Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:45])[CH2:10][C:11]1[CH:44]=[CH:43][CH:42]=[CH:41][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][C:23]2[CH:24]=[N:25][N:26]([CH:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]3)[CH:27]=2)[N:16]=1>C(Cl)Cl>[CH3:21][C:20]1[C:15]([CH2:14][CH2:13][C:12]2[CH:41]=[CH:42][CH:43]=[CH:44][C:11]=2[CH2:10][C:9]([NH2:8])=[O:45])=[N:16][C:17]([NH:22][C:23]2[CH:24]=[N:25][N:26]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH:27]=2)=[N:18][CH:19]=1
Reactant: Cc1cnc(Nc2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)nc1CCc1ccccc1CC(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cnc(Nc2cnn(C3CCNCC3)c2)nc1CCc1ccccc1CC(N)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
TFA (0.5 mL) was added to a solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (A128) (0.040 g, 0.077 mmol) in DCM (5 mL) and the resulting mixture stirred for 18 hours at room temperature. The volatiles were evaporated under reduced pressure and the residue partitioned between 2 M NaOH (10 mL) and EtOAc (25 mL). The organic layer was separated and washed with water (25 mL), brine (25 mL), dried (Na2SO4) and concentrated under reduced pressure to give the title compound 33 as an off white solid (0.015 g, 49%); 1H NMR (400 MHz, d4-MeOH) δ 8.05 (s, 1H), 7.99 (d, J=0.5 Hz, 1H), 7.56 (d, J=0.6 Hz, 1H), 7.27-7.22 (m, 1H), 7.22-7.15 (m, 3H), 4.23 (tt, J=11.7, 4.1 Hz, 1H), 3.64 (s, 2H), 3.23-3.09 (m, 4H), 3.02-2.91 (m, 2H), 2.76 (td, J=12.8, 2.5 Hz, 2H), 2.14-2.05 (m, 5H), 1.98-1.85 (m, 2H). LCMS-A: rt 3.968 min; m/z 420 [M+H]+.
Reaction SMILES: C([C:4]1[S:5][C:6](Cl)=[CH:7][C:8]=1[O:9][CH2:10][C:11]([OH:13])=[O:12])(O)=O.N1C2C(=CC=CC=2)C=CC=1.C(=O)=O.[ClH:28]>[Cu].O>[Cl:28][CH:10]([O:9][C:8]1[CH:7]=[CH:6][S:5][CH:4]=1)[C:11]([OH:13])=[O:12]
Reactant: O=C(O)COc1cc(Cl)sc1C(=O)O
Reactant: Cl
Agent: [Cu]
Agent: O=C=O
Solvent: c1ccc2ncccc2c1
Solvent: O
Product: O=C(O)C(Cl)Oc1ccsc1

Procedure:
A mixture of 1.63 g of the product of Step C, 3.5 ml of quinoline and 0.24 g of Gattermann copper was heated to 200° C. under nitrogen during which 165 ml of carbon dioxide gas evolved for the water and the mixture was then poured into iced water. 5.6 ml of 10N hydrochloric acid were added thereto and the mixture was extracted with ether. The ether phase was dried and evaporated to dryness and the residue was effloresced with petroleum ether (Bp -60°-80° C.) to obtain 1.2 g of 2-chloro-4-thienyloxy-acetic acid melting at 119° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([OH:13])=[O:12].Br[CH2:15][C:16]#[CH:17].C1COCC1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([CH2:17][C:16]#[CH:15])(=[O:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)O)c1
Reactant: C#CCBr
Solvent: O
Solvent: C1CCOC1
Product: C#CCS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Yield: 73.2 %

Procedure:
110.7 g (0.5 mol) of 2-chloro-5-nitrobenzenesulfinic acid were dissolved in 500 ml of water at pH 6.5 and the solution was added to a solution of 65.5 g (0.55 mol) of 3-bromoprop-1-yne and 100 ml of THF. The reaction mixture was then heated to 40°-50° C. After the reaction had ended (check by TLC), the reaction product was extracted with 1.5 l of ethyl acetate, and the organic phase was neutralized and dried over sodium sulfate. The solvent was evaporated off to leave 95 g of 2-chloro-5-nitro-1-(prop-1-yn-3-ylsulfonyl)benzene (melting point 238°-241° C.). ##STR28##
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:6][CH:7]=1.[OH:18][CH2:19][C:20]([NH:22][NH2:23])=O>C(O)CCC>[OH:18][CH2:19][C:20]1[N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)[CH:6]=[CH:7][C:2]2=[N:23][N:22]=1
Reactant: NNC(=O)CO
Reactant: FC(F)(F)c1cccc(-c2ccc(Cl)nn2)c1
Solvent: CCCCO
Product: OCc1nnc2ccc(-c3cccc(C(F)(F)F)c3)nn12

