Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.O>ClCCl>[C:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:13][C:8]([O:7][C:6]2[CH:20]=[CH:21][C:3]([OH:2])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(Oc2ccc(-c3ccccc3)cc2)cc1
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(Oc2ccc(-c3ccccc3)cc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 12.3 %

Procedure:
To a solution of 4-(4-methoxy-phenoxy)-biphenyl (3.2 g, 11.6 mmol) in anhydrous dichloromethane (60 mL) at −78° C. was added borontribromide (1M solution in dichloromethane) (7.52 g, 30 mmol) over a period of 15 min. The reaction mixture was stirred at −78° C. for 1 h, warmed to rt and stirred at rt for 1 h. The mixture was cooled to 0-5° C. Cold water (125 mL) was added over a period of 10 min and the mixture was extracted with dichloromethane (250 mL). The organic layer was dried over anhydrous Na2SO4. The crude mixture was purified by silica gel flash chromatography to obtain the title product (375 mg, 12%).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH:28]=O)[CH:24]=[N:23][CH:22]=[N:21]1>>[N:20]1([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH2:28][N:1]2[CH:2]([C:10]3[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=3[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])[CH:24]=[N:23][CH:22]=[N:21]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-n2cncn2)c1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-n2cncn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 3-(1H-1,2,4-triazol-1-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.70 min.; [M+H]+: 393.15 g/mol.
Reaction SMILES: [CH3:1][N:2]([CH3:4])[CH3:3].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9]Br>CO>[Br-:5].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][N+:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: CN(C)C
Reactant: BrCCCCBr
Solvent: CO
Product: C[N+](C)(C)CCCCBr
Product: [Br-]

Procedure:
(4-bromobutyl)trimethylammonium bromide was prepared by the reaction of trimethylamine and 1,4-dibromobutane in methanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4](Cl)[C:5](=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].[CH:19]([NH2:21])=[S:20]>CO>[CH3:1][O:2][C:3]([C:4]1[S:20][CH:19]=[N:21][C:5]=1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:18]
Reactant: NC=S
Reactant: COC(=O)CCCCCCC(=O)C(Cl)C(=O)OC
Solvent: CO
Product: COC(=O)CCCCCCc1ncsc1C(=O)OC

Procedure:
16.8 g of 9-carbomethoxy-2-chloro-3ketonononoic acid methylester (VI) and 4.5 of thioformamide (VII, R1 = H) were refluxed in 90 ml of methanol for 1 hour, then methanol was evaporated in vacuo, and the distillation residue was dissolved in 150 ml of 2 N hydrochloric acid. The obtained solution was neutralized with a 5 % solution of sodium carbonate, saturated with ammonium sulphate and extracted with 3 × 150 ml of diethyl ether. The ethereal extract was dried over sodium sulphate, then ether was evaporated. Thus 16 g of crude 4-(6-carbomethoxyhexyl)-thiazole-5-carboxylic acid methylester (VIII, R1 = H) were obtained which could be used without any further purification for the preparation of 4-(6-carboxyhexyl)-thiazole-5-carboxylic acid (IX, R1 = H) according to point (e).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([S:28](C)(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH3:32]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH2:32])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O
Reactant: N
Product: CC(C)(O)CCOc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 459, substituting 2-(4-fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 600 mg, 60%). mp 163-164° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.05 (s, 6H), 1.73 (t, J=6 Hz, 2H), 4.30 (s, 1H), 4.52 (t, J=6 Hz, 2H), 7.37 (t, J=9 Hz, 1H), 7.47 (s, 2H, 7.37 (dd, J=9 Hz, J=3 Hz, 2H), 8.83 (d, J=9 Hz, 2H), 8.95 (d, J=9 Hz, 2H), 8.18 (s, 1H); MS (DCI/NH3) m/z 448 (M+H)+. Anal. calcd. for C21H22FN3O5S: C, 56.36; H, 4.95; N, 9.39. Found: C, 55.96; H. 4.89; N, 9.09.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[C:9]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:10]=3[O:11][C:12]=2[CH3:13])[N:7]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C.CO>ClCCCl>[C:21]([NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[C:9]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:10]=3[O:11][C:12]=2[CH3:13])[N:7]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1oc2c([N+](=O)[O-])cccc2c1-c1csc(N)n1
Agent: Cl
Solvent: ClCCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(-c2c(C)oc3c([N+](=O)[O-])cccc23)cs1
Yield: 64 %

