Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:27][CH3:28])=[C:10]([CH2:19][NH:20][C:21](=[O:26])[CH2:22][C:23]([OH:25])=O)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:29][C:30]1[CH:31]=[C:32]([CH2:38][NH2:39])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[Br:29][C:30]1[CH:31]=[C:32]([CH2:38][NH:39][C:23](=[O:25])[CH2:22][C:21]([NH:20][CH2:19][C:10]2[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]3=[N:8][C:9]=2[CH2:27][CH3:28])=[O:26])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)O
Reactant: COc1ccc(CN)cc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1ccc(OC)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
A mixture of 3-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-3-oxopropanoic acid (0.6 g, 1.541 mmol), 1-[3-bromo-4-(methyloxy)phenyl]methanamine (0.389 g, 1.8 mmol), HATU (0.760 g, 2.0 mmol), and triethylamine (0.599 ml, 4.3 mmol) in dichloromethane (40 mL) was stirred overnight at room temperature to give a pale yellow solution. The reaction mixture was diluted with DCM, washed with saturated NaHCO3 and then saturated NaCl. The organic layer was dried over Na2SO4, evaporated to dryness which gave viscous syrup. The viscous syrup was chromatographed on an 80 g Combi-Flash Column in silica with DCM-MeOH (0-8%). The product from this purification was placed on a Chromatotron Plate (2000μ) silica eluting with DCM-MeOH (3.5%) to give N-{[3-bromo-4-(methyloxy)phenyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}propanediamide (800 mg, 88%). LC-MS m/z 587.3 (M+H)+, 0.83 min (ret time).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][N:16]2[CH:22]=1.[CH:23]1([C:27](O)=[O:28])[CH2:26][CH2:25][CH2:24]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([NH:21][C:27]([CH:23]3[CH2:26][CH2:25][CH2:24]3)=[O:28])[CH:18]=[CH:17][N:16]2[CH:22]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(N)cc2n1
Reactant: O=C(O)C1CCC1
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(NC(=O)C3CCC3)cc2n1
Yield: 15 %

Procedure:
As described for Example 47, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridin-7-ylamine (92 mg, 0.32 mmol) was converted, using cyclobutanecarboxylic acid instead of 3-pyridylacetic acid, to the title compound (16.4 mg, 15%) which was obtained as an off-white solid. MS: m/e=373.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:2].[N:18]1([CH2:27][CH2:28][C:29](O)=[O:30])[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]1=[O:20].C(Cl)Cl.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:29](=[O:30])[CH2:28][CH2:27][N:18]1[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]1=[O:20])[CH3:2]
Reactant: CCOC(=O)CNCCNC(=O)OC(C)(C)C
Reactant: Cc1cn(CCC(=O)O)c(=O)[nH]c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)CN(CCNC(=O)OC(C)(C)C)C(=O)CCn1cc(C)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 58.3 %

Procedure:
N-(N′-BOC-aminoethyl)glycine ethyl ester (1 g, 0.0041 mol) was dissolved in DMF (12 mL). DhbtOH (0.73 g, 0.0045 mol) and 3-(1-thyminyl)propanoic acid (0.89 g, 0.0045 mol) were added. Methylene chloride (12 mL) was then added and the mixture was cooled to 0° C. in an ice bath. After addition of DCC (1.01 g, 0.0049 mol), the mixture was stirred at 0° C. for 2 h, followed by 1 h at room temperature. The precipitated DCU was removed by filtration, washed with methylene chloride (25 mL), and a further amount of methylene chloride (50 mL) was added to the filtrate. The organic phase was extracted with sodium hydrogen carbonate (1 volume saturated diluted with 1 volume water, 6×100 mL), potassium sulfate (1 volume saturated diluted with 4 volumes water, 3×100 mL), and saturated aqueous sodium chloride (1×100 mL), dried over magnesium sulfate, and evaporated to dryness, in vacuo. The solid residue was suspended in methylene chloride (15 mL), and stirred for 1 h. The precipitated DCU was removed by filtration and washed with methylene chloride. The filtrate was evaporated to dryness in vacuo, and the residue purified by column chromatography on silica gel, eluting with a mixture of methanol and methylene chloride (gradient from 1 to 6% methanol in methylene chloride). This afforded the title compound as a white solid (1.02 g, 59%). Anal. for C19H30N4O7, found (calc.) C: 53.15 (53.51) H: 6.90 (7.09) N: 12.76 (13.13). The compound showed satisfactory 1H and 13C-NMR spectra.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[K+].O.C1(C)C=CC(S(O[CH2:22][CH:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH3:24])(=O)=O)=CC=1>C(O)C>[CH2:26]([O:25][CH:23]([CH3:22])[CH2:24][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCOC(C)COS(=O)(=O)c1ccc(C)cc1
Reactant: Oc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCOC(C)COc1ccc(O)cc1