Procedure:
A mixture of 7.76 g. of 3-chloro-6-[3-(trifluoromethyl)phenyl]pyridazine, 6.66 g. of hydroxyacethydrazide and 200 ml. of n-butyl alcohol is heated at reflux temperature for 18 hours. The mixture is evaporated in vacuo and the residue is triturated with dichloromethane-hexane. The mixture is filtered and the solid is recrystallized from ethyl acetate to give the product of the Example as off-white crystals, m.p. 224°-226° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[S:4][C:5]([CH2:8]Cl)=[CH:6][N:7]=1.O.C(=O)([O-])[O-:12].[Na+].[Na+].Cl>C(OCC)(=O)C>[ClH:2].[Cl:2][C:3]1[S:4][C:5]([CH2:8][OH:12])=[CH:6][N:7]=1
Reactant: O=C([O-])[O-]
Reactant: ClCc1cnc(Cl)s1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: OCc1cnc(Cl)s1
Temperature: 80 °C

Procedure:
2-Chloro-5-chloromethylthiazole hydrochloride (100 g, 0.49 mole), and water (100 mL) were charged to a flask. The mixture was stirred and heated to 80° C. for 2.5 hours. The reaction mixture was cooled to about 15° C. and sodium carbonate (51.5 g) was added (to raise the pH to about 8-9). The product was extracted with ethyl acetate (1×500 mL and 1×250 mL). The combined organic extracts were stirred for 20 minutes with 3 g of decolorizing carbon (Norit® SA3 about 100 mesh) and filtered through celite. The celite and flask were washed with an additional 100 mL of ethyl acetate and combined with the filtrate. The filtrate was concentrated under reduced pressure to provide a yellow-orange oil. The oil was dissolved in 500 mL of ethyl acetate and cooled to -10° C., under a nitrogen atmosphere. A solution of HCl (17.82 grams, 1 eq.) in ethyl acetate was slowly added. The temperature was maintained below -5° C. After the addition was complete the slurry formed was stirred for 30 minutes. The product was filtered under vacuum and the flask and product washed with ethyl acetate(100 mL). The title compound, an off white powder, was purged with nitrogen gas until dry. Yield 63.3 g; 69.6%..
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]1[N:11]=[C:12]([N:15]2[CH2:18][CH:17](OS(C)(=O)=O)[CH2:16]2)[S:13][CH:14]=1)=[O:7].[C:24]([O-:27])(=[S:26])[CH3:25].[K+]>CN(C)C=O>[C:24]([S:26][CH:17]1[CH2:16][N:15]([C:12]2[S:13][CH:14]=[C:10]([CH2:9][NH:8][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[N:11]=2)[CH2:18]1)(=[O:27])[CH3:25]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)OC1CN(c2nc(CNC(=O)c3ccco3)cs2)C1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(CNC(=O)c3ccco3)cs2)C1
Temperature: 90 °C
Reaction time: 6 h
Yield: 75.4 %

Procedure:
To a solution of 1-[4-(furan-2-carbonylamino)methyl-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (481 mg, 1.34 mmol) (obtained as described in Reference Example 67(3)) in dimethylformamide (14 ml) was added potassium thioacetate (921 mg, 8.07 mmol) at room temperature and the mixture was stirred in an oil bath (90° C.) for 6 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:1) as the eluant to afford 3-acetylthio-1-[4-(furan-2-carbonylamino)methyl-1,3-thiazol-2-yl]azetidine (341 mg, yield 83%) as a pale brown solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)=[CH:9][CH:8]=1)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].[CH3:39][N:40]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[N:41]1>COCCOC>[F:30][C:27]1[CH:26]=[CH:25][C:24]([C:13](=[C:14]2[CH2:19][C:18]([CH3:20])([CH3:21])[CH2:17][C:16]([CH3:22])([CH3:23])[CH2:15]2)[C:10]2[CH:11]=[CH:12][C:7]([C:43]3[CH:42]=[N:41][N:40]([CH3:39])[CH:44]=3)=[CH:8][CH:9]=2)=[CH:29][CH:28]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC1(C)CC(=C(c2ccc(F)cc2)c2ccc(OS(=O)(=O)C(F)(F)F)cc2)CC(C)(C)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1cc(-c2ccc(C(=C3CC(C)(C)CC(C)(C)C3)c3ccc(F)cc3)cc2)cn1
Temperature: 120 °C
Yield: 90.1 %

