Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([N:9]([CH3:21])[C:10](=[O:20])[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:4]1)[CH3:2].[H][H]>C(O)C.[Pt]=O>[NH2:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]([N:9]([C@H:5]2[C@H:6]([OH:8])[CH2:7][N:3]([CH2:1][CH3:2])[CH2:4]2)[CH3:21])=[O:20])=[CH:16][CH:15]=1
Reactant: CCN1C[C@@H](O)[C@H](N(C)C(=O)c2ccc([N+](=O)[O-])cc2)C1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CCN1C[C@@H](O)[C@H](N(C)C(=O)c2ccc(N)cc2)C1
Yield: 40.9 %

Procedure:
A solution of 23 g (79 mmoles) of trans-N-(1-ethyl-4-hydroxy-3-pyrrolidinyl)-N-methyl-4-nitrobenzamide in 250 ml of absolute ethanol was treated with platinum oxide and shaken with hydrogen at ambient temperature in the Parr reduction apparatus for 3 hr. The mixture was filtered and the filtrate was concentrated to give 20.6 g (100%) of crude product. One-half of the residue was crystallized from acetone to give 8.5 g (82%) of white powder; m.p. 142°-145° C.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8](O)=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)C([Cl:25])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([Cl:25])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-(4-Chloro-phenoxy)-2-methyl-propionic acid (0.124 g, 0.58 mmol) and triethylamine (0.09 mL, 0.62 mmol) were combined in CH2Cl2 (2 mL) and cooled to 0° C. Oxalyl chloride (0.05 mL, 0.62 mmol) was added, followed by DMF (3 drops), and the mixture was slowly warmed to room temperature and stirred for 2 hours to give the title compound, which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[S:6](=[O:8])(=[O:7])[C@@H:5]2[C:9](Br)(Br)[C:10](=[O:11])[N:4]2[C@H:3]1[C:14]([OH:16])=[O:15].C([O-])(O)=O.[Na+].OS([O-])=O.[Na+].Cl>O>[CH3:1][C:2]1([CH3:17])[S:6](=[O:7])(=[O:8])[C@@H:5]2[CH2:9][C:10](=[O:11])[N:4]2[C@H:3]1[C:14]([OH:16])=[O:15]
Reactant: CC1(C)[C@H](C(=O)O)N2C(=O)C(Br)(Br)[C@H]2S1(=O)=O
Agent: Cl
Agent: O=C([O-])O
Agent: O=S([O-])O
Solvent: O
Product: CC1(C)[C@H](C(=O)O)N2C(=O)C[C@H]2S1(=O)=O

Procedure:
A mixture of 6,6-dibromopenicillanic acid 1,1-dioxide (3.92 g, 0.01 mole), NaHCO3 (5.04 g, 0.06 mole) and NaHSO3 (2.5 g, 0.024 mole) in 30 mL H2O was heated at 90° for 2 hours. The reaction mixture was cooled, acidified to pH 1.2 with dilute HCl and extracted with ethyl acetate. The extract was dried and evaporated to yield know title product, 180 mg; tlc Rf 0.1 compared to 0.4 for starting material (19:1 ethyl acetate:acetic acid); pnmr/D2O 1.45 (s, 3H), 1.58 (s, 3H), 3.47 (m, 2H), 4.22 (s, 1H), 4.97 (m, 1H).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([OH:14])=O.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:28])=[C:20]([CH:27]=1)[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[Cl:28][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:12]([C:11]2[S:10][CH2:9][CH2:8][O:7][C:6]=2[CH3:5])=[O:14])=[CH:27][C:20]=1[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22]
Reactant: CC(C)OC(=O)c1cc(N)ccc1Cl
Reactant: CC1=C(C(=O)O)SCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CC1=C(C(=O)Nc2ccc(Cl)c(C(=O)OC(C)C)c2)SCCO1
Reaction time: 4 h

