Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NCCC)CC.C([Li])CCC.CCCCCC.[CH2:19]([O:26][C@H:27]1[CH2:32][C@@H:31]2[C@@H:29]([O:30]2)[C@@H:28]1[CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl[Si:43]([CH3:46])([CH3:45])[CH3:44]>COC(C)(C)C.C(OCC)(=O)C.CCCCCCC>[CH2:19]([O:26][C@H:27]1[CH2:32][C@@H:31]([O:30][Si:43]([CH3:46])([CH3:45])[CH3:44])[CH:29]=[C:28]1[CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(COC[C@H]2[C@@H]3O[C@@H]3C[C@@H]2OCc2ccccc2)cc1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCCCCCC
Product: C[Si](C)(C)O[C@H]1C=C(COCc2ccccc2)[C@@H](OCc2ccccc2)C1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a solution of dipropylamine (212 mL, 1.55 mol) in 2-methoxy-2-methylpropane (2000 mL) at −15° C. under a blanket of nitrogen, 2.50 M of n-butyllithium in hexane (567 mL, 1.42 mol) was added slowly over 10 minutes, maintaining a temperature of less than −10° C. The resulting white suspension was stirred for 30 minutes at −15° C. To this suspension was added (1S,2R,3S,5R)-3-(benzyloxy)-2-(benzyloxymethyl)-6-oxabicyclo[3.1.0]hexane (21) (400.00 g, 1.29 mol) slowly as a solution in methyl tert-butyl ether (1200 mL) over 30 minutes, maintaining an internal temperature of less than −10° C. The reaction mixture was stirred for 30 minutes at −15° C. TLC analysis indicated no remaining starting material (20% ethyl acetate/heptane). Chlorotrimethylsilane (204 mL, 1.61 mol) was added while maintaining a temperature of less than −10° C. The mixture was allowed to warm to 0° C. and stirred for 30 minutes. TLC analysis indicated that no alcohol intermediate (20% ethyl acetate/heptane). The reaction mixture was quenched with the slow addition of water (4 L) while maintaining an internal temperature of less than 8° C. The aqueous layer was separated and the organic layer was extracted 3 times with water (3×4 L) and once with saturated sodium chloride in water (4 L). The organic layer was concentrated under reduced pressure to give an orange oil (480 g, 97.4%) which was used without further purification. 1H NMR (300 MHz, CD3OD, δ): 7.18 (m, 10H), 5.65 (s, 1H), 4.55 (t, 1H), 4.30 (m, 5H), 4.02 (s, 2H), 2.58 (m, 1H), 1.47 (m, 1H) and 0.00 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])[C:5]2([CH:22](C([O-])=O)[C:23]([O:25][CH3:26])=[O:24])[C:13]1[C:14]([O:19][CH2:20][CH3:21])=[N:15][CH:16]=[CH:17][CH:18]=1.C(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])[C:5]2([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:13]1[C:14]([O:19][CH2:20][CH3:21])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOc1ncccc1C1(C(C(=O)[O-])C(=O)OC)C(=O)Nc2cc(F)c(Cl)cc21
Agent: O=C=O
Product: CCOc1ncccc1C1(CC(=O)OC)C(=O)Nc2cc(F)c(Cl)cc21

Procedure:
The resulting monomethyl 2-[5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]malonate (4.58 g) was heated in a one-neck flask under a blanket of nitrogen to 150° C. During this, CO2 gas was evolved and methyl [5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]acetate was formed. The reaction mixture was cooled to room temperature, and the substance was mixed with methanol. The crystals which formed were stored in a refrigerator at 5° C. overnight. The solid was filtered off with suction and washed with a little methanol. 3.286 g (8.68 mmol, 80% yield) of the title compound were obtained as a white solid.
Reaction SMILES: COC1C=CC(C[N:10](CC2C=CC(OC)=CC=2)[S:11]([CH2:14][CH2:15][CH:16]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=2[F:30])[C:17]([O:19][CH3:20])=[O:18])(=[O:13])=[O:12])=CC=1>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:10][S:11]([CH2:14][CH2:15][CH:16]([C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[F:30])[C:17]([O:19][CH3:20])=[O:18])(=[O:12])=[O:13]
Reactant: COC(=O)C(CCS(=O)(=O)N(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1)c1ccc([N+](=O)[O-])cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(CCS(N)(=O)=O)c1ccc([N+](=O)[O-])cc1F
Reaction time: 48 h
Yield: 86.1 %

