Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].BrC[C:24]#[N:25].C(OCC)(=O)C>C(#N)C>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:24]#[N:25])[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC1CCN(C#N)CC1
Reaction time: 3 h

Procedure:
Piperidin-4-ylmethyl-carbamic acid tert-butyl ester (4 g, 18.66 mmol) was suspended in 120 ml of acetonitrile. Dried potassium carbonate (2.837 g, 20.53 mmol) was added. A solution of bromoacetonitrile in (3.72 ml, 5 mmolar solution, 18.66 mmol) was added (argon atmosphere) and the mixture was stirred for 3 hours. After addition of aqueous FeSO4 solution and ethyl acetate, the separated solid was filtered and the organic layer separated, dried and evaporated.
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([CH2:11][CH3:12])[N:3]=1.[OH:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:11]([N:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[C:2]([C:17]2[CH:18]=[CH:19][C:14]([OH:13])=[CH:15][CH:16]=2)=[N:3]1)[CH3:12]
Reactant: OB(O)c1ccc(O)cc1
Reactant: CCn1nc(Br)c2ncccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCn1nc(-c2ccc(O)cc2)c2ncccc21
Yield: 36.9 %

Procedure:
A mixture of 3-bromo-1-ethyl-1H-pyrazolo[4,3-b]pyridine (904 mg), (4-hydroxyphenyl)boronic acid (690 mg), Pd(PPh3)4 (139 mg), Na2CO3 (1.48 g), DME (17.5 mL), and H2O (3.5 mL) was refluxed overnight under Ar atmosphere. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue purified by basic silica gel column chromatography (AcOEt) and crystallized from hexane/AcOEt to give the title compound (353 mg).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: COc1cccc2sc(Cl)nc12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc2sc(Sc3ccc4c(c3)CC[C@H]3N(C)C(=O)CC[C@]43C)nc12
Yield: 66.3 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4-methoxybenzothiazole (92 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (4×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 107 mg (66%) of the title compound as an off white solid. mp 200°-205°. FDMS: m/e=424. α[D]589 =+60.56 (c=0.96, chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:15][O:14][C:13]3[CH:16]=[C:17]4[C:21](=[CH:22][C:12]1=3)[CH2:20][CH2:19][O:18]4)[C:5](=[O:11])[NH:6]2.Br[CH2:24][C:25]1[O:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=1.BrCC1CCCCO1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:15][O:14][C:13]3[CH:16]=[C:17]4[C:21](=[CH:22][C:12]1=3)[CH2:20][CH2:19][O:18]4)[C:5](=[O:11])[N:6]2[CH2:24][C:25]1[O:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=1
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: O=C1Nc2cccc(Cl)c2C12COc1cc3c(cc12)CCO3
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cccc(Cl)c2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 4′-chloro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 2-(bromomethyl)-5-(trifluoromethyl)furan to replace 2-(bromomethyl)tetrahydro-2H-pyran, 4′-chloro-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (73%) as a colorless solid: mp 166-169° C.; 1H NMR (300 MHz, CDCl3) δ7.29-7.18 (m, 1H), 7.01 (d, J=8.2 Hz, 1H), 6.89 (d, J=7.82 Hz, 1H), 6.74 (d, J=2.3 Hz, 1H), 6.45-6.34 (m, 2H), 5.11 (d, J=16.2 Hz, 1H), 4.99 (d, J=9.2 Hz, 1H), 4.88 (d, J=9.2 Hz, 1H), 4.81 (d, J=16.2 Hz, 1H), 4.52 (t, J=8.6 Hz, 2H), 2.98 (t, J=8.60 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ177.2, 162.2, 162.0, 151.6, 143.1, 141.8 (q, J=43.0 Hz), 131.6, 130.0, 128.7, 124.6, 118.8 (q, J=267.1 Hz), 119.7, 118.4, 117.1, 112.7, 109.5, 107.2, 92.9, 77.1, 72.4, 58.2, 37.1, 28.9; MS (ES+) m/z 461.9 (M+1), 463.9 (M+1).
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:7]([NH:9][C@H:10]([C:18]([O:20]CC)=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[OH-].[Na+].Cl>CO>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])[C@H:2]([C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 5 °C
Reaction time: 24 h