Procedure:
The Suzuki procedure described for 28 was followed using triflate 25 (150 mg, 0.32 mmol), PdCl2(Ph3P)2 (23 mg, 0.032 mmol), 2 N aqueous Na2CO3 (320 uL, 3.2 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (334 mg, 1.6 mmol), and DME (2 mL). The mixture was heated at 120° C. for 5 min in the microwave. Aqueous work-up followed by purification gave 116 mg (90%) of the title product 31 as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.06 (s, 1H), 7.79 (s, 1H), 7.46 (d, J=8.0 Hz, 2H), 7.2-7.16 (m, 2H), 7.11 (d, J=8.0 Hz, 2H), 3.83 (s, 3H), 1.93 (s, 2H), 1.88 (s, 2H), 1.26 (s, 2H), 0.89 (s, 6H), 0.84 (s, 6H). LCMS (APCI): m/z 403 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[CH:20]([C:23]1[N:27]=[C:26]([C:28]2[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=2[CH:30]=O)[O:25][N:24]=1)([CH3:22])[CH3:21].OOS([O-])=O.[K+]>CN(C=O)C.O>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:30]1[C:29]1[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=1[C:26]1[O:25][N:24]=[C:23]([CH:20]([CH3:22])[CH3:21])[N:27]=1)([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Reactant: CC(C)c1noc(-c2ccccc2C=O)n1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1noc(-c2ccccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
To a mixture of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (135 mg, 0.53 mmol) and 2-(3-isopropyl-1,2,4-oxadiazol-5-yl)-benzaldehyde (139 mg, 0.64 mmol) in DMF (5.0 mL) is added Oxone (325 mg, 0.53 mmol) in H2O (2.0 mL). The reaction mixture is stirred at room temperature for 1 hour and then quenched with saturated sodium thiosulfate aq. (25 mL). The quenched reaction mixture is extracted with EtOAc (25 mL×2) and the combined organic layers are washed with H2O (50 mL×2) and dried with Na2SO4. The filtrate is concentrated under reduced pressure and the residue is purified by silica gel flash column chromatography with 3.5% MeOH in CH2Cl2 as the eluent to afford the title compound (105 mg, 44%) as a white solid. LCMS (ESMS): m/z 454.20 (M++1)
Reaction SMILES: ClC1C=CN=NN=1.Cl[C:9]1[N:14]=[C:13]([O:15][CH2:16][CH3:17])[N:12]=[C:11]([N:18]([CH3:20])[CH3:19])[N:10]=1.C(O)=[O:22]>>[CH3:19][N:18]([CH3:20])[C:11]1[N:12]=[C:13]([O:15][CH2:16][CH3:17])[NH:14][C:9](=[O:22])[N:10]=1
Reactant: O=CO
Reactant: CCOc1nc(Cl)nc(N(C)C)n1
Agent: Clc1ccnnn1
Product: CCOc1nc(N(C)C)nc(=O)[nH]1

Procedure:
The chlorotriazine from (b) (1.2 g.) was heated in formic acid (15 ml.) on a steam bath for 45 minutes, when gas evolution had ceased. The excess of formic acid was removed under reduced pressure and the residue was dissolved in the minimum amount of water, which was brought to pH 6-7 by adding solid sodium bicarbonate. The solution was extracted with chloroform and the extracts dried and evaporated. The residue crystallised from ethanol to give the product (1.1 g.) having a melting point of 215°-216° C. (The melting point sample resolidified and re-melted at 235° C).
Reaction SMILES: Br[CH:2]([CH3:10])[C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1>COCCOC>[CH3:10][C:2]1[N:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]2=[N:11][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=O)C(C)Br
Reactant: Nc1ccccn1
Solvent: COCCOC
Product: CCOC(=O)c1nc2ccccn2c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 115.5 %

