Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].CI.[C:10](O)(=[O:12])[CH3:11]>[Pd].C(OC=C)(=O)C>[C:1]([O:4][CH:5]([O:7][C:10](=[O:12])[CH3:11])[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O
Agent: [Pd]
Solvent: C=COC(C)=O
Solvent: CI
Product: CC(=O)OC(C)OC(C)=O
Reaction time: 1.5 h

Procedure:
Into an autoclave were charged 135 g of acetic anhydride, 15 g of methyl iodide and 4.5 g of palladium (5%) supported on barium sulfate (Kawaken Finechemical Co.). The reaction was effected for 90 minutes in the same way as in Example 9. GC analysis showed that 0.415 g of vinyl acetate and 14.0 g of ethylidene diacetate were formed with considerable amount of acetic acid.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([NH2:5])=[NH:4].[Cl:8][C:9](Cl)(Cl)[S:10]Cl>>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]1[N:5]=[C:9]([Cl:8])[S:10][N:4]=1
Reactant: N=C(N)C(Cl)(Cl)Cl
Reactant: ClSC(Cl)(Cl)Cl
Product: Clc1nc(C(Cl)(Cl)Cl)ns1

Procedure:
The reaction between trichloroacetamidine and trichloromethanesulfenyl chloride to produce 3-trichloromethyl-5-chloro-1,2,4-thiadiazole appears to be a complex set of reactions occurring simultaneously which may be represented as follows: ##SPC1##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:27]=[CH:26][CH:25]=[CH:24][C:11]=2[C:12]([NH:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[CH:18]3)=[O:13])[CH:5]=[CH:4][N:3]=1.[C:28](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:27]=[CH:26][CH:25]=[CH:24][C:11]=2[C:12]([NH:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH3:28])[N:19]=[CH:18]3)=[O:13])[CH:5]=[CH:4][N:3]=1.[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:27]=[CH:26][CH:25]=[CH:24][C:11]=2[C:12]([NH:14][C:15]2[CH:23]=[CH:22][C:21]3[C:17](=[CH:18][N:19]([CH3:28])[N:20]=3)[CH:16]=2)=[O:13])[CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1ccc2[nH]ncc2c1)c1ccccc1NCc1ccnc(Br)c1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc2cc(NC(=O)c3ccccc3NCc3ccnc(Br)c3)ccc2n1
Product: Cn1ncc2cc(NC(=O)c3ccccc3NCc3ccnc(Br)c3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %
Yield: 19 %

Procedure:
4.22 g (10 mmol) of 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(1H-indazol-5-yl)-benzamide is mixed in 30 ml of dimethylformamide while being cooled with ice with 3.6 g (11 mmol) of cesium carbonate and 0.68 ml (11 mmol) of methyl iodide, and it is stirred overnight at room temperature. It is then stirred into 250 ml of ice-cold water, stirring is continued for 15 minutes, and it is suctioned off. The filter cake is quickly dried and chromatographed on silica gel with a gradient of ethyl acetate: hexane =1:1 to 100:0 as an eluant. 1.79 g (41% of theory) of 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(1-methyl-1H-indazol-5-yl)-benzamide with a melting point of 173.8° C. as well as 830 mg (19% of theory) of 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-5-yl)-benzamide with a melting point of 183.8° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=3)[CH2:11][CH2:10]2)[N:5]=[N:4][C:3]=1[CH2:25][C:26]#[N:27].[NH2:28]O.C1C[O:33][CH2:32][CH2:31]1>COC(OC)(N(C)C)C>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=3)[CH2:13][CH2:14]2)[N:5]=[N:4][C:3]=1[CH2:25][C:26]1[N:28]=[C:32]([CH3:31])[O:33][N:27]=1
Reactant: C1CCOC1
Reactant: NO
Reactant: Cc1c(CC#N)nnc(N2CCN(c3ccc(C(F)(F)F)cn3)CC2)c1C
Agent: COC(C)(OC)N(C)C
Product: Cc1nc(Cc2nnc(N3CCN(c4ccc(C(F)(F)F)cn4)CC3)c(C)c2C)no1
Yield: 45 %

