Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(N1CCN([CH2:14][CH2:15][NH:16][C@:17]23[CH2:51][CH2:50][C@@H:49]([C:52]([CH3:54])=[CH2:53])[C@@H:18]2[C@@H:19]2[C@@:32]([CH3:35])([CH2:33][CH2:34]3)[C@@:31]3([CH3:36])[C@@H:22]([C@:23]4([CH3:48])[C@@H:28]([CH2:29][CH2:30]3)[C:27]([CH3:38])([CH3:37])[C:26]([C:39]3[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[CH:41][CH:40]=3)=[CH:25][CH2:24]4)[CH2:21][CH2:20]2)CC1)=O)(C)(C)C.[CH3:55][S:56]([N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)(=[O:58])=[O:57]>>[CH3:35][C@:32]12[C@@:31]3([CH3:36])[C@@H:22]([C@:23]4([CH3:48])[C@@H:28]([CH2:29][CH2:30]3)[C:27]([CH3:37])([CH3:38])[C:26]([C:39]3[CH:40]=[CH:41][C:42]([C:43]([OH:45])=[O:44])=[CH:46][CH:47]=3)=[CH:25][CH2:24]4)[CH2:21][CH2:20][C@@H:19]1[C@H:18]1[C@H:49]([C:52]([CH3:54])=[CH2:53])[CH2:50][CH2:51][C@:17]1([NH:16][CH2:15][CH2:14][N:62]1[CH2:63][CH2:64][N:59]([S:56]([CH3:55])(=[O:58])=[O:57])[CH2:60][CH2:61]1)[CH2:34][CH2:33]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)OC(C)(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CS(=O)(=O)N1CCNCC1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 1-(methylsulfonyl)piperazine as the alkylating reagent in Step 3. The product was isolated as a white solid (220 mg, 89%). LCMS: m/e 720.58 (M+H)+, 2.25 min (method 11). 1H NMR (500 MHz, Acetic) δ 8.04 (d, J=8.2 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 5.37 (d, J=4.6 Hz, 1H), 4.86 (s, 1H), 4.74 (s, 1H), 3.74-3.38 (m, 7H), 3.37-3.25 (m, 1H), 3.17 (br. s., 4H), 2.94 (s, 3H), 2.91-2.80 (m, 1H), 2.35-1.01 (m, 22H), 1.77 (s, 3H), 1.26 (s, 3H), 1.14 (s, 3H), 1.10 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:16]([O:18][C:19]([C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N+:27]([O-])=[CH:26][CH:25]=[CH:24]2)=[O:20])[CH3:17].[CH3:32][NH2:33].O1CCCC1>ClCCl>[CH3:32][NH:33][C:26]1[CH:25]=[CH:24][C:23]2[C:28](=[CH:29][CH:30]=[C:21]([C:19]([O:18][CH2:16][CH3:17])=[O:20])[CH:22]=2)[N:27]=1
Reactant: CCOC(=O)c1ccc2c(ccc[n+]2[O-])c1
Reactant: CN
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2nc(NC)ccc2c1
Temperature: -70 °C
Reaction time: 0.08 h
Yield: 35 %

