Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[N:14]1(C(OC(C)(C)C)=O)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[K+].Cl.O1CCOCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCO.C1(C)C=CC=CC=1>[N:14]1([C:2]2[CH:3]=[N:4][C:5]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[N:6][CH:7]=2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1cnc(N2CCOCC2)nc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: CCO
Product: c1nc(N2CCOCC2)ncc1N1CCNCC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
Under argon atmosphere, 4-(5-bromopyrimidin-2-yl)morpholine (700 mg) and tert-butyl piperazine-1-carboxylate (800 mg) were mixed with toluene (10 ml), and Pd2(dba)3 (130 mg), BINAP (260 mg), and potassium tert-butoxide (500 mg) were added thereto, followed by stirring at 90° C. overnight. The reaction mixture was cooled to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/EtOAc). The purified product thus obtained was mixed with EtOH (10 ml), and 4 M hydrogen chloride/dioxane (7 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and CHCl3 and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 4-[5-(piperazin-1-yl)pyrimidin-2-yl]morpholine (239 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)[N:3]=1.C(OC1C=CC(CO)=CC=1)C1C=CC=CC=1.[NH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C([O-])([O-])=O.[K+].[K+]>>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([N:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[N:3]=2)=[CH:11][CH:12]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Clc1cncc(OCc2ccc(OCc3ccccc3)cc2)n1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: OCc1ccc(OCc2ccccc2)cc1
Agent: [K+]
Product: c1ccc(COc2ccc(COc3cncc(N4CCNCC4)n3)cc2)cc1

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from 2-chloro-6-{[4-(benzyloxy)benzyl]oxy}pyrazine (1.15 g, 3.52 mmol; obtained according to the procedure of example 50, step 1, starting from 4-benzyloxybenzyl alcohol), piperazine (0.894 g, 10.4 mmol) and K2CO3 (0.486 g, 3.52 mmol). The yield of the title compound was 0.57 g (43%) which was obtained as a colorless viscous oil that solidified upon standing. Fragmenting mass analysis supports the stated structure. HRMS m/z calcd for C22H24N4O2 (M)+ 376.1899, found 376.1892.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([OH:12])=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[C:19]1([CH2:25][CH2:26][C:27](Cl)=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>N1C=CC=CC=1>[C:16]([NH:15][CH2:14][CH2:13][CH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([NH:2][C:27](=[O:28])[CH2:26][CH2:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[OH:12])[CH2:7][CH2:8]1)(=[O:18])[CH3:17]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CC(=O)NCCC1CCc2ccc(N)c(O)c21
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NCCC1CCc2ccc(NC(=O)CCc3ccccc3)c(O)c21
Reaction time: 0.25 h
Yield: 55 %

Procedure:
N-[2-(6-Amino-7-hydroxy-2,3-dihydro-1H-inden-1-yl)ethyl]acetamide hydrochloride (100 mg, 0.369 mmol) was dissolved in pyridine (4 mL), 3-phenylpropionyl chloride (60.3 μL, 0.406 mmol) was added under ice-cooling, and the mixture was stirred for 15 min. Water was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=80/20→100/0) to give the title compound (74.4 mg, yield 55%).
Reaction SMILES: [C:1]1([C:7]([CH:9]2[CH2:11][CH2:10]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1>C(Cl)Cl>[C:1]1([C:7]2[C:13]3[N:12]([CH:16]=[CH:15][N:14]=3)[CH2:10][CH2:11][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1c[nH]cn1
Reactant: O=C(c1ccccc1)C1CC1
Solvent: ClCCl
Product: C1=C(c2ccccc2)c2nccn2CC1

Procedure:
Combine 25 g (0.17 mol) of cyclopropyl phenyl ketone with 50 g (0.73 mol) of imidazole, and heat to 200° C. for 18 hr. Isolation from 200 g of silica gel using methylene chloride, followed by crystallization from ether provides the title compound.
Reaction SMILES: Br[C:2]1[C:10]2[CH:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH2:8][NH:7][C:6](=[O:18])[C:5]=2[S:4][C:3]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:31]1([C:37]#[CH:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>CN(C)C=O.CC#N.CC#N.Cl[Pd]Cl.O.CC(=O)OCC>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH:9]2[CH2:8][NH:7][C:6](=[O:18])[C:5]3[S:4][C:3]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[C:2]([C:38]#[C:37][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:10]2=3)=[CH:12][CH:13]=1
Reactant: C#Cc1ccccc1
Reactant: O=C1NCC(c2ccc(Cl)cc2)c2c1sc(N1CCOCC1)c2Br
Agent: Cl[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1NCC(c2ccc(Cl)cc2)c2c1sc(N1CCOCC1)c2C#Cc1ccccc1
Temperature: 50 °C
Yield: 70.1 %