Procedure:
A mixture of 3-(2-aminothiazol-4-yl)-2-methyl-7-nitrobenzo[b]furan hydrochloride (468 mg), acetic anhydride (306 mg) and triethylamine (455 mg) in 1,2-dichloroethane (20 ml) was refluxed for 1 day. To the reaction mixture was added methanol and the mixture was evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from diethyl ether to give 3-(2-acetylaminothiazol-4-yl)-2-methyl-7-nitrobenzo[b]furan (305 mg).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:27])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:19][C@H:18]3[N:14]([CH2:15][CH2:16][CH2:17]3)[C:13]3[N:20]=[C:21]([S:24][CH3:25])[N:22]=[CH:23][C:12]=3[C:11]2=[O:26])[CH:5]=1.C(N(CC)CC)C.[F:35][C:36]([F:41])([F:40])[C:37](O)=O>ClCCl>[CH3:25][S:24][C:21]1[N:22]=[CH:23][C:12]2[C:11](=[O:26])[N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([C:3]4[N:27]=[C:37]([C:36]([F:41])([F:40])[F:35])[O:1][N:2]=4)[CH:5]=3)[CH2:19][C@H:18]3[N:14]([CH2:15][CH2:16][CH2:17]3)[C:13]=2[N:20]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(N)=NO)c1)C2=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3noc(C(F)(F)F)n3)c1)C2=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
(S)—N′-Hydroxy-3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzamidine (190 mg, 0.49 mmol) obtained in Step 1 of Example 75 was dissolved in dichloromethane (1.5 mL), and the mixture was cooled to 0° C. after adding triethylamine (0.14 mL, 0.99 mmol). Thereafter, anhydrous trifluoroacetic acid (0.14 mL, 0.99 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The residue obtained by concentrating the mixture under reduced pressure was then purified by silica gel column chromatography to give (S)-9-methylthio-5-[3-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)phenyl]-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (186 mg, 81%).
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[N:17]1([CH2:22][CH2:23][NH2:24])[CH2:21][CH2:20][CH2:19][CH2:18]1>>[N:17]1([CH2:22][CH2:23][NH:24][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NCCN1CCCC1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Product: O=c1[nH]c2ncccc2c2cc(NCCN3CCCC3)ccc12
Yield: 18.1 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 456 using 6 (100 mg, 0.43 mmol) and 2-pyrrolidin-1-ylethanamine (0.22 mL, 1.73 mmol) to provide 474 (24 mg, 18% yield) as a white powder. LC-MS (M+H=309, obsd.=309). 1H NMR (400 MHz, DMSO-D6) δ 11.59 (s, 1H), 9.65 (s, 1H), 8.75 (d, J=8.0, 1H), 8.39 (m, 1H), 8.05 (d, J=8.7, 1H), 7.42 (s, 1H), 7.28 (dd, J=4.6, 7.9, 1H), 6.95 (d, J=8.7, 1H), 3.65 (s, 4H), 3.41 (s, 2H), 3.10 (s, 2H), 1.96 (d, J=59.8, 4H).
Reaction SMILES: [NH2:1][CH:2]1[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[N+]([O-])(O)=[O:13].[OH-].[Na+]>OS(O)(=O)=O>[NH2:1][CH:2]1[CH:3]2[CH2:11][C:7]3([OH:13])[CH2:6][CH:5]([CH2:10][CH:9]1[CH2:8]3)[CH2:4]2
Reactant: O=[N+]([O-])O
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: NC1C2CC3CC1CC(O)(C3)C2
Reaction time: 8 h
Yield: 14 %