Procedure:
Trifluoromethanesulfonic anhydride (1.92 mL, 11.4 mmol) was added dropwise to a −70° C. solution of 6-(ethoxycarbonyl)quinoline 1-oxide (2.25 g, 10.4 mmol) in dichloromethane (150 mL). The mixture was stirred at −70° C. for 5 minutes. Then a solution of methylamine in tetrahydrofuran (31 mL, 62 mmol, 2 M) was added dropwise. The mixture was stirred at −70° C. for 5 minutes. The reaction was quenched with water (20 mL). The layers were separated and the aqueous was extracted with dichloromethane (3×30 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave the title compound (850 mg, 35%) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ): 8.33 (d, 1H), 8.16-8.13 (m, 1H), 7.90-7.87 (d, 1H), 7.70-7.67 (d, 1H), 6.68 (d, 1H), 5.30 (br. s., 1H), 4.43-4.38 (q, 2H), 3.13-3.12 (d, 3H), 1.44-1.40 (m, 3H).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:31])[C:6]1[CH:11]=[C:10]([NH:12][C:13](=[O:28])[C@:14]([OH:27])([CH3:26])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[CH:9]=[CH:8][C:7]=1[C:29]#[N:30]>C1COCC1.CO>[C:29]([C:7]1[CH:8]=[CH:9][C:10]([NH:12][C:13](=[O:28])[C@:14]([OH:27])([CH3:26])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)=[CH:11][C:6]=1[C:5]([OH:31])=[O:4])#[N:30]
Reactant: COC(=O)c1cc(NC(=O)[C@@](C)(O)COc2ccc(C#N)c(F)c2)ccc1C#N
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@](O)(COc1ccc(C#N)c(F)c1)C(=O)Nc1ccc(C#N)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1 M LiOH (34 ml) was added to a solution of 2-cyano-5-[(S)-3-(4-cyano-3-fluorophenoxy)-2-hydroxy-2-methylpropionylamino]benzoic acid methyl ester (4.52 g, 11.4 mmol) in THF (50 ml) and methanol (6 ml) at 16-18° C. The resulting solution was stirred at room temperature for 2.5 h. The solvents were evaporated and pH was adjusted to 2 with HCl solution. The product was extracted into ethyl acetate. The organic phase was washed with water, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (eluent: CH2Cl2/MeOH 98:2). Trituration in hot CH2Cl2, cooling to room temperature and filtration yielded the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:10]=1)=O)([O-:3])=[O:2].[BH4-].[Na+].B(F)(F)F.CCOCC.C(OCC)(=O)C>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[CH2:7][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:10]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CCCn1cc(C(=O)c2cccc([N+](=O)[O-])c2)c2ccccc21
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)CCCn1cc(Cc2cccc([N+](=O)[O-])c2)c2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 35.9 %

Procedure:
To a solution of ethyl 4-[3-(3-nitrobenzoyl)indol-1-yl]butyrate (0.5 g) in tetrahydrofuran (10 ml) were added sodium borohydride (99.4 mg) and boron trifluoride etherate (0.485 ml) at -25° C., and the mixture was stirred at the same temperature for 2 hours. The mixture was poured into a mixture of ethyl acetate and ice water. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (25 g) eluting with a mixture of ethyl acetate and hexane (1:4) to give ethyl 4-[3-(3-nitrobenzyl)indol-1-yl]butyrate (173 mg) as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[C:10]([CH3:11])=[C:9]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[CH:8]=[C:7]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:6]=1[OH:23])([CH3:4])([CH3:3])[CH3:2].CCCCCC.C([Li])CCC.[C:35](Cl)(=[O:37])[CH3:36].[Cl-].[NH4+]>O1CCCC1>[C:35]([O:23][C:6]1[C:7]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:8][C:9]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[C:10]([CH3:11])[C:5]=1[C:1]([CH3:3])([CH3:4])[CH3:2])(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: Cc1c(OC2CCCCO2)cc(C(C)(C)C)c(O)c1C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)Oc1c(C(C)(C)C)cc(OC2CCCCO2)c(C)c1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
2,6-Di-tert-butyl-3-methyl-4-tetrahydropyranyloxyphenol (4.4 g) was dissolved in anhydrous tetrahydrofuran (50 ml) and a n-hexane solution (1.1 eq.) of n-butyllithium was added dropwise at 0° C. under a nitrogen atmosphere. After stirring the mixture for 30 min, acetyl chloride (1.08 ml, 1.1 eq.) was added and the mixture was allowed to warm to room temperature. After stirring for 3 h, the reaction mixture was poured into a saturated aqueous solution of ammonium chloride and the mixture was subjected to extraction with diethyl ether. The extract was washed with water and saturated brine, then dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 1-acetoxy-2,6-di-tert-butyl-3-methyl-4-tetrahydropyranyloxybenzene [4.09 g (yield, 82.2%)] as a colorless crystal.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]2[CH2:9][O:8]2)[CH:2]=1.[NH2:10][C@H:11]([CH3:31])[CH2:12][C:13]1[C:21]2[C:16](=[C:17]([O:22][CH2:23][C:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:25])[CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1>O.C(O)C>[CH2:29]([N:26]([CH2:27][CH3:28])[C:24](=[O:25])[CH2:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[NH:15][CH:14]=[C:13]2[CH2:12][C@H:11]([NH:10][CH2:9][C@H:7]([OH:8])[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH3:31])[CH3:30]
Reactant: c1cncc([C@@H]2CO2)c1
Reactant: CCN(CC)C(=O)COc1cccc2c(C[C@@H](C)N)c[nH]c12
Solvent: O
Solvent: CCO
Product: CCN(CC)C(=O)COc1cccc2c(C[C@@H](C)NC[C@H](O)c3cccnc3)c[nH]c12
Yield: 20.6 %

