Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]#[CH:6].C([Li])CCC.B(F)(F)F.CCOCC.[CH:21]([C:23]([CH3:25])=[O:24])=[CH2:22]>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][CH2:22][CH2:21][C:23](=[O:24])[CH3:25]
Reactant: C=CC(C)=O
Reactant: C#CCCCCl
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(=O)CCC#CCCCCl
Reaction time: 0.25 h

Procedure:
14.85 Parts of 5-chloropent-1-yne is dissolved in 250 parts by volume of toluene and the resulting solution is cooled to approximately -40°. To that solution is then added 62.8 parts by volume of 2.31 M ethereal butyl lithium and stirring is continued for approximately 15 minutes. 6.87 Parts of boron trifluoride etherate is added and the reaction mixture is stirred for about 2 hours, then allowed to stand for about 16 hours at -5° to -10°. At the end of that time 10.14 parts of methyl vinyl ketone is added at -40° and the reaction mixture is stirred for about 4 hours, then is quenched with water. 50 Parts by volume of 3 N hydrochloric acid is added and the mixture is kept at room temperature for about 16 hours, at the end of which time the aqueous and organic layers are separated. The aqueous layer is extracted with toluene and the organic layer with water. The organic solutions are combined, washed successively with aqueous sodium hydroxide and water, then dried over anhydrous sodium sulfate and stripped to dryness under reduced pressure, thus affording the crude product. This material is purified by distillation under reduced pressure to afford 9-chloro-5-nonyn-2-one, boiling at about 80°-92° at a pressure of 0.11-0.06 mm.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[S:6][CH:7]=1.[CH2:25]([NH:28][CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]>O1CCCC1>[CH2:25]([N:28]([CH2:2][C:3]1[N:4]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[S:6][CH:7]=1)[CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]
Reactant: CN1Cc2c(-c3nc(CCl)cs3)ncn2-c2ccc(F)cc2C1=O
Reactant: CCCNCCC
Solvent: C1CCOC1
Product: CCCN(CCC)Cc1csc(-c2ncn3c2CN(C)C(=O)c2cc(F)ccc2-3)n1
Reaction time: 12 h
Yield: 28.9 %

Procedure:
A suspension of 1.0 g (0.00275 mol) of 3-(4-chloromethyl-thiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 50 ml of tetrahydrofuran was treated with 4.5 ml (0.033 mol) of dipropylamine. After stirring at 50° for 12 hrs. the solution obtained was completely freed from the solvents. The residue was chromatographed over silica gel with dichloromethane/methanol 19:1 as the eluent and recrystallized from hot isopropyl ether. There was obtained 0.34 g (29%) of 3-(4-dipropylaminomethyl-thiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. 134-136°.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]#[C:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])[CH2:6]1)(=[O:3])[CH3:2].C([O:23][C@@H:24]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]#[C:31][CH2:32][N:33]2[CH2:37][CH2:36][CH2:35][C:34]2=[O:38])[CH2:25]1)(=O)C>>[C:1]([O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]#[C:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])[CH2:6]1)(=[O:3])[CH3:2].[OH:3][C@@H:35]1[CH2:36][CH2:37][N:33]([CH2:32][C:31]#[C:30][CH2:29][N:26]2[CH2:27][CH2:28][CH2:24][CH2:25]2)[C:34]1=[O:38].[OH:23][CH:24]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]#[C:31][CH2:32][N:33]2[CH2:37][CH2:36][CH2:35][C:34]2=[O:38])[CH2:25]1
Reactant: CC(=O)O[C@@H]1CCN(CC#CCN2CCCC2=O)C1
Agent: CC(=O)O[C@H]1CCN(CC#CCN2CCCC2=O)C1
Product: O=C1CCCN1CC#CCN1CCC(O)C1
Product: O=C1[C@H](O)CCN1CC#CCN1CCCC1