Procedure:
4,5-Dimethyl-6-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyridazin-3-yl-acetonitrile (120 mg, 0.32 mmol) is combined with hydroxylamine (63 mg, 0.96 mmol) and THF (2 mL). The reaction mixture is heated to reflux for 3 h. Concentrate the reaction and redissolve the residue in dimethylacetamide dimethylacetal (500 μL). Heat this solution for 16 h at reflux. Concentrate the resulting mixture in vacuo. The residue is purified by flash chromatography on silica gel (MeOH/CH2Cl2) to afford the title compound (62.3 mg, 45%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@H:21]([C@@:39]([OH:49])([CH2:43][CH2:44][C:45]([O:47]C)=[O:46])[C:40]([O-:42])=[O:41])/[CH:22]=[CH:23]/[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:38])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:20])[C:14]([O:16]C)=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].C(#N)C.C(N(CC)CC)C.[Br-].[Li+]>O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@H:21]([C@@:39]([OH:49])([CH2:43][CH2:44][C:45]([OH:47])=[O:46])[C:40]([OH:42])=[O:41])/[CH:22]=[CH:23]/[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:38])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:20])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCC(=O)OC)C(=O)[O-])C(=O)OC)cc1
Agent: [Br-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCC(=O)O)C(=O)O)C(=O)O)cc1
Temperature: 50 °C
Yield: 55.7 %

Procedure:
To a mixture of No. 5507802, 5-methyl (S)-2-{(E)-(S)-1-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-10-oxo-heptadec-2-enyl}-2-hydroxy-pentanedioate (18 mg, 0.0262 mmol), acetonitrile (450 μL), and water (9 μL) were added triethylamine (21.9 μL, 0.157 mmol) and lithium bromide (45.6 mg, 0.525 mmol), and the mixture was stirred at 50° C. After confirming the consumption of No. 5507802 by LCMS, 0.1 M hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine, and dried over anhydrous sodium sulfate. The filtrate was then concentrated under reduced pressure. The resulting residue was purified by SP1 (Diol cartridge, 80% ethyl acetate/n-hexane Rf=0.6) to obtain the title compound (9.6 mg, 56% yield, white solid).
Reaction SMILES: [CH3:1][C@H:2]([NH2:11])[C@H:3](O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(N(CC)CC)C>C1COCC1.CCCCCC>[CH3:1][C@@H:2]1[C@@H:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:11]1
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: C[C@H]1N[C@@H]1c1ccccc1
Temperature: 25 °C

Procedure:
To (1R,2S)-(−)-norephedrine (1 g, 6.61 mmol) in THF (20 mL), triphenylphosphine (1.98 ml, 7.94 mmol), diisopropyl azodicarboxylate (1.401 ml, 7.27 mmol) and triethylamine (2.6 ml, 18.8 mmol) was added anr the rm was stirred at room temperature over night. The solvent was evaporated and the crude material was purified on silica eluting with Heptane/EtPAc 1+4 to EtOAc 100% and EtOAc/MeOH 95+5% the fractions containing product were collected giving 2.5 g of with solid containing lot of P(Ph)3O according to LC/MS. This solid was stirred in hexane (50 ml) O/N and than filtered through a pad of Celite 545 giving 0.6 g of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:13]C)[C:10]([CH3:12])([CH3:11])O2)=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:13])[C:10]([CH3:11])([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH3:12])=[CH:6][CH:7]=1
Reactant: COC1(c2ccc(Cl)cc2)OC1(C)C
Reactant: C1COCCN1
Product: CC(C)(C(=O)c1ccc(Cl)cc1)N1CCOCC1