Procedure:
In a 10-mL microwave vial, a suspension of 3-bromo-4-(4-chlorophenyl)-2-(morpholin-4-yl)-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (69.5 mg, 0.162 mmol, single enantiomer of unknown configuration), cesium carbonate (0.146 g, 0.448 mmol) and phenylacetylene (0.107 mL, 0.975 mmol) in N,N-dimethylformamide (0.750 mL) was degassed by bubbling argon balloon for 5-10 min., then 2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (12.6 mg, 0.0265 mmol) and bis(acetonitrile)palladium(II) chloride (2.11 mg, 0.00812 mmol) was added. The vial was sealed, and the mixture was heated at 50° C. for 16 h. The r×n was cooled to rt, and combined with a previous r×n of same scale. The reaction was transferred to a separatory funnel with EA. Water was added, and the layers were separated. The aqueous layer was extracted w/EA. The organic layers were combined, washed w/brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude mixture was purified using column chromatography on silica gel (40 g ISCO column, gradient 100% hexanes to 100% EtOAc over 60 minutes to obtain impure product (51 mg). Final purification by HPLC gave the title product as an off-white solid (10 mg, 7%). LCMS: (FA) ES+ 449, 451. 1H NMR (400 MHz, DMSO) δ 7.47 (d, J=4.2 Hz, 1H), 7.40-7.32 (m, 5H), 7.27-7.23 (m, 2H), 7.21-7.17 (m, 2H), 4.31-4.29 (m, 1H), 3.91 (dd, J=12.9, 5.6 Hz, 1H), 3.79-3.76 (m, 4H), 3.57-3.52 (m, 2H), 3.49-3.44 (m, 2H), 3.30-3.27 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:39][CH2:38][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:28][CH2:27][CH:26]([O:29][Si](C(C)(C)C)(C)C)[CH2:25][CH2:24]4)=[CH:19][C:18]=3[F:37])[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].CO>C1COCC1.C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]4)=[CH:19][C:18]=3[F:37])[CH2:13][CH2:12]2)[CH2:38][CH2:39]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1ccc(C3CCC(O[Si](C)(C)C(C)(C)C)CC3)cc1F)C2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1ccc(C3CCC(O)CC3)cc1F)C2=O
Temperature: 60 °C
Yield: 92 %

Procedure:
2-{4-[4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexyl]-2-fluoro-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (720 mg, 1.29 mmol) was dissolved in THF (10 mL). To this solution at rt was added TBAF (1M in THF) (2 mL, 2 mmol, 1.5 equiv.). The reaction mixture was then heated to 60° C. (bath set) for 5 h. The reaction was complete (TLC, 5% MeOH in DCM). The reaction was diluted with EtOAc (5 mL), quenched with NaHCO3 (saturated aqueous solution, 5 mL). The two layers were separated and the aq. layer was extracted with EtOAc (15 mL×2). The EtOAc solution was combined, washed with brine (10 mL), and dried over K2CO3, filtered, and concentrated. The crude product was purified on a silica gel column eluted with 5% MeOH in DCM to afford 0.53 g (93% yield) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][NH:7][NH2:8])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C([O:17][C:18](=O)[CH:19]=[C:20]([NH2:24])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:24][C:20]1[NH:8][N:7]([CH2:6][C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([C:11]([F:12])([F:13])[F:14])[CH:4]=2)[C:18](=[O:17])[CH:19]=1
Reactant: NNCc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2ccc(Cl)c(C(F)(F)F)c2)[nH]1
Reaction time: 8 h

Procedure:
67 g of 4-chloro-3-trifluoromethylbenzylhydrazine were added dropwise, under nitrogen, to a solution of 46.1 g of β-amino-β-ethoxyacrylic acid ethyl ester and g of p-toluenesulphonic acid in 250 ml of ethanol. After stirring overnight, the solvent was distilled off in vacuo and the residue, which solidified, was filtered off and recrystallised from ethanol. The product was the compound identified above. Melting point: 132°, 25 g (30%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:40])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31](OS(C(F)(F)F)(=O)=O)[C:19]=4[CH2:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:41]([Sn](CCCC)(CCCC)CCCC)[CH:42]=[CH2:43].[Cl-].[Li+].[F-].[NH4+]>CN(C)C=O.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.C(OCC)(=O)C>[CH2:43]([C:31]1[C:19]2[CH2:18][C:17](=[CH:16][CH2:15][CH2:14][N:11]3[CH2:10][CH2:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)([OH:40])[CH2:13][CH2:12]3)[C:27]3[C:22]([O:21][C:20]=2[CH:28]=[CH:29][CH:30]=1)=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:42]=[CH2:41]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: O=S(=O)(Oc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2

