Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8]1[S:9][C:10]2[N:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=[O:14])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Li+].[CH2:21](I)[CH3:22]>>[CH2:21]([N:13]1[C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[N:18][C:10]=2[S:9][C:8]1=[N:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:22]
Reactant: CCI
Reactant: O=c1nc(Nc2ccccc2)sc2ncccc12
Agent: [H-]
Agent: [Li+]
Product: CCn1c(=Nc2ccccc2)sc2ncccc2c1=O

Procedure:
The reaction procedure of Example 11 was followed except that 255 mg of 2-anilino-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 9 mg of lithium hydride and 0.081 ml of ethyl iodide were used. As a result, 204 mg of 3-ethyl-2-phenylimino-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH:10]=[C:9]([C:20]([O:22][CH3:23])=[O:21])[C:8]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:3][CH:2]=1.[CH2:28](I)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH:10]=[C:9]([C:20]([O:22][CH3:23])=[O:21])[C:8]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:3][CH:2]=1
Reactant: COC(=O)c1cc2cc(O)c(OC)cc2c(-c2ccncc2)c1C(=O)OC
Reactant: CCCCCCCCI
Product: CCCCCCCCOc1cc2cc(C(=O)OC)c(C(=O)OC)c(-c3ccncc3)c2cc1OC

Procedure:
1-(4-Pyridyl)-2,3-bis(methoxycarbonyl)-6-hydroxy-7-methoxynaphthalene and octyl iodide are treated in the same manner as in Reference Example 117-(2) to give 1-(4-pyridyl)-2,3-bis(methoxycarbonyl)-6-octyloxy-7-methoxynaphthalene.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Cl)=[C:6](Cl)[CH:5]=1)([O-:3])=[O:2].[S-:12][C:13]1[CH:18]=[CH:17][CH:16]=CC=1.[Na+]>>[S:12]1[CH:16]=[CH:17][CH:18]=[C:13]1[C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[C:16]1[S:12][CH:13]=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: [S-]c1ccccc1
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(-c2cccs2)c(-c2cccs2)c1
Yield: 31 %

Procedure:
The procedure was as previously mentioned using 1-nitro-3,4-dichlorobenzene (10 g, 0.052 M) and sodium thiophenoxide (13.75 g, 0.104 M). mp = 97°-101°. Yield 31%. The reaction product was characterized by NMR, 13CNMR, ir, and Mass Spectra (M+ = 339).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>O1CCCC1>[C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.2 %

Procedure:
1.57 g (10 mmol) of bromobenzene and 4.15 g (30 mmol) of K2CO3 are added to a solution of 1.83 g (15 mmol) of phenylboronic acid in 20 ml of tetrahydrofuran. After the mixture has been stirred at room temperature for 15 minutes, 0.21 g (0.15 mmol) of [{Pd[P(C2F5)2O]2H}2(μ-Cl)2], prepared in accordance with Example 13, is added, and the reaction mixture is heated under reflux for 3 hours. After cooling and addition of 100 ml of water, the reaction mixture is extracted with 200 ml of hexane. The organic phase is washed with water and dried using MgSO4. After filtration and removal of the solvent (in vacuo), 0.99 g of biphenyl is isolated as a white solid. The yield is 64%, based on the bromobenzene employed.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.[NH2:19][C:20]1[C:21]2[CH:34]=[C:33]([C:35]([NH:37][N:38]([CH3:45])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])[S:32][C:22]=2[N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[N:24]=1.CN1CCN(CC2C=CC(C(Cl)=O)=CC=2)CC1.O>N1C=CC=CC=1>[CH3:45][N:38]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[NH:37][C:35]([C:33]1[S:32][C:22]2[N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])[N:24]=[C:20]([NH:19][C:14](=[O:15])[C:13]3[CH:17]=[CH:18][C:10]([CH2:9][N:6]4[CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][CH2:5]4)=[CH:11][CH:12]=3)[C:21]=2[CH:34]=1)=[O:36]
Reactant: CN(NC(=O)c1cc2c(N)nn(C(=O)OC(C)(C)C)c2s1)c1ccccc1
Reactant: CN1CCN(Cc2ccc(C(=O)Cl)cc2)CC1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CN1CCN(Cc2ccc(C(=O)Nc3nn(C(=O)OC(C)(C)C)c4sc(C(=O)NN(C)c5ccccc5)cc34)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.1 %