Procedure:
A solution of (R)-(pyridin-3-yl)oxirane (97 mg, 0.80 mmol) and (R)-2-[3-(2-aminopropyl)-1H-indol-7-yloxy]-N,N-diethylacetamide (243 mg, 0.80 mmol) in water (0.8 mL) and ethanol (8 mL) is refluxed for 5 hours. After concentrated, the resulting residue is purified by preparative TLC (SiO2, 20×20 cm, 0.5 mm, iPrOH/saturated ammonia solution in chloroform=1/10) to give the desired N,N-diethyl-2-{3-[(2R)-2-((2R)-2-hydroxy-2-pyridin-3-ylethylamino)propyl]-1H-indol-7-yloxy}-acetamide (70 mg, yield: 21%).
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH2:32]([N:34]([CH2:39][CH3:40])[CH2:35][CH2:36][NH:37][CH3:38])[CH3:33]>C(Cl)Cl>[CH2:32]([N:34]([CH2:39][CH3:40])[CH2:35][CH2:36][N:37]([CH:18]=[C:17]1[C:16]2[C:15]([CH3:30])([C:14]3[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]4([CH3:31])[CH:8]([C:13]=3[C:21](=[O:22])[C:20]=2[OH:19])[CH2:9][CH2:10][CH:11]4[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]1=[O:24])[CH3:38])[CH3:33]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: CCN(CC)CCNC
Solvent: ClCCl
Product: CCN(CC)CCN(C)C=C1C(=O)OC(COC)C2(C)C1=C(O)C(=O)C1=C2C(OC(C)=O)CC2(C)C(O)CCC12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added N,N-Diethyl-N′-methyl-ethane-1,2-diamine (45 μL, 0.28 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 561 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:18][CH3:19])=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1.[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:13]2[CH2:14][CH2:15][C:16]3[C:6]4[CH:5]=[C:4]([O:18][CH3:19])[C:3]([O:2][CH3:1])=[CH:8][C:7]=4[O:9][C:10](=[O:17])[C:11]=3[CH2:12]2)=[CH:23][CH:22]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COc1cc2oc(=O)c3c(c2cc1OC)CCNC3
Product: COc1cc2oc(=O)c3c(c2cc1OC)CCN(Cc1ccc(Cl)cc1)C3
Yield: 48 %