Procedure:
Following the procedure of Example 46, the (S) or (R) isomers of the desired product were prepared from (S) or (R)-1-[4-[3-(acetyloxy)-1-pyrrolidinyl]-2-butynyl]-2-pyrrolidinone.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].[OH2:18]>CS(O)(=O)=O>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][C:6]2[CH:16]=[CH:17][C:3]([C:1]([NH2:2])=[O:18])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: O
Reactant: COc1ccc(Oc2ccc(C#N)cc2)cc1
Agent: CS(=O)(=O)O
Product: COc1ccc(Oc2ccc(C(N)=O)cc2)cc1
Reaction time: 1 h

Procedure:
4-(4-Cyanophenoxy)-methoxybenzene (7.66 g, 34 mmol) and water (6.13 g, 340 mmol) in methanesulfonic acid (32.7 g) were heated to 80° C. for 16 hours. The cooled mixture was poured onto ice/water and after stirring for 1 hour the solid was collected and air dried yielding 8.4 g of 4-(4-methoxyphenoxy)benzamideas a white solid. GC-MS (m/z, EI): 243 [M]+.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]1[N:26]=[CH:25][NH:24][N:23]=1.C(N(CC)CC)C>ClCCl>[C:1]([N:24]1[CH:25]=[N:26][C:22]([CH3:21])=[N:23]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc[nH]n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 86.6 %

Procedure:
Trityl chloride (19.0 g) was added portionwise to a stirred solution of 3-methyl-1,2,4-triazole (5.6 g, commercial) and triethylamine (9.5 ml) in dichloromethane (200 ml). The mixture was diluted with dichloromethane (100 ml), washed with water (50 ml), dried over magnesium sulphate and evaporated under reduced pressure to give 1-trityl-3-methyl-1,2,4-triazole (19.0 g). Recrystallisation of a 2 g sample from toluene-hexane (1:1) gave pure material (1.32 g, m.p. 194°-196° C.). NMR (CDCl3): δ2.41(3H,s), 7.03-7.40(15H,m), 7.83(1H,s).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[C:8]([O:16][CH3:17])[C:5]=1C=O)([O-:3])=[O:2].ClC1C=CC=C(C(OO)=[O:26])C=1.[OH-].[K+].CO>C(Cl)(Cl)Cl>[OH:26][C:5]1[C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[C:10]([O:12][CH3:13])=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: COc1cc([N+](=O)[O-])c(C=O)c(OC)c1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc([N+](=O)[O-])c(O)c(OC)c1OC
Yield: 71.4 %

Procedure:
A mixture of 2-nitro-4,5,6-trimethoxybenzaldehyde (19.3 g, 0.08 mol) and m-chloroperbenzoic acid (20.7 g, 0.12 mol) in chloroform (350 ml) was heated under reflux for 5 hours. After cooling, the reaction mixture was washed with 10% sodium bicarbonate solution and water. The solvent was removed by evaporation in vacuo and the residue was then treated with a mixture of 10% potassium hydroxide solution (potassium hydroxide 5.0 g, 0.088 mol in 50 ml of water) and methanol (150 ml) at room temperature under nitrogen. The solvent was removed in vacuo and the solid residue was dissolved in water (300 ml) and then acidified with 6N hydrochloric acid. The precipitated product was collected by filtration, washed well with water and dried to give (after recrystallization from 2-propanol) 13.1 g of 2-hydroxy-1-nitro-3,4,5-trimethoxybenzene, mp 72-73° C. 1H-NMR (CDCl3): δ3.87, 3.94, and 4.08 (each 3H, s, 3 ×OMe), 7.32 (1H, s, H-6), 10.78 (1H, exchangeable, OH). Analyses: Calculated for C9H11NO6 : C, 47.16; H, 4.84; N, 6.11. Found: C, 47.11; H, 5.00; N, 6.17.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].[CH2:11]([C:20]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:11]([C:20]1([C:30]([NH:4][C:3]2[C:2]([F:1])=[CH:8][C:7]([F:9])=[CH:6][C:5]=2[F:10])=[O:31])[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: Nc1c(F)cc(F)cc1F
Reactant: CCCCCCCCCC1(C(=O)Cl)CCc2ccccc2C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCC1(C(=O)Nc2c(F)cc(F)cc2F)CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 44 h
Yield: 58.3 %