Procedure:
391 mg (1.55 mmol) of 4-(4-methylpiperazin-1-ylmethyl)benzoyl chloride hydrochloride are added to a solution of 0.30 g (0.77 mmol) of tert-butyl 3-amino-5-(N′-methyl-N′-phenylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate in 16 mL of pyridine under argon. The reaction mixture is stirred at a temperature in the region of 25° C. for 16 hours, a further 294 mg (1.16 mmol) of 4-(4-methylpiperazin-1-ylmethyl)benzoyl chloride are then added and stirring is continued for 5 hours. The reaction mixture is then cooled to a temperature in the region of 10° C. and then treated with 50 mL of water. The mixture is extracted twice with 100 mL of ethyl acetate. The organic phases are combined, washed with water to neutral pH, dried over magnesium sulfate, filtered and then concentrated to dryness under vacuum (3 kPa) at a temperature in the region of 30° C. The residue is purified by chromatography on a cartridge of 25 g of silica gel (0.015-0.040 mm), eluting successively with dichloromethane/methanol mixtures (98/2 by volume, and then 97/3, then 96/4 and finally 95/5) at a flow rate of 15 mL/min. The fractions containing the expected product are combined and then concentrated to dryness under reduced pressure (3 kPa) at a temperature in the region of 30° C. 0.14 g of tert-butyl 5-(N′-methyl-N′-phenylhydrazinocarbonyl)-3-[4-(4-methylpiperazin-1-ylmethyl)benzoylamino]thieno[2,3-c]pyrazole-1-carboxylate is thus obtained in the form of an off-white solid melting at 218° C. tert-Butyl 3-amino-5-(N′-methyl-N′-phenylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate is described in example 8. 4-(4-Methylpiperazin-1-ylmethyl)benzoyl chloride may be prepared according to patent WO 03/066 613 A1.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([NH2:29])=[O:28])[CH2:22]2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][N:40]([C:43](=[O:45])[CH3:44])[CH2:39][CH2:38]2)=[CH:33][CH:32]=1.C[Si](Cl)(C)C>CCCCO>[C:43]([N:40]1[CH2:39][CH2:38][N:37]([C:34]2[CH:35]=[CH:36][C:31]([NH:30][C:2]3[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([NH2:29])=[O:28])[CH2:22]4)[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=3)=[CH:32][CH:33]=2)[CH2:42][CH2:41]1)(=[O:45])[CH3:44]
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N4CCCC(C(N)=O)C4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(N4CCCC(C(N)=O)C4)c4ccn(S(=O)(=O)c5ccc(C)cc5)c4n3)cc2)CC1
Yield: 6.8 %

Procedure:
A mixture of 1-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-3-carboxamide (125 mg, 0.288 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (100 mg, 0.456 mmol) and trimethylsilyl chloride (0.100 mL, 0.79 mmol) in n-BuOH (3 mL) was stirred at 116° C. for 20 h. n-BuOH was removed in vacuo. The residue was purified by HPLC to give 1-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-3-carboxamide (12 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)C)=[CH:9][N:10]=2)[N:7]=1.ClC1C=CC2N(C(C(C3C=C4C(=CC=3F)N(C)N=C4)O)=CN=2)N=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)=[CH:9][N:10]=2)[N:7]=1
Reactant: CC(c1cc2cnn(C)c2cc1F)c1cnc2ccc(Cl)nn12
Agent: Cn1ncc2cc(C(O)c3cnc4ccc(Cl)nn34)c(F)cc21
Product: Cn1ncc2cc(Cc3cnc4ccc(Cl)nn34)c(F)cc21