Procedure:
A mixture of the product of example 169 (240 mg), allyltributyltin (0.19 ml), dichlorobis(triphenylphosphine)palladium(II) (30 mg) and lithium chloride (76 mg), in dimethylformamide (3 ml) was heated under argon at 120° C. for 2 hours. Aqueous ammonium fluoride solution and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography eluting with chloroform-methanol (10:1) to give the titled compound (180 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([NH:25][C:26](=[O:28])[CH3:27])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]([OH:24])([CH3:23])[CH3:22])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=O.CO.[NH3:31]>>[C:26]([NH:25][CH:8]1[C:7]2[S:6][C:5]([C:3]([NH2:31])=[O:2])=[N:14][C:13]=2[C:12]2[CH:15]=[C:16]([C:19]#[C:20][C:21]([OH:24])([CH3:22])[CH3:23])[CH:17]=[CH:18][C:11]=2[O:10][CH2:9]1)(=[O:28])[CH3:27]
Reactant: N
Reactant: COC(=O)c1nc2c(s1)C(NC(C)=O)COc1ccc(C#CC(C)(C)O)cc1-2
Solvent: CO
Product: CC(=O)NC1COc2ccc(C#CC(C)(C)O)cc2-c2nc(C(N)=O)sc21
Yield: 47 %

Procedure:
A solution of 4-Acetylamino-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (81 mg, 0.202 mmol), in methanol-ammonia (5 mL) was stirred at room temperature for 0.5 h. The reaction mixture was concentrated to afford crude product, which was triturated with EtOAc and hexane (1:1) and then filtered to afford compound 4-Acetylamino-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide (36 mg, 47%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.74 (d, J=8.5 Hz, 1H), 8.6 (d, J=2.2 Hz, 1H), 8.49 (s, 1H), 7.92 (s, 1H), 7.34 (dd, J1=8.3 Hz, J2=2.2 Hz, 1H), 7.10 (d, J=8.4 Hz, 2H), 5.53 (m, 1H), 5.45 (s, 1H), 4.37 (m, 1H), 4.18 (m, 1H), 1.89 (s, 3H), 1.49 (s, 6H); LC-MS (ESI & APCI): 386.5 (M+1).
Reaction SMILES: [K].[N+:2]([C:5]1[NH:6][CH:7]=[CH:8][N:9]=1)([O-:4])=[O:3].CS(O[CH2:15][CH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])(=O)=O.C1OCCOCCOCCOCCOCCOC1.C(OCC)(=O)C>C(#N)C.O>[CH2:16]([CH:17]([CH2:20][CH3:21])[CH2:18][CH2:19][N:6]1[CH:7]=[CH:8][N:9]=[C:5]1[N+:2]([O-:4])=[O:3])[CH3:15]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: CCC(CC)CCOS(C)(=O)=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCC(CC)CCn1ccnc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 87.6 %

Procedure:
A solution of 2-nitro-1H-imidazole potassium salt (300 mg, 2.0 mmol), 3-ethylpentyl methanesulfonate (463 mg, 2.4 mmol) and 18-crown-6 (1.1 g, 4.2 mmol) in acetonitrile (10 ml) was heated at 80° C. for 6 hours. After cooling to room temperature, ethyl acetate and water were added and the organic layer was separated off. After washing with water and brine, drying was performed with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (370 mg) as a colorless oil.
Reaction SMILES: C([O-])(=O)C(C)(C)C.[C:8]([CH2:10][CH2:11][Zn+])#[N:9].Br[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.[NH4+].[Cl-]>C1COCC1.CN1C(=O)CCC1>[C:8]([CH2:10][CH2:11][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)#[N:9]
Reactant: N#Cc1ccc(Br)cc1
Reactant: N#CCC[Zn+]
Agent: CC(C)(C)C(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: N#CCCc1ccc(C#N)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 78.6 %

