Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Mg]I)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:14]([C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][C:19]=1[NH:26][C:27](=[O:43])[CH2:28][CH:29]1[C:42]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[O:36][C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)([CH3:17])([CH3:16])[CH3:15]>>[C:14]([C:18]1[CH:23]=[CH:22][C:21]([CH:24]([OH:25])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:20][C:19]=1[NH:26][C:27](=[O:43])[CH2:28][CH:29]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=2[O:36][C:37]2[C:42]1=[CH:41][CH:40]=[CH:39][CH:38]=2)([CH3:17])([CH3:15])[CH3:16]
Reactant: I[Mg]CCCCCC1CCCCC1
Reactant: CC(C)(C)c1ccc(C=O)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Product: CC(C)(C)c1ccc(C(O)CCCCCC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21

Procedure:
Following a procedure similar to that described in Example 14, but using 5-cyclohexylpentylmagnesium iodide and N-(2-t-butyl-5-formylphenyl)-2-(9H-xanthen-9-yl)acetamide (prepared as described in Preparation 15) as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a foam-like substance.
Reaction SMILES: Br.[CH3:2][O:3][C:4]([C:6]1[CH2:7][NH:8][CH2:9][CH2:10][CH:11]=1)=[O:5].C(N(C(C)C)C(C)C)C.C1(C)C=CC(S(O[CH2:31][CH2:32][CH:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[O:35][CH2:34]2)(=O)=O)=CC=1>CN(C)C=O>[CH3:2][O:3][C:4]([C:6]1[CH2:7][N:8]([CH2:31][CH2:32][CH:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[O:35][CH2:34]2)[CH2:9][CH2:10][CH:11]=1)=[O:5]
Reactant: Cc1ccc(S(=O)(=O)OCCC2COc3ccccc3C2)cc1
Reactant: COC(=O)C1=CCCNC1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1=CCCN(CCC2COc3ccccc3C2)C1
Reaction time: 16 h
Yield: 97.6 %

Procedure:
First 3.3 g (14.8 mmol) of 1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrobromide (guvacoline hydrobromide) and then 6.1 g (47.3 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 4.5 g (13.5 mmol) of 3-[2-(p-toluenesulphonyloxy)ethyl]chroman in 70 ml of absolute dimethylformamide. The mixture is stirred for 16 hours at 60° and, after cooling, is concentrated by evaporation under a high vacuum. Water is added to the oily residue and extraction is carried out with diethyl ether. The combined organic phases are extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 3.97 g (97.7%) of 1-[2-(chroman-3-yl)ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester are obtained in the form of a yellow oil. The 1-[2-(chroman-3-yl)ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from methanol/diethyl ether and melts at 175°-177°.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:30])=[C:16]([NH:21][C:22](=[O:29])OCC(Cl)(Cl)Cl)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH2:31][CH2:32][CH2:33][CH2:34][OH:35]>CCCCCC.C(OCC)(=O)C>[OH:35][CH2:34][CH2:33][CH2:32][NH:31][C:22]([NH:21][C:16]1[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]2[O:12][CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]=1[CH3:30])=[O:29]
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OCC(Cl)(Cl)Cl)C(c1ccc(C(C)C)cc1)CO2
Reactant: NCCCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1NC(=O)NCCCO)C(c1ccc(C(C)C)cc1)CO2
Yield: 33 %

Procedure:
Using 2,2,2-trichloroethyl (3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 138 and 3-amino-1-propanol, the title compound was synthesized in the same manner as in Example 143. Yield: 33%. Melting point: 185-186° C. (hexane-ethyl acetate).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH:19]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29]Br)=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:17]2[CH2:16][CH:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:9][CH:10]=3)[CH2:19][CH2:18]2)=[CH:23][CH:22]=1
Reactant: Fc1ccc(OCCBr)cc1
Reactant: C1=C(c2ccc(Oc3ccccc3)cc2)CCNC1
Product: Fc1ccc(OCCN2CC=C(c3ccc(Oc4ccccc4)cc3)CC2)cc1

