C)(C)N(OC4CCCCC4)C(C)(C)C2)OC3)CC(C)(C)N1OC1CCCCC1

Procedure:
The title compound is prepared from bis(1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl)amine and 3,9-dichloro-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane according to the procedure of Example 14.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=O)[C:8]2[NH:13][N:12]=[C:11]([I:14])[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N12CCCN=C1CCCCC2.[CH3:54][O:55][C:56]1[CH:57]=[C:58]([CH2:64][NH2:65])[CH:59]=[CH:60][C:61]=1[O:62][CH3:63]>CN(C=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([NH:65][CH2:64][C:58]2[CH:59]=[CH:60][C:61]([O:62][CH3:63])=[C:56]([O:55][CH3:54])[CH:57]=2)[C:8]2[NH:13][N:12]=[C:11]([I:14])[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(I)n[nH]c2c(=O)[nH]1
Reactant: COc1ccc(CN)cc1OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nc(NCc2ccc(OC)c(OC)c2)c2[nH]nc(I)c2n1
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 322.6 %

Procedure:
To a solution of 5-butyl-3-iodo-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one (5 g, 15.72 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (10.43 g, 23.58 mmol) in anhydrous DMF (250 mL) at room temperature under a nitrogen atmosphere was added 1,8-diazabicyclo[5.4.0]undec-7-ene (4.23 mL, 28.3 mmol) and the reaction mixture was stirred for 2.5 hours. (3,4-Dimethoxyphenyl)methanamine (20 mL, 94 mmol) was added and the mixture was warmed to 40° C. for 3 hours. The reaction mixture was evaporated in-vacuo and the resulting oil partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over MgSO4, filtered and evaporated in-vacuo to yield as a semi-crystalline yellow oil (23.7 g). The residue was absorbed onto Florosil, loaded onto a 330 g silica pre-conditioned cartridge and purified by chromatography using cyclohexane over 1 column volume followed by 0-100% ethyl acetate in cyclohexane gradient over 14 column volumes followed by ethyl acetate over 4 column volumes. Appropriate fractions containing only the desired material by LC-MS analysis were combined and evaporated in-vacuo to yield the title compound as a pale yellow foam (4.58 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])[CH3:2].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CCCCCC>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][Br:13])[CH3:2]
Reactant: CCOC(=O)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: CCOC(=O)c1ccccc1CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.2 %

Procedure:
2-Methylbenzoic acid ethyl ester (2.00 g, 11.9 mmol) was dissolved in carbon tetrachloride (60 ml), and the solution was added with N-bromosuccinimide (2.56 g, 14.4 mmol) and a catalytic amount of benzoylperoxide and then heated under reflux. After one hour, the reaction mixture was cooled to room temperature and added with hexane (40 ml) to remove insoluble solids by filtration. The filtrate was evaporated under reduced pressure to obtain the title compound 3.16 g as yellow oil. the product was used in the next reaction without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1([CH2:22][NH:23]C(OC(C)(C)C)=O)[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:5][CH2:4]1.[ClH:31].C(O)(C)C>>[ClH:31].[ClH:31].[NH2:23][CH2:22][C:3]1([O:2][CH3:1])[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:5][CH2:4]1
Reactant: COC1(CNC(=O)OC(C)(C)C)CCN(CCCCS(=O)(=O)c2ccccc2)CC1
Agent: Cl
Solvent: CC(C)O
Product: COC1(CN)CCN(CCCCS(=O)(=O)c2ccccc2)CC1

Procedure:
1H-NMR (CDCl3,ppm)δ: 1.42-1.86(17 H,m), 2.22-2.50(6 H,m), 3.09-3.19(7 H,m), 4.68(1 H,br), 7.54-7.70(3 H,m), 7.89-7.93(2 H,m) (2) 4-Methoxy-1-(4-phenylsulfonylbutyl)-4-tert-butoxycarbonylaminomethylpiperidine (2.58 g) and 15% hydrochloric acid-isopropyl alcohol (15 ml) were reacted and treated in the same manner as in Preparation Example 138(2) to give 2.2 g of 4-aminomethyl-4-methoxy-1-(4-phenylsulfonylbutyl)piperidine dihydrochloride.
Reaction SMILES: [CH2:1]([N:8]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:9](=[O:29])[CH2:10][C:11]1[CH:12]=[C:13]([CH:26]=[CH:27][CH:28]=1)[O:14][CH2:15][C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([O:20]C)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.O>[CH2:1]([N:8]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:9](=[O:29])[CH2:10][C:11]1[CH:12]=[C:13]([CH:26]=[CH:27][CH:28]=1)[O:14][CH2:15][C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([OH:20])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCN(Cc1ccccc1)C(=O)Cc1cccc(OCc2ccccc2C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCN(Cc1ccccc1)C(=O)Cc1cccc(OCc2ccccc2C(=O)O)c1
Reaction time: 312 h
Yield: 12.2 %

