Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[O:9])[CH2:3][CH2:2]1.[CH:22]1([C:25](O)=[O:26])[CH2:24][CH2:23]1>>[CH:22]1([C:25]([N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:13][CH:12]=3)=[O:9])[CH2:3][CH2:2]2)=[O:26])[CH2:24][CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)NC1CCNCC1
Reactant: O=C(O)C1CC1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)NC1CCN(C(=O)C2CC2)CC1

Procedure:
Intermediate 42 (76 mg, 0.25 mmol) was reacted with cyclopropane carboxylic acid by Method E. Flash chromatography eluted with EtOAc and recrystallization from EtOAc:hexane afforded compound 52 (47 mg, 51%) as a white solid: Mp 195-196° C. 1H NMR (500 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.47 (d, J=9.0 Hz, 2H), 7.22 (d, J=8.7 Hz, 2H), 6.25 (d, J=7.7 Hz, 1H), 4.15 (t, J=14.8 Hz, 2H), 3.77-3.68 (m, 1H), 3.25 (t, J=11.5 Hz, 1H, obscured), 2.81 (t, J=11.1 Hz, 1H), 1.98 (m, 1H), 1.93-1.75 (m, 2H), 1.41-1.17 (m, 2H), 0.75-0.65 (m, 4H). Purity 100%. HRMS calculated for C17H20F3N3O3+H+ 372.1535. found (ESI(+), [M+H]) 372.1546.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].C(O)(=O)C>C1C=CC=CC=1>[N:11]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[CH2:5][CH:8]([OH:10])[CH3:9].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:9])=[CH:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccccn1
Reactant: CC(=O)c1ccc(Br)cc1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CC(=Cc1ccccn1)c1ccc(Br)cc1
Product: CC(O)Cc1ccccn1
Yield: 63 %
Yield: 26 %

Procedure:
2-p-Bromophenyl)- 1-(2-pyridyl-2-propanol is prepared from p-bromoacetophenone and 2-picoline according to the method of Villani, et al., J. Med. Chem., 13, 359 (1970) in 63% yield. This alcohol (129.1 g.) is dehydrated by heating in 1150 ml. of acetic acid-12N hydrochloric acid (3:1) at reflux temperature for 4 hr. The mixture is evaporated in vacuo, made basic with concetrated ammonium hydroxide, and extracted with ethyl acetate. The ethyl acetate extract is washed with water and brine, dried over sodium sulfate, and evaporated to give a dark brown oil. A solution of the oil in benzene is passed through a columm of silica gel. Evaporation of the eluate gave 46.4 g. (26% yield) of crystalline 2-(p-bromophenyl)-1-(2-pyridyl)propene, m.p. 71.5°-73.5° C. (corr.).
Reaction SMILES: O([BH-](OC(C)=O)OC(C)=O)C(C)=O.[Na+].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH:23]1([O:28][C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[CH:32]=O)[CH2:27][CH2:26][CH2:25][CH2:24]1.ClCCCl>CC(O)=O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:32][C:31]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:29]([O:28][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:30]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: Nc1ccc(Br)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc(CNc2ccc(Br)cc2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.6 %

Procedure:
Sodium triacetoxyl-borohydride (470 mg, 2.21 mmol) was added to a solution of 4-bromo-phenylamine (252 mg, 1.47 mmol) and 3-cyclopentyloxy-4-methoxy-benzaldehyde (324 mg, 1.47 mmol) in 10 ml of 1,2-dicloroethtane (DCE), 0.5 ml of HOAc was added. The mixture was stirred overnight at room temperature, followed by addition of 15 ml of DCE. The organic phase was washed with water and dried over sodium sulfate. The solvent was removed by rotovap to give 656 mg of crude (4-bromo-phenyl)-(3-cyclopentyloxy-4-methoxy-benzyl)amine. It was used for next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][CH2:12][CH:13]([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:8][C:7]([CH3:22])=[CH:6][N:5]2[C:23]=1[C:24](O)=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[NH2:61][CH:62]([CH2:67][CH2:68][CH2:69][C:70]([F:73])([F:72])[F:71])[C:63]([CH3:66])([OH:65])[CH3:64]>CN(C=O)C.O>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][CH2:12][CH:13]([C:14]([F:17])([F:15])[F:16])[C:18]([F:19])([F:20])[F:21])=[CH:8][C:7]([CH3:22])=[CH:6][N:5]2[C:23]=1[C:24]([NH:61][CH:62]([CH2:67][CH2:68][CH2:69][C:70]([F:71])([F:72])[F:73])[C:63]([OH:65])([CH3:64])[CH3:66])=[O:25]
Reactant: Cc1cc(OCCC(C(F)(F)F)C(F)(F)F)c2nc(C)c(C(=O)O)n2c1
Reactant: CC(C)(O)C(N)CCCC(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(OCCC(C(F)(F)F)C(F)(F)F)c2nc(C)c(C(=O)NC(CCCC(F)(F)F)C(C)(C)O)n2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg (0.390 mmol) of 2,6-dimethyl-8-[4,4,4-trifluoro-3-(trifluoromethyl)butoxy]imidazo[1,2-a]-pyridine-3-carboxylic acid Example 91A and 163 mg (0.429 mmol) of HATU were initially charged in 2 ml of DMF. 0.2 ml (1.17 mmol) of N,N-diisopropylethylamine and 101 mg (0.429 mmol) of rac-3-amino-7,7,7-trifluoro-2-methylheptan-2-ol hydrochloride Example 103A were then added, and the mixture was stirred at RT overnight. 10 ml of water were added, the reaction solution was extracted twice with 20 ml of ethyl acetate and the combined organic phases were washed with 20 ml of water and with 20 ml of sat. aqueous NaCl solution, dried over MgSO4, filtered and concentrated. The residue was purified by preparative RP-HPLC (ACN:water+0.1% HCOOH). The product fractions were combined and concentrated to dryness and the residue was dissolved in a mixture of 1.5 ml of tert-butanol and 2 ml of water and lyophilized overnight. This gave 91 mg of the target compound (98% pure, 40% of theory).
Reaction SMILES: [C:1]([NH:24][CH:25]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:26]([O:28][C:29]1[CH:39]=[CH:38][CH:37]=[CH:36][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].[F:44][C:45]1[CH:50]=[C:49]([F:51])[CH:48]=[CH:47][C:46]=1C1C=CC(O)=C(C(O)=O)C=1>>[C:1]([NH:24][CH:25]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:26]([O:28][C:29]1[CH:39]=[CH:38][C:37]([C:48]2[CH:47]=[CH:46][C:45]([F:44])=[CH:50][C:49]=2[F:51])=[CH:36][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NC(CC(C)C)C(=O)Oc1ccccc1C(=O)OCC
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NC(CC(C)C)C(=O)Oc1ccc(-c2ccc(F)cc2F)cc1C(=O)OCC

