Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]=[C:12]=S)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(N=C=NC(C)C)(C)C.[NH2:23][C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][C:33]=1[NH:34][CH2:35][CH2:36][CH2:37][N:38]([CH3:47])[CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1)[C:27]([O:29][CH3:30])=[O:28]>O1CCCC1>[CH3:30][O:29][C:27]([C:26]1[CH:31]=[CH:32][C:33]2[N:34]([CH2:35][CH2:36][CH2:37][N:38]([CH3:47])[CH2:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=3)[C:12]([NH:11][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)=[N:23][C:24]=2[CH:25]=1)=[O:28]
Reactant: COc1cc(N=C=S)cc(OC)c1
Reactant: COC(=O)c1ccc(NCCCN(C)CCc2ccccn2)c(N)c1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)nc(Nc1cc(OC)cc(OC)c1)n2CCCN(C)CCc1ccccn1
Temperature: 25 °C
Yield: 76 %

Procedure:
3,5 dimethoxyphenylisothiocyanate (571 mg, 1 eq) and diisopropylcarbodiimide (1.35 ml, 4 eq) are added successively to a solution of methyl 3-amino-4-({3-[methyl(2-pyridin-2-ylethyl)amino]propyl}amino)benzoate (1.0 g, 1 eq) in tetrahydrofuran (10 ml). The mixture is heated under reflux for 18 hours then cooled down to ambient temperature and concentrated under reduced pressure at 40° C. The residue is taken up in ethyl acetate (100 ml) and water (40 ml). After decanting and extracting, the combined organic phases are washed with salt water, dried over Na2SO4 then evaporated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent: dichloromethane/methanol 99:1 to 98:2) produces the expected compound in the form of a beige foam (1.12 g; 76% yield).
Reaction SMILES: C(OC(=O)[N:7]([CH2:27][C:28]1[CH:37]=[CH:36][C:31]2[O:32][CH2:33][CH2:34][O:35][C:30]=2[CH:29]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][C:17]2=[O:26])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:32]1[C:31]2[CH:36]=[CH:37][C:28]([CH2:27][NH:7][CH:8]3[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=[CH:18][C:17]4=[O:26])[CH2:10][CH2:9]3)=[CH:29][C:30]=2[O:35][CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cnc3ccccc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1cnc2ccccc2n1CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
To 3 mL of a dichloromethane solution containing 0.21 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 3 mL of trifluoroacetic acid was added and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, chloroform and water were added, and adjusted to pH 13 with 20% aqueous sodium hydroxide solution. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 0.16 g of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)quinoxalin-2(1H)-one as a light brown oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:21])[NH:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:22]([O:28][CH2:29]Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].Cl.CN([CH:35]=[O:36])C>C(OCC)(=O)C>[CH2:3]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:21])[N:16]([CH2:29][O:28][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[N:18]2)=[CH:13][C:12]=1[O:36][CH3:35])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Reactant: CN(C)C=O
Reactant: CC(C)(C)C(=O)OCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCc1ccccc1
Reaction time: 1.5 h
Yield: 84 %

Procedure:
Sodium hydride (1.44 g of a 60% suspension in mineral oil, 36 mmol) was added in portions over 20 minutes to a solution of 7-benzyloxy-3,4-dihydroquinazolin-4-one (8.46 g, 30 mmol), (prepared as described for the starting material in Example 70), in DMF (70 ml) and the mixture stirred for 1.5 hours. Chloromethyl pivalate (5.65 g, 37.5 mmol) was added dropwise and the mixture stirred 2 hours at ambient temperature. The mixture was diluted with ethyl acetate (100 ml) and poured onto ice/water (400 ml) and 2M hydrochloric acid (4 ml). The organic layer was separated and the aqueous layer extracted with ethyl acetate, the combined extracts were washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with a mixture of ether and petroleum ether, the solid was collected by filtration and dried under vacuum to give 7-benzyloxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (10 g, 84%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[K+].Cl>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:10]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCc1ccccc1
Reactant: CCc1ccccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCc1ccccc1OCc1ccccc1
Reaction time: 3 h