Procedure:
85.1 g (0.4 mol) of 2-(4-chlorophenyl)-3,3-dimethyl-2-methoxyoxirane and 139.4 g (1.6 mols) of morpholine are combined and warmed to reflux temperature. After 22 hours the mixture is cooled and morpholine is removed by distillation. The residue is taken up in ether, and the solution is extracted with dilute hydrochloric acid. The hydrochloric acid solution is rendered alkaline and extracted with ether. The ether solution is dried with Na2SO4 and concentrated. The residue is recrystallised from ethanol.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]#[CH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:13]1[CH:14]=[CH:15][N:16]=[C:17]2[C:22]=1[N:21]=[C:20]([O:23][CH3:24])[CH:19]=[CH:18]2.CC(=O)OCC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][C:10]#[C:11][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[N:21]=2)[N:16]=[CH:15][CH:14]=1)([CH3:5])([CH3:6])[CH3:7]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: COc1ccc2nccc(Br)c2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2nccc(C#CCNC(=O)OC(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 44.3 %

Procedure:
To a solution of N-Boc propargyl amine (3.25 g, 20.9 mmol) and 8-bromo-2-methoxy-[1,5]naphthyridine (5.00 g, 20.9 mmol; prepared as in WO 2006/032466) and TEA (17.5 mL, 6 eq.) in DMF (120 mL) were added Pd(PPh3)2Cl2 (755 mg, 1.08 mmol) and CuI (432 mg, 2.27 mmol). The mixture was degassed with a stream of N2 for 15 min and then stirred at rt for 5 h. The mixture was partitioned between water and EA, the org. layer was washed several times with water and a sat. NH4Cl solution, dried over MgSO4 and concentrated. Chromatography on SiO2 (Hex/EA 1:1, EA) gave the coupling product as a beige solid (2.90 g, 44% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)[NH2:17].Cl.C(=O)(O)[O-].[Na+]>O.C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([NH:17][C:16]2[CH:18]=[CH:19][C:20]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]4[NH:28][CH:29]=[CH:30][C:23]=34)=[C:14]([F:13])[CH:15]=2)[N:3]=1
Reactant: Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Reactant: COC(=O)c1cc(Cl)nc(N)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)nc(N)n1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
0.209 g (1.12 mmol) of methyl 2-amino-6-chloropyrimidine-4-carboxylate (prepared according to G. Doyle Daves, Fred Baiocchi, Roland K. Robins, and C. C. Cheng, J. Org. Chem., 26 (1961), 2755-2763) and 0.4 g (1.12 mmol) of [3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]amine (example XIX) are suspended in 5 ml of water and 5 ml of ethanol. 0.11 ml (1.34 mmol) of 37% strength hydrochloric acid is added. The mixture is stirred at 100° C. for 18 hours. After cooling, the mixture is neutralized using an aqueous saturated sodium bicarbonate solution. The resulting precipitate is filtered off with suction and dried. This gives 0.46 g of product (68% of theory).
Reaction SMILES: OC[C:3]1[CH:39]=[CH:38][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([N:12](C(OC(C)(C)C)=O)[CH2:13][C@H:14]([O:23][Si](CC)(CC)CC)[CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][C:5]=2[CH:4]=1.Cl.[C:41]([O:44][CH2:45]C)(=[O:43])[CH3:42]>>[OH:23][C@H:14]([CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13][NH:12][CH:10]1[CH2:9][CH2:8][CH2:7][C:6]2[CH:38]=[CH:39][C:3]([CH2:45][O:44][C:41](=[O:43])[CH3:42])=[CH:4][C:5]=2[CH2:11]1
Reactant: CCOC(C)=O
Reactant: CC[Si](CC)(CC)O[C@H](COc1ccccc1)CN(C(=O)OC(C)(C)C)C1CCCc2ccc(CO)cc2C1
Agent: Cl
Product: CC(=O)OCc1ccc2c(c1)CC(NC[C@H](O)COc1ccccc1)CCC2