Procedure:
The title compound was prepared as a yellow solid in analogy to the synthesis of compound 68.2 from (6-chloroimidazo[1,2-b]pyridazin-3-yl)(6-fluoro-1-methyl-1H-indazol-5-yl)methanol. LCMS (method B): [MH]+=316, tR=2.56 min.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C:16]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]2[C:19]([C:20]3([CH3:31])[CH2:30][CH:21]3[CH2:22][O:23]2)=[CH:18][CH:17]=1)=O)(C)(C)C>ClCCl>[NH2:15][C:16]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]2[C:19]([C:20]3([CH3:31])[CH2:30][CH:21]3[CH2:22][O:23]2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1c(NC(=O)OC(C)(C)C)ccc2c1OCC1CC21C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c(N)ccc2c1OCC1CC21C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
Trifluoroacetic acid (4 mL) was added to a solution of methyl (1aRS,7bSR)-5-(tert-butoxycarbonylamino)-7b-methyl-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 51, 0.6 g) in dichloromethane (4 mL) and the resultant dark solution was stirred at room temperature for 1 hour. The solution was evaporated to dryness and the residue was partitioned between water and ethyl acetate and treated with a small amount of solid sodium bicarbonate until the pH of the aqueous layer was >7. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give methyl (1aRS,7bSR)-5-amino-7b-methyl-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (0.402 g) as a red/orange solid.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.Cl[C:9](Cl)([O:11][C:12](=[O:18])[O:13][C:14](Cl)(Cl)Cl)Cl.C(Cl)Cl.CO>C(Cl)Cl>[NH2:3][CH2:6][CH2:7][CH:9]1[CH2:14][O:13][C:12](=[O:18])[O:11]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: NCCC1COC(=O)O1
Yield: 263.2 %

Procedure:
To a solution of the diol (9 g, 37.66 mmol) in CH2Cl2 (200 mL) was added triethylamine (15.2 g, 151 mmol) at −20˜30° C. under N2. After several minutes, triphosgene (5.5 g, 18.83 mmol) was added to the mixture dropwise at this temperature and stirred at −20˜30° C. for half an hour. Then the mixture was stirred at room temperature for 15 h. TLC (CH2Cl2/MeOH=10:1) showed the starting material was almost consumed. To the mixture was added water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, concentrated under vacuum and purified through silica gel chromatography (CH2Cl2/MeOH=10:1) to give the corresponding cyclized dioxolane (6.5 g, 55%) as pale solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[CH3:12][NH:13][C:14](Cl)=[O:15]>C1(C(C)C)C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:14](=[O:15])[NH:13][CH3:12]
Reactant: CNC(=O)Cl
Reactant: Oc1ccc2ccccc2c1
Solvent: CC(C)c1ccccc1
Product: CNC(=O)Oc1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
72 parts by weight of β-naphthol are dissolved in 250 parts by weight of cumene at 80° C. 46.7 parts by weight of methylcarbamyl chloride are stirred into this solution over a period of 10 minutes while nitrogen is simultaneously bubbled through the solution. The reaction is complete after 15 minutes. The hot reaction solution is cooled to 0° C and the precipitated β-naphthyl-N-methylcarbamate is isolated. The yield is 85% of theory.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[C:17]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11].[CH2:22](Br)[CH:23]=[CH2:24].O>CN(C)C=O>[CH3:20][CH:19]([O:18][C:17]1[C:8]([O:7][CH2:24][CH:23]=[CH2:22])=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])[CH3:21]
Reactant: COC(=O)c1cccc(OC(C)C)c1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1c(OC(C)C)cccc1C(=O)OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79 %