Procedure:
To a reactor were charged 8.77 g (71 mmol) of 2-ethylphenol, 10.00 g (79 mmol) of benzyl chloride, 8.06 g (144 mmol) of KOH, and 30 g of DMF, and the mixture was stirred at 65° C. to 85° C. for 3 hours. To this mixture, 55 g of hydrochloric acid and 50 g of toluene were added, the organic layer was washed with water, and the solvent was evaporated. The residue was purified by column chromatography (n-hexane) to yield the desired product, 1-benzyloxy-2-ethylbenzene, as colorless liquid (9.23 g, Yield: 61%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH:18]=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18][NH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.9 %

Procedure:
A solution of tert-butyl 3-aminopyrrolidine-1-carboxylate (1.5 g; 8.05 mmol; 1.00 eq and 3,4-dichlorobenzaldehyde (1339.00 mg; 7.65 mmol; 0.95 eq.) in methanol (10.00 ml) and acetic acid (1.00 ml) was stirred for 30 minutes at ambient temperature, then sodium cyanoborohydride (9.66 ml; 9.66 mmol; 1.20 eq.) was added. The reaction mixture was stirred for an additional 12 hours at ambient temperature at which time the reaction was quenched by pouring into aqueous ammonia (30 mL). The resulting inorganic precipitate was filtered off, and washed with dichloromethane (50 mL). The organic layer was separated and the remaining aqueous layer was extracted with dichloromethane (50 mL×3). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The resultant oil is purified under flash chromatography using silicon column with gradient of ethyl acetate in hexanes to afford the desired intermediate, tert-Butyl 3-((3,4-dichlorobenzyl)amino)pyrrolidine-1-carboxylate (2.47 g; 7.16 mmol; 88.9%), as a clear viscous oil. LC-MS (M+H=346, obsd.=288 (M-57))
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([NH2:19])=[O:18].Cl.C(NCCCN=C=NCC)C.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([NH:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([NH2:19])=[O:18])=[O:10])=[CH:11][CH:12]=1
Reactant: O=C(O)COc1ccc(Br)cc1
Reactant: NC(=O)c1cccc(N)c1
Agent: CCN=C=NCCCNCC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(NC(=O)COc2ccc(Br)cc2)c1
Reaction time: 8 h
Yield: 21.5 %

Procedure:
To a mixture of (4-bromo-phenoxyacetic acid (392.5 mg, 1.8 mmol), 3-amino-benzamide (408.2 mg, 3.0 mmol), N-(3-ethylaminopropyl)-N′-ethyl carbodiimide HCl (EDC) (517.6 mg, 2.7 mmol) and 1-hydroxybenzotriazole (HOBt) (365.3 mg, 2.7 mmol) in DMF (18 mL) was added N,N-diisopropylethylamine, redistilled (DIPEA) (0.47 ml, 2.7 mmol). The mixture was stirred overnight and then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by recrystallization from the mixture of Ethyl acetate and MeOH to give 3-[2-(4-bromo-phenoxy)acetyl-amino]-benzamide as a white solid (134.9 mg, 21.52% yield).
Reaction SMILES: O[C:2]1([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][C:5]2[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:4]=2[CH2:3]1.Cl>CC(O)=O.[Pd]>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:4]2[CH2:3][CH:2]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH2:6][C:5]=2[CH:13]=1
Reactant: CCOC(=O)CC1(O)Cc2ccc(OC)cc2Cc2ccccc21
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)CC1Cc2ccc(OC)cc2Cc2ccccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.3 %