Procedure:
A solution of N-(3-hydroxymethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyl-oxy)propyl]-tert-butoxycarbonylamine (188 mg) in ethyl acetate (2 ml) was treated with 4N hydrogen chloride in ethyl acetate (2 ml) for 3 hours. The mixture was evaporated in vacuo and washed with diethyl ether three times. The residue was triturated in diisopropyl ether, and precipitated powder was collected by filtration to afford 6-[(2S)-2-hydroxy-3-phenoxypropyl]amino-3-acetyloxymethyl-6,7,8,9-tetrahydro-5H-benzocycloheptene (113 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:12])=[CH:7][CH:8]=2)[N:3]=1.[Li]CCCC.CON(C)[C:21](=[O:23])[CH3:22]>C1COCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:21](=[O:23])[CH3:22])[C:6]([F:12])=[CH:7][CH:8]=2)[N:3]=1
Reactant: CON(C)C(C)=O
Reactant: Fc1ccc2ccc(Cl)nc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1c(F)ccc2ccc(Cl)nc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 15.1 %

Procedure:
To a solution of 2-chloro-7-fluoroquinoline (ECA International Corp, Palatine, Ill.; 300 mg, 1.652 mmol) in THF (5.0 mL) at −78° C. was added nBuLi, 1.6 M in hexanes (1.24 mL, 1.98 mmol) slowly dropwise. The solution was stirred at −78° C. for 30 min. A solution of N-methoxy-N-methylacetamide (0.25 mL, 2.48 mmol) in THF (0.5 mL) was added slowly dropwise via syringe. After 10 min, the reaction was warmed to RT. After 15 min, the reaction was quenched by addition of saturated aq. NH4Cl. The reaction was partitioned between saturated NH4Cl and EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by silica gel chromatography, using 0-50% EtOAc/hexane. The pure fractions were combined and concentrated in vacuo to give 1-(2-chloro-7-fluoroquinolin-8-yl)ethanone (56 mg, 0.250 mmol, 15.16% yield): 1H NMR (400 MHz, DMSO-d6) δ ppm 8.57 (d, J=8.6 Hz, 1H), 8.25 (dd, J=9.1, 6.2 Hz, 1H), 7.65-7.74 (m, 2H), 2.68 (s, 3H). m/z (ESI, +ve ion) 224.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[O:20][N:19]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[C:14](=[O:16])[NH:17][C:18]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[O:20][N:19]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: CC(C)(C)OC(=O)N1CCOCC1C(=O)O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCOCC1C(=O)Nc1cc(C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of morpholine-3,4-dicarboxylic acid 4-tert-butyl ester (100 mg; 0.432 mmol) and 3-amino-5-t-butylisoxazole (58.9 mg; 0.42 mmol) in anhydrous pyridine (1.2 mL) is added phosphorous oxychloride (0.039 mL; 0.432 mmol). The reaction mixture is left stirring at room temperature for 1 hour. After this time, the reaction mixture is quenched with saturated NH4Cl aqueous solution and extracted with ethyl acetate twice. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using methanol/methylene chloride provides the title compound, m/z 354 [M+H+].
Reaction SMILES: CCCCCC.C([Li])CCC.C(NC(C)C)(C)C.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][C:28](=[O:32])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].Cl[CH2:34][C:35]1[CH:43]=[CH:42][C:38]2[O:39][CH2:40][O:41][C:37]=2[CH:36]=1.[Cl-].[NH4+]>O1CCCC1>[O:39]1[C:38]2[CH:42]=[CH:43][C:35]([CH2:34][CH:27]3[C:28](=[O:32])[NH:29][CH2:30][CH2:31][N:26]3[C:24]([O:23][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:25])=[CH:36][C:37]=2[O:41][CH2:40]1
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCNC(=O)C1Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
Under argon atmosphere, 17.5 ml of 1.58M n-butyl lithium-n-hexane solution was dropped into a mixture of 25 ml of tetrahydrofuran and 2.78 g of diisopropylamine under cooling ice, followed by 30 minutes' stirring under the same condition. Thereafter a solution of 2.50 g of 1-tert-butoxycarbonyl-3-oxopiperazine (which was prepared by following Tetrahedron Lett., 1980, 21, 3019-3020) in 60 ml of tetrahydrofuran was added by dropping under cooling with ice, followed by 3 hours' stirring under the same condition, further dropping of a solution of 2.30 g of 5-chloromethyl-benzo[1,3]dioxole in 20 ml of tetrahydrofuran under cooling with ice, and an hour's stirring under the same condition. The solution was warmed to room temperature and stirred for 18 hours. After addition of saturated aqueous ammonium chloride solution, the solution was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and the solvent was distilled therefrom under reduced pressure. The residue was purified on silica gel column chromatography (ethyl acetate) to provide 2.84 g (68%) of 2-benzo[1,3]dioxol-5-ylmethyl-1-tert-butoxycarbonyl-3-oxopiperazine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C1COCC1.CCO.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([F:14])=[CH:16][CH:17]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1ccc(Nc2ccnc(Cl)n2)cc1
Temperature: 65 °C
Reaction time: 10 h
Yield: 30.5 %