Procedure:
Methyl 2-[(3-{2-[benzyl(hexyl)amino]-2-oxoethyl}phenoxy)methyl]benzoate (59 mg, 0.125 mmol) in THF (1 ml) was cooled in an ice-bath. Lithium hydroxide (6 mg, 0.249 mmol) in water (1 ml) was dropped in. The cooling-bath was then removed and the mixture was stirred for 13 days and then evaporated in vacuum to remove THF. The residue was acidified with 1% hydrochloric acid, pH˜4, and extracted with ethyl acetate. The organic phase was dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 1 g/6 ml) using DCM and MeOH/DCM (0.5:99.5, then 1:99) as eluant gave 7 mg the desired product, yield 8% (two steps).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:26].[N:36]1([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16]([N:45]3[CH2:46][CH2:47][CH:42]([N:36]4[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]4)[CH2:43][CH2:44]3)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:26]
Reactant: O=C1c2c(-c3ccccc3)cc(Cl)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C1CCN(C2CCNCC2)CC1
Product: O=C1c2c(-c3ccccc3)cc(N3CCC(N4CCCCC4)CC3)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 47.8 %

Procedure:
In a similar manner to Example 1, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (40.0 mg) was reacted with 4-(piperidine-1-yl)piperidine (32.7 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-9-[4-(piperidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (24.0 mg, 48%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1/[C:9](=[N:13]\[NH:14][C:15]([NH2:17])=[NH:16])/[C:10]([NH2:12])=O.[OH-].[K+]>C(O)C>[CH:5]1[CH:6]=[C:7]([Cl:8])[C:2]([Cl:1])=[C:3]([C:9]2[N:13]=[N:14][C:15]([NH2:17])=[N:16][C:10]=2[NH2:12])[CH:4]=1
Reactant: N=C(N)N/N=C(/C(N)=O)c1cccc(Cl)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nnc(-c2cccc(Cl)c2Cl)c(N)n1

Procedure:
(E)-2-(2',3'-dichlorophenyl)-2-(guanidinylimino)acetamide (2.5 g) was dissolved in hot ethanol (40 ml). Potassium hydroxide (2.0 g, equivalent to 5% w/v) was added and the solution was irradiated by exposure to bright sunlight and a tungsten lamp (15W).
Reaction SMILES: [Cl:1][C:2]1[C:14]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[OH:16])=[C:13]([Cl:23])[CH:12]=[CH:11][C:3]=1[C:4]([O:6]C(C)(C)C)=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[C:14]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[OH:16])=[C:13]([Cl:23])[CH:12]=[CH:11][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc(Cl)c(C(O)c2ccccn2)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(Cl)c(C(O)c2ccccn2)c1Cl

Procedure:
3.5 g (9.9 mmol) of tert-butyl 2,4-dichloro-3-((2-pyridyl)(hydroxymethyl))benzoate in 120 ml of toluene and 60 ml of water together with 1.9 g of p-toluenesulfonic acid are heated under reflux for 9 h. After cooling, the organic phase is separated off and the aqueous phase is admixed with a solution of 23.8 g of sodium dihydrogen phosphate in 280 ml of water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and freed from the solvent under reduced pressure. Yield: 1.9 g; 1H NMR, δ [ppm], (DMSO-d6): 6.5 (m), 7.2 (m), 7.5 (d), 7.6 (d), 7.95 (m), 8.4 (d), 13.5 (broad s)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:33])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][C:22]([CH2:26][N:27]3[CH2:32][CH2:31][S:30][CH2:29][CH2:28]3)=[CH:23][C:24]=2[Cl:25])=[O:19])=[CH:4][CH:3]=1.S([O-])(O[O-])(=O)=[O:35].[K+].[K+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:33])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][C:22]([CH2:26][N:27]3[CH2:28][CH2:29][S:30](=[O:35])[CH2:31][CH2:32]3)=[CH:23][C:24]=2[Cl:25])=[O:19])=[CH:4][CH:3]=1
Reactant: O=S(=O)([O-])O[O-]
Reactant: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1sc(CN2CCSCC2)cc1Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1sc(CN2CCS(=O)CC2)cc1Cl
Reaction time: 0.08 h
Yield: 57.5 %