Procedure:
To 2-aminoadamantane (10 g, 54 mmol) was added H2SO4 (150 mL) and HNO3 (15 ml) at 0° C. and the mixture was stirred overnight. The mixture was poured onto ice and adjusted to pH=10-11 using 40% aq NaOH under ice bath. The mixture was extracted with CH2Cl2. The organic layer was dried, filtered and concentrated to give 4-aminoadamantan-1-ol (3.0 g, 14%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:8]([CH:10]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:11]([O-:13])=[O:12])=O.Cl.[C:23]1(C)C=CC=C[CH:24]=1>>[NH:1](/[CH:8]=[C:10](/[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)\[C:11]([O:13][CH2:23][CH3:24])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(C=O)C(=O)[O-])cc1
Reactant: Nc1ccccc1
Reactant: Cc1ccccc1
Agent: Cl
Product: CCOC(=O)/C(=C\Nc1ccccc1)c1ccc(OC)cc1
Yield: 71 %

Procedure:
A solution of aniline (1.85 ml, 20.30 mmol) and ethyl ∀-formyl-4-methoxyphenylacetate (4.96 g, 1.1 eq) in toluene (15 ml) is refluxed for 18 hours. After cooling, the reaction mixture is diluted with toluene (10 ml) and then acidified with 10% HCl. After extraction, the organic phase obtained is dried over MgSO4 and then evaporated under reduced pressure. The residue is purified by chromatography on a column of silica (eluent: 4/6 PE/CH2Cl2) to give 4.29 g (71%) of compound 18 (Z isomer) in the form of a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6])[CH3:2].C(N(CC)CC)C.[N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH:26]=O)=[CH:18][CH:17]=1>Cl.ClCCl>[N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][NH:6][C@@H:5]([CH3:7])[C:4]([O:3][CH2:1][CH3:2])=[O:8])=[CH:18][CH:17]=1
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=Cc1ccnc2ccccc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)NCc1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.1 %

Procedure:
A mixture of 2 g of L-alanine ethyl ester in hydrochloride form and 1.83 ml of triethylamine in 30 ml of dichloromethane is stirred at room temperature for 10 minutes. Next, 2.05 g of quinoline-4-carbaldehyde are added. The reaction medium is stirred at room temperature for 15 hours and then concentrated under reduced pressure. 35 ml of ethanol are then added; the solution is cooled to 0° C. and 0.49 g of sodium borohydride is then added portionwise. Stirring is continued for 15 hours at room temperature. The precipitate formed is filtered off; the filtrate is concentrated under reduced pressure. The residue is purified by flash chromatography on a column (SiO2, CH2Cl2/MeOH, 95/5 by volume as eluent, Ar). 0.71 g of ethyl (S)-2-[(quinol-4-ylmethyl)amino]propanoate is obtained in the form of a pink oil.
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[Cl:9][C:10]1[S:14][C:13]([N:15]=[C:16]=[O:17])=[CH:12][CH:11]=1.O>CN(C=O)C.C1(C)C=CC=CC=1>[Cl:9][C:10]1[S:14][C:13]([NH:15][C:16]([N:8]=[C:7]2[NH:6][C:4](=[O:5])[CH2:3][N:2]2[CH3:1])=[O:17])=[CH:12][CH:11]=1
Reactant: CN1CC(=O)N=C1N
Reactant: O=C=Nc1ccc(Cl)s1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CN1CC(=O)NC1=NC(=O)Nc1ccc(Cl)s1
Temperature: 80 °C
Yield: 30.6 %