Procedure:
Prepared by the procedure of Example 3 from 8,9-dimethoxy-1,2,3,4-tetrahydro-chromeno[3,4-c]-pyridin-5-one* and 4-chlorobenzaldehyde. Yield 48%; mp 173°-175° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16]2[CH:17]=[CH:18][C:19](C(O)=O)=[CH:20][C:15]=2[NH:14][CH:13]1[C:24]([O:29][CH3:30])([O:27][CH3:28])[O:25][CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](O[N:48]2N=[N:55][C:50]3[CH:51]=[CH:52][CH:53]=C[C:49]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.NC1C=NC=CC=1.C(N(CC)CC)C.CN([CH:81]=[O:82])C>CCOC(C)=O>[N:48]1[CH:53]=[CH:52][CH:51]=[C:50]([NH:55][C:81]([C:18]2[CH:19]=[CH:20][C:15]3[N:14]=[C:13]([C:24]([O:27][CH3:28])([O:25][CH3:26])[O:29][CH3:30])[N:12]([CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:16]=3[CH:17]=2)=[O:82])[CH:49]=1
Reactant: COC(OC)(OC)C1Nc2cc(C(=O)O)ccc2N1CCCNC(=O)OC(C)(C)C
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CN(C)C=O
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1cccnc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(OC)(OC)c1nc2ccc(C(=O)Nc3cccnc3)cc2n1CCCNC(=O)OC(C)(C)C
Temperature: 45 °C
Yield: 99 %

Procedure:
A solution of 1-(3-tert-butoxycarbonylamino-propyl)-2-trimethoxymethyl-3H-benzimidazole-5-carboxylic acid (Intermediate A, 70 mg, 0.17 mmol) and PyBOP (95 mg, 0.18 mmol) in DMF (1 mL) was stirred for 10 min, and 3-aminopyridine (17 mg, 0.18 mmol) and triethylamine (46 μL, 0.33 mmol) are added. The solution is heated in a block heater at 45° C. for 20 h. The solution is diluted with EtOAc and is washed with Na2CO3, H2O, and brine. The organic layer is dried (MgSO4) and evaporated to afford the title compound (102 mg, 0.16 mmol, 99%) as an oil that was used in the next step without purification.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].I[CH2:34][CH:35]([CH3:37])[CH3:36]>CS(C)=O.C(OCC)(=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[N:26]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([O:32][CH2:5][CH:6]([CH3:14])[CH3:7])=[O:31])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)O)c[nH]c34)no2)cc1Cl
Reactant: CC(C)CI
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)COC(=O)CCc1cn(CC(C)C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium hydroxide (64 mg) was added to a solution of 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E1) (100 mg) and 1-iodo-2-methylpropane (0.2 mL) in dimethyl sulfoxide (DMSO) (1 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate. The organic solution was washed with water. The organic solution was dried over sodium sulfate. After concentration, the residue was purified via column chromatography to afford 2-methylpropyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-(2-methylpropyl)-1H-indol-3-yl]propanoate (D124) (77 mg). MS (ES): C30H36ClN3O4 requires 537; found 538.3 (M+H+).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][SH:4].F[C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14].C(N(CC)CC)C>O1CCCC1>[CH2:3]([S:4][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14])[CH:2]=[CH2:1]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: C=CCS
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCSc1cc(F)ccc1[N+](=O)[O-]
Reaction time: 4 h
Yield: 63.5 %

Procedure:
A solution of 2.3 g (0.031 mole) of allylthiol in 25 ml of tetrahydrofuran was added to 5.0 g (0.031 mole) of 2,4-difluoronitrobenzene in 25 ml of tetrahydrofuran at -30° C. To this mixture was added dropwise 3.1 g (0.031 mole) of triethylamine. The temperature was allowed to rise to room temperature and stirring was continued for four hours. The tetrahydrofuran was evaporated under reduced pressure, and water and diethyl ether were added to the residue. The ether layer was separated and dried over anhydrous potassium carbonate. The ether was evaporated under reduced pressure, leaving a liquid residue. This residue was distilled at 105° C./1.2 mm of Hg, yielding 4.2 g of 2-allylthio-4-fluoronitrobenzene. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[C:3]=1[CH3:19].[Li]CCCC.[CH:25](=[O:28])[CH2:26][CH3:27]>C1COCC1>[CH3:19][C:3]1[C:4]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])=[N:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH:25]([OH:28])[CH2:26][CH3:27]
Reactant: CCC=O
Reactant: Cc1cc(C)c(Oc2nc(C)cc(Br)c2C)c(C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(O)c1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Reaction time: 0.33 h