Procedure:
Methyl .alpha.-[2-[[bis[(4-methoxyphenyl)methyl]amino] sulfonyl]ethyl]-2-fluoro-4-nitrobenzeneacetate (41.6 g, 74.3 mmol) is dissolved in methylene chloride (200 ml) and trifluoroacetic acid (50 ml). The solution is stirred for 2 days then the solvents evaporated. The residue is dissolved in ethyl acetate (750 ml) and washed with sodium bicarbonate solution (200 ml) and brine (100 ml). After drying (MgSO4), filtration and evaporation the title compound is obtained as a solid (20.5 g, 86%) mp 99-101°.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][NH:7][C:8](=[O:18])[C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH3:16])=[C:11]([NH2:17])[CH:10]=1)=[O:4].P(Cl)(Cl)(Cl)=O.[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=O)=[CH:28][CH:27]=1)#[N:25]>C(OCC)(=O)C>[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30]2[N:15]([CH3:16])[C:12]3[CH:13]=[CH:14][C:9]([C:8]([NH:7][CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[O:18])=[CH:10][C:11]=3[N:17]=2)=[CH:28][CH:27]=1)#[N:25]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CNc1ccc(C(=O)NCCC(=O)OC)cc1N
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc(C#N)cc1)n2C
Temperature: 90 °C

Procedure:
4.7 g of 3-amino-4-methylamino-benzoic acid-[N-(2-methoxycarbonyl-ethyl)-amide] are first stirred at ambient temperature with 40 ml of phosphorusoxychloride, then 3.1 g of 4-cyano-benzoylchloride are added and the mixture is heated to 90° C. for 8 hours. The phosphorusoxychloride is distilled off in vacuo, the residue is stirred into 500 ml of water at 30° C. and neutralised by the addition of sodium bicarbonate in batches. The precipitate is suction filtered and extracted with ethyl acetate. The ethyl acetate phases are evaporated down, the residue is combined with the precipitate and purified by chromatography on silica gel (eluant:ethyl acetate/ethanol=100:1 to 100:5). The product obtained is decocted with ethyl acetate for final purification. Yield: 1,86 g (27% of theory), Rf value: 0.51 (silica gel; ethyl acetate/ethanol=9:1)
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:30]([N:37]1[CH2:44][CH:43]2[O:45][CH:39]([CH2:40][NH:41][CH2:42]2)[CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:27][N:26]([CH3:28])[C:25]([C:7]1[N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([N:41]4[CH2:40][CH:39]5[O:45][CH:43]([CH2:44][N:37]([CH2:30][C:31]6[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=6)[CH2:38]5)[CH2:42]4)=[O:22])=[CH:18][N:17]=3)[N:13]=[CH:14][C:9]=2[CH:8]=1)=[O:29]
Reactant: c1ccc(CN2CC3CNCC(C2)O3)cc1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CN(Cc6ccccc6)CC(C4)O5)cn3)nc2n1C1CCCC1
Yield: 43.4 %

Procedure:
Following general amide formation method 1, 6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (200 mg, 0.507 mmol, 1.0 eq) was combined with 3-benzyl-9-oxa-3,7-diaza-bicyclo[3.3.1]nonane (162 mg, 0.558 mmol, 1.1 eq) (Reference: PCT Int. Appl. 2006137769, 2 Dec. 2006) which gave 2-[5-(7-Benzyl-9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carbonyl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide as solid (131 mg) in 39% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.64-1.83 (m, 3H) 2.04 (d, J=7.07 Hz, 2H) 2.12 (d, J=6.57 Hz, 2H) 2.58 (br. s., 4H) 3.18 (s, 6H) 3.45 (br. s., 3H) 3.49-3.57 (m, 1H) 3.67-3.80 (m, 1H) 3.84 (br. s., 2H) 4.02 (br. s., 1H) 4.66-4.88 (m, 2H) 6.51 (s, 1H) 7.22-7.28 (m, 1H) 7.31-7.37 (m, 5H) 7.85 (dd, J=8.84, 2.27 Hz, 1H) 8.27 (br. s., 1H) 8.43 (s, 1H) 8.51 (br. s., 1H) 8.78 (s, 1H). MS m/z 595.6 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1.[Br:13]N1C(=O)CCC1=O.Br>Br.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[CH:4]([Br:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1
Reactant: COC(=O)Cc1cccc(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: Br
Solvent: ClC(Cl)Cl
Product: COC(=O)C(Br)c1cccc(Cl)c1
Yield: 68.5 %