Procedure:
17.0 g of hydroquinone, 11.4 g of 85% KOH, 7.5 ml of water and 200 ml of ethanol were added into a four-necked flask, and after the reaction for 5 hours, the mixture was elevated in temperature to 50° C. and 33 g of (2'-octyloxypropyl) p-toluenesulfonate was added dropwise thereto. After the reaction for 5 hours, the mixture was heated at reflux for 11 hours and thereafter ethanol was evaporated. The residue was added into 600 ml of water and acidified with hydrochloric acid. The mixture was extracted with 500 ml of hexane and the extract was dried over anhydrous Na2SO4, followed by recrystallization. Yield: 4.2 g (16%). Optical rotation [α]D26.2° =-11.3°.
Reaction SMILES: [CH3:1][Li].Br[C:4]1[N:8]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:7]=[C:6]([C:21]#[N:22])[C:5]=1[S:23][CH3:24].CI>C(OCC)C.O1CCCC1>[Cl:20][C:10]1[CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:14]([Cl:15])[C:9]=1[N:8]1[C:4]([CH3:1])=[C:5]([S:23][CH3:24])[C:6]([C:21]#[N:22])=[N:7]1
Reactant: CSc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1Br
Reactant: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CI
Product: CSc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C
Temperature: 0 °C

Procedure:
A 1.4 M solution of methyllithium (31 ml) in ethyl ether was added to a stirred solution of 5-bromo-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylthio-1H-pyrazole-3-carbonitrile (17.67 g) in dry tetrahydrofuran (THF) at −65° C. over 15-minutes and allowed to warm to 0° C. over 3-hours. After recooling to −65° C., methyl iodide (3.06 ml) in THEF was added over 3 minutes, the mixture warmed to −20° C. over 1.5 hours, and then partitioned between aqueous ammonium chloride and dichloromethane. The organic phase was dried (magnesium sulfate), evaporated and purified by flash chromatography on silica gel eluting with hexane/methyl tert-butylether to give 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-methyl-4-methylthio-1H-pyrazole-3-carbonitrile (6.2 g) having a purity of 90.7 area percent by HPLC.
Reaction SMILES: [CH3:1][C:2]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])=[N:8][N:7]=1)([CH3:5])[CH:3]=O.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][C:2]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=2)[CH2:14][CH2:15][CH3:16])=[N:8][N:7]=1)([CH3:3])[CH2:5][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)(C)C=O)s1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)(C)CN2CCOCC2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1,1-dimethyl-2-oxo-ethyl)-[1,3,4]thiadiazol-2-yl]-amide (41 mg), morpholine (25 mg), acetic acid (0.02 ml) in methylene chloride (1 ml) was stirred at room temperature for 1 hr, and sodium triacetoxyborohydride (42 mg) was added. The mixture was stirred at room temperature for at least two days. The mixture was quenched with diluted NaOH and extracted with methylene chloride. The organic layer was separated, concentrated to dryness and the residue was purified by silica gel column chromatography using 35% to 65% ethyl acetate in hexane as eluent to give the title compound. The title compound was prepared as the corresponding HCl salt by adding HCl/doxane, followed by concentration to give a solid. LC_MS retention time 1.7 min M+1=497.0, M−1=495.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([CH3:28])=[N:25][C:24]=2[CH:29]=1.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([CH3:28])=[N:25][C:24]=2[CH:29]=1)(=[O:11])=[O:10]
Reactant: Cc1nc2cc(N)ccc2o1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc2cc(NS(=O)(=O)c3cc(Cl)ccc3Cl)ccc2o1
Reaction time: 0.08 h
Yield: 63 %