Procedure:
10% Pd/C (242 mg, 0.23 mmol) was added to a solution of ethyl (±)-10,11-dihydro-10-hydroxy-3-methoxy-5H-dibenzo[a,d]cycloheptene-10-acetate (741.1 mg, 2.27 mmol) and conc. HCl (0.19 mL, 2.27 mmol) in glacial AcOH (23 mL), and the mixture was shaken on a Parr apparatus at RT under H2 (50 psi). After 6 h, the reaction was filtered through celite®, and the filter pad was washed with EtOAc. The filtrate was concentrated, and the residue was reconcentrated from toluene. The resulting faintly yellow, oily residue was chromatographed (silica gel, 20% EtOAc/hexanes) to afford the title compound as a colorless oil (643.6 mg, 91%): TLC Rf 0.57 (20% EtOAc/hexanes); 1H NMR (250 Hz, CDCl3) δ 7.05-7.22 (m, 4H), 7.01 (d, J=8.2 Hz, 1H), 6.76 (d, J=2.7 Hz, 1H), 6.67 (dd, J=8.2, 2.7 Hz, 1H), 4.30 (d, J=15.0Hz, 1H), 4.11-4.25 (m, 2H), 3.85 (d, J=15.0 Hz, 1H),3.70-3.90 (m, 1H), 3.77 (s, 3H), 3.31 (dd, J=15.0,4.1 Hz, 1H), 2.93 (dd, J=15.0, 9.2 Hz, 1H), 2.64 (dd, J=15.6, 5.0Hz, 1H), 2.52 (dd, J=15.6, 9.3 Hz, 1H), 1.27 (t, J=7.1 Hz, 3H); FTIR (CCl4) 1734, 1611, 1504, 1285,1263, 1155, 1044cm-1 ;MS (ES) m/e 333.0 (M+Na)+, 328.0 (M+NH4)+, 311.0 (M+H)+, 265.0 (M+H-EtOH)+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.[NH2:26][CH2:27][CH2:28][SH:29].B(F)(F)F>O1CCCC1>[S:29]1[C:2]2([CH2:7][CH2:6][N:5]([C:8]3[CH:13]=[CH:12][C:11]([N:14]4[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]4=[O:24])=[CH:10][C:9]=3[F:25])[CH2:4][CH2:3]2)[NH:26][CH2:27][CH2:28]1
Reactant: NCCS
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Agent: FB(F)F
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)NCCS4)c(F)c2)C(=O)O1
Yield: 68 %

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(4-oxo-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.0 mmol), 2-aminoethanethiol (1.0 mmol) and BF3.etherate (2.0 mmol) in tetrahydrofuran (10 ml) at a temperature 65° C. for 12 hours in 68% yield.
Reaction SMILES: [F:1][C:2]1[C:3]([C:14](Cl)=[N:15][OH:16])=[CH:4][C:5]2[C:9]([CH3:11])([CH3:10])[O:8][B:7]([OH:12])[C:6]=2[CH:13]=1.[Cl:18][C:19]1[CH:24]=[C:23]([C:25]([C:27]([F:30])([F:29])[F:28])=[CH2:26])[CH:22]=[C:21]([Cl:31])[CH:20]=1>CN(C=O)C>[Cl:18][C:19]1[CH:24]=[C:23]([C:25]2([C:27]([F:30])([F:28])[F:29])[O:16][N:15]=[C:14]([C:3]3[C:2]([F:1])=[CH:13][C:6]4[B:7]([OH:12])[O:8][C:9]([CH3:11])([CH3:10])[C:5]=4[CH:4]=3)[CH2:26]2)[CH:22]=[C:21]([Cl:31])[CH:20]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CC1(C)OB(O)c2cc(F)c(C(Cl)=NO)cc21
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2cc(F)c(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 25.4 %