Procedure:
A mixture of (3-Chloro-phenyl)-acetic acid methyl ester (2.0 g, 10.8 mmol), N-bromosuccinimide (1.95 g, 11.0 mmol) and 3 drops of hydrobromic acid (48% solution) in chloroform (100 mL) was heated under reflux for three days. Additional amounts of N-bromosuccinimide and hydrobromic acid were added to drive the reaction to completion. The reaction mixture was concentrated to dryness, taken up in methylene chloride and loaded onto a column of silica gel. Elution with 10% ethyl acetate/hexanes gave Bromo-(3-chloro-phenyl)-acetic acid methyl ester (1.95 g, 69% yield) as a colorless oil. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH:16]([CH2:21][C@H:22]3[CH2:42][CH2:41][C:24]4([O:28][C@H:27]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C@@H:26]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[O:25]4)[CH2:23]3)[C:17]([O:19]C)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1.[OH-].[Na+].CO>C1COCC1>[CH:1]1([C:4]2[CH:5]=[C:6]([CH:16]([CH2:21][C@H:22]3[CH2:42][CH2:41][C:24]4([O:28][C@H:27]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[C@@H:26]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[O:25]4)[CH2:23]3)[C:17]([OH:19])=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:14][CH2:15]2)(=[O:12])=[O:11])[CH2:2][CH2:3]1
Reactant: COC(=O)C(C[C@H]1CCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(C[C@H]1CCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A mixture of methyl 2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]propionate (66.5 g), 4 M aqueous sodium hydroxide solution (66.5 mL), methanol (66.5 mL), and THF (133 mL) was stirred under heating and reflux for 30 minutes, and left to be cooled at room temperature, and the organic solvent was evaporated under reduced pressure. To the residue was added chloroform (500 mL), and concentrated hydrochloric acid (25 mL) was then added thereto under ice-cooling. The organic layer was washed with saturated brine (200 mL×2) and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure to obtain 2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]propionic acid (64.8 g) as an off-white amorphous substance.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CN(C)[C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1N.I/C=C/CCCC>[Cu]I.C1(C)C=CC=CC=1>[CH:25]([C:2]1([CH:7]=[CH:6][CH:5]=[CH:4][CH2:3]1)[C:1]([NH2:9])=[O:8])=[CH:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CN(C)[C@@H]1CCCC[C@H]1N
Reactant: NC(=O)c1ccccc1
Agent: [Cu]I
Agent: CCCC/C=C/I
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CCCCC=CC1(C(N)=O)C=CC=CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 668.6 %

Procedure:
A 15 mL resealable Schlenk tube was charged with CuI (9.6 mg, 0.0504 mmol, 5.0 mol %), benzamide (145 mg, 1.20 mmol), K3PO4 (430 mg, 2.03 mmol), evacuated and backfilled with argon. trans-N,N-Dimethyl-1,2-cyclohexanediamine (16 μL, 0.102 mmol, 10 mol %), trans-1-iodo-1-hexene (143 μL, 1.00 mmol), and toluene (1.0 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 25° C. for 24 h. The resulting light blue suspension was allowed to reach room temperature and then filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of ethyl acetate. The filtrate was concentrated, the residue was dissolved in 5 mL of dichloromethane and purified by flash chromatography on silica gel (2×15 cm, hexane-ethyl acetate, 15 mL fractions). Fractions 12-19 provided 140 mg (69% yield) of the desired product as white needles.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH:13]([CH3:18])[C:14]([O:16]C)=[O:15])[CH2:8][CH2:7]1.O.[OH-].[Li+].CO>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH:13]([CH3:18])[C:14]([OH:16])=[O:15])[CH2:8][CH2:7]1
Reactant: COC(=O)C(C)CN1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(CN1CCN(Cc2ccc(Cl)c(Cl)c2)CC1)C(=O)O
Reaction time: 21 h
Yield: 98.6 %

