Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH2:13][CH2:12][C:11]([CH3:14])=[CH:10][CH2:9][CH2:8][C:7]([CH3:15])=[CH:6][CH2:5][CH2:4][CH:3]=1.[CH3:16][OH:17]>>[CH3:16][O:17][C:2]1([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]=[C:7]([CH3:15])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:14])[CH2:12][CH2:13]1
Reactant: CO
Reactant: CC1=CCCC=C(C)CCC(C)=CCC1
Product: COC1(C)CCCC=C(C)CCC=C(C)CC1
Temperature: 25 °C
Yield: 95 %

Procedure:
340 g (1.67M) of 2,5,9-trimethyl-cyclododeca-1,5,9-triene and 110 g of acidic diatomaceous earth in 5000 ml of methanol (containing less than 0.05% of water) were refluxed during 40 h. After cooling at room temperature and filtration, the mixture was concentrated at reduced pressure to yield, after a distillation, 366 g of a product having b.p. 79°-110°/0.01 Torr. After fractional distillation, 212 g of starting 2,5,9-trimethyl-cyclododeca-1,5,9-triene (b.p. 43°-52°/0.1 Torr) and 140 g of the desired product, b.p. 78°-82°/0.01 Torr (yield 95% based on the converted starting material). IR (film): 1470 cm-1 ;
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]=1[NH:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Br)=[CH:23][CH:22]=1)(C)(C)C.[CH3:31][O:32][P:33]([O:36]C)[O:34][CH3:35]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:31][O:32][P:33]([CH2:27][C:24]1[CH:23]=[CH:22][C:21]([C:20](=[O:29])[NH:19][C:9]2[CH:10]=[C:11]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)[CH:12]=[CH:13][C:8]=2[NH2:7])=[CH:26][CH:25]=1)(=[O:36])[O:34][CH3:35]
Reactant: COP(OC)OC
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CBr)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COP(=O)(Cc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1)OC
Temperature: 100 °C
Reaction time: 18 h

Procedure:
[2-(4-Bromomethyl-benzoylamino)-4-thiophen-2-yl-phenyl]-carbamic acid tert-butyl ester (0.20 g, 0.41 mmol) was made 2.0 M in anhydrous toluene and to this stirring solution was added trimethylphosphite (0.06 g, 0.45 mmol). The resulting reaction mixture was sealed and stirred at 100° C. for 18 h. The reaction mixture was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate. The organic layer was further washed with brine then dried (MgSO4) and concentrated in vacuo. The residue was dissolved in DMF:MeOH and purified by HPLC (45-95% MeCN in water w/0.025% TFA). Pure fractions were identified, combined, and concentrated in vacuo. The residue was dissolved in 2:1 DCM:TFA and stirred at ambient temperature. After 1 hour the mixture was concentrated in vacuo, diluted with EtOAc, washed with saturated aqueous sodium bicarbonate, brine, dried (MgSO4), then concentrated in vacuo to give the title compound: 1H NMR (DMSO-d6, 600 MHz) 9.68 (s, 1H), 7.92 (d, J=8.4 Hz, 2H), 7.45 (s, 1H), 7.37-7.41 (m, 2H), 7.32-7.34 (m, 1H), 7.26-7.29 (m, 1H), 7.21-7.23 (m, 1H), 7.01-7.04 (m, 1H), 6.78 (d, J=8.4 Hz, 2H), 5.14 (s, 2H), 3.60 (d, J=11.4 Hz, 6H), 3.37 (d, J=22.2 Hz, 2H). MS: cal'd 417 (MH+), exp 417 (MH+)
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([SH:8])=[N:6][N:7]=1.[CH3:9][N:10]=[C:11]=[O:12]>O1CCOCC1.C(N(CC)CC)C>[CH3:9][NH:10][C:11]([N:2]([CH3:1])[C:3]1[S:4][C:5]([SH:8])=[N:6][N:7]=1)=[O:12]
Reactant: CN=C=O
Reactant: CNc1nnc(S)s1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CNC(=O)N(C)c1nnc(S)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
To a stirred slurry of 126 g of 2-methylamino-5-mercapto-1,3,4-thiadiazole in 525 ml of dioxane containing a few drops of triethylamine is added 49 g of methyl isocyanate. After stirring two hours at room temperature, the solid is collected by filtration and washed with hexane giving 165 g, melting at 162°-3°. This product is heated on the steam bath 11/2 -2 hours with 250 ml of triethylamine, during which time the initial solid is converted to a heavy amber oil. The supernatent liquid is decanted and the oil is dissolved in water and neutralized with dilute hydrochloric acid to pH 2-3. The precipitated solid is collected and washed with water and air dried, giving 132 g of N,N'-dimethyl-N'-(5-mercapto-1,3,4-thiadiazol-2-yl)urea, m.p. 230° (dec.).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:33])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:14][CH:13]=1.[CH3:34][C:35]1[S:39][CH:38]=[N:37][CH:36]=1.CCOCC>C1(C)C=CC=CC=1>[Br-:1].[CH3:34][C:35]1[S:39][CH:38]=[N+:37]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:9][C:10](=[O:33])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:14][CH:13]=2)[CH:36]=1
Reactant: Cc1cncs1
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2ccccc2CBr)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2ccccc2C[n+]2csc(C)c2)cc1
Product: [Br-]
Yield: 89.5 %