Procedure:
To a stirred suspension of 2.5 g (22.5 mM) of creatinine in 30 ml of anhydrous DMF was added a solution of 2.87 g (18 mM) of 5-chloro-2-thienyl isocyanate in 15 ml of toluene. The resulting mixture was heated at 80° C. for 3.5 hrs., cooled, and poured into a mixture of 250 ml of water and 50 ml of toluene. The precipitate was collected and recrystallized from ethyl acetate to give 1.5 g of the above urea as a tan solid, m.p. 204°-205° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:40]=[CH:41][CH:42]=1)[CH2:7][CH2:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:39]=[CH:38][C:23]([CH2:24][N:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[CH:22][CH:21]=2)[N:10]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:25]1([CH2:24][C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:11]3[N:10]=[C:9]([CH2:8][CH2:7][C:6]4[CH:5]=[C:4]([CH:42]=[CH:41][CH:40]=4)[C:1]([NH2:2])=[O:3])[C:14]([C:15]([F:17])([F:16])[F:18])=[CH:13][N:12]=3)=[CH:39][CH:38]=2)[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Nc3ncc(C(F)(F)F)c(CCc4cccc(C(N)=O)c4)n3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cccc(CCc2nc(Nc3ccc(CN4CCNCC4)cc3)ncc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.3 %

Procedure:
tert-Butyl 4-(4-((4-(3-carbamoylphenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl)piperazine-1-carboxylate (I146) (65 mg, 0.11 mmol) was dissolved in DCM (10 mL) then TFA (1 mL) was added and the resulting mixture stirred at room temperature for 18 hours. The volatiles were evaporated under reduced pressure and the residue partitioned between 10% sodium hydroxide (25 mL) and ethyl acetate (25 mL). The aqueous phase was extracted with ethyl acetate (3×25 mL) then the combined ethyl acetate phases washed with brine, dried over sodium sulfate and evaporated. The residue was washed with toluene (2×2 mL) and DCM (2×0.5 mL) to give the title compound (37) (22 mg, 40% yield) as a white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.19 (s, 1H), 8.66 (s, 1H), 7.94 (s, 1H), 7.78 (s, 1H), 7.74-7.64 (m, 3H), 7.40-7.35 (m, 2H), 7.35-7.29 (m, 1H), 7.23 (d, J=8.2 Hz, 2H), 3.38 (s, 2H), 3.17-3.02 (m, 4H), 2.75-2.61 (m, 4H), 2.29 (s, 4H). LCMS Method C: rt 4.52 min; m/z 485.1 [M+H]+; m/z 483.1 [M−H]−.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21]C2C=CC=CC=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]=[C:36]=[O:37]>>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][C:36]([NH:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[Br:28])=[O:37])(=[O:13])=[O:12])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=C=Nc1ccccc1Br
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccccc2Nc2ccccc2)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccccc2NC(=O)Nc2ccccc2Br)cc1
Yield: 23.8 %

Procedure:
The urea was synthesized from 2-[(4-acetamidophenyl)sulfonylamino]phenyl aniline(1 mmol) and 2-bromo phenyl isocyanate(1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.12 g, 24%). EI-MS m/z 501(M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16](I)[C:17]=1[O:18][CH3:19])[CH2:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1.C([Si:23]([CH3:26])([CH3:25])[CH3:24])#C.O.[CH2:28](N(CC)CC)[CH3:29]>CN(C)C=O.[Cu]I>[CH3:24][Si:23]([CH3:26])([CH3:25])[C:16]1[CH:15]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:17]=1[O:18][CH3:19])[CH:6]([C:28]#[CH:29])[C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(I)c1OC
Reactant: CCN(CC)CC
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Product: C#CC(c1cc(OC)c(OC)c([Si](C)(C)C)c1)c1cnc(N)nc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 59 %