Procedure:
Thionyl chloride (6.5 g, 0.055 mole) was added to a stirring slurry of 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxylic acid (8.0 g, 0.050 mole) in methylene chloride (50 ml). The mixture was stirred at 35°-40° C. for 4 hours, during which the solid completely dissolved. The solution was then evaporated under reduced pressure at about 35° C. to remove hydrogen chloride, sulfur dioxide and unreacted thionyl chloride. The residue, crude 5,6-dihydro-2-methyl-1,4-oxathiin-3-carbonyl chloride, which solidified, was dissolved in methylene chloride (50 ml). The solution was chilled in ice and treated dropwise with a solution of 1-methylethyl 5-amino-2-chlorobenzoate (10.7 g, 0.050 mole) and triethylamine (5.5 g, 0.055 mole) in methylene chloride (50 ml). The addition was carried out over about 2 hours, after which the reaction mixture was left stirring overnight at room temperature.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Br:13]Br.C(O)(=O)C>ClCCl.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][C:5]([CH:6]=[O:7])=[CH:8][C:9]=1[Br:13]
Reactant: Nc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Nc1c(Br)cc(C=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Amino-3-nitro-benzaldehyde (2.1 g) was dissolved in 25 ml of dichloromethane. Bromine (2 ml) and acetic acid (1 ml) were added and the mixture was stirred for 2 h at room temperature. The mixture was diluted with ethyl acetate and washed with aq. NaHSO3. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 1/0→0/1 (v/v) as eluent.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C@H:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:14][C:15]1[CH:16]=[C:17]([CH2:32][OH:33])[CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=1>>[F:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=1)[CH2:32][O:33][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C@H:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: C[C@@H]1Cn2c(cc(Cl)nc2=O)N1C
Reactant: OCc1ccc(Oc2ccc(C(F)(F)F)nc2)c(F)c1
Product: C[C@@H]1Cn2c(cc(OCc3ccc(Oc4ccc(C(F)(F)F)nc4)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from (R)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (3-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:20]3[CH2:24][C:23]4([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[O:22][N:21]=3)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].Cl.[NH2:31][OH:32].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:20]3[CH2:24][C:23]4([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[O:22][N:21]=3)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][C:16](=[N:31][OH:32])[CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(NC3CCC(=O)CC3)c(C3=NOC4(CCCCC4)C3)cnc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCn1ncc2c(NC3CCC(=NO)CC3)c(C3=NOC4(CCCCC4)C3)cnc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-{[1-Ethyl-5-(1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]amino}cyclohexanone (0.025 gm, 0.063 mmol) (example 17), hydroxylamine hydrochloride (0.008 gm, 0.126 mmol) and potassium carbonate (0.043 gm, 0.315 mmol) were taken in acetonitrile and the reaction mixture was stirred at room temperature for about 6 h. Excess of solvent was removed under reduced pressure and solid separated was washed with hexane and dried in vacuum.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([S:19]([O-:22])(=O)=[O:20])=[C:10]2[O:15][C:16](=[O:18])[CH3:17])(=[O:3])[CH3:2].[Na+].P(Cl)(Cl)([Cl:26])=O>CN(C)C=O>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([S:19]([Cl:26])(=[O:22])=[O:20])=[C:10]2[O:15][C:16](=[O:18])[CH3:17])(=[O:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)Nc1cccc2c(OC(C)=O)c(S(=O)(=O)[O-])ccc12
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc2c(OC(C)=O)c(S(=O)(=O)Cl)ccc12
Reaction time: 1 h

Procedure:
The 5-acetamido-1-acetoxynaphthalene-2-sulfonyl chloride was prepared by dropwise treatment of a suspension of dry sodium 5-acetamido-1-acetoxynaphthalene-2-sulfonate in 100 ml. phosphoryl chloride with 5.5 ml. dry dimethylformamide in a nitrogen atmosphere. The reaction mixture was stirred 1 hour and then poured over 600 ml. of crushed ice. The crude product was filtered and dissolved immediately in 500 ml. chloroform. The solution was treated with activated charcoal and dried over anhydrous magnesium sulfate to give 10.8 g. (44%) of a resinous yellow product which showed a single spot on a thin-layer chromotography.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[C:18]([F:21])([F:20])[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][OH:14])=[CH:11][C:10]=1[C:18]([F:19])([F:21])[F:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Benzyloxy-3-trifluoromethyl-benzoic acid (CAB03046, 3.555 g, 12 mmol) in THF (20 mL) was added dropwise to a suspension of lithium aluminum hydride (1.0 g, 26.3 mmol) in THF (20 mL). The mixture was stirred for another 30 minutes at room temperature and then quenched by addition of 2N NaOH (5 mL). The white precipitate was filtered off and washed with dichloromethane (100 mL), the filtrate was dried over sodium sulphate and concentrated under reduced pressure. The resulting oil was crystallised from diethyl ether/hexane. Yield: 3.31 g (98%). 1H-NMR (400 MHz, CDCl3)=1.72 (t, J=5.9 Hz, 1H, —OH), 4.66 (d, J=5.9 Hz, 2H, —CH2OH), 5.21 (s, 2H, —CH2Ph), 7.02 (d, J=8.2 Hz, 1H), 7.30-7.48 (m, 6H), 7.61 (d, J=2.3 Hz, 1H). LRMS (FAB+): 91.1 (100), 265.2 (45), 282.2 (40, [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[S:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][N:5]=1.[NH2:24][C@@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@@H:26]1[OH:34].CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O>CN1C(=O)CCC1>[OH:34][C@H:26]1[CH2:27][C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:25]1[NH:24][C:16]1[S:17][C:13]2[CH:12]=[C:11]([O:10][C:8]3[CH:7]=[CH:6][N:5]=[C:4]([C:3]([NH:2][CH3:1])=[O:23])[CH:9]=3)[CH:22]=[CH:21][C:14]=2[N:15]=1
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)sc3c2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CNC(=O)c1cc(Oc2ccc3nc(N[C@@H]4c5ccccc5C[C@@H]4O)sc3c2)ccn1
Temperature: 105 °C
Reaction time: 24 h
Yield: 73.3 %