Procedure:
To a solution of 1.0 g (6.8 mmole) 2,4,6-trifluoroaniline and 830 mg (6.8 mmole) 4-dimethylaminopyridine in 40 ml methylene chloride cooled to 5° C. under nitrogen was added a solution of 2.12 g (6.6 mmole) 2-n-nonyl-1,2,3,4-tetrahydro-2-naphthoyl chloride in 10 ml methylene chloride. The resulting solution was stirred at room temperature for 44 hours. Fifty milliters of methylene chloride was then added and the solution was washed sequentially with 30 ml aqueous hydrochloric acid, 30 ml water and 30 ml brine. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The residue (2.5 g) was purified by column chromatography on silica gel eluting with 2:1 methylene chloride-hexane to yield 1.66 g (58% yield) of the desired product as a white, low melting solid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[C:17]12([NH:27][C:28](=[O:31])[CH:29]=[CH2:30])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2.C(N(CC)CC)C>CO>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:30][CH2:29][C:28]([NH:27][C:17]23[CH2:24][CH:23]4[CH2:22][CH:21]([CH2:20][CH:19]([CH2:25]4)[CH2:18]2)[CH2:26]3)=[O:31])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: C=CC(=O)NC12CC3CC(CC(C3)C1)C2
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)c1cc(SCCC(=O)NC23CC4CC(CC(C4)C2)C3)cc(C(C)(C)C)c1O

Procedure:
Following the method of Example 4, 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (1.19 g, 0.005 mole), the title compound of Example 5 (1.03 g, 0.005 mole) and triethylamine (0.5 ml) were stirred in methanol (100 ml) for 12 hours at room temperature under argon. The solvent and triethylamine were removed on a rotary evaporator and the product purified by chromatography on silica, recrystallized from ethyl aceate/hexane, filtered and dried in vacuo, m.p. ca. 172.5°-173.5° C.
Reaction SMILES: [CH2:1]([O:19][CH:20]([CH2:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:21][N:22]([CH3:24])[CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[O:45]=[C:46]([CH2:57][CH2:58][C:59](=[O:65])[CH2:60][CH2:61][C:62](=[O:64])[CH3:63])[CH2:47][CH2:48][O:49][C:50](=[O:56])[CH2:51][CH2:52][CH2:53][CH2:54][Br:55]>CC(C)=O>[Br-:55].[CH2:1]([O:19][CH:20]([CH2:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:21][N+:22]([CH2:54][CH2:53][CH2:52][CH2:51][C:50]([O:49][CH2:48][CH2:47][C:46](=[O:45])[CH2:57][CH2:58][C:59](=[O:65])[CH2:60][CH2:61][C:62](=[O:64])[CH3:63])=[O:56])([CH3:24])[CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCC=CCCCCCCCCOCC(CN(C)C)OCCCCCCCCC=CCCCCCCCC
Reactant: CC(=O)CCC(=O)CCC(=O)CCOC(=O)CCCCBr
Solvent: CC(C)=O
Product: CCCCCCCCC=CCCCCCCCCOCC(C[N+](C)(C)CCCCC(=O)OCCC(=O)CCC(=O)CCC(C)=O)OCCCCCCCCC=CCCCCCCCC
Product: [Br-]
Temperature: 80 °C
Reaction time: 24 h
Yield: 38.9 %