Procedure:
The same procedure was followed as in Example 11 using the compound (8) synthesized in Example 1 and 2-(4-fluorophenyl)oxyethyl bromide to produce the above.
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][S:13]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])(=[O:15])=[O:14])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[Cl:24][C:25]1[N:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=1>>[Cl:1][C:2]1[C:3](/[C:4](/[OH:6])=[CH:31]\[C:29]2[CH:28]=[CH:27][N:26]=[C:25]([Cl:24])[N:30]=2)=[CH:8][CH:9]=[CH:10][C:11]=1[NH:12][S:13]([C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[F:23])(=[O:15])=[O:14]
Reactant: Cc1ccnc(Cl)n1
Reactant: COC(=O)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1Cl
Product: O=S(=O)(Nc1cccc(/C(O)=C\c2ccnc(Cl)n2)c1Cl)c1c(F)cccc1F
Yield: 73.5 %

Procedure:
Following a procedure analogous to Intermediate 5, Step B using methyl 2-chloro-3-(2,6-difluorophenylsulfonamido)benzoate (31 g, 85.9 mmol) and 2-chloro-4-methylpyrimidine (12.2 g, 94.5 mmol) the title compound was obtained (33 g, 73.5% yield). 1H NMR (400 MHz, CDCl3) δ ppm 13.47-13.52 (br, 0.96H), 8.50-8.56 (m, 0.13H), 8.38 (d, J=5.3 Hz, 1H), 7.78-7.82 (m, 0.15H), 7.62-7.73 (m, 2H), 7.40-7.50 (m, 1.18H), 7.17-7.30 (m, 1.77H), 6.90-6.97 (m, 2.29H), 6.83 (d, J=5.3 Hz, 1H), 5.65 (s, 1H), 4.28 (s, 0.26H). MS (ES+): 458 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[N:8]([CH3:11])[N:9]=[CH:10][C:3]=12.C[Si]([C:16]#[C:17][C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:11][N:8]1[C:4]2=[CH:5][N:6]=[CH:7][C:2]([C:16]#[C:17][C:18]3[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=3)=[C:3]2[CH:10]=[N:9]1
Reactant: C[Si](C)(C)C#Cc1cccc(N)c1
Reactant: Cn1ncc2c(Br)cncc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: Cn1ncc2c(C#Cc3cccc(N)c3)cncc21
Temperature: 80 °C

Procedure:
In an adaption of GP 3c, 639 mg of 4-bromo-1-methyl-1H-pyrazolo[3,4-c]pyridine (Intermediate 2.1, 3 mmol, 1 eq), 931 mg 3-trimethylsilanylethynyl-phenylamine (4.9 mmol, 1.6 eq.), 106 mg dichlorobis(triphenylphosphine)palladium (II) (PdCl2(PPh3)2) (0.15 mmol, 5 mol %) and 115 mg copper (I) iodide (0.6 mmol, 0.2 eq.) were dissolved in 15 mL THF (0.2 M) and treated with 3.6 mL tetra-n-butylammonium fluoride solution (1.0 M in THF, 3.6 mmol, 1.2 eq.). The resulting mixture was heated to 80° C. in a Biotage Initiator microwave oven for 30 min. Extractive work-up followed by column chromatography provided the target compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[CH:19](Br)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][O:30][C:31]1[N:36]=[CH:35][C:34]([CH2:37][O:38][C:39]2[CH:44]=[CH:43][N:42]=[C:41]([NH2:45])[N:40]=2)=[CH:33][CH:32]=1>CCO>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:45]=[C:41]4[N:40]=[C:39]([O:38][CH2:37][C:34]5[CH:35]=[N:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=5)[CH:44]=[CH:43][N:42]4[C:19]=3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Reactant: COc1ccc(COc2ccnc(N)n2)cn1
Solvent: CCO
Product: COc1ccc(COc2ccn3c(-c4ccccc4)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)nc3n2)cn1
Yield: 119.2 %

