Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[C:6]([CH:9]=1)[CH:7]=O.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[C:6]([CH2:7][N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]2)[CH:9]=1
Reactant: O=Cc1cc(Cl)ccc1N1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(Cl)ccc2N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
A 100 mL round-bottom flask was charged with 5-chloro-2-(pyrrolidin-1-yl)benzaldehyde (1.80 g, 8.58 mmol, 1.10 equiv), tert-butyl piperazine-1-carboxylate (1.45 g, 7.79 mmol, 1.00 equiv), 1,2-dichloroethane (20 mL). The mixture was stirred 30 min at room temperature. Sodium triacetoxyborohydride (4.96 g, 23.4 mmol, 3.01 equiv) was added. The resulting solution was stirred overnight at room temperature. The resulting mixture was washed with H2O (2×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/4) to yield 2.50 g (77% yield) of tert-butyl 4-[[5-chloro-2-(pyrrolidin-1-yl)phenyl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 380 [M+H]+.
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.CC1C=CC(S(O[CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=O)=O)=CC=1.[CH3:32][C:33]1[CH:37]=[C:36]([N:38]2[CH2:42][CH2:41][NH:40][C:39]2=[O:43])[S:35][C:34]=1[C:44]([O:46][CH2:47][CH3:48])=[O:45]>>[CH3:32][C:33]1[CH:37]=[C:36]([N:38]2[CH2:42][CH2:41][N:40]([CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:39]2=[O:43])[S:35][C:34]=1[C:44]([O:46][CH2:47][CH3:48])=[O:45]
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccccc2)cc1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)cc1C
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(N2CCN(CCc3ccccc3)C2=O)cc1C
Yield: 63 %

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with phenethyl 4-methylbenzenesulfonate to react with ethyl 3-methyl-5-(2-oxoimidazolidin-1-yl)thiophene-2-carboxylate, the title compound was obtained as a colorless solid in 63% yield: 1H NMR (300 MHz, CDCl3) δ 7.35-7.19 (m, 5H), 6.12 (s, 1H), 4.27 (q, J=7.1 Hz, 2H), 3.78-3.71 (m, 2H), 3.56 (t, J=7.4 Hz, 2H), 3.47-3.39 (m, 2H), 2.90 (t, J=7.4 Hz, 2H), 2.49 (s, 3H), 1.33 (t, J=7.1 Hz, 3H); MS (ES+) m/z 359.3 (M+1).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:11]([NH:13][C@H:14]([C:36]([OH:38])=[O:37])[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:35])[NH:20]S(C1C(C)=C(C)C(OC)=CC=1C)(=O)=O)=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.N[C@H](C(O)=O)CCCNC(=N)N.N[C@H](C(O)=O)CC1C=CC(O)=CC=1>FC(F)(F)C(O)=O.C1(SC)C=CC=CC=1>[NH2:1][C@H:2]([C:11]([NH:13][C@H:14]([C:36]([OH:38])=[O:37])[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:20])[NH2:35])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: COc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](Cc2ccc(O)cc2)NC(=O)OC(C)(C)C)C(=O)O)c(C)c1C
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Agent: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O
Reaction time: 2 h

Procedure:
In 5 ml of mixed solution of trifluoroacetic acid-thioanisole (9:1) was dissolved 400 mg of Boc-Tyr-Arg(Mtr)OH and the resulting mixture was allowed to stand at room temperature for 2 hours. The trifluoroacetic acid was distilled off under reduced pressure, ether was added to the residue and the resulting precipitate was collected by filtration. The precipitate was dissolved in a small amount of water, passed through a column (1×10 cm) of Amberlite IRA-410 (acetate-form) and lyophilized. The lyophilizate was dissolved in a small amount of water, chromatographed on a carboxymethyl-cellulose column (2.2×8 cm) and eluted by the linear gradient method using water (300 ml) and 0.1 M ammonium acetate (300 ml). The fractions from 100 to 150 ml were pooled and lyophilized. Yield 175 mg, [α]D21 -17.4° (c=0.5, H2O); amino acid analysis (acid hydrolysis): Arg 1.00(1), Tyr 0.94(1); average recovery 86.5%.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][C:17]([C:19]1[N:20]=[CH:21][NH:22][C:23]=1[C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:29][C:28]=1[CH3:40])=[O:25])=[O:18].C(N(C(C)C)CC)(C)C>C1COCC1.CC(N(C)C)=O>[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][C:17]([C:19]1[N:20]=[CH:21][NH:22][C:23]=1[C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]2[CH2:39][CH2:38][N:37]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:36][CH2:35]2)=[CH:29][C:28]=1[CH3:40])=[O:25])=[O:18]
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(OC2CCNCC2)ccc1NC(=O)c1[nH]cnc1C(=O)Nc1nc2ccccc2[nH]1
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCC(Oc2ccc(NC(=O)c3[nH]cnc3C(=O)Nc3nc4ccccc4[nH]3)c(C)c2)CC1
Reaction time: 0.08 h
Yield: 6.4 %