Procedure:
A mixture of 3.0 g of N-[2-(bromomethyl)phenyl]-4-(tetradecyloxy)benzeneacetamide and 2.88 g of 5-methylthiazole in 25 ml of toluene is heated at reflux under argon for 2.5 hours. The mixture is poured into 200 ml of ether, cooled, the solid collected, washed with ether and dried to give 3.2 g of the desired product as a white powder, m.p. 124°-127° C.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.Cl[CH2:10][C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1COCC1.O>[I:3][C:4]1[CH:5]=[N:6][N:7]([CH2:10][C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:8]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Ic1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(=O)Cn1cc(I)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (6 g, 250 mmol, 60 wt % in mineral oil) was added to mixture of 4-iodo-1H-pyrazole (10 g, 50 mmol) in THF (200 mL) at room temperature under N2. The mixture was stirred at room temperature for 1 hour. Ethyl 4-chloro-3-oxobutanoate (11.6 g, 75 mmol) was added and the mixture was stirred at room temperature for 12 hours. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: EtOAc) to afford ethyl 4-(4-iodo-1H-pyrazol-1-yl)-3-oxobutanoate. MS ESI calc'd. for C9H12IN2O3 [M+H]+ 323. found 323. 1H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 7.48 (s, 1H), 5.05 (s, 2H), 4.19-4.15 (m, 2H), 3.40 (s, 2H), 1.28-1.24 (m, 3H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCO.CCCO.CCCO.CCCO.[Zr:24]>CC1C=CC(C(C)C)=CC=1>[O-:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Zr+4:24].[O-:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Zr]
Reactant: Oc1ccccc1
Solvent: Cc1ccc(C(C)C)cc1
Solvent: CCCO
Product: [O-]c1ccccc1
Product: [Zr+4]
Yield: 45.1 %

Procedure:
Phenol (50 g), zirconium n-propoxide (10 g), and p-cymene (100 ml) were combined. The mixture was distilled through a 10 cm Vigreux column until all volatile components were removed. The cooled product was taken up in a mixture of methylene chloride (100 ml) and toluene (200 ml). This was filtered, and then concentrated under reduced pressure to a volume of ca. 50 ml. The concentrate was filtered to give 6.3 g of solid which was washed with petroleum ether, and dried under high vacuum for one hour to give white solid product.
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[S:21]1[CH2:25][C:24](=[O:26])[NH:23][C:22]1=[O:27].N1CCCCC1>CCO>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:2](=[O:1])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][CH:25]2[S:21][C:22](=[O:27])[NH:23][C:24]2=[O:26])=[CH:7][CH:6]=1
Reactant: O=C1CSC(=O)N1
Reactant: COc1ccccc1C(O)COc1ccc(C=O)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccccc1C(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 80.2 %