Procedure:
A mixture of crude {1-[4-(2-bromo-2-phenyl-acetyl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester [Int-1-A] (1.2 g, 82% purity), crude 4-(6-methoxy-pyridin-3-ylmethoxy)-pyrimidin-2-ylamine (0.66 g, 65% purity) and activated 3 Å molecular sieves in EtOH (7.5 mL) was heated at reflux for 2 hours. LC-MS indicated the reaction to be incomplete. A further 0.66 g portion of 4-(6-methoxy-pyridin-3-ylmethoxy)-pyrimidin-2-ylamine was added and the mixture was heated at reflux for 3 hours. On cooling the mixture was partitioned between EtOAc and water, decanted and the separated organic phase washed with brine, dried and concentrated to give the title compound (1.86 g) as a yellow solid which was used in the next step without further purification.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:25]=[CH:24][C:7]([CH2:8][C:9]2[CH2:13][C:12]([CH2:19][O:20]C(=O)C)([CH2:14][O:15]C(=O)C)[O:11][N:10]=2)=[CH:6][CH:5]=1>C(O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[CH2:13][C:12]([CH2:19][OH:20])([CH2:14][OH:15])[O:11][N:10]=2)=[CH:24][CH:25]=1
Reactant: CC(=O)OCC1(COC(C)=O)CC(Cc2ccc(F)cc2)=NO1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: OCC1(CO)CC(Cc2ccc(F)cc2)=NO1
Yield: 81.3 %

Procedure:
A solution of 58.3 g of KOH in 900 ml of ethanol is added to 138 g of 3-(p-fluorobenzyl)-5,5-bis-(acetoxymethyl)-isoxazoline, and the mixture is refluxed for 12 hours. After the mixture has been cooled, the precipitated salt is filtered off and the solvent is removed under reduced pressure. Acetone is added, after which precipitated solid is again filtered off under suction and the filtrate is evaporated down. The oil obtained can be purified by column chromatography [silica gel; eluent: toluene/acetone (initially 9/1, subsequently 1/1)]. 83 g of 3-(p-fluorobenzyl)-5,5-bis-(hydroxymethyl)-isoxazoline of melting point 93°-97° C. are obtained. ##STR12##
Reaction SMILES: [CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH:18]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:19]([O:21]CC)=[O:20])[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1N=NN(C(C2C=CC=CC=2)C(OCC)=O)N=1)CCCCCCCCC>>[CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH:18]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:19]([OH:21])=[O:20])[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1nnn(C(CCCCC)C(=O)OCC)n1
Agent: CCCCCCCCCCc1nnn(C(C(=O)OCC)c2ccccc2)n1
Product: CCCCCCCCCCCCc1nnn(C(CCCCC)C(=O)O)n1

Procedure:
When in the general procedure of Example 79 an appropriate amount of ethyl (±)-5-dodecyl-α-pentyl-2H-tetrazole-2-acetate was substituted for ethyl (±)-5-decyl-α-phenyl-2H-tetrazole-2-acetate, the title compound was obtained.
Reaction SMILES: [OH-].[K+].N([CH:10]([C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)P(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[N+:36]([C:39]1[CH:46]=[CH:45][C:42]([CH:43]=[O:44])=[CH:41][CH:40]=1)([O-:38])=[O:37]>CO.C1COCC1>[N+:36]([C:39]1[CH:40]=[CH:41][C:42]([C:43](=[O:44])[CH2:10][C:27]2[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=2)=[CH:45][CH:46]=1)([O-:38])=[O:37]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc(C(Nc2ccccc2)P(=O)(Oc2ccccc2)Oc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Cc1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
A solution of KOH (7.56 g, 0.13 mol) in MeOH (75 ml) was added to the phosphonate ester 33 (62.1 g, 0.13 mol) in THF (400 ml) at -78° C. for 0.5 hour and p-nitrobenzaldehyde (20.3 g, 0.13 mol) in 200 ml of THF was added over 0.5 hour. The reaction was warmed to room temperature and stirred an additional 2 hours. THF was removed under reduced pressure. The residue was taken up in EtOAc and washed twice with 5% aqueous NaHCO3 and once with brine. The ethyl acetate was removed under reduced pressure. The dark red enemine was dissolved in CH3OH (600 ml) and concentrated HCl (0.2 ml) was added. The solution was stirred for 1 hour at room temperature and diluted with H2O (500 ml). The solid was filtered, washed with ether and dried to afford 34 (35.6 g, 82.0%), m.p. 131°-133° C.
Reaction SMILES: CC1(C)N([O])C(C)(C)CCC1.[K+].[Br-].[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19]1[S:20][CH:21]=[C:22]([CH2:24][OH:25])[N:23]=1.Cl[O-].[Na+].C([O-])(O)=O.[Na+]>O.C(Cl)Cl>[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19]1[S:20][CH:21]=[C:22]([CH:24]=[O:25])[N:23]=1
Reactant: OCc1csc(-c2cccs2)n1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: O=Cc1csc(-c2cccs2)n1