Procedure:
In a dry and argon-flushed Schlenk-flask, equipped with a magnetic stirring bar and a septum, (2-cyanoethyl)zinc pivalate (1t) (2.35 g, 2150 mg/mmol, 1.09 mmol) was dissolved in a mixture of THF (3.0 mL) and NMP (1.0 mL). 4-Bromobenzonitrile (168 mg, 0.92 mmol) was added followed by PEPPSI-iPr (14 mg, 0.02 mmol) and the mixture was stirred for 12 h at 50° C. Then sat. aq. NH4Cl (10 mL) was added and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic phases were dried (Na2SO4). Evaporation of the solvents in vacuo and purification by flash chromatography (silica gel, ihexane/Et2O=3:1) afforded 4-(2-cyanoethyl)benzonitrile (entry 26) (113 mg, 80%) as a pale yellow oil.
Reaction SMILES: CS(O[CH2:6][C:7]1([CH3:28])[CH2:16][CH2:15][C:14]2[C:9](=[C:10]([CH3:27])[C:11]([CH3:26])=[C:12]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]=2[CH3:17])[O:8]1)(=O)=O.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH2:19]([O:18][C:12]1[C:13]([CH3:17])=[C:14]2[C:9](=[C:10]([CH3:27])[C:11]=1[CH3:26])[O:8][C:7]([CH2:6][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([CH3:28])[CH2:16][CH2:15]2)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C1CNCCN1
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(COS(C)(=O)=O)O2
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(CN1CCNCC1)O2
Yield: 47.8 %

Procedure:
The title compound (7 g, 47%) was prepared as a syrupy liquid from (2RS)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-ylmethyl methanesulphonate (15 g) and piperazine (19 g) by an analogous procedure to that described in preparation 1.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][N:11]=[C:10]([NH:15][CH3:16])[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:19]=[C:20]([CH:33]=[CH:34][C:35]=1[CH3:36])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[CH:25]=1)=[O:22].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:14][C:13]1[C:8]([C:7]2[C:2]([NH:17][C:18]3[CH:19]=[C:20]([CH:33]=[CH:34][C:35]=3[CH3:36])[C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[CH:25]=3)=[O:22])=[N:3][CH:4]=[CH:5][CH:6]=2)=[N:9][C:10]([NH:15][CH3:16])=[N:11][CH:12]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(C)C)c2)cc1N
Reactant: CNc1ncc(F)c(-c2cccnc2Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CNc1ncc(F)c(-c2cccnc2Nc2cc(C(=O)Nc3cccc(C(C)C)c3)ccc2C)n1

Procedure:
[4-(2-Chloro-pyridin-3-yl)-5-fluoro-pyrimidin-2-yl]-methyl-amine (62 mg, 0.26 mmol), 3-amino-N-(3-isopropyl-phenyl)-4-methyl-benzamide (84 mg, 0.31 mmol), Pd(OAc)2 (6 mg, 0.03 mmol), rac-BINAP (16 mg, 0.03 mmol) and K2CO3 (719 mg, 5.2 mmol) in toluene (3.0 mL) were reacted overnight at 130° C. The reaction was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filter, concentrated and purified by reverse-phase HPLC (Gilson, acidic mobile phase) yielding the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[NH2:20][OH:21].Cl.C([O-])(=O)C.[Na+]>O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[N:20][OH:21])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-benzyloxybenzaldehyde (4.24 g, 20 mmol) was dissolved with stirring in a mixed solution of ethanol and water (3:1, 100 ml) at 0.2 M. To this added were NH2OH.HCl (2.78 g, 40 mmol) and sodium acetate (2.46 g, 30 mmol,) and the mixture was stirred at room temperature for about 30 minutes. The completion of the reaction was confirmed by liquid chromatography, and then water and ethanol were distilled under reduced pressure to obtain a pale yellow solid compound. The solid compound was extracted three times with water and ethyl acetate, the organic solvent layer was distilled off under reduced pressure, and then a crude compound was recrystallized from ethyl acetate/hexane (1:10) to obtain a white solid compound. The following reaction was performed on the thus-obtained solid without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([CH3:25])([CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:23])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:2].[BH4-].[Na+].O>CO>[CH2:19]([O:18][C:16](=[O:17])[C:15]([CH3:21])([CH3:22])[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([OH:23])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:25])([CH3:24])[C:4]([O:3][CH2:1][CH3:2])=[O:26])[CH3:20]
Reactant: CCOC(=O)C(C)(C)CCCCC(=O)CCCCC(C)(C)C(=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)C(C)(C)CCCCC(O)CCCCC(C)(C)C(=O)OCC
Reaction time: 2 h
Yield: 91.3 %