Procedure:
Ethyl chloroformate (0.1 mmol) in anhydrous THF was slowly added to a solution of N4-(1H-benzo[d]imidazol-2-yl)-N5-(2-methyl-4-(piperidin-4-yloxy)phenyl)-1H-imidazole-4,5-dicarboxamide (0.10 mmol) and diisopropylethylamine (0.20 mmol) in anhydrous DMA (5 mL) at 0° C. LCMS indicated that the reaction was complete in 5 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by preparative reverse phase HPLC (ammonium acetate/acetonitrile) to give 3.4 mg of ethyl 4-({4-[({4-[(1H-benzimidazol-2-ylamino)carbonyl]-1H-imidazol-5-yl}carbonyl)amino]-3-methylphenyl}oxy)piperidine-1-carboxylate. 1H-NMR (400 MHz, DMSO-d6): δ 12.19 (s, 1H), 8.13 (s, 1H), 7.48 (m, 2H), 7.11 (m, 2H), 6.96 (s, 1H), 6.88 (dd, 1H), 4.60 (m, 1H), 4.05 (m, 2H), 3.70 (m, 2H), 3.30 (m, 1H), 2.26 (s, 3H), 1.91 (m, 2H), 1.57 (m, 2H), 1.19 (t, 3H). MS (EI): 532.4 (MH+).
Reaction SMILES: [C-]#N.[K+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.Cl[CH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1.OCCCC1C=C[N:47]=[CH:46]C=1>C(#N)C>[C:46]([CH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)#[N:47]
Reactant: ClCCCc1ccncc1
Reactant: OCCCc1ccncc1
Agent: [C-]#N
Agent: [K+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: CC#N
Product: N#CCCCc1ccncc1

Procedure:
Potassium cyanide (11.18 g) and dibenzo-18-crown-6 (1.0 g) are added to a solution of 4-(3-chloropropyl)-pyridine (6.68 g) prepared from 4-(3-hydroxypropyl)pyridine, in 300 ml of dry acetonitrile under nitrogen. The mixture is refluxed for 24 hours, the solvent evaporated and the residue partitioned between methylene chloride and water. The aqueous phase is further extracted with methylene chloride (3×100 ml) and the combined extracts are dried over sodium sulfate, decolorized with charcoal and evaporated to yield 4-(3-cyanopropyl)pyridine as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:16])[C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.CN1CCCC1=O>CCOCC>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:16])[C:9]([F:15])=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2c(F)c(F)c(F)c(F)c21
Reactant: C1COCCN1
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: CCn1cc(C(=O)O)c(=O)c2c(F)c(F)c(N3CCOCC3)c(F)c21
Temperature: 65 °C
Yield: 38.5 %