Procedure:
To a stirring solution of 4-[2-hydroxy-2-(2-methoxyphenyl)ethoxy]benzaldehyde (1.71 g, 6.28 mmol) in absolute EtOH (50 ml) was added 2,4-thiazolidinedione (0.81 g, 6.91 mmol) and piperidine (0.68 mL, 6.9 mmol), and the resulting solution was heated to reflux. The reaction was refluxed overnight and then evaporated in vacuo. The residue was dissolved in EtOAc and this solution was washed with aqueous HOAc (pH 5-6), brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was adsorbed onto silica gel and chromatographed on silica gel eluting with 20-40% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 1.87 g (80%) of the title compound as a light yellow solid. MS (ESI−) for C19H17NO5S m/z 370.1 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[O:6][C:7]3[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=3[CH2:9][N:10]([C:11]([NH:13][CH2:14][C:15](=[O:18])[CH:16]=[CH2:17])=[O:12])[C:4]=2[CH:3]=1.[CH2:25]([SH:27])[CH3:26].N1CCCCC1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[O:6][C:7]3[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=3[CH2:9][N:10]([C:11]([NH:13][CH2:14][C:15](=[O:18])[CH2:16][CH2:17][S:27][CH2:25][CH3:26])=[O:12])[C:4]=2[CH:3]=1
Reactant: CCS
Reactant: C=CC(=O)CNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CCSCCC(=O)CNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
A solution of 8-chloro-N-(2-oxo-3-butenyl)dibenz[b,f][1,4]oxazepin-10(11H)-carboxamide (1.00 gram), ethanethiol (0.23 mL), piperidine (0.092 mL), and N-benzyltrimethylammonium hydroxide (0.092 mL) in methylene chloride (16 mL) and methanol (4 mL) was stirred at room temperature for 5 hours. The reaction was diluted with methylene chloride (100 mL), washed with 100 mL each of 1N HCl (two times), water, saturated aqueous sodium bicarbonate, and brine, dried over MgSO4, and evaporated in vacuo. The crude product was purified by flash chromatography through silica gel 60 (350 mL) using 92:8 methylene chloride: ethyl acetate to yield a colorless oil. The yield of the title compound was 0.38 gram. (32%).
Reaction SMILES: CC([CH2:4][C:5]([CH3:7])=[O:6])C.[CH2:8]([CH:10]1[O:12][CH2:11]1)Cl.[C:13]12([C:23]3[CH:28]=[C:27]([C:29]45[CH2:38][CH:33]6[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]6)[CH2:30]4)[CH2:36]5)[C:26]([OH:39])=[CH:25][C:24]=3[OH:40])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2.[OH-].[Na+]>C(Cl)(Cl)Cl.CS(C)=O>[C:29]12([C:27]3[CH:28]=[C:23]([C:13]45[CH2:20][CH:19]6[CH2:21][CH:15]([CH2:16][CH:17]([CH2:18]6)[CH2:22]4)[CH2:14]5)[C:24]([O:40][CH2:8][CH:10]4[O:12][CH2:11]4)=[CH:25][C:26]=3[O:39][CH2:4][CH:5]3[O:6][CH2:7]3)[CH2:36][CH:35]3[CH2:37][CH:31]([CH2:32][CH:33]([CH2:34]3)[CH2:38]1)[CH2:30]2
Reactant: Oc1cc(O)c(C23CC4CC(CC(C4)C2)C3)cc1C12CC3CC(CC(C3)C1)C2
Reactant: ClCC1CO1
Reactant: CC(=O)CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: c1c(OCC2CO2)c(C23CC4CC(CC(C4)C2)C3)cc(C23CC4CC(CC(C4)C2)C3)c1OCC1CO1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A 500 mL four-necked flask equipped with a reflux condenser, a stirrer, a thermometer, and a nitrogen inlet tube was charged with 57 mL of MIBK, 157 mL of DMSO, and 98 g (1.057 mol) of epichlorohydrin and replaced with nitrogen for 30 minutes. To this solution, 52.01 g (0.137 mol) of 4,6-bis(1-adamantyl)-1,3-dihydroxybenzene synthesized in Example 1 was added, and the flask was replaced with nitrogen for 30 minutes and then heated at 45° C. while stirring. This solution was added with 11.6 g (0.290 mol) of sodium hydroxide over 0.5 hour and the solution was stirred for 1.5 hours. Then, 2.9 g (0.0725 mol) of sodium hydroxide was added and the solution was further stirred for 1 hour. The reaction mixture was cooled to room temperature, and 300 mL of chloroform was added. After washing with 500 mL of water, an aqueous 0.1 mol/L HCl solution was added to the mixture and the organic layer was separated. After further washing with water until the aqueous phase became neutral, the organic layer was concentrated and dried until the weight became constant in a reduced pressure drier at 100° C. to obtain 4,6-bis(1-adamantyl)-1,3-diglycidyloxybenzene as a pale-yellow solid (yield: 92%, LC purity: 99.20%, epoxy equivalent: 267, melting point: 193° C.).
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[C:29]([CH3:30])=[CH:28][S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:20]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[C:29]([CH3:30])=[CH:28][S:27][C:17]=3[N:18]=2)[CH:22]=1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: Cc1csc2nc(-c3cccnc3)nc(Cl)c12
Product: Cc1csc2nc(-c3cccnc3)nc(NCCc3ccc4c(c3)OCCO4)c12