Procedure:
Methyl 2-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]propionate (470 mg, 1.36 mmol) and lithium hydroxide monohydrate (185 mg, 4.41 mmol) were dissolved in water (5 ml) and methanol (15 ml) and stirred at room temperature. After 21 h, the solvents were removed under reduced pressure. The resulting residue was taken up in a mixture of methylene chloride and water, and the aqueous layer was made acidic (pH 4) with 1M HCl. The layers were separated and the aqueous phase was extracted with several portions of methylene chloride. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford 2-(RS)-[4-(3,4-dichloro-benzyl)piperazin-1-ylmethyl]propionic acid (444 mg) as a pale-yellow foam.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][CH:15]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=2)[C:16]2[N:17]=[N:18][N:19]([CH2:21][Si](C)(C)C)[CH:20]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][CH:15]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=2)[C:16]2[N:17]=[N:18][N:19]([CH3:21])[CH:20]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CC(=O)NC(c2ccc(F)c(F)c2)c2cn(C[Si](C)(C)C)nn2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(C(NC(=O)Cc2ccc(C(C)(C)C)cc2)c2ccc(F)c(F)c2)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a 10 ml round bottom flask containing a solution of 2-(4-tert-butylphenyl)-N-((3,4-difluorophenyl){1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}-methyl)acetamide (0.062 mg, 0.132 mmol) in 1.0 ml of anhydrous THF at rt was added 1.0N tetrabutylammonium fluoride in THF (0.145 ml, 0.145 mmol). The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum. Purification by preparative HPLC (20-90% CH3CN/H2O over 30 min, 0.05% added TFA, C18 column) to afford 0.046 g (88%) of the title compound. Purification by super fluid (CO2/MeOH) chiral column yielded first enathiomer (19 mg) (36.2%), and second enathiomer (21 mg) (40%) 1H NMR (CDCl3, 400 MHz) δ 7.359 (m, 2H), 7.307 (s, 1H), 7.183 (m, 2H), 7.009 (m, 3H), 6.769 (d, J=7.32 Hz, 1H), 6.216 (d, J=7.57 Hz, 1H), 4.059 (s, 3H), 3.581 (ABq, J=15.75 Hz, 2H), 1.311 (s, 9H). ES-MS [M+1]+: 399.2.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([N:19]([C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[S:22])[NH2:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[CH2:12]([N:19]([C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[S:22])[NH:20][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NN(Cc1ccccc1)C(=S)Nc1ccccc1
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1C(=O)NN(Cc1ccccc1)C(=S)Nc1ccccc1
Temperature: 90 °C

Procedure:
Phthalic anhydride (3.7 g, 0.25 mole) and 2-benzyl-4-phenyl-3-thiosemicarbazide (6.43 g, 0.25 mole) were dissolved in 100 ml of dimethylformamide and heated at 90° C. for three hours. The solution was cooled then poured into ice water with stirring. The title product was filtered off as a solid material. Recrystallization gave a substance having a melting point of 140°-142°.
Reaction SMILES: [NH2:1][C:2]1([C:15]#[N:16])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[NH2:24][C:25]1[C:26]([C:33]([NH:35][C:36](=N)SC)=[O:34])=[N:27][C:28]([Cl:32])=[C:29]([NH2:31])[N:30]=1>CC(O)C>[CH2:8]([N:5]1[CH2:6][CH2:7][C:2]2([NH:1]/[C:36](=[N:35]\[C:33]([C:26]3[C:25]([NH2:24])=[N:30][C:29]([NH2:31])=[C:28]([Cl:32])[N:27]=3)=[O:34])/[NH:16][CH2:15]2)[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: N#CC1(N)CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Nc1nc(N)c(C(=O)/N=C2/NCC3(CCN(Cc4ccccc4)CC3)N2)nc1Cl
Temperature: 70 °C