Procedure:
TEMPO (5.1 mg; 0.0329 mmol) and a solution of KBr (39.2 mg; 0.329 mmol) in water (0.5 ml) were added to a solution of (2-thiophen-2-ylthiazole-4-yl)methanol (0.65 g; 3.29 mmol) in CH2Cl2 (12 ml), followed, after cooling to 0-5° C., by dropwise addition of a solution of 7.1% sodium hypochlorite (4.1 ml; 4.1 mmol) and NaHCO3 (245 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([NH:20][CH2:21][CH3:22])[C:17]([C:23]([O:25]CC)=[O:24])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].O>C(O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:19]=[C:18]([NH:20][CH2:21][CH3:22])[C:17]([C:23]([OH:25])=[O:24])=[CH:16][N:15]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNc1nc(N2CCN(Cc3ccccc3)CC2)ncc1C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCNc1nc(N2CCN(Cc3ccccc3)CC2)ncc1C(=O)O
Yield: 81.1 %

Procedure:
After refluxing for 1 hour a mixture of 106.4 g (0.29 mol) of ethyl 2-(4-benzylpiperazino)-4-ethylaminopyrimidine-5-carboxylate (the compound synthesized in Referential Example 64), 38.0 g (0.58 mol) of a 85% aqueous solution of potassium hydroxide, 100 ml of water and 400 ml of ethanol, ethanol was distilled off under reduced pressure. The residue was added with water and then neutralized with hydrochloric acid. The precipitated crystals were collected by filtration and were then dried to obtain 80.3 g of the above-identified compound (yield: 82%).
Reaction SMILES: [C:1]([CH:5]([C:21]1[CH:26]=[CH:25][C:24]2[O:27][CH2:28][O:29][C:23]=2[CH:22]=1)[O:6][C:7]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:10]([CH2:11]O)=[CH:9][C:8]=1[CH2:18][CH2:19][CH3:20])([O:3][CH3:4])=[O:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:50].CC#N>C1COCC1>[C:1]([CH:5]([C:21]1[CH:26]=[CH:25][C:24]2[O:27][CH2:28][O:29][C:23]=2[CH:22]=1)[O:6][C:7]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:10]([CH2:11][Br:50])=[CH:9][C:8]=1[CH2:18][CH2:19][CH3:20])([O:3][CH3:4])=[O:2]
Reactant: BrC(Br)(Br)Br
Reactant: CCCc1cc(CO)cc(CCC)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC#N
Product: CCCc1cc(CBr)cc(CCC)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.1 %

Procedure:
To a solution of the product of Step B (0.53 g, 1.38 mmol) in dry THF (10 mL) were added Ph3P (0.49 g, 2.06 mmol), CBr4 (0.69 g, 2.06 mmol) and CH3CN (2 mL), and the mixture was stirred at room temperature for 14 h. At the end of this period, the reaction mixture was concentrated in vacuo to provide an oil, which was then purified by flash chromatography on silica-gel using ethyl acetate-hexane (1:9) to provide the titled product as a thick colorless oil (0.57 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11](=O)[CH2:10][CH2:9][CH2:8]2.[CH3:14][O:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][O:21][CH3:22]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([N:18]([CH2:19][CH2:20][O:21][CH3:22])[CH2:17][CH2:16][O:15][CH3:14])[CH2:9][CH2:8]2
Reactant: COCCNCCOC
Reactant: COc1cccc2c1C(=O)CCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COCCN(CCOC)C1CCc2cccc(OC)c2C1
Reaction time: 48 h
Yield: 78.4 %