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-3-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-ethylenedioxyphenethylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(=O)(=O)(O)O.[Cl:14]Cl>>[Cl:14][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:8])=[O:7]
Reactant: ClCl
Reactant: CCCCCC(=O)O
Agent: O=S(=O)(O)O
Product: O=C(O)CCCCCCl

Procedure:
144 parts by mass of the caproic acid were added to 1,000 parts by mass of 27N sulfuric acid saturated with chlorine and were reacted for 6 hours at 25° C. to obtain 93 parts by mass of 6-chlorocaproic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.[C:17]([O-])(=O)[CH3:18].[Na+].[BH4-].[Na+].[C:24](O)(=O)C>C(O)C.O.CC(C)=O>[C:13]([C:4]1[C:5]2[O:9][CH2:8][C:7]([CH3:10])([CH3:11])[C:6]=2[CH:12]=[C:2]([NH:1][CH:17]([CH3:18])[CH3:24])[CH:3]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(=O)O
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)c1cc(N)cc2c1OCC2(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCO
Product: CC(C)Nc1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2
Yield: 94.9 %

Procedure:
Following general procedure J and using 5-amino-7-t-butyl-3,3-dimethyl-2,3-dihydro-benzofuran (Compound 14, 0.55 g, 2.5 mmol), sodium acetate (0.85 g, 6.25 mmol) and sodium borohydride (0.76 g, 20 mmol) in 6.5 mL of ethanol, 6.5 mL of water, 5 mL of acetone (excess) and acetic acid (3.15 g, 52.5 mmol), the title compound (0.62 g, 95%) was obtained as an oil which was purified by flash column chromatography using 5% ethyl acetate in hexanes as the eluent. 1H NMR (300 MHz, CDCl3): δ 6.40 (d, 1H, J=2.3 Hz), 6.31 (d, 1H, J=2.3 Hz), 4.17 (s, 2H), 3.58 (heptet, 1H, J=6.3 Hz), 3.00-3.25 (br s, 1H), 1.37(s, 9H), 1.33 s, 6H), 1.24 (d, 6H, J=6.2 Hz).
Reaction SMILES: [O:1]1CCO[CH2:3][CH2:2]1.[Cl:7][C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=1.C([Sn](CCCC)(CCCC)C(OCC)=C)CCC.C1C(=O)N([Br:40])C(=O)C1>C(OCC)(=O)C>[Br:40][CH2:3][C:2]([C:11]1[N:10]=[N:9][C:8]([Cl:7])=[CH:13][CH:12]=1)=[O:1]
Reactant: C1COCCO1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ccc(Cl)nn1
Agent: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Product: O=C(CBr)c1ccc(Cl)nn1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a stirring solution of dioxane (100 mL, degassed) was added 3,6-dichloropyridazine (5.0 g, 34 mmol), Cl2Pd(PPh3)2 (2.4 g, 3.4 mmol), and tributyl(1ethoxyvinyl)tin (18.2 g, 50 mmol). The reaction was heated to 100° C. and stirred for 1 h. The reaction was then concentrated, followed by the addition of EtOAc (100 mL) and potassium fluoride (50 mL of a saturated aqueous solution). The mixture was stirred for 30 min and then filtered through a pad of Celite. The filtrate was concentrated and then dissolved in THF (80 mL) and water (80 mL). NBS (18.1 g, 102 mmol) was then added, and the reaction was stirred for 20 min at rt. The reaction mixture was poured into ethyl acetate (200 mL), washed twice with brine (50 mL), dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography to afford 4.2 g of 2-bromo-1-(6-chloropyridazin-3-yl)ethanone.
Reaction SMILES: C(Cl)(C(Cl)=O)=O.[CH:7]([CH:10]1[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH:11]1[N:17]1[C:21](=[O:22])[CH2:20][CH:19]([C:23]([OH:25])=O)[CH2:18]1)([CH3:9])[CH3:8].CCN(C(C)C)C(C)C.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.Cl>C(Cl)Cl.CN(C=O)C>[CH:7]([CH:10]1[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH:11]1[N:17]1[CH2:18][CH:19]([C:23]([N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:25])[CH2:20][C:21]1=[O:22])([CH3:8])[CH3:9]
Reactant: CC1CCC(C(C)C)C(N2CC(C(=O)O)CC2=O)C1
Reactant: C1CCNCC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1CCC(C(C)C)C(N2CC(C(=O)N3CCCCC3)CC2=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.3 %