Procedure:
Ethyl 4-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoyloxy)-2′,4′-difluorobiphenyl-3-carboxylate was prepared as described for ethyl 2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoyloxy)benzoate, using the appropriate 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylic acid starting material. Mass calculated for C43H53F2NO5=701.88; found: [M+H]+=702.4.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:22]([F:25])([F:24])[F:23])=[C:12]([N:15]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]3[CH3:21])[CH:13]=2)[NH:8][C:7](=[O:26])[C:6]1=[O:27])(O)=[O:2].[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O.O>[CH2:28]([NH:35][C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:22]([F:23])([F:25])[F:24])=[C:12]([N:15]3[C:16]([CH3:21])=[CH:17][CH:18]=[C:19]3[CH3:20])[CH:13]=2)[NH:8][C:7](=[O:26])[C:6]1=[O:27])=[O:2])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1ccc(C)n1-c1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2CC(=O)O
Reactant: NCc1ccccc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(C)n1-c1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2CC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.7 %

Procedure:
1.6 g (4.2 mmol) of the compound of Example 72 and 0.5 ml (4.6 mmol) of benzylamine were dissolved in 50 ml of anhydrous dimethylformamide under a nitrogen atmosphere. At 0° C., 1 ml (4.6 mmol) of diphenylphosphoryl azide dissolved in 10 ml of anhydrous dimethylformamide, and 1.3 ml (9.2 mmol) of triethylamine were successively added dropwise. The mixture was then stirred at room temperature for 16 h and subsequently diluted with water, acidified and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was recrystallized from ethanol to yield 1.1 g (56%) of the product. Melting point >250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:40][CH3:41])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH2:27][CH:26]5[CH2:30][N:31](C(OC(C)(C)C)=O)[CH2:32][CH:25]45)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:40][CH3:41])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH2:27][CH:26]5[CH2:30][NH:31][CH2:32][CH:25]45)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCCC2CN(C(=O)OC(C)(C)C)CC21
Agent: Cl
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCCC2CNCC21
Yield: 100.5 %

Procedure:
To a solution of tert-butyl 1-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propyl)hexahydro-1H-pyrrolo[3,4-b]pyridine-6(2H)-carboxylate (0.60 g) in CH2Cl2 was added a solution of 3M HCl in EtOAC. Solid was precipitated out after 2 h reaction. The reaction mixture was filtered, and the residue was dried to give the title compound as a yellow solid (0.50 g, 80.00%), HPLC: 96.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 486.3 (M+1); 1H NMR (400 MHz, d6-DMSO) δ: 1.99 (m, 3H), 1.56 (m, 2H), 1.94-1.98 (m, 2H), 2.19 (d, J=4.8 Hz, 1H), 2.50-2.53 (m, 2H), 2.85-2.87 (m, 2H), 2.91-2.95 (m, 1H), 3.37 (s, 3H), 4.05-4.07 (m, 3H), 4.13-4.14 (m, 1H), 4.15-4.17 (m, 2H), 7.44 (s, 1H), 7.50 (t, J=4.4 Hz, 1H), 7.83-7.88 (m, 1H), 8.07-8.09 (m, 1H), 8.99-9.02 (m, 1H), 9.15 (s, 1H) ppm.
Reaction SMILES: [NH2:1][OH:2].C1COCC1.C[O:9][C:10](=O)[CH:11]([N:16]([CH3:31])[C:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)=[O:18])[C:12]([NH:14][CH3:15])=[O:13]>C(O)C>[C:22]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:21]=[CH:20][C:19]([C:17]([N:16]([CH3:31])[CH:11]([C:12]([NH:14][CH3:15])=[O:13])[C:10]([NH:1][OH:2])=[O:9])=[O:18])=[CH:24][CH:23]=1
Reactant: NO
Reactant: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(-c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: CNC(=O)C(C(=O)NO)N(C)C(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59 %