Procedure:
A mixture of 8.7 g of 5-(3,4-dimethoxy-5-iodobenzyl)-pyrimidine-2,4-diamine, 6.2 ml of ethynyltrimethylsilane, 80 mg of bis-trimethylphosphine-palladium dichloride and 1 mg of copper(I) iodide in 25 ml of triethylamine and 25 ml of dimethylformamide is stirred at 60° for 16 hrs. After cooling to room temperature the reaction mixture is treated with 400 ml of water and extracted three times with 200 ml of methylene chloride each time. The combined organic phases are washed twice with 250 ml of water, once with 250 ml of a saturated sodium chloride solution and dried over magnesium sulphate. The crude product is chromatographed on silica gel with methylene chloride/methanol 9:1. 4.73 g (59%) of 5-[3-trimethylsilyl-ethynyl-4,5-dimethoxy-benzyl]-pyrimidine-2,4-diamine are obtained as beige crystals. M.p. 189°-190°.
Reaction SMILES: O[C:2]1[CH:15]=[C:14]([OH:16])[CH:13]=[C:12]([OH:17])[C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[C:31](=[O:34])([O-])[O-].[K+].[K+].Cl>C1(C)C=CC=CC=1.CN(C)C(=O)C.[I-].[K+]>[OH:17][C:12]1[CH:13]=[C:14]([O:16][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:15]=[C:2]([O:34][CH2:31][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:4][CH2:3][CH2:2][CH2:15][CH3:14])[C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: CCCCCCCCCCCCBr
Reactant: O=C([O-])[O-]
Reactant: O=C(c1ccccc1)c1c(O)cc(O)cc1O
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOc1cc(O)c(C(=O)c2ccccc2)c(OCCCCCCCCCCCC)c1
Temperature: 110 °C
Reaction time: 7 h
Yield: 72.3 %

Procedure:
A mixture of 4.5 g (20 mmol) of 2,4,6-trihydroxybenzophenone, 9.8 g (40 mmol) of 1-bromododecane, 2.7 g (20 mmol) of potassium carbonate and 30 mg (0.2 mmol) of potassium iodide in 50 ml of toluene and 20 ml of N,N-dimethylacetamide is stirred at 110° C. for 7 h. The reaction mixture is cooled and then neutralized with 10% HCl. The organic solution is washed with water and then with saturated sodium chloride solution. The residue which remains after drying over MgSO4, filtering and concentrating by evaporation is purified by chromatography over silica gel (toluene/hexane 3:2). The product is recrystallized from isopropyl alcohol. 4.1 g of the compound are obtained as pale yellow crystals having a melting point of 37°-38° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C:17]2=[CH:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:22])[CH:4]=1.[CH3:23][O-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C:17]2=[CH:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][C:11](=[CH2:23])[C:12]2=[O:22])[CH:4]=1
Reactant: COC1=CC2=CC[C@@H]3C(=CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C1C[C@H]2[C@@H]3CC=C4C=C(OC)CC[C@]4(C)C3=CC[C@]2(C)C1=O
Reaction time: 1 h

Procedure:
3-Methoxyandrosta-3,5,9(11)-trien-17-one (IAa, 20 g) in THF (220 ml) was combined with dimethyloxylate (11.8 g) and sodium methoxide (25%, 18.4 ml) at 0° under nitrogen. After the reactants were combined, the ice was removed. After one hour, TLC shows the reaction has gone cleanly. Triethylamine (7.0 ml), acetic acid (1.0 ml), paraformaldehyde (3 g), and methanol (28 ml) were added and the mixture stirred overnight at 20°-25°. TLC showed the reaction had gone to completion. The reaction mixture was washed with phosphate buffer (121 ml) and water (202 ml). The mixture was extracted with methylene chloride (48 ml) and again with methylene chloride (40 ml). The methylene chloride extracts were combined and back-extracted with water (80 ml) and saline (10 ml). The organic mixture was concentrated under reduced presure to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([C:11]=1Br)[CH2:9][CH2:8][C:7]1[CH:13]=[CH:14][CH:15]=[CH:16][C:6]=1[C:5]2=[O:17].C(O)C.[H][H]>[Pd].C(N(CC)CC)C>[CH:3]1[CH:2]=[CH:11][N:10]2[CH2:9][CH2:8][C:7]3[CH:13]=[CH:14][CH:15]=[CH:16][C:6]=3[C:5](=[O:17])[C:4]=12
Reactant: O=C1c2ccccc2CCn2c1cc(Br)c2Br
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2CCn2cccc21