Procedure:
To a solution of 2,4-dichloropyrimidine (260 g, 1.75 mol) in THF (780 mL) and EtOH (3100 mL) is added NaHCO3 (244 g, 2.91 mol). To the slurry which results is added 4-fluoroaniline (162 g, 1.46 mol) in one portion and the resulting mixture allowed to warm to 65° C. and held at this temperature for 10 hours. The reaction if not completed in a single day can be cooled over night. Re-heating the next day to 70° C. for an additional 10 hours is usually sufficient for completion of the reaction. The reaction solution is diluted with EtOAc (4.5 L) and washed with water (3×2 L). The combined aqueous layers are extracted with EtOAc (3 L). The combined organic layers are dried over MgSO4 and filtered. The filter cake is washed with acetone (2×1 L) then with 5% MeOH/acetone (2×500 mL). The filtrate is concentrated until a thick slurry is obtained (ca. 1 L volume), hexane (3.5 L) is added and the solution cooled to about 4° C. for 16 hours. The thick slurry is collected by filtration, washed with hexane (2×500 mL), and dried (20 mmHg, room temperature) to afford 99.43 g (79.3% yield) of the desired product as a white solid. 1H NMR (300 MHz, CD3OD) δ 8.06 (d, J=6.0 Hz, 1H), 7.59 (m, 2H), 7.11 (m, 2H), 6.64 (d, J=6.0 Hz, 1H); MS (ESI) m/z 224 (M+1).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[C:22]([OH:23])=[C:21]([O:24][CH3:25])[C:20]([O:26][CH3:27])=[CH:19][C:18]=1[CH3:28])(=[O:3])[CH3:2].[O:29]=O>CN(C)C=O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[C:22](=[O:23])[C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[C:19](=[O:29])[C:18]=1[CH3:28])(=[O:3])[CH3:2]
Reactant: O=O
Reactant: COc1cc(C)c(CCCCCCCCCCCCOC(C)=O)c(O)c1OC
Solvent: CN(C)C=O
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCCCOC(C)=O)=C(C)C1=O