Procedure:
To a solution of compound 1-B (1.25 g, 5.98 mmol) in DME (5 mL) was added 2-aminopyridine (0.563 g, 5.98 mmol) and the reaction mixture was allowed to warm to room temperature and stir for 18 h. The precipitate was filtered, washed with DME and dried in vacuo to afford 1.41 g of a white solid. The solid was dissolved in MeOH (20 mL) and refluxed for 18 h. The reaction mixture was cooled and the solvent evaporated under reduced pressure. The crude residue was partitioned between EtOAc and 10% NaHCO3, the layers separated and the organic phase washed with 10% NaHCO3, H2O, brine, dried over Na2SO4, filtered and the solvent evaporated under reduced pressure to afford 0.902 g of a white solid. The crude solid was purified by flash column chromatography (SiO2) eluting with a heptanes-EtOAc gradient to afford compound 1-C as a white solid (0.842 g, 69%). 1H-NMR (CDCl3): δ 7.90-7.92 (d, 1H), 7.65-7.68 (d, 1H), 7.21-7.25 (q, 1H), 6.88-6.92 (t, 1H), 4.44-4.50 (q, 2H), 2.80 (s, 3H), 1.44-1.48 (t, 3H); MS: m/z 205.2 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:23]=[CH:22][CH:21]=[C:20]4[C:16]=3[CH2:17][CH2:18][CH:19]4[NH:24][CH2:25][CH2:26][OH:27])[N:11]=2)=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[K+].[K+].Br[CH2:35][CH:36]([CH3:38])[CH3:37]>CC(N(C)C)=O>[OH:27][CH2:26][CH2:25][NH:24][CH:19]1[C:20]2[C:16](=[C:15]([C:12]3[N:11]=[C:10]([C:7]4[CH:8]=[CH:9][C:2]([O:1][CH2:35][CH:36]([CH3:38])[CH3:37])=[C:3]([CH:6]=4)[C:4]#[N:5])[O:14][N:13]=3)[CH:23]=[CH:22][CH:21]=2)[CH2:17][CH2:18]1
Reactant: N#Cc1cc(-c2nc(-c3cccc4c3CCC4NCCO)no2)ccc1O
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)COc1ccc(-c2nc(-c3cccc4c3CCC4NCCO)no2)cc1C#N
Temperature: 75 °C
Reaction time: 6 h
Yield: 36.8 %

Procedure:
Prepared using General Procedure 11. To a solution of 2-hydroxy-5-(3-(1-(2-hydroxyethylamino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)benzonitrile 102 (15.0 mg, 0.041 mmol) in DMA (2 mL) was added K2CO3 (16.9 mg, 0.12 mmol) and 1-bromo-2-methylpropane (11.3 mg, 0.08 mmol). The mixture was stirred 6 h at 75° C. The solvent was evaporated and the mixture was partitioned between EA and brine. The organic layer was dried over MgSO4, filtered, and the solvent evaporated. The final compound was purified by preparative HPLC to give 6.31 mg (37%) of 5-(3-(1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isobutoxybenzonitrile 103 as a white solid. LCMS-ESI (m/z) calculated for C24H16N4O3: 418.5; found 419.2 [M+H]+, tR=2.61 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27](O)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[N+:46]([C:49]1[CH:68]=[CH:67][C:52]([CH2:53][O:54][C:55]([O:57][CH2:58][CH2:59][N:60]2[CH2:66][CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)=[O:56])=[CH:51][CH:50]=1)([O-:48])=[O:47]>C(#N)C.C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([N:63]3[CH2:64][CH2:65][CH2:66][N:60]([CH2:59][CH2:58][O:57][C:55]([O:54][CH2:53][C:52]4[CH:67]=[CH:68][C:49]([N+:46]([O-:48])=[O:47])=[CH:50][CH:51]=4)=[O:56])[CH2:61][CH2:62]3)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: O=C(OCCN1CCCNCC1)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCCN(CCOC(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
860 mg of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid [prepared as described in Preparation 1(b)] were dissolved in 8 ml of anhydrous acetonitrile, and 410 mg of N,N'-carbonyldiimidazole were added to the resulting solution. The resulting mixture was then stirred at room temperature for 30 minutes, after which a solution of 1250 mg of 4-[2-(4-nitrobenzyloxycarbonyl)oxyethyl]homopiperazine bis(trifluoroacetate) in 5 ml of acetonitrile and 860 μl of diisopropylethylamine were added, in that order. The resulting mixture was then stirred at room temperature for 35 hours. At the end of this time, the reaction mixture was diluted with 100 ml of ethyl acetate and washed with an aqueous solution of sodium hydrogencarbonate and with an aqueous solution of sodium chloride, in that order. The organic layer was then dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through silica gel using mixtures of ethyl acetate and methanol ranging from 98:2 to 95:5 by volume as the eluent. Those fractions containing the title compound were collected and concentrated by evaporation under reduced pressure, to afford 900 mg of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:37])[CH2:16][N:17]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:18]2([CH3:29])[CH2:26][C:25]3[C:20](=[CH:21][C:22]([CH3:28])=[C:23]([CH3:27])[CH:24]=3)[CH2:19]2)=[CH:11][C:10]=1[N+:38]([O-:40])=[O:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:41](OC(=O)C)(=[O:43])[CH3:42]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:37][C:41](=[O:43])[CH3:42])[CH2:16][N:17]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:18]2([CH3:29])[CH2:26][C:25]3[C:20](=[CH:21][C:22]([CH3:28])=[C:23]([CH3:27])[CH:24]=3)[CH2:19]2)=[CH:11][C:10]=1[N+:38]([O-:40])=[O:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc2c(cc1C)CC(C)(N(Cc1ccccc1)C[C@H](O)c1ccc(OCc3ccccc3)c([N+](=O)[O-])c1)C2
Solvent: c1ccncc1
Product: CC(=O)O[C@@H](CN(Cc1ccccc1)C1(C)Cc2cc(C)c(C)cc2C1)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Reaction time: 18 h