Procedure:
7-Oxo-2,2,12,12-tetramethyltridecanedioic acid diethyl ester (9.2 g, 25 mmol) was dissolved in methanol (200 mL) and the solution was cooled in an ice-water bath. Sodium borohydride (0.95 g, 25 mmol) was added. After 2 h, another portion of sodium borohydride (0.95 g, 25 mmol) was added and stirring was continued for 2 h. The reaction mixture was hydrolyzed with water (200 mL). The aqueous solution was extracted with dichloromethane (3×150 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give the product (8.5 g, 92%) as an oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 4.11 (q, 4H, J=7.0 Hz), 3.60-3.50 (m, 1H), 1.66-1.32 (m, 11H), 1.24 (pseudo-t, 12H, J=7.0 Hz), 1.15 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 178.0, 71.7, 60.1, 42.1, 40.6, 37.3, 26.0, 25.1, 24.9, 14.2. HRMS (LSIMS, nba): Calcd. for C21H41O3 (MH+): 373.2954, found: 373.2936. HPLC: 88.90% purity.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1.[BH3-][C:32]#[N:33].[Na+]>CO>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:3][C:2]2[NH:1][CH:5]=[CH:32][N:33]=2)=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1
Reactant: O=Cc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1cnc2c(c1)CCCC2N(Cc1ccc(CNc2ncc[nH]2)cc1)Cc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 120 h
Yield: 19.4 %

Procedure:
Using General Procedure A: To a stirred solution of 4-{[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzaldehyde (200 mg, 0.49 mmol) and the amine (41 mg, 0.49 mmol) from above in MeOH (5 mL) was added NaBH3CN (94.3 mg, 1.5 mmol) and the mixture was stirred at room temperature for 5 days. Purification of the crude yellow foam by column chromatography on silica gel (100:1:1—CH2Cl2:MeOH:NH4OH) afforded AMD9741 (26 mg, 15%) as a brown solid (22mg, 10%). 1H NMR (CDCl3) δ 1.61-1.76 (m, 1H), 1.92-2.09 (m, 2H), 2.17-2.27 (m, 1H), 2.68-2.76 (m, 1H), 2.80-2.90 (m, 1H), 3.64 (s, 2H), 3.89 (d, 1H, J=16.5 Hz), 4.05-4.14 (m, 2H), 4.22 (s, 2H), 4.39 (br s, 1H), 6.54 (s, 2H), 7.06 (d, 2H, J=7.8 Hz), 7.15-7.20 (m, 3H), 7.25 (d, 2H, J=6.9 Hz), 7.43 (d, 1H, J=7.8 Hz), 7.54 (br s, 2H), 8.67 (d, 1H, J=4.5 Hz); 13C NMR (CDCl3) δ 19.22, 21.83, 27.12, 45.73, 46.41, 51.49, 58.49, 111.83, 112.90, 115.59, 119.64, 120.29, 125.33, 126.71, 132.76, 135.33, 135.86, 136.22, 144.75, 148.75, 154.19, 155.23. ES-MS m/z 464.3 (M+H). Anal. Calcd. for C28H29N7.1.4CH2Cl2: C, 60.62; H, 5.50; N, 16.83. Found: C, 60.53; H, 5.48; N, 16.94.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[C:4]([C:7]1[CH:11]=[CH:10][N:9]([S:12]([C:15]2[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:8]=1)(=[O:6])[CH3:5].[Cl:22]C(=C(Cl)C(Cl)=C(Cl)C(Cl)Cl)C=O>CO>[Cl:22][CH2:5][C:4]([C:7]1[CH:11]=[CH:10][N:9]([S:12]([C:15]2[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:8]=1)=[O:6]
Reactant: O=CC(Cl)=C(Cl)C(Cl)=C(Cl)C(Cl)Cl
Reactant: CC(=O)c1ccn(S(=O)(=O)c2ccc(C)cc2)c1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2ccc(C(=O)CCl)c2)cc1
Temperature: 25 °C
Yield: 52.6 %

Procedure:
In a 100 cm3 one neck flask fitted with a condenser and a calcium chloride guard, 4 g of 3-acetyl-1-tosyl pyrrole 2 (15 mmoles) was introduced together with 30 cm3 of methanol. Then 4.5 g of 2,3,4,5,6,6-hexachloro-2,4-hexadiene-1-one (15 mmoles) was set under reflux during 6 hours and maintained under stirring at ambient temperature during one night. The solvent was evaporated and the crude product (8.5 g) was dissolved in 15 cm3 of chloroform, filtered (the pentachlorophenol was not very soluble in this solvent) and separated on silica gel column (250 g; 60-200 82 m; eluting with 1-29-70 acetic acid-ethyl acetate-heptane; VR =650 cm3) to give 2.35 g of white crystals 3 (M=297.5, yield: 53%).