Procedure:
To a solution (20 ml) of 6-(12-acetoxydodecyl)-2,3-dimethoxy-5-methylphenol (1.1 g) in dimethylforamide is added bis(salicylidene)ethylenediiminocobalt(II) (40 mg), and the mixture is stirred at room temperature in an oxygen gas stream at atmospheric pressure for 72 hours. The solvent is distilled off and the product is extracted with ether. The ether layer is washed with water and dried over anhydrous sodium sulfate, and solvent is distilled off to give crude crystals. Recrystallization from ether-hexane (1:1) gives orange-yellow needles of 6-(12-acetoxydodecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (0.84 g). m.p. 47° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]([C:13]2[N:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[N:4]=1.C(N(CC)CC)C.[Cl:27][CH2:28][C:29](Cl)=[O:30]>C1COCC1>[Cl:27][CH2:28][C:29]([NH:19][C:16]1[CH:17]=[N:18][C:13]([C:5]2[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=2)=[CH:14][CH:15]=1)=[O:30]
Reactant: O=C(Cl)CCl
Reactant: COc1cc(C(F)(F)F)nc(-c2ccc(N)cn2)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(C(F)(F)F)nc(-c2ccc(NC(=O)CCl)cn2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cool (0° C.) solution of compound of example 59 (0.08 g, 0.296 mmol) in THF (5 mL) was added triethylamine (0.044 g, 0.44 mmol) and chloroacetylchloride (0.050 g, 0.44 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. THF was removed under reduced pressure, and reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 50% ethyl acetate in petroleum ether as an eluent) to obtain the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](OCC)=O)[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[N:21]1([C:27](=S)CC(N)=O)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(N(CC)CC)C.CC[OH:42]>>[CH3:10][C:8]1[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=1[C:11]1[N:12]=[C:13]([CH2:16][C:27]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:42])[S:14][CH:15]=1
Reactant: CCOC(=O)c1nc(-c2sc(NC(C)=O)nc2C)cs1
Reactant: CCO
Reactant: NC(=O)CC(=S)N1CCOCC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2csc(CC(=O)N3CCOCC3)n2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
N-[5-(bromoacetyl)-4-methyl-1,3-thiazol-2-yl]acetamide, hydrobromide salt (Intermediate 1) (300 mg; 0.84 mmol; 1 eq) and 3-morpholin-4-yl-3-thioxo-propionamide (157.7 mg; 0.84 mmol; 1 eq) are dissolved in EtOH (10 ml). Triethylamine (0.29 ml; 2.09 mmol; 2.5 eq) is added. The mixture is stirred overnight at RT. Solvents are evaporated and the crude product is dissolved in EtOAc and washed with water, brine and dried over MgSO4. After filtration and evaporation of the solvents, the resulting yellow solid is dissolved in a DCM, Et2O and EtOH mixture. Concentration of this solution results in the precipitation of Compound (56) as yellow solid (126.2 mg; 41%)
Reaction SMILES: Cl.[CH2:2]1[C:7]2([CH2:12][CH2:11][CH:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH2:9][CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3]1.CCN(C(C)C)C(C)C.Cl[C:28]([O:30][CH:31]1[CH:38]2[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:40][CH:32]1[CH2:33]3)[CH2:37]2)=[O:29].Cl>C(Cl)Cl>[CH3:17][O:16][C:14](=[O:15])[CH2:13][CH:10]1[CH2:11][CH2:12][C:7]2([CH2:2][CH2:3][N:4]([C:28]([O:30][CH:31]3[CH:32]4[CH2:40][CH:36]5[CH2:35][CH:34]([CH2:39][CH:38]3[CH2:37]5)[CH2:33]4)=[O:29])[CH2:5][CH2:6]2)[CH2:8][CH2:9]1
Reactant: COC(=O)CC1CCC2(CCNCC2)CC1
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CC1CCC2(CC1)CCN(C(=O)OC1C3CC4CC(C3)CC1C4)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
A vial was charged with methyl 2-(3-azaspiro[5.5]undecan-9-yl)acetate HCl salt (31 mg, 0.12 mmol) and DIEA (45 μL, 0.25 mmol). A solution of 2-adamantyl chloroformate (25 mg, 0.12 mmol) in CH2Cl2 (2 mL) was added and the mixture was stirred overnight at rt. A 10-mL Chem-Elut cartridge was wetted with 5% aq HCl (6 mL) and allowed to stand for 5 min. The reaction mixture was applied to the cartridge and eluted with ether (20 mL). The eluate was evaporated to dryness and the residue was purified by preparative HPLC to afford (2-adamantyl) 9-(2-methoxy-2-oxoethyl)-3-azaspiro[5.5]undecane-3-carboxylate (35 mg, 74%). LC-MS Method 1 tR=2.52 min, m/z=404; 1H NMR (CDCl3) δ=1.05-2.10 (27H), 2.23 (d, 2H), 3.41 (m, 4H), 3.69 (s, 3H), 4.82 (s, 1H).