Procedure:
(COCl)2 (10 g, 79 mmol, 6.9 mL) and DMF (50 μL) were carefully added to 1-(2-isopropyl-5-methyl-cyclohexyl)-5-oxo-pyrrolidine-3-carboxylic acid (obtained as in EXAMPLE II, 10 g, 37.4 mmol) suspended in anhydrous CH2Cl2 (150 mL). The reaction mixture slowly turned into a homogeneous solution over about 3 hours, which was then concentrated in vacuo and dissolved in anhydrous CH2Cl2. The reaction mixture was subsequently added dropwise to a mixture of DIEA (9.7 g, 74.8 mmol) and piperidine (3.99 g, 56 mmol) at 0° C. with stirring. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was poured into HCl (1 N) and extracted with CH2Cl2. The organic phases were collected, washed with brine, dried, and evaporated. Column chromatography with dichloromethane:methanol (95:5) provided 1-(2-isopropyl-5-methyl-cyclohexyl)-4-(piperidine-1-carbonyl)-pyrrolidin-2-one (10.8 g).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[CH:6]=[CH:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]3[C:10](=[O:11])[C:4]=2[CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([NH:1][C:2]1[CH:16]=[CH:15][C:5]2[CH:6]=[CH:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]3[C:10](=[O:11])[C:4]=2[CH:3]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2ccn3cccc3c(=O)c2c1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2ccn3cccc3c(=O)c2c1

Procedure:
9-Amino-11H-pyrrolo[2,1-b][3]benzazepin-11-one (2.1 g., 11.4 mmoles) dissolved in 15 ml. pyridine is treated with acetic anhydride (2 ml.) at room temperature for 19 hours. The volatiles are removed under vacuum and the residue is dissolved in chloroform, and chromatographed on silica gel. Elution with chloroform yields 9-acetamido-11H-pyrrolo[2,1-b][3]benzazepin-11-one.
Reaction SMILES: ClC1C=C(SC2[C:18]3[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=3)NC=2CCC(N)=O)C=C(Cl)C=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][C:40]=3[CH3:42])[NH:35][C:34]=2[C:43]([OH:45])=[O:44])=[CH:28][CH:27]=1.C(Cl)(=O)C(Cl)=O.C(O)C1C=CC=CC=1.N1C=CC=CC=1>C1COCC1>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][C:40]=3[CH3:42])[NH:35][C:34]=2[C:43]([O:45][CH2:19][C:15]2[CH:16]=[CH:17][CH:18]=[CH:13][CH:14]=2)=[O:44])=[CH:30][CH:31]=1
Reactant: Cc1cccc2[nH]c(C(=O)O)c(Sc3ccc(Cl)cc3)c12
Reactant: Cc1ccc2c(Sc3cc(Cl)cc(Cl)c3)c(CCC(N)=O)[nH]c2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: OCc1ccccc1
Product: Cc1cccc2[nH]c(C(=O)OCc3ccccc3)c(Sc3ccc(Cl)cc3)c12
Yield: 20 %