Procedure:
4-Amino-1-benzyl-piperidine-4-carbonitrile (Intermediate G) (200 mg, 0.91 mmol) in dry propan-2-ol (10 ml) is treated with triethylamine (0.25 ml) followed by 1-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea (Intermediate A) (355 mg, 0.91 mmol). The mixture is heated at 70° C. for 5 hours and then allowed to cool to room temperature. The precipitate is collected and washed with methanol to afford the title compound as a light yellow solid, 190 mg; [M+H]+ 415
Reaction SMILES: CN.C(O)C.[CH:6]([N:9](CC)C(C)C)(C)C.[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1>ClCCl>[Cl:15][C:16]1[N:21]=[C:20]([NH:9][CH3:6])[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: ClCCl
Solvent: CCO
Product: CNc1nc(Cl)ncc1[N+](=O)[O-]
Yield: 85.4 %

Procedure:
A solution of methyl amine-ethanol (7.6 ml) and N,N-diisopropylethylamine (13.2 ml) were dissolved into 150 ml dichloromethane. The mixture was added dropwise to a solution of 2,4-dichloro-5-nitropyrimidine (10.0 g) in dichloromethane (30 ml) at 0° C. After the completion of the dropwise addition, the mixture was kept at the same temperature to react for half an hour. Purification was conducted by a column chromatography to obtain a yellow solid (8.3 g) in a yield of 85.4%. 1H NMR (400 MHz, CDCl3): δ 9.05 (s, 1H), 8.41 (s, 1H), 3.22 (s, 3H) ppm.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[SH:23].C(=O)([O-])[O-].[K+].[K+].N1C=CC=CC=1>CN(C)C=O.O>[N+:10]([C:5]1[CH:4]=[CH:3][C:2]([S:23][C:14]2[CH:15]=[CH:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]=2)=[CH:9][C:6]=1[C:7]#[N:8])([O-:12])=[O:11]
Reactant: N#Cc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Sc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: N#Cc1cc(Sc2ccc3ccccc3c2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
A stirred solution of 10.0 grams (0.055 mole) of 5-chloro-2-nitrobenzonitrile and 8.8 grams (0.055 mole) of 2-naphthalenethiol in 80 mL of N,N-dimethylformamide was cooled to 0° C., and 7.6 grams (0.055 mole) of potassium carbonate was added. Upon completion of addition, the reaction mixture was stirred at 0° C. for 1 hour. Thin layer chromatographic (TLC) analysis of the reaction mixture after this time indicated that the reaction had not gone to completion. The reaction mixture was then allowed to warm to ambient temperature, where it was stirred for about 18 hours. The reaction mixture was stirred with 80 mL of pyridine and then was diluted with water until a solid precipitate formed. The solid was collected by filtration and was washed in turn with an aqueous solution of 10% pyridine, water, an aqueous solution of 1 % hydrochloric acid, and finally with water. The solid was then dissolved in ethyl acetate and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residual solid. The solid was subjected to column chromatography on silica gel. Elution was accomplished with 10% ethyl acetate in heptane. The product-containing fractions were combined and concentrated under reduced pressure, yielding 13.5 grams of 2-nitro-5-(naphth-2-ylthio)benzonitrile. A small sample was recrystallized from ethyl acetate/hexane, mp 139°-140° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]([CH3:11])([C:6](=[O:10])[CH2:7][CH2:8][CH3:9])[CH3:5].O>CCOCC>[Br:1][CH:7]([CH2:8][CH3:9])[C:6](=[O:10])[C:4]([CH3:11])([CH3:5])[CH3:3]
Reactant: BrBr
Reactant: CCCC(=O)C(C)(C)C
Solvent: CCOCC
Solvent: O
Product: CCC(Br)C(=O)C(C)(C)C
Reaction time: 14 h
Yield: 109.7 %