Procedure:
A mixture of 4 (430 mg, 0.69 mmol) and 6 (252 mg, 0.8 mmol) in acetone (5 ml) was stirred in a sealed-tube at RT for 24 h and than at 80° C. for another 24 h. After cooling, the solvent was evaporated in vacuo. Purification by flash chromatography on silica (10% methanol in dichloromethane) gave ME53 as an orange oil (264 mg, 44%).
Reaction SMILES: ClC[C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C[O:20][C:21](=[O:34])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][C:25]=1[CH2:31][CH2:32][CH3:33].[CH2:35](C1C=CC=CC=1O)CC>>[CH2:31]([C:25]1[CH:26]=[C:27]([S:30][CH2:35][C:8]2[CH:3]=[CH:4][C:5]([C:9]3[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=3)=[CH:6][CH:7]=2)[CH:28]=[CH:29][C:24]=1[O:23][CH2:22][C:21]([OH:20])=[O:34])[CH2:32][CH3:33]
Reactant: FC(F)(F)c1ccc(-c2cccc(CCl)c2)cc1
Reactant: CCCc1ccccc1O
Reactant: CCCc1cc(S)ccc1OCC(=O)OC
Product: CCCc1cc(SCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)ccc1OCC(=O)O

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 48B and (4-Mercapto-2-propyl-phenoxy)-acetic acid methyl ester, prepared from 2-propylphenol in a manner analagous to Example 2. MS m/z 475 (M+1).
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:27]=[CH:26][C:8]([CH2:9][CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[C:14]([O:23][CH3:24])[C:15]([O:21][CH3:22])=[CH:16][CH:17]=3)[CH:12]2[CH3:25])=[CH:7][CH:6]=1)([O-])=O>CO.O.[Pd].C(O)C>[ClH:1].[NH2:2][C:5]1[CH:27]=[CH:26][C:8]([CH2:9][CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:17](=[CH:16][C:15]([O:21][CH3:22])=[C:14]([O:23][CH3:24])[CH:13]=3)[CH:12]2[CH3:25])=[CH:7][CH:6]=1
Reactant: COc1ccc2c(c1OC)C(C)N(CCc1ccc([N+](=O)[O-])cc1)CC2
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: O
Product: COc1cc2c(cc1OC)C(C)N(CCc1ccc(N)cc1)CC2
Reaction time: 20 h
Yield: 72.3 %

Procedure:
A solution of N-(4-nitrophenethyl)-1,2,3,4-tetrahydro-7,8-dimethoxy-1-methylisoquinoline hydrochloride (66.3 g, 0.17 m) in methanol (1 liter) and water (10 ml) was placed in an 1100 ml pressure bottle and 5% Pd/C catalyst (5.0 g) added under nitrogen. The mixture was hydrogenated at 40 psi in a Parr apparatus for 20 hr. The catalyst was removed by filtration and the solvent evaporated leaving an oily residue. The residue was dissolved in 95% ethanol (300 ml) and after 24 hr a solid had crystallized out which was collected by filtration and air dried giving 44.3 g (82%) of N-(4-aminophenethyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline monohydrochloride. The free base could be obtained by basifying a solution of this salt with NaOH and extracting with CHCl3. Evaporation of the solvent and crystallization of the resulting oil from cyclohexane gives the base in 80% efficiency as a white solid. Melting point after drying at 60° for 26 hr under high vacuum 102°-103°.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:18]=[C:17]([NH2:19])[C:16]([O:20][CH3:21])=[C:15]([NH2:22])[N:14]=2)=[N:6]1.C(N(CC)CC)C.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38].[OH-].[Na+]>CN(C=O)C.O>[NH2:19][C:17]1[N:18]=[C:13]([C:7]2[C:8]3[CH2:12][CH2:11][CH2:10][C:9]=3[N:5]([CH2:4][C:3]3[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=3[F:1])[N:6]=2)[N:14]=[C:15]([NH:22][C:37](=[O:38])[CH2:36][O:35][CH3:34])[C:16]=1[O:20][CH3:21]
Reactant: COCC(=O)Cl
Reactant: COc1c(N)nc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COCC(=O)Nc1nc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc(N)c1OC
Temperature: 50 °C