Procedure:
Dipeptide Ketoacids (General Procedure). To a stirred solution of 0.53 g (1,13 mmol) Z-Leu-Phe-COOEt in 6.0 ml methanol was added 1.27 ml (1.27 mmol) 1M NaOH. The color of the reaction mixture turned dark yellow and a small amount of solid was deposited. The reaction was run at room temperature and progress of the hydrolysis was checked on TLC. After 24 h. no more substrate was detected. The reaction mixture was chilled in one ice bath at 5° C., acidified with 1M HCl to pH=3 and extracted with AcOEt (2×50 mL). The organic extract were washed with 2×50 ml H2O and if necessary, decolorized with carbon and dried over MgSO4. After evaporation of the solvent (rotavaporator), the residue (thick oil) were titurated with 2×25 ml n-hexane and dried in vacuo. Yield 0.39 g (78%) of colorless, very thick oil. TLC, main spot at Rf =0.24, trace of impurity at Rf =0.78, I. Mass spectrum, FB-MS [(M+1)/Z]=441.
Reaction SMILES: C(O)C.[Na:4].[CH:5]1[CH2:9][CH:8]=[CH:7][CH:6]=1.O.[CH3:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[Na:4].[CH2:14]([CH:15]=[C:6]1[CH:5]=[CH:9][CH:8]=[CH:7]1)[CH2:13][CH:12]=[CH2:11]
Reactant: C1=CCC=C1
Reactant: CCCCC
Agent: [Na]
Solvent: CCO
Solvent: O
Product: C=CCCC=C1C=CC=C1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Then a sodium solution of ethanol was prepared by combining 4.3 g of sodium with 150 mL of ethanol. The solution was cooled to 0° C. and then 30 g of the phenyl alkenyl ketone was added. Then 30 mL of cyclopentadiene was slowly added to the solution and the mixture stirred for 4 hrs. Then 100 mL of water and 100 mL of pentane were added. The ethanol-water layer was then extracted twice with pentane. The organic layer was dried over filtered silica and the solvent removed in a vacuum to yield 6-phenyl, 6-(but-3-enyl) fulvene.
Reaction SMILES: Cl.[CH3:2][C:3]([N+:13]([O-])=O)([CH3:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]>CCO.O.[Zn]>[NH2:13][C:3]([CH3:12])([CH3:2])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]
Reactant: CC(C)(C(O)c1ccccc1)[N+](=O)[O-]
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: CC(C)(N)C(O)c1ccccc1
Reaction time: 4 h

Procedure:
37% Hydrochloric acid (1 mL) was added to a stirred solution of 2-methyl-2-nitro-1-phenylpropan-1-ol (26c, 0.12 g, 0.6 mmol in EtOH (10 mL) and water (5 mL). Zinc powder (0.241 g, 3.6 mmol) was slowly added in small portions, the mixture was stirred for 4 hours at +70° C. The mixture was filtered to remove solid zinc residues and concentrated to ⅓ volume by evaporation, diluted with water (50 mL) and washed with ether (125 mL). The acidic waterphase was made basic using KOH (aq) solution, the formed slurry was extracted with ether (3×150 mL). The organic phase was dried (MgSO4) filtered and evaporated. The crude product was further purified by HPLC. Yield 60 mg (60%).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]2([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[S:14](=[O:22])(=[O:21])[NH:13]2)[CH2:9]1)C1C=CC=CC=1.C(O)=O>CO.[Pd]>[NH:8]1[CH2:12][CH2:11][C:10]2([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[S:14](=[O:22])(=[O:21])[NH:13]2)[CH2:9]1
Reactant: O=S1(=O)NC2(CCN(Cc3ccccc3)C2)c2ccccc21
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: O=S1(=O)NC2(CCNC2)c2ccccc21
Yield: 41.3 %

Procedure:
To a solution of 1′-benzylspiro[1,2-benzisothiazole-3,3′-pyrrolidine]1,1-dioxide (170 mg, 0.00054 mol) in methanol were added Pd black (150 mg) and formic acid (0.2 mL, 0.005 mol). The resulting reaction mixture was refluxed overnight, then cooled to r.m., and then filtered and concentrated to give the desired compound (50 mg, 42% Yield). MS (ESI): 225.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:27][C:26]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[C:31]#[N:32])=[CH:25][C:24](=O)[O:23]1>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]=1[NH:19][C:24](=[O:23])[CH2:25][C:26]([C:28]1[CH:35]=[CH:34][CH:33]=[C:30]([C:31]#[N:32])[CH:29]=1)=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccco2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccco2)cc1NC(=O)CC(=O)c1cccc(C#N)c1