Procedure:
To the solution of N-methyl-4-(2-(methylsulfinyl)benzo[d]thiazol-6-yloxy)picolinamide (300 mg, 0.86 mmol) in 5 ml of NMP was added (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol (597 mg, 4 mmol) and DIPEA (300 μL, 1.73 mmol). The reaction solution was stirred at 105° C. for 24 hours. The crude reaction solution was purified on prep HPLC and evaporated in vacuo to give 4-(2-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide (347 mg, 0.63 mmol) as TFA salt. ES/MS m/z 433.1 (MH+).
Reaction SMILES: Br[C:2]1(Br)[C:4]2([CH2:8][C@@H:7]([C:9]([OH:11])=[O:10])[N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:5]2)[CH2:3]1.C[Si]([SiH]([Si](C)(C)C)[Si](C)(C)C)(C)C.CC(N=NC(C#N)(C)C)(C#N)C>C1(C)C=CC=CC=1.CCOC(C)=O>[C:15]([O:14][C:12]([N:6]1[C@H:7]([C:9]([OH:11])=[O:10])[CH2:8][C:4]2([CH2:3][CH2:2]2)[CH2:5]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CC2(C[C@H]1C(=O)O)CC2(Br)Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[Si](C)(C)[SiH]([Si](C)(C)C)[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC2(CC2)C[C@H]1C(=O)O
Temperature: 110 °C
Yield: 38.6 %

Procedure:
To a degassed solution of (6S)-1,1-dibromo-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (580 mg, 1.45 mmol) in toluene (6 mL) was added the tris(trimethylsilyl)silane (1.35 mL, 4.36 mmol, 3.0 eq) and AIBN (24 mg, 0.145 mmol, 0.1 eq). The solution was heated at 110° C. for 3 hours. Another batch of tris(trimethylsilyl)silane (0.45 mL 1.45 mmol, 1.0 eq) and AIBN (10 mg) was added. The solution was heated at 110° C. for 2 more hours. A third batch of tris(trimethylsilyl)silane (0.45 mL 1.45 mmol, 1.0 eq) and AIBN (10 mg) was added. The solution was heated at 110° C. for 2 more hours. After being allowed to cool down, the solution was diluted with EtOAc (5 mL). This organic phase was extracted with aqueous K2CO3 (1 M, 10 mL×3). The combined aqueous extractions were cooled (ice/water) and acidified to pH 2 with concentrated HCl. This acidified aqueous phase was extracted with EtOAc (×3), dried (Na2SO4), filtered and evaporated. The residue was dried under vacuum to afford the desired compound as colorless oil (135 mg, 39%).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[C:11](=[O:12])[NH:10][C:9](=[O:13])[O:8]2)=[CH:4][CH:3]=1.C([O:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]=O)[CH:31]=2)=[C:25]([CH3:38])[CH:24]=1)(=O)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+:56]>O.C1COCC1>[OH:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][NH:1][C:2]3[CH:15]=[CH:14][C:5]([CH2:6][N:7]4[C:11](=[O:12])[N-:10][C:9](=[O:13])[O:8]4)=[CH:4][CH:3]=3)[CH:31]=2)=[C:25]([CH3:38])[CH:24]=1.[Na+:56]
Reactant: CC(=O)OCCOc1cc(C)c(-c2cccc(C=O)c2)c(C)c1
Reactant: Nc1ccc(Cn2oc(=O)[nH]c2=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc(OCCO)cc(C)c1-c1cccc(CNc2ccc(Cn3oc(=O)[n-]c3=O)cc2)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 26.5 %