Procedure:
To a solution of 2,5-dichlorobenzenesulphonyl chloride (52 mg, 0.21 mmol) in dichloromethane (1.5 mL) was added pyridine (40 μL, 0.5 mmol) and the mixture was stirred under N2 for 5 min, after which time 5-amino-2-methylbenzoxazole (30 mg, 0.20 mmol) was added. The resulting mixture was stirred for 1 h at room temperature, then saturated NaHCO3 solution was added (8 mL) and the mixture was extracted into ethyl acetate (15 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a pale pink solid (45 mg, 63%), single spot at Rf 0.53 (1:1 hexane:ethyl acetate). mp 193.5-193.9° C., HPLC purity 98% (tR 2.27 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 7.86 (1H, d, J=2.2 Hz), 7.39 (4H, m), 7.12 (1H, dd, J=8.4, 1.8 Hz), 2.58 (3H, s). LCMS: 355.07 (M−). FAB-MS (MH+, C14H10Cl2N2O3S): calcd 356.9867, found 356.9878.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=[NH:11])[NH:8][C:9]#N)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:14].N#N.[CH3:19][C:20]#[N:21]>>[Cl:14][C:9]1[N:8]=[C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:11]=[C:20]([CH3:19])[N:21]=1
Reactant: CC#N
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#CNC(=N)c1ccc(Cl)s1
Agent: N#N
Product: Cc1nc(Cl)nc(-c2ccc(Cl)s2)n1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of reactant 3 in CH3CN was added reactant 2 and POCl3. The mixture was stirred at 70° C. overnight under. N2. TLC showed starting material was consumed. The mixture was then poured into NaHCO3 (aq) carefully and the precipitate collected. The dried sample was confirmed as desired product 2-chloro-4-(5-chlorothiophen-2-yl)-6-methyl-1,3,5-triazine 4.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.C(Cl)Cl.[C:15]([S:19]([NH:21][CH:22]1[CH2:27][CH2:26][CH:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:20])([CH3:18])([CH3:17])[CH3:16]>C(OCC)(=O)C>[C:15]([S:19]([NH:21][CH:22]1[CH2:27][CH2:26][CH:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]1)(=[O:9])=[O:20])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)C1CCC(NS(=O)C(C)(C)C)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCC(NS(=O)(=O)C(C)(C)C)CC1
Reaction time: 3 h

Procedure:
Metachloroperbenzoic acid (1.25 g) was added, under cooling with ice, to a methylene chloride solution (10 mL) containing ethyl 4-tert-butylsulfinylaminocyclohexane-carboxylate (1.0 g) as prepared by the above-described preparation method, and stirring was effected at room temperature for 3 hrs. The reaction mixture, after being diluted with ethyl acetate, was washed with an aqueous saturated sodium-hydrogencarbonate and sodium-chloride solutions successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant residue was separated and purified by silica-gel chromatography (C-300, hexane:ethyl acetate=1:1) to give ethyl 4-tert-butylsulfonylamino-cyclohexanecarboxylate composed mainly of the trans isomer (673 mg).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[CH3:5][C:6]([O:9][C:10]([NH:12][CH:13]([C:20]([OH:22])=O)[CH2:14][C:15]1[N:19]=[CH:18][S:17][CH:16]=1)=[O:11])([CH3:8])[CH3:7]>>[C:6]([O:9][C:10](=[O:11])[NH:12][C@H:13]([C:20](=[O:22])[N:3]([CH3:4])[CH3:2])[CH2:14][C:15]1[N:19]=[CH:18][S:17][CH:16]=1)([CH3:5])([CH3:7])[CH3:8]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)NC(Cc1cscn1)C(=O)O
Agent: Cl
Product: CN(C)C(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C

Procedure:
Dimethylamine hydrochloride (1.2 mmol) and Boc-L-3-(4-thiazolyl)alanine (1.0 mmol) were coupled according to Procedure A (0-25° C. reaction temperature) and the product purified by chromatography on silica gel eluted with 1-16% ethanol in dichloromethane containing 0.5% ammonium hydroxide. Yield 124 mg, 41%.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[NH:10][C:9](=O)[CH2:8][O:7][C:6]=2[N:12]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[NH:10][C:9](=[S:28])[CH2:8][O:7][C:6]=2[N:12]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1COc2nc(Br)c(-c3ccccc3)cc2N1
Solvent: Cc1ccccc1
Product: S=C1COc2nc(Br)c(-c3ccccc3)cc2N1
Yield: 65.8 %