Procedure:
To a −78° C. solution of 4-bromo-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine in dry THF was added nBuLi and stirred at that temperature for 20 minutes. Excess propionaldehyde was added and stirred for 2 hours at −78° C. The mixture was quenched with water, extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated. After column chromatography, an off-white solid was obtained, mp. 119-120° C.1H NMR(CDCl3) d 6.86(s,3H), 4.90(m,1H), 2.281(s,3H), 2.28(s,3H), 2.21(s,3H), 2.02(s,6H), 1.65-1.8(m,2H), 1.00(t,3H) ppm.
Reaction SMILES: S([O-])([O-])(=O)=O.[Al+3].S([O-])([O-])(=O)=O.S([O-])([O-])(=O)=O.[Al+3].[C:18]([O-:21])(=[O:20])[CH3:19].[C:22]([O-:25])(=[O:24])[CH3:23].[C:26]([O-])(=O)[CH3:27].[C:30]([O-])(=O)[CH3:31].C([O-])(=O)C.[NH2:38][CH2:39]CNCCN.[Na+].[Na+].[Na+].[Na+].[Na+].[OH2:50]>>[C:39]([NH2:38])(=[O:50])[CH:26]=[CH2:27].[C:22]([OH:25])(=[O:24])[CH2:23][CH2:30][CH2:31][CH2:19][C:18]([OH:21])=[O:20]
Reactant: CC(=O)[O-]
Reactant: O
Reactant: NCCNCCN
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [Na+]
Product: C=CC(N)=O
Product: O=C(O)CCCCC(=O)O

Procedure:
An aqueous monomer solution was prepared containing aluminium sulphate as follows: 107.1 gms of acrylamide, 4.3 gms of adipic acid, 0.6 gms of a 40% solution of pentasodium diethylene triamine pentaacetate in water, 81.4 gms of 40% aqueous polyDADMAC and sufficient water to give 375.1 gms. were mixed together to form a clear solution and adjusted to pH 4.6.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(Cl)(Cl)=O.[CH3:18]O>>[CH3:18][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: CO
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 81 %

Procedure:
To a mixture of 4-amino-3-nitro-benzoic acid (10.0 g, 54.9 mm0l) suspended in methanol (150 mL) was added thionyl chloride (3.99 mL, 54.9 mmol). The mixture was heated to reflux overnight, then cooled to room temperature and filtered. The solid recovered by filtration was rinsed with cold methanol and dried to give 8.68 g (81%) of 4-amino-3-nitro-benzoic acid methyl ester.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:11]=1[CH2:12][OH:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=NN=N1.[CH2:25]([O:28][P:29]([O:37][CH2:38][CH:39]=[CH2:40])N(C(C)C)C(C)C)[CH:26]=[CH2:27].C([O:45]O)(C)(C)C>>[P:29]([O:13][CH2:12][C:11]1[C:14]([O:18][CH3:19])=[CH:15][CH:16]=[CH:17][C:10]=1[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])([O:28][CH2:25][CH:26]=[CH2:27])([O:37][CH2:38][CH:39]=[CH2:40])=[O:45]
Reactant: CC(C)(C)OO
Reactant: COc1cccc(CO[Si](C)(C)C(C)(C)C)c1CO
Reactant: C=CCOP(OCC=C)N(C(C)C)C(C)C
Agent: c1nnn[nH]1
Product: C=CCOP(=O)(OCC=C)OCc1c(CO[Si](C)(C)C(C)(C)C)cccc1OC
Yield: 60.4 %