Procedure:
A mixture of 2-(4-aminobenzyl)-1,2,4-oxadiazolidine-3,5-dione (365 mg), 2-[(3′-formyl-2,6-dimethylbiphenyl-4-yl)oxy]ethyl acetate (660 mg), acetic acid (0.3 ml), THF (20 ml) and Molecular Sieves 4A (1 g) was stirred at room temperature for 22 hours. Sodium triacetoxyborohydride (560 mg) was added to the reaction mixture, followed by stirring at room temperature for 22 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure, toluene was added to the residue, the solvent was again evaporated under a reduced pressure, and then the residue was purified by silica gel column chromatography (hexane-ethyl acetate). Methanol (10 ml) and sodium methoxide (52 mg) were added to the resulting pale yellow foamy substance (406 mg), followed by stirring for 2 hours while heating at 60° C. The solvent was evaporated under a reduced pressure, and chloroform was added to the residue, followed by washing with water and a saturated sodium chloride aqueous solution and drying over anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure, and THF (5 ml), methanol (5 ml) and a 1 M sodium hydroxide aqueous solution (0.81 ml) were added to the resulting pale yellow foamy substance (373 mg), followed by stirring at room temperature for 5 minutes. The solvent was evaporated under a reduced pressure, the residue was purified by an ODS column chromatography (water-acetonitrile), the resulting pale yellow foamy substance was made into a solid by adding diethyl ether. The solid was collected by filtration and then dried by heating under a reduced pressure to obtain sodium 2-[4-({[4′-(2-hydroxyethoxy)-2′,6′-dimethylbiphenyl-3-yl]methyl}amino)benzyl]-3,5-dioxo-1,2,4-oxadiazolidin-4-ide (226 mg) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]3[C:14]([O:23][CH3:24])=[C:15]4[C:20](=[O:21])[N:19]([CH3:22])[CH2:18][CH2:17][N:16]4[C:10]=3[C:9]([CH:25](O)[CH3:26])=[N:8]2)=[CH:4][CH:3]=1.S(Cl)([Cl:32])=O>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]3[C:14]([O:23][CH3:24])=[C:15]4[C:20](=[O:21])[N:19]([CH3:22])[CH2:18][CH2:17][N:16]4[C:10]=3[C:9]([CH:25]([Cl:32])[CH3:26])=[N:8]2)=[CH:4][CH:3]=1
Reactant: COc1c2n(c3c(C(C)O)nn(Cc4ccc(F)cc4)c(=O)c13)CCN(C)C2=O
Reactant: O=S(Cl)Cl
Product: COc1c2n(c3c(C(C)Cl)nn(Cc4ccc(F)cc4)c(=O)c13)CCN(C)C2=O

Procedure:
A solution of 2-(4-fluorobenzyl)-10-methoxy-4-(1-hydroxyethyl)-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (0.12 g, 0.30 mmol) in thionyl chloride (3.3 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under vacuum. The residue was concentrated from a solution in benzene under vacuum and triturated with diethyl ether. The solid precipitated was filtered and vacuum dried to provide the title compound.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([C:11](=[O:25])[CH2:12][CH2:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]3[CH2:22][CH2:23][CH2:24][C@H:18]3[CH2:17]2)=[O:15])[CH:6]=[CH:7][C:8]=1OC.[Cl:26]C1C=CC(C(CCC(O)=O)=O)=CC=1>>[Cl:26][C:8]1[CH:7]=[CH:6][C:5]([C:11](=[O:25])[CH2:12][CH2:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]3[CH2:22][CH2:23][CH2:24][C@H:18]3[CH2:17]2)=[O:15])=[CH:4][CH:3]=1
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Reactant: COc1ccc(C(=O)CCC(=O)N2CCN3CCC[C@H]3C2)cc1OC
Product: O=C(CCC(=O)N1CCN2CCC[C@H]2C1)c1ccc(Cl)cc1

Procedure:
279 mg of the title compound were prepared as described for 1-(3,4-dimethoxyphenyl)-4-((S)-hexahydropyrrolo[1,2-a]pyrazin-2-yl)butane-1,4-dione, using 3-(4-chlorobenzoyl)propionic acid instead of 3-(3,4-dimethoxybenzoyl)propionic acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[C:10]([CH3:11])[C:3]=12.[F:12][C:13]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:14]=1[NH2:15].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)(C)C.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]>[F:12][C:13]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][CH:7]=1
Reactant: Cc1c[nH]c2nccc(Cl)c12
Reactant: Nc1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Product: Cc1c[nH]c2nccc(Nc3ccc([N+](=O)[O-])cc3F)c12
Temperature: 25 °C