Procedure:
Cesium carbonate (2.05 g, 6.2 mmol) was added to a solution of methyl 2-hydroxy-3-(propan-2-yloxy)benzoate (123c, 539 mg, 2.40 mmol) in N,N-dimethylformamide (9.6 mL), causing a thick paste to form. Allyl bromide (0.25 mL, 3.0 mmol) was added and the mixture stirred at room temperature for 1.5 hours. Deionized water (15 mL) was added, and the solution extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried over magnesium sulfate, filtered, concentrated under vacuum, and purified by column chromatography (ethyl acetate/heptane) to give methyl 3-(propan-2-yloxy)-2-(prop-2-en-1-yloxy)benzoate (123d, 474.5 mg, 79% yield) as a colorless oil.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[O:22][CH:21]=[N:20][C:19]=2[CH2:23][CH3:24])=[N:16][CH:17]=1.[Cl:25]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.O>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[O:22][C:21]([Cl:25])=[N:20][C:19]=2[CH2:23][CH3:24])=[N:16][CH:17]=1
Reactant: CCc1ncoc1-c1ccc(Br)cn1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc(Cl)oc1-c1ccc(Br)cn1
Temperature: 25 °C
Yield: 89 %

Procedure:
LiHMDS (1.0 M in THF, 8.5 mL, 8.5 mmol) was added dropwise to a solution of Example 44A (1.97 g, 7.78 mmol) in THF (26 mL) at −78° C. After 30 min solid hexachloroethane (1.84 g, 7.78 mmol) was added in one portion and the reaction mixture was stirred while warming to ambient temperature overnight. The reaction was diluted with water and extracted with EtOAc. The organic extract was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography on silica gel (Analogix® Intelliflash 280™; SF25-120 g column; 100% hexane 0-5 min, then 0% to 25% EtOAc/hexanes eluant, 5-40 min) afforded 1.99 g (89%) of the title compound as a yellow oil that solidified on standing. 1H NMR (300 MHz, CDCl3) δ 8.67 (dd, J=2.4, 0.6, 1H), 7.86 (dd, J=8.5, 2.4, 1H), 7.47 (dd, J=8.5, 0.6, 1H), 3.02 (q, J=7.5, 2H), 1.27 (t, J=7.5, 3H). MS (DCI+) m/z 287/289 (M+H).
Reaction SMILES: FC(F)(F)C([O-])=O.[S:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH3+:14].Br[C:16]1[C:17]2[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:23]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:22][C:18]=2[N:19]=[CH:20][N:21]=1.CCN(C(C)C)C(C)C>C(O)CCC>[C:25]1([C:24]2[C:17]3[C:16]([NH:14][CH2:13][CH:9]4[CH2:10][CH2:11][CH2:12][S:8]4)=[N:21][CH:20]=[N:19][C:18]=3[O:22][C:23]=2[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Brc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Reactant: [NH3+]CC1CCCS1
Agent: O=C([O-])C(F)(F)F
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(-c2oc3ncnc(NCC4CCCS4)c3c2-c2ccccc2)cc1
Yield: 75.7 %

Procedure:
A mixture of (tetrahydrothiophen-2-yl)methylammonium trifluoroacetate 223 (60 mg, 0.25 mmol) and 4-bromo-5,6-diphenylfuro[2,3-d]pyrimidine 69 (46 mg, 0.15 mmol) was stirred in n-butanol (2 mL) and DIPEA (0.25 mL) was added. The mixture was heated at reflux for 1 hour, cooled and the solvent was evaporated. The residue was purified by flash column chromatography to afford 230 (44 mg, 73%) as a yellow oil. 1H NMR (CDCl3): 8.32 (1H, s); 7.56-7.40 (7H, m); 7.23-7.15 (3H, m); 5.00 (1H, br t, J=4 Hz); 3.69-3.60 (1H, m); 3.55-3.35 (2H, m); 2.75-2.60 (2H, m); 1.95-1.75 (3H, m) and 1.60-1.48 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:43][O:44][C:45]1[C:46]2[N:59]=[C:58]([NH2:60])[S:57][C:47]=2[C:48]([N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)=[N:49][CH:50]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:60][C:58]2[S:57][C:47]3[C:48]([N:51]4[CH2:56][CH2:55][O:54][CH2:53][CH2:52]4)=[N:49][CH:50]=[C:45]([O:44][CH3:43])[C:46]=3[N:59]=2)=[O:9])=[CH:5][N:4]=1
Reactant: COc1ccc(C(=O)O)cn1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2nc3c(OC)cnc(N4CCOCC4)c3s2)cn1