Procedure:
300 mg of 2-[1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]-5-methoxy pyrimidine-4,6-diamine 1-6-1 were suspended in 3.8 mL DMF. After addition of 86 mg of triethylamine (0.85 mmol, 1.0 eq.) and 92 mg of methoxyacetylchloride (0.85 mmol, 1.0 eq.), the resulting reaction mixture was heated for four h at 50° C. For completition of reaction further 64 mg of triethylamine (0.64 mmol, 0.75 eq.) and 69 mg of methoxyacetylchloride (0.64 mmol, 0.75 eq.) were added and the suspension was heated for two h at 50° C. After cooling and dilution with water, the pH was adjusted to 7 using 3N aqueous sodium hydroxide solution. The precipitated crude product was filtered off and dried in vacuo yielding 267 mg (0.63 mmol, 74%) of target compound. The crude material was pure enough for further processings.
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:9]=1.[I:40]N1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O>[CH3:37][Si:34]([CH3:36])([CH3:35])[CH2:33][CH2:32][O:31][CH2:30][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:38])[CH3:39])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:40])=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a mixture of tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (5 g, 8.65 mmol) in DMF (15 mL) was added N-iodosuccinimide (1.86 g, 8.27 mmol) and the resulting mixture was allowed to stir at room temperature for 1 hour. The mixture diluted with EtOAc (100 mL), washed with water (20 mL). The aqueous layer was extracted with EtOAc (20 mL) once, and combined organic layer was washed with water (20 mL) three times, brine once and dried (MgSO4). After concentration, the residue was purified by column chromatography on silica gel. Elution with EtOAc/Hex (0-30%) gave tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (4.55 g, 75%).
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH:6]([CH3:10])[CH2:7][CH2:8][N:9]=1.[NH2:11][C:12]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[CH:17][C:13]=1[C:14](O)=[O:15]>CN(C=O)C.O>[CH3:10][CH:6]1[CH2:7][CH2:8][N:9]2[C:3](=[N:11][C:12]3[C:13]([C:14]2=[O:15])=[CH:17][CH:18]=[C:19]([C:21]([OH:23])=[O:22])[CH:20]=3)[CH2:4][CH2:5]1
Reactant: Nc1cc(C(=O)O)ccc1C(=O)O
Reactant: COC1=NCCC(C)CC1
Solvent: O
Solvent: CN(C)C=O
Product: CC1CCc2nc3cc(C(=O)O)ccc3c(=O)n2CC1
Temperature: 25 °C
Yield: 2.2 %

Procedure:
A solution of (E)-7-methoxy-4-methyl-3,4,5,6-tetrahydro-2H-azepine (1.1 g) and 2-aminoterephthalic acid (1.4 g, 7.7 mmol) in DMF (30 mL) was stirred at 100° C. for 4 h. After it was cooled to room temperature, the reaction was diluted with water (80 mL) and extracted with ethyl acetate (2×60 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by silica gel chromatography to give 47 mg of desired product.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1C(=O)C2C(=CC=CC=2)C1=O.O.NN.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[CH2:4][NH2:5]
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc([N+](=O)[O-])cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NN
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NCc1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 68.5 %