Procedure:
A solution of 8 mg (50 μmol) of 4-chloro-3-methyl-1H-pyrrolo[2,3-b]pyridine, 9 mg (60 μmol) of 2-fluoro-4-nitroaniline, 4 mg (5 mmol) of tris(dibenzylideneacetone)dipalladium and 5 mg (10 μmol) of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine and 10 mg (70 μmol) of potassium carbonate in 1.00 ml of degassed tert-butanol is stirred at 100° C. in a sealed pressure vessel for 3 h. After cooling to RT, the mixture is filtered through Celite, the Celite is washed with methanol and the filtrates are concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 1:1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][CH:5]=2.[H-].[Na+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C)C=O>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][N:3]1[C:4]2[C:9](=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH3:1])[CH3:22]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C)cc2cc([N+](=O)[O-])ccc21
Reaction time: 1 h
Yield: 78.6 %

Procedure:
2-Methyl-5-nitro-1H-indole (5.3 g) was dissolved in dimethyl formamide (20 ml) and to it added sodium hydride (1.2 g) for the mixture to be stirred for 1 hour. Ethyl bromoacetate (6.8 g) was added all at once and a precipitate started to form. The mixture was quenched with 1% aqueous acetic acid and the precipitate collected by filtration and washed thoroughly with water, triturated with diethyl ether and dried under vacuum to give pure sub-title product (6.2 g).
Reaction SMILES: [CH:1]1([S:4]([C:7]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]3[CH3:22])[N:13]=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:38])OC4C=CC=CC=4)=[CH:25][CH:24]=3)[N:11]=2)([CH3:9])[CH3:8])(=[O:6])=[O:5])[CH2:3][CH2:2]1.C1(S(C[C:46]2C=C(N3CCOC[C@@H]3C)N=C(C3C=CC(NC(=O)OC4C=CC=CC=4)=CC=3)[N:47]=2)(=O)=O)CC1>>[CH:1]1([S:4]([C:7]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]3[CH3:22])[N:13]=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:47][CH3:46])=[O:38])=[CH:25][CH:24]=3)[N:11]=2)([CH3:8])[CH3:9])(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)C2CC2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)C2CC2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Product: CNC(=O)Nc1ccc(-c2nc(N3CCOC[C@@H]3C)cc(C(C)(C)S(=O)(=O)C3CC3)n2)cc1

Procedure:
The following compounds were made in an analogous fashion from either phenyl N-[4-[4-(2-cyclopropylsulfonylpropan-2-yl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate or phenyl N-[4-[4-(cyclopropylsulfonylmethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate and the appropriate amine.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1.Cl>N1C=CC=CC=1.O>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:14][C:15]([OH:17])=[O:16])[CH:8]=[CH:9][CH:10]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Solvent: O
Product: O=C(O)C=Cc1cccc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 86.3 %

Procedure:
In an inert atmosphere, 3-(trifluoromethyl)benzaldehyde (13.26 g, 76.15 mmol) was dissolved in pyridine (58 ml) and malonic acid (15 g, 145 mmol) was added and the mixture was warmed to 50° C. followed by slow addition (over 5 minutes) of piperidine (5.8 ml, 58.6 mmol). The resulting suspension was warmed to 75° C. and stirring was continued for 3.5 h. The reaction mixture was cooled to 0° C. and poured onto an ice-cold solution of concentrated hydrochloric acid (12 M, 32 ml) in water (400 ml). The precipitated product was filtered off and dried at HV to give 14.21 g (68%) of 3-(3-trifluoromethyl-phenyl)-acrylic acid. LC-MS: tR=0.88 min; [M+H]+=no ionisation.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.[SH:27][CH2:28][CH2:29][CH2:30]O.B(F)(F)F>>[O:1]1[C:3]2([CH2:4][CH2:5][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:7][CH2:8]2)[CH2:2][S:27][CH2:28][CH2:29][CH2:30]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Reactant: OCCCS
Agent: FB(F)F
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CSCCCO4)c(F)c2)C(=O)O1

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.3 mmol) with 3-mercaptopropanol (0.36 mmol), BF3.etherate (catalytic) in tetrahydrofuran (10 ml) at 70-80° C. for 14 hours followed by silica gel column chromatographic purification to provide title compound in 48% yield.