Procedure:
From 6-methoxynicotinic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 402 (M+H+, 100).
Reaction SMILES: [C:1]([O:7][C:8]1[CH:9]=[C:10]([C:21](=[O:24])[CH2:22]C)[CH:11]=[CH:12][C:13]=1[O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(OC1C=C(C(=O)C)C=CC=1OC(=O)C(C)(C)C)(=O)C(C)(C)C.OC1C=C(C(=O)CC)C=CC=1O.C(Cl)(=O)C(C)(C)C.[Br:67]Br>C(N(CC)CC)C>[Br:67][CH2:22][C:21]([C:10]1[CH:11]=[CH:12][C:13]([O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[C:8]([O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[CH:9]=1)=[O:24]
Reactant: BrBr
Reactant: CCC(=O)c1ccc(OC(=O)C(C)(C)C)c(OC(=O)C(C)(C)C)c1
Agent: CC(=O)c1ccc(OC(=O)C(C)(C)C)c(OC(=O)C(C)(C)C)c1
Agent: CC(C)(C)C(=O)Cl
Agent: CCC(=O)c1ccc(O)c(O)c1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Oc1ccc(C(=O)CBr)cc1OC(=O)C(C)(C)C

Procedure:
3',4'-Bis(pivaloyloxy)propiophenone was first prepared as a mobile liquid (63.6 g.), in a similar manner to 3',4'-bis(pivaloyloxy)acetophenone in Example 1, starting from 3', 4'-dihydroxypropiophenone (40 g.), pivaloylchloride (63.3 ml.) and triethylamine (73.2 ml.). This mobile liquid (40.1 g.) was then reacted with bromine (7.2 ml.) in a similar manner to that used in Example 1 to obtained 2-bromo-3',4'-bis(pivaloyloxy)acetophenone. The crude bromo compound thus obtained was purified by dry column chromatography on silica gel as described in Example 1 to give pure 2-bromo-3',4'-bis(pivaloyloxy)propiophenone as a solid (18.4 g), m.p. 58°-60° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8][C:7]([C:15]([NH:17][C@@H:18]([CH2:27][S:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[CH2:19][O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[O:16])=[CH:6]2.CCN(CC)CC.[C:45](Cl)(=[O:50])[C:46]([CH3:49])([CH3:48])[CH3:47]>C(Cl)Cl>[CH3:47][C:46]([CH3:49])([CH3:48])[C:45]([O:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8][C:7]([C:15]([NH:17][C@@H:18]([CH2:27][S:28][CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)[CH2:19][O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[O:16])=[CH:6]2)=[O:50]
Reactant: COc1ccc(CSC[C@@H](COC(=O)C(C)(C)C)NC(=O)c2cc3cc(CO)cc([N+](=O)[O-])c3[nH]2)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CSC[C@@H](COC(=O)C(C)(C)C)NC(=O)c2cc3cc(COC(=O)C(C)(C)C)cc([N+](=O)[O-])c3[nH]2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2,2-Dimethyl-propionic acid (R)-2-[(5-hydroxymethyl-7-nitro-1H-indole-2-carbonyl)-amino]-3-(4-methoxy-benzylsulfanyl)-propyl ester (3.1 g, 6.01 mmol) prepared in Step A of Preparation 41 was dissolved in DCM, to which was added Et3N (1.68 mL, 12.02 mmol). Pivaloyl chloride (0.92 mL, 6.61 mmol) was added thereto, and the mixture was stirred for 12 h at room temperature. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (eluent: EtOAc/n-Hex=1/1) to give the title compound.
Reaction SMILES: C([O:5][C:6]([C:8]1([C:14]2[CH:25]=[CH:24][C:17]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:21]([O:20][C:18]([C:17]1[CH:16]=[CH:15][C:14]([C:8]2([C:6]([OH:7])=[O:5])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:25][CH:24]=1)=[O:19])([CH3:23])[CH3:22]
Reactant: CC(C)OC(=O)c1ccc(C2(C(=O)OC(C)(C)C)CCCCC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)OC(=O)c1ccc(C2(C(=O)O)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92.7 %