Procedure:
Slowly add bromine (10.87 ml, 212.15 mmol) to 2,2-dimethylhexane-3-one (27.20 g, 212.15 mmol) in ether (200 ml) and allow the reaction to stir for 14 h. Combine the reaction mixture with water (200 ml) and partition. Dry the organic layer over Na2SO4, filter and then concentrate the filtrate to provide the title compound as a yellow oil (48.2 g, quant). 1NMR (400 MHz, CDCl3) δ ppm: 1.01 (t, J=7.6 Hz, 3H), 1.27 (s, 9H), 2.03 (m, 2H), 4.58 (t, J=7.2 Hz, 1H). High Res. ES-MS: 207.0348; calc. for C8H15BrO+H, 207.0384.
Reaction SMILES: OS(O)(=O)=O.[BrH:6].[NH2:7][C:8]1[NH:12][N:11]=[C:10]([CH3:13])[C:9]=1[C:14]1[S:15][C:16]2[CH:22]=[C:21]([CH2:23]O)[CH:20]=[CH:19][C:17]=2[N:18]=1.[OH-].[Na+]>>[Br:6][CH2:23][C:21]1[CH:20]=[CH:19][C:17]2[N:18]=[C:14]([C:9]3[C:10]([CH3:13])=[N:11][NH:12][C:8]=3[NH2:7])[S:15][C:16]=2[CH:22]=1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(CO)cc2s1
Reactant: Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1n[nH]c(N)c1-c1nc2ccc(CBr)cc2s1
Temperature: 25 °C

Procedure:
To a solution of concentrated H2SO4 (0.3 mL) and hydrobromic acid (0.6 mL, 48%) was added [2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazol-6-yl]-methanol (52 mg, 0.2 mmol). The resulting mixture was refluxed for 2 hrs. Upon cooling to room temperature, the mixture was poured into ice water resulting a milky solution. The suspension was neutralized to pH 3-4 with 5% NaOH solution. The resulting cream coloured solid was isolated by filtration, washed with water and air-dried to yield 58 mg of 4-(6-bromomethylbenzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine. The crude material was used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:11]=[CH:12]/[C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[O:16]1[CH2:21][CH2:20][NH:19][C:18]2[CH:22]=[CH:23][CH:24]=[CH:25][C:17]1=2.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl.O>[O:16]1[CH2:21][CH2:20][N:19]([C:13](=[O:15])/[CH:12]=[CH:11]/[C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:18]2[CH:22]=[CH:23][CH:24]=[CH:25][C:17]1=2
Reactant: COc1ccc(/C=C/C(=O)O)cc1OC
Reactant: c1ccc2c(c1)NCCO2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(/C=C/C(=O)N2CCOc3ccccc32)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
To a solution of (E)-3-(3,4-dimethoxyphenyl)acrylic acid (0.46 g, 2.22 mmol) and 3,4-dihydro-2H-benzo[b][1,4]oxazine (0.20 g, 1.48 mmol) in DCM (15 mL) was added EDC.HCl (0.71 g, 3.70 mmol), HOBt (0.60 g, 3.70 mmol) and Et3N (0.37 g, 3.70 mmol). The mixture was stirred at room temperature overnight then diluted with water and extracted with DCM. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel using petroleum ether/ethyl acetate 5:1 (v:v) as eluent to give (E)-1-(2,3-dihydrobenzo[b][1,4]oxazin-4-yl)-3-(3,4-dimethoxyphenyl)prop-2-en-1-one (230 mg, 32%). 1H-NMR (400 MHz, CDCl3) δ 3.88 (s, 3H), 3.91 (s, 3H), 4.08 (m, 2H), 4.37 (m, 2H), 6.86 (d, J=8.4 Hz, 1H), 6.90 (m, 1H), 6.92 (d, J=15.2 Hz, 1H), 6.96 (dd, J=8.0, 1.6 Hz, 1H), 6.99 (d, J=2.0 Hz, 1H), 7.08-7.13 (m, 2H), 7.20 (br d, J=7.6 Hz, 1H), 7.02 (d, J=15.6 Hz, 1H); LC-MS (ES-API); rt 8.72 min; m/z calculated for C19H19NO4 [M+H]+ 326.1, found 326.1.