Procedure:
A mixture of 6-bromo-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (0.26 g, 0.852 mmol) and Lawesson's Reagent (0.34 g, 0.852 mmol) in toluene (10 ml) was heated at 120 degree for 16 h. The reaction mixture was concentrated to dryness and was added DCM (5 ml) and diisopropyl ether (20 ml). The precipitate was filtered to give product (0.18 g). 1H NMR (500 MHz, DMSO-d6): 12.9 (br, 1H), 7.35-7.55 (m, 5H), 7.32 (s, 1H), 5.16 (s, 2H).
Reaction SMILES: CC1[O:7][CH:6]([CH3:8])[O:5][CH:4]([CH3:9])O1.[Na+].[I-:11].[C:12]([O:15][C:16]1C=[CH:20][CH:19]=[CH:18][C:17]=1C(Cl)=O)(=[O:14])[CH3:13]>C(Cl)Cl>[C:12]([O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:8]=1[C:6]([O:5][CH:4]([I:11])[CH3:9])=[O:7])(=[O:14])[CH3:13]
Reactant: CC1OC(C)OC(C)O1
Reactant: [I-]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Oc1ccccc1C(=O)OC(C)I
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
To a mixture of 2,4,6-trimethyl-1,3,5-trioxane (245 mg, 1.85 mmol) and NaI (0.972 g, 6.48 mmol) in DCM (15 mL) was added a solution of 2-(chlorocarbonyl)phenyl acetate in DCM (5 mL, 0° C.). The resulting mixture was allowed to stir (RT, 16 h). The mixture was filtrated and concentrated under reduced pressure. The crude was purified by silica chromatography (EtOAc-PE, 0-10%) to afford 1-iodoethyl 2-acetoxybenzoate (0.75 g, 40%) as a light yellow oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][NH2:12])[N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]=2[CH:19]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2[CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1.C(N(CC)CC)C>C(O)(C)C>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][NH:12][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][N:25]4[CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][O:31]3)[N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]=2[CH:19]=1
Reactant: NCc1nc2ccc(F)cc2n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Fc1ccc2nc(CNc3ncnc4c3ncn4C3CCCCO3)n(-c3ccccc3)c2c1
Yield: 70.5 %

Procedure:
(6-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)methylamine hydrochloride (0.113 g, 0.4 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.19 g, 0.8 mmol), triethylamine (0.28 mL, 2 mmol) in isopropanol (2 mL) was heated to 80° C. in a sealed tube for 6 h. The reaction mixture was partitioned between DCM and water and the organic layer was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-3.5% MeOH in DCM) to afford the title compound as a colourless gum, (0.125 g, 70%). LCMS (Method B): RT 2.99 min [M+H]+ 444.19.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]([NH:15][C:16]([CH3:18])=[O:17])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])C=C.O.CN1C[CH2:24][CH2:23][C:22]1=O>>[OH:4][C:5]1[C:14]([CH2:24][CH:23]=[CH2:22])=[C:13]([NH:15][C:16]([CH3:18])=[O:17])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: C=CCOc1cc(NC(C)=O)ccc1C(=O)OC
Reactant: CN1CCCC1=O
Solvent: O
Product: C=CCc1c(NC(C)=O)ccc(C(=O)OC)c1O