Procedure:
A solution of 1.76 g (10 mmol) 8-methoxy tetralone, 2.66 g (20 mmol) N,N-bis(-2-methoxyethyl)amine, and 25 mg p-toluenesulfonic acid in toluene was heated to reflux under a N2 atmosphere. The flask was equipped with a Dean-Stark trap to collect H2O. TLC analysis was used to monitor the reaction. After 48 hours, the solvent was removed in vacuo. The crude ene-amine was hydrogenated using 450 mg 10% pd/C in 50 mL MeOH at 50 psi H2 for 24 hours. The reaction mixture was filtered over celite and the filtrate purified by liquid chromatography on 400 g of silica gel-60 (230-400 mesh), eluting with hexane/ethyl acetate/isopropanol (10:5:1). Fractions homogeneous by TLC were combined and concentrated in vacuo to give pure title compound as a yellow oil (2.3 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[NH:7][C:6]=2[CH:15]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[C:22]([Cl:38])=[CH:21][N:20]=1>CO.C(Cl)Cl>[Cl:38][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[N:24][C:19]([NH:1][C:2]2[C:3]([O:16][CH3:17])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[NH:7][C:6]=3[CH:15]=2)=[N:20][CH:21]=1
Reactant: CCN1CC(=O)Nc2cc(N)c(OC)cc2C1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Solvent: CO
Solvent: ClCCl
Product: CCN1CC(=O)Nc2cc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N(C)C)n3)c(OC)cc2C1
Yield: 17.6 %

Procedure:
In an analogous manner to procedure 1656g, 8-amino-4-ethyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (60 mg, 0.26 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide (88 mg, 0.26 mmol) were coupled to provide 2-[5-chloro-2-(4-ethyl-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-N,N-dimethyl-benzenesulfonamide (25 mg, 18%) as a pale yellow solid following preparative tlc (10% MeOH-DCM); NMR (400 MHz, CDCl3) δ 9.36 (s, 1H), 8.44 (d, J=8 Hz, 1H), 8.18 (s, 1H), 8.08 (s, 1H), 7.93 (d, J=8 Hz, 1H), 7.65 (m, 2H), 7.37 (m, 1H), 7.09 (s, 1H), 6.82 (s, 1H), 3.94 (s, 3H), 3.76 (s, 2H), 3.43 (s, 2H), 2.77 (m, 8H), 1.22 (t, J=7 Hz, 3H); MS (m/e) 546 (M+1); mp 175° C.
Reaction SMILES: C[Al](C)C.[CH2:5]([N:7]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[N:19]=[CH:18][C:17]([C:20]([O:22]C)=O)=[CH:16][N:15]=2)[CH2:9][CH2:8]1)[CH3:6].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:34][CH2:35][C:36]2[CH:37]=[C:38]([NH2:41])[NH:39][N:40]=2)[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1>C1(C)C=CC=CC=1>[CH3:33][O:32][C:30]1[CH:29]=[C:28]([CH2:34][CH2:35][C:36]2[CH:37]=[C:38]([NH:41][C:20]([C:17]3[CH:18]=[N:19][C:14]([N:10]4[CH2:11][CH2:12][CH2:13][N:7]([CH2:5][CH3:6])[CH2:8][CH2:9]4)=[N:15][CH:16]=3)=[O:22])[NH:39][N:40]=2)[CH:27]=[C:26]([O:25][CH3:24])[CH:31]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: CCN1CCCN(c2ncc(C(=O)OC)cn2)CC1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCN1CCCN(c2ncc(C(=O)Nc3cc(CCc4cc(OC)cc(OC)c4)n[nH]3)cn2)CC1
Temperature: 60 °C
Reaction time: 18 h
Yield: 21.7 %