Procedure:
Prepared from (2-amino-4-furan-2-yl-phenyl)-carbamic acid tert.-butyl ester (Example G7) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. Obtained as a beige powder (271 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:4]=1[NH:5][C:6]1[NH:7][C:8](=[O:17])[C:9]([C:12]([O:14]CC)=[O:13])=[CH:10][N:11]=1.[OH-].[Na+].O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:4]=1[NH:5][C:6]1[NH:7][C:8](=[O:17])[C:9]([C:12]([OH:14])=[O:13])=[CH:10][N:11]=1
Reactant: CCOC(=O)c1cnc(Nc2cc(OC)ccc2OC)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(OC)c(Nc2ncc(C(=O)O)c(=O)[nH]2)c1
Reaction time: 1 h
Yield: 67.6 %

Procedure:
Ethyl 1,6-dihydro-2-(2,5-dimethoxyanilino)-6-oxo-5-pyrimidinecarboxylate (6 g) and sodium hydroxide (2 g) are added to water (100 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic acid, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate is collected by filtration and added to water (50 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the resulting product is collected by filtration and dried at 80° C. under reduced pressure to give 1,6-dihydro-2-(2,5-dimethoxyanilino)-6-oxo-5-pyrimidinecarboxylic acid (3.7 g). M.p. 260°-262° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11](Cl)(=[O:13])=[O:12])[C:7](=[O:15])[CH:6]([CH3:16])[CH2:5]2.[NH3:17]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11](=[O:13])(=[O:12])[NH2:17])[C:7](=[O:15])[CH:6]([CH3:16])[CH2:5]2
Reactant: CC1Cc2cc(Cl)c(S(=O)(=O)Cl)cc2C1=O
Reactant: N
Product: CC1Cc2cc(Cl)c(S(N)(=O)=O)cc2C1=O

Procedure:
According to Example 1 (d), the reaction of 5-chloro-6-chlorosulfonyl-2-methyl-1-indanone with liquid ammonia yields the raw product having a melting point of from 180° to 184° C. After recrystallization from ethanol, the compound melts at 190° to 192° C.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.CS(O)(=O)=O.[NH2:32][CH2:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[C:39](=[O:43])[N:38]([CH:44]1[CH2:49][CH2:48][C:47](=[O:50])[NH:46][C:45]1=[O:51])[C:37]2=[O:52].CCOC(C)=O>CN(C)C=O>[O:51]=[C:45]1[CH:44]([N:38]2[C:37](=[O:52])[C:36]3[C:40](=[CH:41][CH:42]=[C:34]([CH2:33][NH:32][C:12]([C:9]4[CH:8]=[CH:7][C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[CH:11][N:10]=4)=[O:14])[CH:35]=3)[C:39]2=[O:43])[CH2:49][CH2:48][C:47](=[O:50])[NH:46]1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCS(=O)(=O)c1ccc(C(=O)O)nc1
Agent: CS(=O)(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)nc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 32.3 %

Procedure:
A stirred mixture of 5-ethanesulfonyl-pyridine-2-carboxylic acid (0.34 g, 1.60 mmol) and CDI (0.27 g, 1.70 mmol) in N,N-dimethylformamide (15 mL) was heated to 40° C. under nitrogen. After 2 h, 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione methane sulfonate (0.61 g, 1.60 mmol) was added and the mixture was heated at 40° C. for 2 h. The mixture was cooled to rt and EtOAc (75 mL) was added. The organic layer was washed with sat. aq. NaHCO3 (3×75 mL) then concentrated in vacuo. The crude residue was purified by column chromatography (EtOAc/hexanes, gradient, product eluted at 80-90% EtOAc). The product fractions were combined and concentrated to give 5-ethanesulfonyl-pyridine-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.25 g, 32% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 6.15 min (96.20%); mp: 265-267° C.; 1H NMR (DMSO-d6) δ 1.15 (t, J=7.4 Hz, 3H), 2.00-2.20 (m, 1H), 2.52-2.67 (m, 2H), 2.77-3.01 (m, 1H), 3.48 (q, J=7.4 Hz, 2H), 4.69 (d, J=6.2 Hz, 2H), 5.14 (dd, J=5.4, 12.7 Hz, 1H), 7.73-8.04 (m, 3H), 8.29 (d, J=8.3 Hz, 1H), 8.49 (dd, J=2.3, 8.1 Hz, 1H), 9.10 (d, J=1.7 Hz, 1H), 9.86 (t, J=6.3 Hz, 1H), 11.12 (s, 1H); 13C NMR (DMSO-d6) δ 6.83, 21.99, 30.93, 42.58, 49.01, 49.34, 122.17, 122.68, 123.54, 129.87, 131.59, 133.63, 137.04, 138.13, 147.09, 147.60, 153.38, 163.02, 166.97, 167.12, 169.80, 172.72; LCMS: MH=485; Anal Calcd for C22H20N4O7S: C, 54.54; H, 4.16; N, 11.56. Found: C, 54.82; H, 3.92; N, 11.57.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6](F)[CH:5]=[CH:4][N:3]=1.[CH:9]([C@H:12]1[CH2:16][O:15][C:14](=[O:17])[NH:13]1)([CH3:11])[CH3:10].[H-].[Na+]>CN(C=O)C.O>[F:1][C:2]1[N:7]=[C:6]([N:13]2[C@@H:12]([CH:9]([CH3:11])[CH3:10])[CH2:16][O:15][C:14]2=[O:17])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: Fc1ccnc(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(F)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.6 %