Procedure:
A mixture of 289 mg of 1-ethyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 300 mg of morpholine and 5.6 ml of 1-methyl-2-pyrrolidone was heated in a stoppered flask at 65° C. for one hour. Ether was added, the solid collected, dissolved in 200 ml of acetone, filtered and boiled down to about 50 ml. The solid was collected, giving 137 mg of the desired product, mp 281°-283° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:43])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16]([CH2:18][CH2:19][CH2:20][C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])=[O:17])[C:5](=[O:28])[N:4]([C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[C:31]([C:38](F)(F)F)[CH:30]=2)[C:3]1=[O:42].NC1C=[CH:49][C:48]([N:51]2C(=O)C(C)(C)N(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)[C:52]2=[O:79])=[CH:47][C:46]=1C>>[CH3:1][C:2]1([CH3:43])[C:3](=[O:42])[N:4]([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:52]([NH:51][CH:48]([CH3:49])[CH2:47][CH3:46])=[O:79])=[C:31]([CH3:38])[CH:30]=2)[C:5](=[O:28])[N:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16]([CH2:18][CH2:19][CH2:20][C:21]([F:27])([F:26])[C:22]([F:23])([F:25])[F:24])=[O:17]
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F
Reactant: Cc1cc(N2C(=O)N(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)ccc1N
Product: CCC(C)NC(=O)Nc1ccc(N2C(=O)N(CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)cc1C
Yield: 63 %

Procedure:
The experimental protocol used is the same as that described for the synthesis of the compound of Example 2, the compound of Example 25 replacing the compound of Example 1. A colourless oil is obtained with a yield of 63%.
Reaction SMILES: CC1C[O:5][C:4]2([CH2:11][C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([CH3:15])=[CH:7]2)O1.[CH2:16]([Li])[CH2:17][CH2:18][CH3:19].O.[Li]>CCCCCC>[CH2:16]([C:9]1([OH:14])[C:10]([CH3:12])([CH3:13])[CH2:11][C:4](=[O:5])[CH:7]=[C:8]1[CH3:15])[CH2:17][CH2:18][CH3:19]
Reactant: CC1=CC2(CC(C)(C)C1=O)OCC(C)O2
Reactant: [Li]CCCC
Agent: [Li]
Solvent: O
Solvent: CCCCCC
Product: CCCCC1(O)C(C)=CC(=O)CC1(C)C
Reaction time: 0.25 h

Procedure:
A solution of 20 g of 2,7,9,9-tetramethyl-1,4-dioxaspiro[4,5]dec-6-en-8-one (prepared by the method of Example III) in hexane is stirred while a solution of n-butyl lithium in hexane is added dropwise. When no additional exotherm occurs, the addition is stopped and the mixture is stirred for about 15 minutes. Water is added with stirring to hydrolyze the lithium salt. The organic layer is separated, and the hexane is allowed to evaporate leaving oily crystals which are recrystallized from cyclohexane yielding 10 g of 4-butyl-4-hydroxy-3,5,5-trimethyl-2-cyclohexen-1-one, melting point 90°-93° C. The compound exhibits the following spectral characteristics:
Reaction SMILES: [CH2:1]([P:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[Cl:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]>C1(C)C=CC=CC=1>[Cl-:14].[CH2:10]([P+:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:11][CH2:12][CH3:13]
Reactant: O=C(O)CCCCl
Reactant: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCCC[P+](CCCC)(CCCC)CCCC(=O)O
Product: [Cl-]

Procedure:
Tri-n-butyl phosphine (0.1 mole) and 4-chlorobutyric acid (0.1 mole) were refluxed in toluene for 4 hours. Evaporation of the solvent from the reaction mixture left a viscous liquid whose infrared spectrum and elemental analysis corresponded to a compound of the formula
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([CH3:12])[C:3]=1[NH2:4].[N:13]([O-])=O.[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]2[C:3]=1[NH:4][N:13]=[CH:12]2
Reactant: O=N[O-]
Reactant: Cc1cc([N+](=O)[O-])cc(Cl)c1N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)c2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-6-methyl-4-nitroaniline (5.49 g, 29.4 mmole) in acetic acid (150 mL) was added sodium nitrite (2.03 g, 29.4 mmole) pre-dissolved in water (5 mL). The resulting brown slurry was stirred overnight at room temperature, then at 60° C. for a further 4 hours. The bulk of the solvent was removed by evaporation in-vacuo and the resulting black residue re-dissolved in EtOAc (100 mL) and washed in brine (2×70 mL). The organic layer was dried (MgSO4), filtered and concentrated to give a mixture of starting material and product 91 mg(1.49 g). The crude mixture was taken through to the next step; 1H NMR (400 MHz, DMSO) δ 8.25(1H, s), 8.50(1H, s), 8.85(1H, s), 14.30(1H, br s).MS (ES+): m/e=198 (minus Boc).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][CH2:12][C:11]=2[CH:17]=1.S(Cl)([Cl:20])=O>N1C=CC=CC=1>[Cl:20][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][CH2:12][C:11]=2[CH:17]=1
Reactant: O=C1Nc2ccc(OCCCCO)cc2CO1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C1Nc2ccc(OCCCCCl)cc2CO1
Temperature: 25 °C