Procedure:
To a solution of (R)-1-(4-Benzyloxy-3-nitro-phenyl)-2-[benzyl-(2,5,6-trimethyl-indan-2-yl)amino]-ethanol in pyridine is added acetic anhydride and the mixture stirred for 18 hours. The reaction mixture is quenched with water and after addition of ethyl acetate washed twice with aqueous KHSO4 solution, twice with aqueous NaHCO3 and once with brine. The product is purified by chromatography (silica, ethyl acetate/hexane 1:4). ES+ MS m/e 579 (MH+)
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10](=[O:12])[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][C:7]=2[CH:18]=1.S(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[Cl:21][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10](=[O:12])[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][C:7]=2[CH:18]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cc2cc(CO)ccc2oc1=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc2cc(CCl)ccc2oc1=O

Procedure:
A mixture of 1 g of ethyl 6-hydroxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate (3.9 mmol) and 10 ml of thionyl chloride is refluxed for 3 h. The solution obtained is evaporated under reduced pressure. The residue is re-suspended in 10 ml of dry toluene and the solvent is evaporated off under reduced pressure. The last two steps are repeated twice. The residue obtained is taken up in chloroform and the organic phase is washed three times with 0.1 N HCl solution and then dried over MgSO4. The solvent is removed by distillation under reduced pressure and the residue is recrystallized from CHCl3/Petroleum ether.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[NH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=1[CH3:21].CCN(C(C)C)C(C)C>C1COCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=1[CH3:21])=[O:8]
Reactant: O=C(Cl)CCCCCBr
Reactant: COC(=O)c1ccc(N)c(C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)CCCCCBr)c(C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2.14 g (10 mmol) 6-bromo-hexanoylchloride in 5.0 ml THF is slowly added dropwise with stirring at ambient temperature to 1.65 g (10 mmol) methyl 4-amino-3-methyl-benzoate in 50 ml THF with 2 ml DIPEA. After 16 hours stirring at ambient temperature the mixture is evaporated down i. vac., the residue is dissolved in dichloromethane, washed twice with water and dried over sodium sulphate. The residue remaining after evaporation i. vac. is further reacted without any more purification.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[O:14]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:26]([CH2:25][C:24]1[CH:27]=[CH:28][C:21]([O:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:22][CH:23]=1)[CH2:11]2
Reactant: NCc1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)c1c(Cl)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1c2c(Cl)cccc2CN1Cc1ccc(Oc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 34.3 %

Procedure:
A mixture of 2-bromomethyl-6-chloro-benzoic acid methyl ester (0.132 g, 0.5 mmol), 4-phenoxy benzylamine (0.124 g, 0.7 mmol), and K2CO3 (0.152 g, 1.1 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-chloro-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.06 g, 34%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.24 (s, 2H), 4.76 (s, 2H), 6.98-7.46 (m, 12H). GC-MS: m/z 349 (M)+.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][NH:11][C:12]1[C:17]([C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23]2[CH:28]=[CH:27][N:26]3[N:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[C:25]3[N:24]=2)=[CH:16][C:15]([F:35])=[CH:14][N:13]=1)=O)(C)(C)C.[ClH:36]>C(O)(C(F)(F)F)=O>[ClH:36].[NH2:8][CH2:9][CH2:10][NH:11][C:12]1[C:17]([C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23]2[CH:28]=[CH:27][N:26]3[N:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[C:25]3[N:24]=2)=[CH:16][C:15]([F:35])=[CH:14][N:13]=1
Reactant: CC(C)(C)OC(=O)NCCNc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: NCCNc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1

Procedure:
A solution of (R)-5-(2-(2-(2-(tert-butoxycarbonylamino)ethylamino)-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (31 mg, 0.064 mmol) in HCl (4 N dioxane, 798 μL) and TFA (50% DCM, 2 mL) was stirred at ambient temperature for 1 hour before it was concentrated and dried under high vacuum to yield to give the desired product as off-white solid, which was used in the next step directly without further purification, assuming quantitative conversion. MS (apci) m/z=386.1 (M+H).