Procedure:
To a suspension of N-(4-chlorophenyl)-2-[((3-chloro-5-(thiomorpholin-4-yl)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide (0.1 g, 0.2 mmol) in methanol (20 mL) at 0° C. was added a solution of potassium peroxymonosulfate (0.13 g, 0.2 mmol) in water (5 mL). After 5 minutes, the reaction was quenched by addition of aqueous 5% sodium bisulfite solution. The mixture was extracted with methylene chloride/methanol, and the organic phase dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 0.064 g (62% yield) of N-(4-chlorophenyl)-2-[((3-chloro-5-(1-(oxo)thiomorpholin-4-yl)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide, as a pale yellow powder; NMR (DMSO-d6/TFA) 11.2 (s, 1), 10.7 (s, 1), 8.3 (d, 1), 7.9 (s, 1), 7.7 (m, 2), 7.6 (m, 1), 7.4 (m, 3) 4.7 (s, 2), 3.7 (m, 2), 3.5 (m. 2), 2.9 (br s, 4) ppm.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[O:19]([C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[C:22]=1[C:23](Cl)=[O:24])[CH3:20].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[O:19]([C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[C:22]=1[C:23]([N:12]1[C:13]2[C:18](=[CH:17][N:16]=[CH:15][CH:14]=2)[C:10]([C:7]2[CH2:8][CH:9]3[N:4]([CH2:3][CH2:2][CH2:1]3)[CH2:5][CH:6]=2)=[CH:11]1)=[O:24])[CH3:20]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: C1=C(c2c[nH]c3ccncc23)CC2CCCN2C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(OC)c1C(=O)n1cc(C2=CCN3CCCC3C2)c2cnccc21

Procedure:
from 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-5-Azaindole (10 mg, 0.0418 mmol), 2,6-dimethoxylbenzoyl chloride (20 mg, 0.0997 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (1 mL) at RT.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[CH:22]=1.[NH:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26]>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26])=[CH:22][C:11]=3[S:12][CH:13]=2)=[CH:16][CH:17]=1
Reactant: Fc1ccc(-c2csc3cc(OCCCCBr)ccc23)cc1
Reactant: OCCNCCO
Product: OCCN(CCO)CCCCOc1ccc2c(-c3ccc(F)cc3)csc2c1

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and diethanolamine were converted to yield 2-[{4-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-(2-hydroxy-ethyl)-amino]-ethanol as white semisolid, MS: 404 (MH+).
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[CH3:5][CH:6]([CH2:9][CH2:10][CH3:11])[CH:7]=O.[OH-].C([N+]1C=CN(C)C=1C)CCC>>[CH3:3][C:2](=[CH:5][CH:6]([CH3:7])[CH2:9][CH2:10][CH3:11])[CH:1]=[O:4]
Reactant: CCCC(C)C=O
Reactant: CCC=O
Agent: CCCC[n+]1ccn(C)c1C
Agent: [OH-]
Product: CCCC(C)C=C(C)C=O