Procedure:
To a solution of the crude compound 6-fluoro-N,1-dihydroxy-3,3-dimethyl-1,3-dihydro benzo[c][1,2]oxaborole-5-carbimidoyl chloride (300 mg, 0.92 mmol) and 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (222 mg, 0.92 mmol) in DMF (5 mL) at rt was added TEA (152 μL, 1.1 mmol). The reaction mixture was stirred for 12 h, poured into ice-water and extracted with DCM (60 mL×3). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC eluted with PE-EA (3:2) and then purified by combiflash to give the title compound 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)-6-fluoro-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (108 mg; yield 29% over 3 steps) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.379 (s, 1H), 7.815-7.848 (m, 2H), 7.660 (s, 2H), 7.513 (d, J=10.0 Hz, 1H), 4.401 (d, J=18.4 Hz, 1H), 4.254 (d, J=18.8 Hz, 1H), 1.485 (s, 6H) ppm; HPLC purity: 100% at 220 nm and 100% at 254 nm; MS: m/z=462.0 (M+1, ESI+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH:30]1([CH2:36][CH2:37]O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.Cl.[K+].[Br-]>C(Cl)(Cl)Cl>[CH:30]1([CH2:36][CH2:37][O:24][C:23]([C:18]2([C:20]([O:22][CH2:9][CH2:8][CH:4]3[CH2:5][CH2:6][CH2:7][CH2:2][CH2:3]3)=[O:21])[O:17][C:16]3[CH:26]=[CH:27][C:13]([CH2:12][CH:11]([NH:10][CH2:9][CH:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[OH:29])[CH3:28])=[CH:14][C:15]=3[O:19]2)=[O:25])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: OCCC1CCCCC1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(Cc1ccc2c(c1)OC(C(=O)OCCC1CCCCC1)(C(=O)OCCC1CCCCC1)O2)NCC(O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 2-cyclohexylethanol according to the procedure of Example 30 as an off-white foam (HCl salt); 1H NMR (CDCl3) δ 0.80-1.80 (m, 26H), 1.32 (d, J=6.3 Hz, 3H), 2.80 (m, 1H), 3.18 (m, 2H), 3.48 (m, 2H), 4.32 (t, J=6.9 Hz, 4H), 5.45 (bd, J=9.7 Hz, 1H), 6.80 (m, 3 H), 7.25 (m, 2H), 7.45 (s, 1H), 8.70 (bs, 1H), 10.0 (bs, 1H); IR (KBr): 1765 cm-1 (C=O); MS (CI) m/z 642 (MH+); [α]D25 -24° (c, 1.0, CHCl3). Anal. Calcd. for C36H48ClNO7 ·HCl: C, 63.71; H, 7.13; N, 2.06; Cl, 10.45. Found: C, 63.07; H, 7.54; N, 2.07; Cl, 12.81.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:11]([C:12]2[S:13][C:14]3[CH2:15][NH:16][CH2:17][CH2:18][C:19]=3[N:20]=2)[N:10]=[C:9]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[S:8]1)=[N+:2]=[N-:3].C=O.[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>ClCCCl>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:11]([C:12]2[S:13][C:14]3[CH2:15][N:16]([CH3:37])[CH2:17][CH2:18][C:19]=3[N:20]=2)[N:10]=[C:9]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[S:8]1)=[N+:2]=[N-:3]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1c1nc2c(s1)CNCC2
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: CN1CCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCCN=[N+]=[N-])c3ccccc3)sc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a solution of 2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (0.050 g, 0.100 mmol) in 1 mL DCE was added formaldehyde (0.033 g, 37 wt % in water, 0.401 mmol) followed by sodium triacetoxyborohydride (0.023 g, 0.110 mmol). The resulting suspension was stirred vigorously at room temperature overnight then was treated with saturated Na2CO3 solution (10 mL) and stirred for 10 minutes. The mixture was extracted with EtOAc (3×10 mL) and the combined organic phases were washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (0-3% MeOH/DCM) to afford the desired product as a yellow foam (0.046 g, 89%).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([F:17])=[CH:13][CH:14]=2)[C:9]1=[O:18])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([F:17])=[CH:13][CH:14]=2)[C:9]1=[O:18]
Reactant: CC=CCC1Cc2ccc(F)cc2C1=O
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: O=CCC1Cc2ccc(F)cc2C1=O
Reaction time: 1.67 h
Yield: 92 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 100 minutes while stirring through a solution, cooled to -70°, of 18.9 g of (RS)-2-(2-buten-1-yl)-6-fluoro-1-indanone in 300 ml of anhydrous dichloro-methane and 60 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 102 ml of dimethyl sulfide, the mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated in a vacuum, the residue was treated with 300 ml of dichloromethane and, after the addition of 43 ml of water and 43 ml of trifluoroacetic acid, stirred at room temperature for 3 hours. The mixture was subsequently poured into 200 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 100 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 200 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate, concentrated in a vacuum and the crude product obtained was crystallized from diethyl ether/hexane. 16.5 g (92%) of (RS)-2-(2-oxo-ethyl)-6-fluoro-1-indanone were obtained as a white solid with m.p. 62°.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]#[N:29])[CH:23]=3)=[CH:17][C:16]=2[F:30])=[O:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=[O:32].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+]>CC(C)=O.O>[C:1]([C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:13])[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]([NH2:29])=[O:32])[CH:23]=3)=[CH:17][C:16]=2[F:30])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc(C#N)c3)cc2F)ncn1
Agent: OO
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)cc2F)ncn1
Temperature: 60 °C
Reaction time: 16 h
Yield: 42.4 %