Procedure:
A solution of 2,4-difluoropyrimidine (3.5 mL, 41 mmol) and (S)-4-isopropyloxazolidin-2-one (5.3 g 41 mmol) in 30 mL DMF was cooled to 0° C. under N2 atmosphere. NaH (2.1 g of 60% suspension, 53 mmol) was slowly added. Bubbling exotherm observed. Internal temp was kept below 5° C. After 5 minutes, cold bath was removed. Reaction mixture (a sandy suspension) was allowed to warm to room temp and stir 18 h. The reaction mixture was diluted with water (100 mL) and extracted with (3×75 mL) EtOAc. Organic layer was washed with 50 mL each water, and brine. Dried over Na2SO4, and concentrated on silica gel in vacuo. Column chromatography (EtOAc/heptane 10 to 100% gradient) gave 3.1 g (S)-3-(2-fluoropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (IV) as a crystalline white solid (33%). 1H NMR (400 MHz, CDCl3) δ 8.50 (dd, J=5.8, 2.2 Hz, 1H), 8.19 (dd, J=5.8, 3.8 Hz, 1H), 4.79 (dt, J=8.1, 3.5 Hz, 1H), 4.48-4.34 (m, 2H), 2.64 (heptd, J=7.0, 3.6 Hz, 1H), 1.01 (d, J=7.0 Hz, 3H), 0.90 (d, J=6.9 Hz, 3H). MS m/z 471.8 and 471.8 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[CH:10]=[O:11].[C:12]1([CH3:20])[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1>O1CCCC1>[CH3:20][C:12]1[CH:17]=[CH:16][C:15]([CH:10]([C:2]2[NH:1][C:5]3=[CH:6][N:7]=[CH:8][CH:9]=[C:4]3[CH:3]=2)[OH:11])=[CH:14][CH:13]=1
Reactant: O=Cc1cc2ccncc2[nH]1
Reactant: Cc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: Cc1ccc(C(O)c2cc3ccncc3[nH]2)cc1
Reaction time: 3 h
Yield: 77 %

Procedure:
1H-pyrrolo[2,3-c]pyridine-2-carboxaldehyde (180 mg, 1.23 mmol) was dissolved in tetrahydrofuran (6 mL) under a nitrogen atmosphere. p-Tolylmagnesium bromide in tetrahydrofuran (2.48 mL, 2.48 mmol) was added dropwise. After stirring for 3 h, the reaction mixture was quenched by pouring into a 2:1 solution of saturated ammonium chloride and water, then extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with water and then brine, dried over sodium sulfate, and concentrated to provide the crude material. Purification by Biotage chromatography (silica, 0 to 18% methanol in methylene chloride) to provide (4-methylphenyl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methanol (226 mg, 77%) as an off-white solid: mp 78-82° C.; 1H NMR (500 MHz, CD3OD) δ2.32 (3H, s), 5.95 (1H, s), 6.36 (1H, s), 7.17 (2H, d, J=7.9 Hz), 7.34 (2H, d, 8.0 Hz), 7.51 (1H, m), 8.00 (1H, d, J=5.6 Hz), 8.59 (1H, s); ESI MS m/z 239 [C15H14N2+H]+; HPLC (Method A) >99% (AUC), tR=15.1 min.
Reaction SMILES: [OH-].[Na+:2].O.O.[Na+].[OH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O-:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.O.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[Na+:2].[CH2:18]([O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O-:16])(=[O:14])=[O:15])=[CH:9][CH:8]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=S(=O)([O-])c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=S(=O)([O-])c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Aqueous NaOH (40 mL of a 15% aqueous solution, 150 mmol) is added to 20 g (86.2 mmol) of 4-hydroxybenzenesulfonic acid sodium salt dihydrate at RT. An additional 20 mL of water is added, and the mixture is warmed slightly to dissolve the salt. Benzyl bromide (19.2 g, 112.1 mmol) in 8 mL of ethanol is then added in several portions. The mixture is heated to reflux. After 30 min, additional 20 mL of water is added, and heating is continued for 3.5 h, followed by continued stirring at RT overnight. After cooling in the refrigerator for 3 h, the solid product is collected by filtration and washed with water (20 mL), ethanol (40 mL), and ether (40 mL) and then dried overnight under vacuum to give 4-benzyloxybenzenesulfonic acid sodium salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.[O:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:10](=[O:12])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: c1ccoc1
Reactant: COc1cccc(CC(=O)O)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(CC(=O)c2ccco2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
3-Methoxyphenylacetic acid (20 g, 120.35 mmol) was dissolved in CH2Cl2 (200 mL), and furan (24.6 g, 361.39 mmol) and trifluoroacetic anhydride (37.8 g, 180 mmol) were added to the solution. The reaction was kept being stirred overnight at room temperature. The reaction was quenched with saturated NaHCO3 to pH=6.9, and the organic reagent in the mixture was evaporated. The residue was extracted with EtOAc, and the organic layer was washed with brine, dried over MgSO4, and evaporated. The resulting residue was purified by chromatography on a silica gel column using hexane-EtOAc as eluent to give 1-(furan-2-yl)-2-(3-methoxyphenyl)ethan-1-one as yellow oil: 20 g (yield: 77%)
Reaction SMILES: C(O)(=O)C.Cl.C([CH2:9][C:10]1(C)[C:23](=[O:24])[C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][C:13]=2[CH2:12][CH2:11]1)(O)=O>O>[CH3:9][CH:10]1[C:23](=[O:24])[C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][C:13]=2[CH2:12][CH2:11]1
Reactant: CC1(CC(=O)O)CCc2ccc3ccccc3c2C1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC1CCc2ccc3ccccc3c2C1=O
Yield: 95 %