Procedure:
Following the method used to prepare 24a, the use of 1a (0.21 mmol) and oxalyl chloride in THF followed by allowing the intermediate acid chloride to react with benzyl alcohol (33 μL, 0.32 mmol) in the presence of pyridine (54 μL, 0.68 mmol) provided 17 mg (20%) of product 17 as a pale yellow foam. 1H NMR (300 MHz, DMSO-d6) δ 2.59 (s, 3H), 5.36 (s, 2H), 6.89 (d, J=7 Hz, 1H), 6.95 (d, J=9 Hz, 1H), 7.22 (d, J=8 Hz, 2H), 7.24-7.27 (m, 2H), 7.31-7.39 (m, 5H), 7.43 (d, J=8 Hz, 1H), 12.45 (s, 1H). LC-MS (CI): m/z 408.1 [(M+H)+ C23H18ClNO2S requires 407.6]. Purity (100%). Calcd for C23H18ClNO2S: C, 67.72; H, 4.45; N, 3.43; S, 7.86; Cl, 8.69. Found: C, 67.48; H, 4.43; N, 3.42; S, 7.85; Cl, 8.98.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:15][Si](C=[N+]=[N-])(C)C>CO.C1COCC1.C(OCC)C>[NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([O:6][CH3:15])=[O:5]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1cc(N)c(C(=O)O)c(OC)c1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1c(N)cc(OC)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a mixture of 2-amino-4,6-dimethoxybenzoic acid (7.888 g, 40 mmol) in MeOH (40 mL) and THF (40 mL) at room temperature was dropped 2.0 M solution of (trimethylsilyl)diazomethane in diethyl ether. The mixture was stirred at room temperature overnight. After the solvent was evaporated under reduced pressure, water and EtOAc was added to the residue. The organic layer was separated, dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by silica gel chromatography with 20-40% EtOAc/hexane as eluants to afford methyl 2-amino-4,6-dimethoxybenzoate as a solid (6.462 g, 76%). 1H NMR (300 MHz, CDCl3) δ 5.83 (d, 1H), 5.78 (d, 1H), 5.53 (br, 2H), 3.86 (s, 3H), 3.80 (s, 3H), 3.77 (s, 3H); LC-MS (ESI) m/z 212 (M+H)+.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][O:15][C:16]1[N:21]=[C:20]([C@H:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:27]2[CH:32]=[CH:31][N:30]3[N:33]=[CH:34][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:29]3[N:28]=2)[CH:19]=[CH:18][CH:17]=1.CO.C1COCC1.NN.O>O>[NH2:3][CH2:12][CH2:13][CH2:14][O:15][C:16]1[N:21]=[C:20]([C@H:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:27]2[CH:32]=[CH:31][N:30]3[N:33]=[CH:34][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:29]3[N:28]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cccc(OCCCN4C(=O)c5ccccc5C4=O)n3)nc12
Agent: NN
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cccc(OCCCN)n3)nc12
Temperature: 50 °C
Yield: 85.3 %

Procedure:
To a solution of (R)-ethyl 5-(2-(6-(3-(1,3-dioxoisoindolin-2-yl)prop oxy)pyridin-2-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.11 g, 0.20 mmol) in 1:1 MeOH/THF (12 mL) was added hydrazine-H2O (0.10 g, 2.0 mmol). The reaction mixture was heated at 50° C. for 24 hours. After cooling, the reaction mixture was poured into water then extracted with DCM (3×20 mL). The combined organics were dried (MgSO4), filtered, and concentrated to afford the desired product (70 mg, 84% yield). MS (apci) m/z=441.1 (M+H).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]4[CH:18]=[C:17]([CH:19]=O)[CH:16]=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.Cl.[CH3:22][NH:23][CH3:24].C(O)(=O)C.[BH3-]C#N.[Na+]>CO.C1COCC1>[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]4[CH:18]=[C:17]([CH2:19][N:23]([CH3:24])[CH3:22])[CH:16]=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: CNC
Reactant: O=Cc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)Cc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Temperature: 63 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
To a solution of 2-(4-cyclopropylpiperazin-1-yl)benzothiazole-6-carboxaldehyde (500 mg, 1.7 mmol) in methanol (14 mL) and THF (28 mL) was added dimethylamine hydrochloride (277 mg, 3.4 mmol), acetic acid (22 mg, 0.4 mmol) and NaCNBH3 (158 mg, 2.7 mmol). The mixture was stirred at 63° C. overnight. Then the resulting mixture was concentrated under reduced pressure and the residue was diluted with dichloromethane (15 mL). The mixture was washed with brine and the organic phase was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 367 mg (32%) of [2-(4-cyclopropylpiperazin-1-yl)benzothiazol-6-ylmethyl]dimethyl-amine as a trifluoroacetate salt.