Procedure:
84 g of methyl 2-allyloxy-4-acetaminobenzoate and 84 g of N-methylpyrrolidone were introduced into a 500 ml round-bottomed flask. The contents were heated quickly to reflux which was then maintained for 30 minutes, and the solution was then cooled slightly and poured into water. Crystallation was immediate. The same operations were repeated with the same quantities of methyl 2-allyloxy-4-acetaminobenzoate and N-methylpyrrolidone and the products from the two trials were combined and cooled, drained, washed with water and dried at 50° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH:6]2[OH:11].C(N(CC)CC)C.[CH3:23][Si:24](Cl)([CH3:26])[CH3:25].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH:6]2[O:11][Si:24]([CH3:26])([CH3:25])[CH3:23]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)CC1Cc2c(Br)cccc2C1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC1Cc2c(Br)cccc2C1O[Si](C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
A 300-ml three-necked round flask equipped with a stirring bar, a Dimroth condenser, a dropping funnel and a thermometer was charged with 34.4 g (127.8 mmol) of 4-bromo-2-i-butyl-1-hydoxyindane, 23.1 ml (166.2 mmol) of triethylamine and 118 ml of methylene chloride. To the mixture was added dropwise 20 ml of a methylene chloride solution containing 19.45 ml (153.4 mmol) of trimethylsilyl chloride under a nitrogen atmosphere while cooling with ice bath. After the addition was completed, the temperature was elevated to room temperature, and the mixture was further stirred for 1.5 hours. The reaction mixture was poured onto a mixture of 200 ml of ice water and 20 ml of a saturated aqueous solution of sodium bicarbonate. Then, the organic phase was separated, and the aqueous phase was further extracted with 50 ml of methylene chloride two times. The combined organic phase was washed with 100 ml of a saturated NaCl aq., followed by dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure. The residue was distilled under reduced pressure to obtain 41.8 g of the desired product (mixture of two isomers) as a pale yellow liquid (yield: 96%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[CH:11]([O-])([O-])OC.[CH2:16]([O:19][C:20]1[C:21]([NH2:30])=[CH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH3:18]>>[CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[C:6](=[CH:11][NH:30][C:21]2[C:20]([O:19][CH2:16][CH2:17][CH3:18])=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)[C:4](=[O:5])[O:3]1
Reactant: COC([O-])[O-]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCCOc1cc2ccccc2cc1N
Product: CCCOc1cc2ccccc2cc1NC=C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
Meldrum's acid (2.59 g, 17.9 mmol) was added to methyl orthoformate (16 ml), and the mixture was stirred for 2 hours while heating under reflux. 3-Propoxynaphthalen-2-ylamine (2.5 g, 12.4 mmol) was added thereto, and the resulting mixture was stirred for 4 hours while heating under reflux. The reaction mixture was cooled to room temperature and then concentrated to dryness under reduced pressure to recrystallize the residue from methanol, giving a pale brown powder of 2,2-dimethyl-5-[(3-propoxynaphthalen-2-ylamino) methylene][1,3]dioxane-4,6-dione (4.19 g, yield: 95%).
Reaction SMILES: [NH2:1][C:2](=[O:35])[CH2:3][CH2:4][N:5]([CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:24][C@H:25]3[CH2:30][CH2:29][C@H:28]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]3)[CH:20]=2)[CH:15]=1)C(=O)OC(C)(C)C.[CH3:36][C:37](OC(C)=O)=[O:38]>CC(O)=O>[C:37]([NH:1][C:2](=[O:35])[CH2:3][CH2:4][NH:5][CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:24][C@H:25]3[CH2:26][CH2:27][C@H:28]([C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:29][CH2:30]3)[CH:20]=2)[CH:15]=1)(=[O:38])[CH3:36]
Reactant: CC(C)(C)OC(=O)N(CCC(N)=O)Cc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)NC(=O)CCNCc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
The mixture of tert-butyl 3-amino-3-oxopropyl((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)carbamate (241 mg, 0.5 mmol) in Ac2O and AcOH (6 mL, 1:5), was stirred at 90° C. for 2 h. The reaction mixture was concentrated in vacuum and the residue was purified by chromatography with silica gel (DCM/MeOH=15/1) to give the title compound as a white solid (100 mg, yield: 50%). ESI-MS (M+H+): 425.3. HPLC: 94.82%. 1H NMR (400 MHz, CDCl3) δ: 7.70 (d, 1H), 7.68 (d, 1H), 7.49 (s, 1H), 7.21 (d, 1H), 7.17-7.14 (m, 2H), 6.50 (br, 1H), 5.49 (br, 1H), 4.71 (s, 2H), 4.24-4.30 (m, 1H), 3.71 (t, 2H), 2.57 (t, 2H), 2.27 (d, 2H), 2.18 (s, 3H), 1.89 (d, 2H), 1.48-1.42 (m, 2H), 1.09-1.20 (m, 3H), 0.88 (s, 9H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH3:20])[CH:10]([NH2:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O-])([O-])=O.[K+].[K+].ClC(OCC)=O.B>C1COCC1.O>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH3:20])[C@H:10]([NH:21][CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(F)ccc1C1CN(Cc2ccccc2)CC1N
Reactant: O=C([O-])[O-]
Agent: B
Agent: CCOC(=O)Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1C
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 56.1 %

Procedure:
To a solution of rac-(3S,4R)-1-benzyl-4-(4-fluoro-2-methyl-phenyl)-pyrrolidin-3-ylamine (130 mg, 0.46 mmol) in THF (6 ml) was added a solution of K2CO3 (126 mg, 0.91 mmol) in H2O (2 ml). After 10 minutes, ethyl chloroformate (0.05 ml, 0.48 mmol) was added and stirring was continued at RT for an additional 2 h. The intermediate carbamate was then extracted with Et2O, dried over Na2SO4 and concentrated under vacuo to give viscous oil. The oil was taken up in THF (5 ml) and a solution of borane in THF (1M) was added (1.9 ml). The reaction mixture was then heated at 65° C. over night, cooled to RT and carefully quenched with conc. HCl (2 ml). The mixture was then heated at 80° C. for 2 h, cooled to RT, concentrated under vacuo, diluted with Et2O (30 ml) and neutralized with an aqueous solution of NaHCO3. The organic phases were dried over Na2SO4 and the product purified by flash chromatography (SiO2, CH2Cl2/MeOH 9:1) to afford 77 mg (56%) of rac-[(3S,4R)-1-benzyl-4-(4-fluoro-2-methyl-phenyl)-pyrrolidin-3-yl]-methyl-amine as a colorless oil. ES-MS m/e: 299.3 (M+H+).