Procedure:
Sixty grams (0.253 mol) of 6-(4-hydroxy-butoxy)-4H-3,1-benzoxazin-2-one and 5 ml of pyridine are added to 300 ml of thionyl chloride, under stirring, at ambient temperature. After refluxing for two hours, the excess thionyl chloride is distilled off in a rotary evaporator, and the residue is taken up in chloroform and is stirred with the same volume of ice water for 30 minutes. Then, the chloroform phase is removed, washed twice with water, and dried with sodium sulfate, and the chloroform is distilled off. The residue is recrystallized from toluene/diisopropylether (3:1).
Reaction SMILES: Br[CH:2](Br)[C:3]1[C:4]([CH:9](Br)Br)=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:13](#[N:18])/[CH:14]=[CH:15]/[C:16]#[N:17].[I-].[Na+]>CN(C)C=O>[C:16]([C:15]1[C:14]([C:13]#[N:18])=[CH:9][C:4]2[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:2]=1)#[N:17]
Reactant: N#C/C=C/C#N
Reactant: BrC(Br)c1ccccc1C(Br)Br
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc2ccccc2cc1C#N

Procedure:
That is, α,α,α',α'-tetrabromo-o-xylene [the formula (V)] in an amount of 0.1 mol and fumaronitrile in an amount of 0.178 mol are reacted at 75° C. for 7 hours in the presence of 0.67 mol of sodium iodide in anhydrous N,N-dimethylformamide to yield 2,3-dicyanonaphthalene of the formula (VI). Subsequently, 57.3 mmol of the 2,3-dicyanonaphthalene is reacted with ammonia in the presence of sodium methoxide in methanol with heating for 3 hours to yield 1,3-diiminobenzo(f)isoindoline of the formula (VII). Further, 30.6 mmol of the 1,3-diiminobenzo(f)isoindoline was reacted with 47.1 mmol of silicon tetrachloride in anhydrous tetralin and anhydrous tri-n-butyl-amine under reflux for about 3 hours to give dichlorosilicon naphthalocyanine [SiNoX2 (X=Cl)] which can be represented by the formula (II) except that the two OHs are replaced by two Cl's. Then, this compound is treated with concentrated sulfuric acid and then concentrated ammonia water to give dihydroxysilicon naphthalocyanine [SiNcX2 (X=OH)] of the formula (II).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]2[CH2:10][CH2:9][N:8]([C:11]([N:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=4)[CH2:15][CH2:14]3)=[O:12])[CH2:7]2)[CH:3]=[N:2]1.[NH2:32][N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.OC1C2N=NNC=2C=CC=1.CCN=C=NCCCN(C)C.Cl>O1CCOCC1.CN(C)C=O>[N:33]1([NH:32][C:27](=[O:29])[C:26]2[CH:30]=[CH:31][C:23]([N:16]3[C:17]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:13]([C:11]([N:8]4[CH2:9][CH2:10][CH:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH2:7]4)=[O:12])[CH2:14][CH2:15]3)=[CH:24][CH:25]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: NN1CCCCC1
Reactant: O=C(O)c1ccc(N2CCN(C(=O)N3CCC(c4cn[nH]c4)C3)c3ccccc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(NN1CCCCC1)c1ccc(N2CCN(C(=O)N3CCC(c4cn[nH]c4)C3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 58.5 %