Procedure:
Trimethylaluminium (1.25 ml, 2.50 mmol) was added dropwise to a stirred suspension of methyl 2-(4-ethyl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate (265 mg, 1.00 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (248 mg, 1.00 mmol) in toluene (5.01 ml) at 25° C. The resulting solution was stirred at 60° C. for 18 h. The cooled reaction mixture was quenched into methanol (50 mL) and treated with HCl (2M aqueous solution, to pH7 or lower) and purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford impure product. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing desired product still contained an impurity, so they were concentrated to dryness and purified by crystallisation from MeCN to afford the title compound (104 mg, 22%) as a cream solid.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:7][NH:8]C(=O)OCC1C=CC=CC=1)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([NH:4][CH2:5][CH:6]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:7][NH2:8])(=[O:3])[CH3:2]
Reactant: CC(=O)NCC(CNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(=O)NCC(CN)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of benzyl tert-butyl [3-(acetylamino)propane-1,2-diyl]biscarbamate (1.3 g, 3.6 mmol) in methanol (40 mL) was added 10% palladium on carbon (0.13 g, 10% w/w). The reaction mixture was stirred under a hydrogen atmosphere at room temperature. After 14 hours, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl [1-(acetylamino)-3-aminopropan-2-yl]carbamate. MS ESI calc'd. for C10H22N3O3 [M+H]+ 232. found 232. 1H NMR (400 MHz, CD3OD) δ 3.78-3.73 (m, 1H), 3.29-3.24 (m, 2H), 2.89-2.70 (m, 2H), 1.96 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([O:15][CH3:16])[C:12]=1[O:13][CH3:14])[C:7]([O-:9])=[O:8].Cl.[Cl:18][CH2:19][CH2:20][NH:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[I-].[Na+]>CN(C)C=O>[ClH:18].[CH3:19][CH2:20][N:21]([C:10]1[C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:4]([O:3][CH3:2])=[CH:5][C:6]=1[C:7]([OH:9])=[O:8])[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: ClCCNC1CCCCC1
Reactant: COc1cc(C(=O)[O-])cc(OC)c1OC
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(c1c(C(=O)O)cc(OC)c(OC)c1OC)C1CCCCC1

Procedure:
To 1.7 g. of sodium-3,4,5-trimethoxy-benzoate 1.45 g. of N-2-chloroethyl-cyclohexylamine hydrochloride and some sodium iodide crystals are added, whereafter 30 ml. of dimethyl formamide are introduced. After cooling toe precipitated crystals are filtered and the filtrate is evaporated. The residue is recrystallized from 96% of ethanol under clarifying with activated charcoal. Thus N-2-ethyl-cyclohexylamino-3,4,5-trimethoxy-benzoate-hydrochloride is obtained. M.p.: 208°-210° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.[OH-].[K+].[N:12]1[CH:17]=[CH:16][CH:15]=[C:14](B(CC)CC)[CH:13]=1>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[Br:9][C:4]1[CH:3]=[C:2]([C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)[CH:7]=[C:6]([Br:8])[CH:5]=1
Reactant: CCB(CC)c1cccnc1
Reactant: Brc1cc(Br)cc(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1cc(Br)cc(-c2cccnc2)c1
Reaction time: 0.08 h

Procedure:
Tetrakis-(triphenylphosphine)palladium (915 mG; 0.75 mM) was added to a stirred solution of 1,3,5-tribromobenzene (6.3 G; 20 mM) in 75 mL of anhydrous tetrahydrofuran under nitrogen at R.T. After stirring 5 mins., tetra n-butyl ammonium bromide (483 mG; 1.5 mM), followed by powdered potassium hydroxide (2.52 G, 45 mM) and 3-pyridyldiethyl borane (2.2 G; 15 mM) were added in that order. The resulting reaction mixture was heated to reflux 2 hrs., cooled, diluted with 100 mL of ethyl acetate, washed with 10×25 mL of sat'd. sodium chloride solution, and dried over anhyd. magnesium sulfate. Solvent removal, and purification on silica gel using ethyl acetate:hexane (2:3) mixture as solvent gave 1.9 G of 3-(3',5'-dibromophenyl)pyridine as a colorless oil boiling at 137°-139°/~1 mm, which slowly became a glassy solid.