Procedure:
A mixture of 1-(6-tert-butylpyrimidin-4-yl)-3-[4-(2-cyanopyridin-4-yloxy)-2-fluoro-phenyl]urea (141 mg, 0.35 mmol) and sodium percarbonate (with 25% H2O2) (218 mg, 1.4 mmol, 4.0 eq) in 2:1 v/v acetone/water (11 mL) was stirred at 60° C. for 16 h. The reaction was partitioned between ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. Trituration from methanol afforded the title compound (63 mg, 43%) as a white solid. 1H-NMR (DMSO-d6) 10.32 (broad s, 1H), 10.08 (broad s, 1H), 8.75 (d, J=1.2 Hz, 1H), 8.51 (d, J=5.4 Hz, 1H), 8.23 (t, J=9.3 Hz, 1H), 8.12 (broad s, 1H), 7.71 (broad s, 1H), 7.61 (d, J=1.2 Hz, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.36 (dd, J=11.4, 2.4 Hz, 1H), 7.18 (dd, J=5.7, 2.7 Hz, 1H), 7.08 (ddd, J=9.0, 2.7, 1.5 Hz, 1H), 1.26 (s, 9H); LC-MS m/z 425 [M+H]+, RT=3.16 min.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)(=[O:3])[CH3:2].[CH3:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][C:16]=1[CH:24]=O.N1CCCCC1>C(O)C>[C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[CH:24][C:16]1[NH:17][C:18]2[C:23]([C:15]=1[CH3:14])=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:3])[CH3:2]
Reactant: Cc1c(C=O)[nH]c2ccccc12
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(=O)c1ccc2c(c1)C(=Cc1[nH]c3ccccc3c1C)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
A mixture of 5-acetyl-2-oxindole (70 mg), 3-methylindole-2-carbaldehyde (56 mg) (prepared according to Synthetic Communications, 1986, 16, 1799) and piperidine (30 mg) in ethanol (1 mL) was held in a sealed tube at 90° C. overnight. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum to give 83 mg (75% yield) of 5-acetyl-3-(3-methyl-1H-indol-2-ylmethylene)-1,3-dihydro-indol-2-one.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH2:21][CH:20]([N:22](OC)[CH3:23])[CH2:19][CH2:18][N:13]3[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:4][CH:3]=1>C(O)(=O)C.O.[Zn]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH2:21][CH:20]([NH:22][CH3:23])[CH2:19][CH2:18][N:13]3[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:26][CH:27]=1
Reactant: CON(C)C1CCn2c(nc(C(=O)NCc3ccc(F)cc3)c(O)c2=O)C1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CNC1CCn2c(nc(C(=O)NCc3ccc(F)cc3)c(O)c2=O)C1

Procedure:
To a solution of crude N-(4-fluorobenzyl)-3-hydroxy-8-[methoxy(methyl)amino]-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide in acetic acid/water (2:1) was added zinc dust (300% in weight). The mixture was stirred at room temperature and after 1.5 h further zinc dust (300% in weight) was added. After 24 h zinc was filtered off and the filtrate was concentrated to dryness. The residue was dissolved in methanol and applied on a SCX resin cartridge. The cartridge was washed with water and methanol and then eluted with ammonia in methanol (2N). The eluent was concentrated to dryness. The crude product so obtained was used in the subsequent step without further purification.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[Cl:9][C:10]([Cl:15])([Cl:14])[CH:11](O)O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:9][C:10]([Cl:15])([Cl:14])[C@@H:11]1[N:1]2[CH2:8][CH2:7][CH2:6][C@H:2]2[C:3](=[O:5])[O:4]1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: OC(O)C(Cl)(Cl)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@H]12
Yield: 62.5 %

Procedure:
A suspension of L-proline (10.0 g, 87.0 mmol) and chloral hydrate (21.6 g, 130 mmol) in chloroform (100 mL) was heated at reflux for 6 h under a soxlet adapter charged with sodium sulfate. The cooled mixture was washed with water (2×), dried (MgSO4) and concentrated in vacuo. The product was recrystalised from boiling absolute ethanol to give the title compound as white needles (13.3 g, 63%). 1H NMR (400 MHz, CDCl3): 1.65-1.83 (1H, m), 1.86-2.01 (1H, m), 2.04-2.31 (2H, m), 3.06-3.18 (1H, m), 3.36-3.49 (1H, m), 4.12 (1H, dd, J 4.6, 4.0), 5.16 (1H, s).