Procedure:
0.4 g of 4-[4-{[3-(1H-pyrazol-4-yl)pyrrolidin-1-yl]carbonyl}-3,4-dihydroquinoxalin-1(2H)-yl]benzoic acid, 0.19 g of 1-aminopiperidine, 0.26 g of hydroxybenzotriazole, 0.37 g of EDC.HCl and 7 ml of a dioxane/dimethylformamide 5/2 mixture are introduced into a 100 ml round-bottomed flask equipped with a magnetic stirrer. The reaction mixture is stirred at ambient temperature for 20 h and concentrated under vacuum. The residue is chromatographed on silica gel eluted with a dichloromethane/acetone/methanol/NH4OH 88/10/2/0.2 and then 82/15/3/0.3 mixture. After triturating in ethyl ether, 0.28 g of N-(piperidin-1-yl)-4-{4-[3-(1H-pyrazol-4-yl)pyrrolidine-1-carbonyl]-3,4-dihydro-2H-quinoxalin-1-yl}benzamide is obtained.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][O:8][CH2:9][N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH2:19])C(=O)C2=CC=CC=C12.O.NN.C(O)C>COCCO>[NH2:5][CH2:6][CH2:7][O:8][CH2:9][N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][CH:13]=[N:14][C:15]=2[NH2:19]
Reactant: Nc1ncnc2c1ncn2COCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: COCCO
Solvent: CCO
Product: NCCOCn1cnc2c(N)ncnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.1 %

Procedure:
A mixture of 9-(2-phthalimidoethoxymethyl)adenine (3.38 g), hydrazine hydrate (1.0 ml of an 85% aqueous solution) and ethanol (150 ml) was heated at reflux for 2 hours. 2-Methoxyethanol (50 ml) was added and refluxing continued for an additional 2 hours. The solvent was removed under reduced pressure and 1N hydrochloric acid (50 ml) added. The mixture was stirred at ambient temperature for 30 minutes and allowed to stand at 0° C. overnight. The solution was filtered and the filtrate diluted with water (100 ml) and stirred with excess basic ion exchange resin {Rexyn 201 (OH)} until a negative silver nitrate test was obtained. It was then filtered and most of the water removed under reduced pressure. The aqueous solution was cooled and the resulting solid removed by filtration. This was recrystallized from isopropanol to give 9-(2-aminoethoxymethyl)adenine (1.0 g), m.p. 170°-171° C.
Reaction SMILES: [N:1]1([CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)=[O:12])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([O-])([O-])=O.[K+].[K+].[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.CCO>COCCOC.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.O>[N:1]1([CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[Cl:27])=[CH:16][CH:15]=2)=[O:12])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(Cn1cnc2ccccc21)Nc1ccc(Br)cc1
Reactant: OB(O)c1ccccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: O=C(Cn1cnc2ccccc21)Nc1ccc(-c2ccccc2Cl)cc1
Temperature: 110 °C
Yield: 31.3 %

Procedure:
2-Benzimidazol-1-yl-N-(4-bromophenyl)-acetamide (100 mg, 0.30 mmol) (Example 6A), PdCl2(PPh3)2 (22 mg, 0.03 mmol), K2CO3 (120 mg, 0.8 mmol) and 2-chlorophenylboronic acid (71 mg, 0.45 mmol) were combined and dissolved in DME (0.5 mL), EtOH (0.5 mL) and H2O (0.2 mL). This mixture was heated in a microwave at 110° C. for 10 minutes. SCX purification of the reaction mixture, followed by further purification using prep LCMS yielded the desired product (34 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 5.21 (2H, s), 7.2-7.3 (2H, m), 7.36-7.45 (5H, m), 7.55 (2H, d, J=8 Hz), 7.67-7.72 (3H, m), 8.25 (1H, s), 10.59 (1H, s). MS (ES) m/z: 362.3 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].C([O-])([O-])=O.[K+].[K+].[CH2:26](Br)[CH:27]([CH3:29])[CH3:28]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19]
Reactant: Fc1ccc(Oc2cc3cn[nH]c3cc2Br)c(F)c1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(Br)cc21
Temperature: 80 °C
Yield: 42.7 %