Procedure:
A cross-aldol condensation reaction of propanal and 2-methyl-pentanal in the basic ionic liquid medium 1-butyl-2,3-dimethyl imidazolium hydroxide was run to form 2,4-dimethyl-2-heptenal. The basic ionic liquid 1-butyl-2,3-dimethyl imidazolium hydroxide (8.7 mmol, 1.50 g), 2-methyl-pentanal (1 79.7 mmol, 18.0 g), and nonane (7.8 mmol, 1.01 g) were heated to 100° C. After the addition of propanal (44.7 mmol, 2.6 g), the reaction mixture was refluxed at 87° C. for 3 hours. The resulting products were analyzed using GC and GC/MS techniques. The product isolation was carried out by vacuum distillation. Catalyst evaluation results are presented in Table 4.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)[CH3:2].[C:21](O)(=[O:23])[CH3:22].C(OC(=O)C)(=O)C>O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:21](=[O:23])[CH3:22])=[CH:17][CH:18]=2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(N)cc2)cc1
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCOC(=O)Cc1ccc(Oc2ccc(NC(C)=O)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a mixture of 6.8 g of ethyl[p-(p-aminophenoxy)phenyl]acetate, 7.5 ml of acetic acid, 5.4 ml of water and 8.75 g of crushed ice, maintained at 0°-5° C. is added 2.8 g of acetic anhydride. The temperature immediately rises to 15° C. The stirring is continued for two hours, and extracted with two 50 ml portions of ether. The combined extracts are washed with 50 ml of H2O, 50 ml of saturated NaHCO3, 50 ml of saturated brine, and dried over MgSO4. Evaporation of the solvent affords the product as a tan solid, mp 95°-102° C. A portion is recrystallized from ethanol-hexane to give the product, mp 105°-107° C.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=O.[S:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]([N:33]3[C@H:38]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:37](=[O:43])[NH:36][C@H:35]([CH:44]4[CH2:52][C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[CH2:45]4)[C:34]3=[O:53])[C:23]([NH:25][C:26]3C=CC=CC=3O)=[O:24])=[CH:21][C:16]=2[CH:15]=[CH:14]1.CNC.O1CCCC1>ClCCl>[S:13]1[C:17]2[CH:18]=[CH:19][C:20]([C@@H:22]([N:33]3[C@H:38]([CH2:39][CH:40]([CH3:41])[CH3:42])[C:37](=[O:43])[NH:36][C@H:35]([CH:44]4[CH2:52][C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[CH2:45]4)[C:34]3=[O:53])[C:23]([N:25]([CH3:26])[CH3:1])=[O:24])=[CH:21][C:16]=2[CH:15]=[CH:14]1
Reactant: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)Nc1ccccc1O)c1ccc2sccc2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)N(C)C)c1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.7 %

Procedure:
Carbonyldiimidazole (100 mg) was suspended in anhydrous dichloromethane (1 mL) and the suspension was left at room temperature for 15 minutes. 2RS)-2-(1-benzothien-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyphenyl)ethanamide (200 mg) was then added and the mixture was stirred at room temperature for 5 hours 20 minutes. The resulting brown solution was then treated with a 2.0M solution of dimethylamine in tetrahydrofuran (1.0 mL, 6 equiv.) and the resulting mixture was stirred for 30 minutes and then left to stand at room temperature for 18 hours 15 minutes. The reaction mixture was evaporated under reduced pressure. The crude product was purified by silica column chromatography eluting with 1:1 v/v ethyl acetate:cyclohexane. The required fractions were combined and evaporated in vacuo to give (2R)-2-(benzothien-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide as a white solid (90 mg).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]#[N:8].[CH:9](=O)[CH2:10][CH2:11][CH2:12][CH3:13].C([BH3-])#N.[Na+]>CO>[CH2:9]([NH:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]#[N:8])[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCC=O
Reactant: N#Cc1[nH]cnc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCCNc1nc[nH]c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
4-amino-1H-imidazole-5-carbonitrile (10.0 g, 0.0925 mol) and pentanal (11 mL, 0.10 mol) were mixed in methanol (100 mL). After stirring at room temperature for 2 hours, Sodium cyanoborohydride (7.0 g, 0.11 mol) was added to the mixture. The mixture was continued to stir overnight. The reaction mixture was concentrated, diluted with EtOAc (1 L) and washed with sat. NaHCO3 (30 ml) and then brine (50 ml) solutions respectively. The organic layers were dried over Na2SO4, concentrated and purified with combi-flash silica gel chromatography (20%-80% EtOAc in hexane) to yield the desired product (11.5 g, 70%). LCMS calculated for C9H15N4(M+H): 179. found: 179.1.
Reaction SMILES: C(Cl)(=O)C.[OH:5][C@H:6]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:22]2[C:21](=[O:27])[CH2:20][C@@:19]2([CH3:28])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C:16](=[O:18])[CH3:17])[CH2:7]1.[Br:29]Br.O>CO>[Br:29][CH2:17][C:16](=[O:18])[C@@H:15]1[C@:19]2([CH3:28])[C@H:12]([C@H:11]3[C@H:22]([C:21](=[O:27])[CH2:20]2)[C@:23]2([CH3:26])[C@H:8]([CH2:7][C@@H:6]([OH:5])[CH2:25][CH2:24]2)[CH2:9][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: BrBr
Solvent: O
Solvent: CO
Solvent: CC(=O)Cl
Product: C[C@]12CC[C@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12