Procedure:
According to a similar procedure to that described in Example 1-(10), 2-[(tert-butyldimethylsilyl)oxymethyl]-6-methoxybenzyl alcohol (1.13 g, 4.00 mmol) obtained from Example 21-(2), tetrazole (672.3 mg, 9.6 mmol), bis(allyloxy)(diisopropylamino)phosphine (described in Tetrahedron Lett., 30, 4219 (1989); 1.37 g, 5.6 mmol), and tert-butyl hydroperoxide (80% di-tert-butyl peroxide solution; Merck; 0.9 g, 8 mmol) were reacted, and the reaction mixture was worked up to afford, after extraction, an oily residue. The residue was subjected to chromatography on a silica gel (60 g) column (eluent; ethyl acetate:hexane=1:6˜1:2) to give the title compound (1.07 g, 60% yield) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2.CN[C@@H]1CCCC[C@H]1NC.[I-:35].[Na+]>C(O)CCC.C(OCC)(=O)C.[Cu]I>[I:35][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2
Reactant: Cc1cc(Br)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reactant: [I-]
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: Cc1cc(I)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 120 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a solution of 5-Bromo-7-methyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (300 mg, 0.713 mmol) in butanol (3 ml), (1R,2R)—N,N′-dimethylcyclohexane-1,2-diamine (20 mg, 0.142 mmol), copper(I) iodide (13.6 mg, 0.07 mmol) and sodium iodide (214 mg, 1.43 mmol) were added. The resulting mixture was stirred at 120° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water, brine, dried over anhydrous sodium sulphate, filtered, concentrated. Column chromatography (30% EtOAc/Hexanes) provided the title compound as a yellow oil (274 mg, 85%). 1H NMR (300 MHz, CDCl3): δ 7.55-7.57 (m, 2H), 7.30-7.35 (m, 2H), 7.16-7.20 (m, 2H), 4.74 (s, 2H), 4.318 (s, 2H), 2.69 (s, 3H).
Reaction SMILES: C([Li])CCC.CCCCCC.[C:12]([C:18]1[N:19]=[CH:20][N:21]2[CH:25]=[CH:24][S:23][C:22]=12)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].[CH2:26]([Sn:30](Cl)([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH3:29].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:12]([C:18]1[N:19]=[CH:20][N:21]2[CH:25]=[C:24]([Sn:30]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:26][CH2:27][CH2:28][CH3:29])[S:23][C:22]=12)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)(C)C(=O)c1ncn2ccsc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)C(C)(C)C)c2s1
Reaction time: 0.33 h

Procedure:
A 1.6 N n-butyllithium/n-hexane solution (2.9 ml) was added to a solution of 0.92 g of 7-pivaloylimidazo[5,1-b]thiazole in 20 ml of dry THF in an argon atmosphere at −50° C. The mixture was stirred at the same temperature for 20 min. Tri-n-butylstannyl chloride (1.3 ml) was added thereto, followed by stirring for 20 min. A saturated aqueous ammonium chloride solution was added to the reaction mixture. Ethyl acetate was added thereto. The mixture was washed with water and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:3) to give 0.82 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:17])([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[NH:30]1[C:34]([C:35]2[CH:36]=[C:37]([NH2:41])[CH:38]=[CH:39][CH:40]=2)=[N:33][N:32]=[N:31]1>ClC(Cl)C.CN(C=O)C>[NH:33]1[C:34]([C:35]2[CH:36]=[C:37]([NH:41][C:14]([C:11]3([CH3:17])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]3)=[O:16])[CH:38]=[CH:39][CH:40]=2)=[N:30][N:31]=[N:32]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C)(C(=O)Nc2cccc(-c3nnn[nH]3)c2)CC1
Reaction time: 0.67 h
Yield: 70 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (100 mg, 0.41 mmol) in dichloroethane (2.0 mL) were added DMF (2 drops) and pyridine (0.13 g, 1.6 mmol), followed by oxalyl chloride (57 mg, 0.45 mmol). The mixture was stirred for 40 minutes, and 3-(1H-tetrazol-5-yl)-phenylamine was added. The mixture was stirred for 2 hours, and a pink precipitate formed. The mixture was filtered, and the filtrate was washed with 1.0 N aq. HCl and brine, dried over MgSO4, and concentrated to give the title compound in 70% yield. MS (ES+) [M+H]+=387.