Procedure:
To a stirred solution of 2-(2-fluoro-4-nitrobenzyl)isoindoline-1,3-dione (500 mg, 1.665 mmol) in tetrahydrofuran were added hydrazine monohydrate (333 mg, 6.661 mmol) and p-toluenesulfonic acid monohydrate (29 mg, 0.167 mmol). The reaction mixture was refluxed for 6 h, then cooled to room temperature, diluted with ethyl acetate. The mixture was washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was removed in vacuo. The crude was purified by column chromatography to give (2-fluoro-4-nitrophenyl)methanamine (194 mg, 68%).
Reaction SMILES: C(OC(=O)NC(C1SC(SC)=C(S(C2C=C(Br)C3N(CC4C=CC([N+]([O-])=O)=CC=4F)C=NC=3C=2)(=O)=O)C=1)=N)(C)(C)C.C(OC(=O)[NH:48][C:49]([C:51]1[S:52][C:53]([S:80][CH3:81])=[C:54]([S:56]([C:59]2[CH:78]=[C:77]([Br:79])[C:62]3[N:63]=[CH:64][N:65]([CH2:66][C:67]4[CH:72]=[CH:71][C:70]([N+:73]([O-:75])=[O:74])=[CH:69][C:68]=4[F:76])[C:61]=3[CH:60]=2)(=[O:58])=[O:57])[CH:55]=1)=[NH:50])(C)(C)C.[F:83][C:84]([F:89])([F:88])[C:85]([OH:87])=[O:86]>C(Cl)Cl>[F:83][C:84]([F:89])([F:88])[C:85]([OH:87])=[O:86].[Br:79][C:77]1[C:62]2[N:63]=[CH:64][N:65]([CH2:66][C:67]3[CH:72]=[CH:71][C:70]([N+:73]([O-:75])=[O:74])=[CH:69][C:68]=3[F:76])[C:61]=2[CH:60]=[C:59]([S:56]([C:54]2[CH:55]=[C:51]([C:49]([NH2:50])=[NH:48])[S:52][C:53]=2[S:80][CH3:81])(=[O:57])=[O:58])[CH:78]=1
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cc(Br)c2ncn(Cc3ccc([N+](=O)[O-])cc3F)c2c1
Agent: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cc(Br)c2c(c1)ncn2Cc1ccc([N+](=O)[O-])cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cc(Br)c2ncn(Cc3ccc([N+](=O)[O-])cc3F)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
A solution of ({4-[7-bromo-1-(2-fluoro-4-nitro-benzyl)-1H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophen-2-yl)-imino-methyl)-carbamic acid tert-butyl ester and ({4-[7-bromo-3-(2-fluoro-4-nitro-benzyl)-3H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophen-2-yl)-imino-methyl)-carbamic acid tert-butyl ester ((from above step a) 0.005 g, 0.007 mmol) in CH2Cl2 (1 mL) was cooled to 0° C. and treated with 25% trifluoroacetic acid in CH2Cl2 (1.00 mL). The mixture was allowed to warm to room temperature and was stirred 3 h. Solvents were removed in vacuo. Preparatory HPLC (10–80% acetonitrile in 1% TFA/water over 30 min.) afforded the product 4-[7-bromo-3-(2-fluoro-4-nitro-benzyl)-3H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate (0.002 g, 47%) as a white solid. 1H NMR (MeOD): δ 8.714 (s, 1H), 8.308 (s, 1H), 8.231 (d, 1H, J=1.6 Hz), 8.106 (m, 2H), 8.047 (d, 1H, J=0.8 Hz), 7.556 (t, 1H, J=8.4 Hz), 5.854 (s, 2H), 2.630 (s, 3H). C20H15BrFN5O4S3: 583.95 (M+1) found 585.05.
Reaction SMILES: [CH2:1]([N:4]([CH2:22][CH2:23][CH3:24])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]2[O:18][CH:19]=[CH:20][N:21]=2)[CH:16]=1)[C:10]([O:12]C)=[O:11])=[O:6])[CH2:2][CH3:3]>CO.[OH-].[K+].O>[CH2:22]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]2[O:18][CH:19]=[CH:20][N:21]=2)[CH:16]=1)[C:10]([OH:12])=[O:11])=[O:6])[CH2:23][CH3:24]
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2ncco2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Yield: 88.2 %

Procedure:
A solution of methyl 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoate (315 mg, 0.95 mmol) in methanol (3 mL) and potassium hydroxide (3 mL of a 1.0 M solution in water, 3 mmol) was stirred at room temperature for 30 min. The solvent was removed under reduced pressure, the residue was dissolved in water, and extracted with ethyl acetate. The aqueous layer was acidified to pH 3 with 1 M hydrochloric acid, extracted with chloroform (3×100 mL), and the combined organic layers were concentrated under reduced pressure to afford 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoic acid (265 mg): 1H NMR (300 MHz, CD3OD) δ 8.71 (s, 1H), 8.08 (s, 2H), 8.05 (s, 1H), 7.34 (s, 1H), 3.52 (t, J=8 Hz, 2H), 3.26 (t, J=8 Hz, 2H), 1.75 (q, J=8 Hz, 2H), 1.59 (q, J=8 Hz, 2H), 1.02 (t, J=8 Hz, 3H), 0.74 (t, J=8 Hz, 3H).