Procedure:
To a solution of isopropyl 4-[1-(tert-butoxycarbonyl)cyclohexyl]benzoate (13) (0.136 g, 0.39 mmol) in dichloromethane (1.5 ml) was added trifluoroacetic acid (0.5 ml) and the mixture was stirred at ambient temperature under argon atmosphere for 2.5 hours. The volatiles were evaporated and the residue was chromatographed on silica gel with toluene-dioxane-acetic acid (95:5:1) as eluent to give the title compound (0.105 g, 92%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3].CC(=CC)C.Cl([O-])=[O:27].[Na+].P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>O.C(O)(C)(C)C>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]([OH:27])=[O:18])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: [O-][Cl+][O-]
Reactant: C=CC(=O)OCCCCCCOc1ccc(C=O)cc1
Agent: CC=C(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
In a 2 liter three-necked round-bottomed flask, fitted with a mechanical stirrer, dropping funnel, and ground glass stopper, were charged 4-(6'-acryloyloxyhexyloxy)benzaldehyde (from Example 12) (22 grams; 0.1 mole), tertiary-butyl alcohol (500 mL), and 2-methyl-2-butene (available from Aldrich Chemical Co., Milwaukee, Wis.) (232 grams; 3 moles). The reaction mixture was stirred at room temperature. Over two hours, a solution of sodium chlorite (available from Aldrich Chemical Co., Milwaukee, Wis.) (65 grams; 0.7 mole) and sodium phosphate, monobasic monohydrate (available from Aldrich Chemical Co., Milwaukee, Wis.) (75 grams; 0.5 mole) in water (300 mL) was added. The reaction mixture was stirred for 12 hours at ambient temperature at which time the organic solvents were concentrated by rotary evaporator. The residue was then dissolved in diethyl ether (500 mL) and the mixture was made acidic (pH~2) by addition of 4N HCl. The mixture was poured into a separatory funnel and the organic layer was processed. The residue was recrystallized from ethanol. Spectral analysis confirmed the presence of 4-(6'-acryloyloxyhexyloxy)benzoic acid. The crystals weighed 15 grams which represents a 65 percent yield based on starting material.
Reaction SMILES: Cl.[Cl-].[CH3:3][N:4]([CH3:7])[CH2:5][CH3:6].[C:8]([NH2:13])([CH2:11][CH3:12])([CH3:10])[CH3:9]>>[C:8]([NH:13][CH2:6][CH2:5][N:4]([CH3:7])[CH3:3])([CH2:11][CH3:12])([CH3:10])[CH3:9]
Reactant: CCN(C)C
Reactant: CCC(C)(C)N
Agent: Cl
Agent: [Cl-]
Product: CCC(C)(C)NCCN(C)C
Yield: 59.6 %

Procedure:
Into a 300 mL-volume flask equipped with a stirrer and a thermometer were placed 20.6 g (143 mmol) of 2-(dimethylamino)ethane chloride hydrochloride and 74.0 g (859 mmol) of t-pentylamine. And then, the mixture was heated to reflux for 8 hours. After the completion of the reaction, the reaction mixture was filtrated and washed with 100 ml of hexane twice, and the hexane layer was concentrated under reduced pressure. The resultant concentrate was distilled under reduced pressure (120° C., 11.0 kPa), to provide 13.5 g of 1-t-pentylamino-2-dimethylaminoethane. (Isolation yield: 60%)