Procedure:
6-Bromo-5-(2,4-difluorophenoxy)-1H-indazole (60.0 g, 185 mmol) was dissolved in DMF and treated with K2CO3 (76.5 g, 554 mmol) and with isobutyl bromide (126.4 g, 923 mmol). The mixture was stirred and heated to 80° C. for 16 hours. An additional 15 g of K2CO3 were added and the mixture was vigorously stirred for 24 hours more. The reaction mixture was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and dissolved in ether (1 L). The mixture was washed with 1:5 brine/water (2×600 mL). The aqueous phases were extracted with ether (300 mL) and the combined organics were dried (MgSO4) and concentrated under reduced pressure. The crude product was chromatographed on a Biotage Flash 75 in two batches (about 35 g each) eluting with 5% ethyl acetate in hexanes. The combined purified products yielded 30.1 g of the desired product as a solid (43% yield). MS (ESI+) m/z 381, 383 (M+1, Br pattern) detected; 1H NMR (400 mHz, CDCl3) δ 7.86 (s, 1H), 7.72 (s, 1H), 7.16 (s, 1H), 6.98 (m, 1H), 6.92 (m, 1H), 6.82 (m, 1H), 4.12 (d, 2H), 2.34 (m, 1H), 0.94 (d, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4](Cl)[N:3]=1.Cl.[Br:11][C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][NH:18][CH2:19]2)=[CH:14][C:13]=1[F:22].[CH3:23][N:24]1[CH2:29][CH2:28][N:27](C)[CH2:26][CH2:25]1.C(O)(C)(C)C.CN1CCNCC1>>[Br:11][C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][N:18]([C:4]3[CH:5]=[C:6]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)[N:7]=[C:2]([NH2:1])[N:3]=3)[CH2:19]2)=[CH:14][C:13]=1[F:22]
Reactant: Fc1cc2c(cc1Br)CNCC2
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CN1CCN(C)CC1
Agent: CN1CCNCC1
Agent: Cl
Solvent: CC(C)(C)O
Product: CN1CCN(c2cc(N3CCc4cc(F)c(Br)cc4C3)nc(N)n2)CC1
Temperature: 90 °C
Yield: 56.2 %

Procedure:
A mixture of 2-amino-4,6-dichloropyrimidine (0.149 g, 0.908 mmol), 7-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.242 g, 0.908 mmol) and, 1,4-dimethylpiperazine (487 uL, 3.63 mmol) in tert-butyl alcohol (2.00 mL, 20.9 mmol) was heated at 90° C. for 2 h. After cooling, 1-methylpiperazine (202 uL, 1.82 mmol) was added. The mixture was heated at 120° C. overnight. After cooling, the volatiles were removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column with methanol in DCM (0-10%) to give the desired product (215 mg, 56.2%). LCMS (M+H)+: m/z=421.1/423.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]#[N:32])=[CH:21][CH:20]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:42](Cl)(=[O:47])[CH2:43][CH2:44][CH2:45][CH3:46].N>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([C:11]1([N:17]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]#[N:32])=[CH:23][CH:24]=2)[C:42](=[O:47])[CH2:43][CH2:44][CH2:45][CH3:46])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(=O)Cl
Reactant: N#Cc1ccccc1-c1ccc(CNC2(C(=O)OCc3ccccc3)CCCCC2)cc1
Agent: N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)C1(C(=O)OCc2ccccc2)CCCCC1
Reaction time: 1 h

Procedure:
A solution of 2.9 g (6.8 mmol) of N-(1-benzyloxycarbonylcyclohexyl)-N-(2'-cyanobiphenyl-4-ylmethyl)-amine and 4.4 ml (26 mmol) of Hunig base in 50 ml of ethyl acetate is treated with 1.1 g (9 mmol) of pentanoyl chloride, and the mixture is heated to reflux for 24 hours. After cooling, the reaction mixture is treated with 20 ml of aqueous ammonia solution (2N) and stirred for 1 hour. The organic phase is separated, washed in succession with 2 N-hydrochloric acid, saturated sodium hydrogencarbonate solution and brine, dried and evaporated. The N-(1-benzyloxycarbonylcyclohexyl)-N-(2'-cyanobiphenyl-4-ylmethyl)-N-pentanoyl-amine is thus obtained in the form of a brown oil [Rf : 0.44 (toluene/methanol=19:1)], which is used for further reactions in crude form.