Procedure:
In a 1-neck 500 ml flask topped with a reflux condenser 250 ml of acetic acid, 50 ml of conc. hydrochloric acid and 50 ml of water were mixed together. To this mixture was added 27.7 g (0.0846 mole) of 3-carboxymethyl-3methyl-1,2,3,4-tetrahydro-4-phenanthron and the reaction mixture was refluxed for 31/2 hours under nitrogen. The mixture was diluted with 300 ml water and cooled in the refrigerator overnight. Next morning offwhite solids were collected by filtration, washed with water and dried under vacuum to give 16.9 g (95.02% by weight yield) of 3-methyl-1,2,3,4-tetrahydro-4-phenanthrone as an off-white solid. M.P. 61°-63° C.; M/e 211; λmax 309 (6,970) methanol.
Reaction SMILES: C(N(CC)CC)C.[C:8]([OH:31])(=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(Cl)(=O)OCC.[C:38](O)(=[O:46])[C:39]1[C:40](=[CH:42][CH:43]=[CH:44][CH:45]=1)[NH2:41]>C(Cl)Cl>[CH2:9]([C:8]1[O:31][C:38](=[O:46])[C:39]2[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=2[N:41]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: Nc1ccccc1C(=O)O
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCCCCc1nc2ccccc2c(=O)o1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 74.5 %

Procedure:
Triethylamine (1.58 ml) was added to a suspension of behenic acid (3.51 g) in methylene chloride (35 ml). Then, ethyl chlorocarbonate (1.08 ml) was dropwise added to the mixture while being cooled with ice. After being stirred for 1.5 hours at 0° C., the mixture, with a mixed solution of anthranilic acid (1.42 g) and triethylamine (1.44 ml) in methylene chloride (7 ml) dropwise added thereto, was stirred for 3 hour at 0° C. and for 15 hours at room temperature successively, and then cooled with ice. The reaction mixture, with triethylamine (1.58 ml) and ethyl chlorocarbonate (1.08 ml) dropwise added thereto, was stirred for 1 hour at 0° C. and for 2.5 hours at room temperature successively, and then concentrated. The residue, with chloroform added thereto, was washed with water and saturated brine successively. The organic layer was dried over sodium sulfate anhydride, and then concentrated. The residue was purified by silica gel column chromatography (silica gel 100 g, hexane-chloroform), thereby yielding 3.39 g of the aimed compound as colorless solid.
Reaction SMILES: C([NH:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:10]1[F:22])C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[NH2:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:11][C@H:10]1[F:22]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NCc2ccccc2)[C@H](F)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](F)C1

Procedure:
Tert-butyl (3R,4S)-4-benzylamino-3-fluoro-piperidine-1-carboxylate (2.13 g) is suspended in THF and mixed with a spatula tip of Pd(OH)2 and hydrogenated under H2 pressure (7 bar). For working up the catalyst is filtered off and the solvent is eliminated in vacuo and the residue is used in the next step without any further purification.