Procedure:
A suspension of 25 g. (0.070 mole) of 2,3-dibromo-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-one in 200 ml. ethanol containing 25 ml. of triethylamine and 1 gm. of 10% Pd on charcoal was hydrogenated under 3 atmospheres of hydrogen to yield 6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-one, m.p. 54°-55° C. after removal of catalyst, recrystallization from petroleum ether and drying under vacuum. The same compound is also obtained by hydrogenolysis of the 2,3-dichloro ketone and the 1,2,3-tribromoketone.
Reaction SMILES: [Si]([O:8][C@H:9]([C:43]1[CH:44]=[CH:45][C:46]([OH:54])=[C:47]([NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH:48]=1)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([C@@H:27]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:28][CH2:29][N:30]([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[CH:21]=1)(C(C)(C)C)(C)C.F.F.F.C(N(CC)CC)C.CO.N>O1CCCC1>[NH3:11].[CH:34]([N:30]([CH:31]([CH3:33])[CH3:32])[CH2:29][CH2:28][C@@H:27]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[OH:26])[O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]([C:43]1[CH:44]=[CH:45][C:46]([OH:54])=[C:47]([NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH:48]=1)[OH:8])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)([CH3:36])[CH3:35]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(OCCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(O)c(NS(C)(=O)=O)c2)ccc1O)C(C)C
Agent: F
Agent: N
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(OCCCCCCCNC[C@H](O)c2ccc(O)c(NS(C)(=O)=O)c2)ccc1O)C(C)C

Procedure:
N-(5-{(1R)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-[(7-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenoxy}heptyl)amino]ethyl}-2-hydroxyphenyl)methanesulfonamide (Preparation 20, 68 mg, 0.087 mmol) was dissolved in tetrahydrofuran (3 ml) and N,N-diethylethanamine trihydrofluoride (71 μl, 0.43 mmol) was added dropwise. After 18 hours a mixture of methanol (4 ml) and 880 ammonia (8 ml) were added and after 15 minutes the solvent was removed in vacuo. The residue was dissolved in dichloromethane and the solvent removed in vacuo again and the residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (97/310.3 to 88/12/1.2 by volume) to furnish the title compound as a white solid, 30 mg.
Reaction SMILES: [ClH:1].[F:2][C:3]([F:36])([F:35])[C:4]1[CH:5]=[C:6]([C@H:14]([N:16]([CH3:34])[C:17]([N:19]2[C@@H:25]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[CH3:33])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:18])[CH3:15])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.[CH2:37]=O>CO.[Pd]>[ClH:1].[F:36][C:3]([F:2])([F:35])[C:4]1[CH:5]=[C:6]([C@H:14]([N:16]([CH3:34])[C:17]([N:19]2[C@@H:25]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[CH3:33])[CH2:24][CH2:23][N:22]([CH3:37])[CH2:21][CH2:20]2)=[O:18])[CH3:15])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: C=O
Reactant: Cc1cc(F)ccc1[C@H]1CCNCCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1cc(F)ccc1[C@H]1CCN(C)CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
A mixture of example 4 (10 mg), aqueous formaldehyde (29 μL) and 10% Pd/C (5 mg) in anhydrous MeOH (1 mL) was hydrogenated at r.t. and Patm. for 1 hour. The mixture was filtered and the organic layer was concentrated in vacuo. The residue was triturated with Et2O/pentane to give the title compound (5 mg) as a whitish solid.