Procedure:
Acetyl chloride (9.71 ml) was added to a stirred solution of (3β,5α)-3-hydroxypregnane-11,20-dione (97.1 g) [prepared as described by Cameron et al., J. Chem. Soc., 1955, 2807] in methanol (2.4 l) and a solution of bromine (18.5 ml) in methanol (1 l) was then added over 30 min at room temperature. The reaction mixture was poured into water (30 l) and the precipitated solid was filtered off, washed with water and dissolved in dichloromethane. After drying the solution over sodium sulfate, the solvent was removed under reduced pressure to give crude (3β,5α)-21-bromo-3-hydroxypregnane-11,20-dione (120 g). δ (CDCl3) 0.61 (s,3H), 1.02 (s,3H), 3.00-3.20 (m,1H), 3.49-3.62 (m,2H) and 3.85 (s,2H). Potassium acetate (240 g), potassium iodide (6 g) and glacial acetic acid (250 ml) were added to a solution of (3β,5α)-21-bromo-3-hydroxypregnane-11,20-dione (120 g) in acetone (4.8 l) and the mixture was heated under reflux for 3 h. The reaction mixture was poured into water (50 l) and the precipitated solid was filtered off, washed with water and dissolved in dichloromethane. After drying the solution over sodium sulfate, the solvent was removed under reduced pressure. The residue was chromatographed over silica gel and the purified product was crystallised from diethyl ether to give (3β,5α)-21-(acetyloxy)-3-hydroxypregnane-11,20-dione (26 g) m.p. 163°-165° C.; [α]D +103.3° (c 0.97). 4-Toluenesulfonyl chloride (52 g) was added to a solution of (3β,5α)-21-(acetyloxy)-3-hydroxypregnane-11,20-dione (26 g) in pyridine (260 ml) and the solution was stirred for 4 h at room temperature. The reaction mixture was poured into water (2.6 l) and the precipitated solid was filtered off, washed with water and dissolved in dichloromethane. After drying the solution over sodium sulfate, the solvent was removed under reduced pressure. Crystallisation of the residue from methanol gave (3β,5α)-21-(acetyloxy)-3-{[(4-methylphenyl)sulfonyl]oxy}pregnane-11,20-dione (35 g). m.p. 155°-156° C.; [α]D +62.4° (c 1.11).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]#[CH:28].C(Br)(Br)(Br)[Br:30]>ClCCl>[Br:30][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]#[CH:28]
Reactant: C#CCCCCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C#CCCCCCCBr
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Dehydrated dichloromethane (20 mL) and triphenylphosphine (5.91 g, 22.5 mmol) were added to 8-hydroxy-1-octyne (1.95 g, 15 mmol). The mixture was cooled to 0° C. and was then dropwise added to dehydrated dichloromethane (10 mL) containing carbon tetrabromide (7.46 g, 22.5 mmol), followed by stirring at room temperature for 2 hours. After separation between dichloromethane (100 mL) and 5% sodium bicarbonate (150 mL), the organic layer was washed with saturated brine (150 mL). The organic layer was dried over sodium sulfate and then concentrated. The concentrated product was purified by silica gel column chromatography (dichloromethane:methanol=from 100:0 to 99:1) to yield 8-bromo-1-octyne (crude).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]3[O:16][CH2:15][CH2:14][O:13][C:10]=3[CH:11]=2)[CH:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:5][C:4]1=[S:23])[CH3:2]>C(Cl)(Cl)Cl.O=[Mn]=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]3[O:16][CH2:15][CH2:14][O:13][C:10]=3[CH:11]=2)[C:6]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:5][C:4]1=[S:23])[CH3:2]
Reactant: CCN1C(=S)NC(c2ccccc2)c2cc3c(cc21)OCCO3
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CCn1c(=S)nc(-c2ccccc2)c2cc3c(cc21)OCCO3
Temperature: 25 °C
Reaction time: 72 h
Yield: 45 %

Procedure:
A mixture of 1-ethyl-6,7-ethylenedioxy-4-phenyl-3,4-dihydroquinazolin-2(1H)-thione (77 mg, 0.24 mmol) and MnO2 (180 mg, 2.07 mmol) in 5 mL of CHCl3 was stirred at rt for 3 days. The solids were filtered off and the solution concentrated in vacuo. The crude residue was subjected to flash column chromatography eluting with EtOAc:hexane to give the title compound (35 mg, 46%). 1H NMR (CDCl3): 7.72 (dd, 2H), 7.53-7.49 (m, 3H), 7.38 (s, 1H), 7.09 (3, 1H), 4.90 (m, 2H), 4.48-4.30 (m, 4H), 1.55 (t, 3H).