Procedure:
A 50% aqueous solution (0.20 mL) of hydroxylamine was added to a THF (0.25 mL)-ethanol (0.20 mL) solution of 4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}biphenyl (30 mg) as obtained in Example 1-(1), and the mixture was stirred for 4 hours at room temperature. The solvents were distilled off under reduced pressure, and the resulting residue was purified by preparative silica gel thin-layer chromatography (chloroform/methanol=8/1). Upon addition of IPE, the precipitated solid was separated by filtration, and dried to obtain 2-[(biphenyl-4-ylcarbonyl)(methyl)amino]-N-hydroxy-N′-methylpropanediamide (Compound 1, light yellow solid) (17 mg, 59%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][S:12][C:8]2[C:6]3[N:7]=[C:2]([N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]4)[C:5]=3[N:11]=[CH:10][N:9]=2)=[CH:19][CH:18]=1
Reactant: O=S1CCN(c2nc(Cl)nc3c(SCc4ccc(Cl)cc4)ncnc23)CC1
Reactant: C1CNCCN1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(SCc4ccc(Cl)cc4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(4-chlorobenzyl-thio)-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 232°-234° C.) and piperazine.
Reaction SMILES: [N:1]#[C:2][Br:3].[NH2:4][C:5]1[C:6]([Cl:21])=[N:7][C:8]2[C:13]([C:14]=1[NH:15][CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])=[CH:12][CH:11]=[CH:10][CH:9]=2>C(O)C>[BrH:3].[Cl:21][C:6]1[C:5]2[N:4]=[C:2]([NH2:1])[N:15]([CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: CC(C)(O)CNc1c(N)c(Cl)nc2ccccc12
Reactant: N#CBr
Solvent: CCO
Product: Br
Product: CC(C)(O)Cn1c(N)nc2c(Cl)nc3ccccc3c21
Temperature: 25 °C

Procedure:
Cyanogen bromide (4.78 g, 45.2 mmol) was added to a solution of 1-[(3-amino-2-chloro-4-quinolinyl)amino]-2-methyl-2-propanol (André et al, U.S. Pat. No. 4,988,815, Example 13, 10.0 g, 37.6 mmol) in ethanol (200 mL), and the solution was heated overnight at 90° C. and allowed to cool to ambient temperature. A precipitate formed and was isolated by filtration, washed once with diethyl ether, and then washed several times with dichloromethane to provide 9.28 g of 1-(4-chloro-2-amino-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol hydrobromide as a gray powder.
Reaction SMILES: Br[CH2:2][C:3]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[O:17]1[CH2:18][CH2:19][N:14]([CH2:2][C:3]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:4]=2[C:5]#[N:6])[CH2:15][CH2:16]1
Reactant: C1COCCN1
Reactant: N#Cc1cccc([N+](=O)[O-])c1CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cccc([N+](=O)[O-])c1CN1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.5 %

Procedure:
To a stirred solution of 2-(bromomethyl)-3-nitrobenzonitrile (1.10 g, 4.56 mmol) and morpholine (0.80 g, 9.13 mmol) in CH2Cl2 (15 mL) was added triethylamine (1.85 g, 18.25 mmol) dropwise at 0° C. The mixture was stirred at room temperature for 1.5 h and evaporated to dryness under reduced pressure. The residue was diluted with water (10 mL) and extracted with CH2Cl2 (3×50 mL). The CH2Cl2 solution was dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 2-(morpholinomethyl)-3-nitrobenzonitrile (1.02 g, 90%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.90 (br d, 1H, J=8.0 Hz), 7.84 (dd, 1H, J=8.0, 1.2 Hz), 7.56 (t, 1H, J=8.0 Hz), 3.99 (s, 2H), 3.60 (br t, 4H, J=4.4 Hz), 2.46 (br s, 4H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)=[CH:3][CH:2]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[N:26]=[C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[S:24][N:23]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[N:1]1[CH:2]=[CH:3][C:4]([NH:7][C:8]([N:30]2[CH2:29][CH2:28][N:27]([C:25]3[S:24][N:23]=[C:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=4)[N:26]=3)[CH2:32][CH2:31]2)=[O:15])=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccncc1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1ccncc1)N1CCN(c2nc(-c3ccccn3)ns2)CC1
Yield: 23 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl pyridin-4-ylcarbamate (198 mg, 0.735 mmol), 1-(3-pyridin-2-yl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.809 mmol) and diisopropylethylamine (0.139 ml, 0.809 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 80° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with a mixed solution of ethyl acetate/tetrahydrofuran (1:1). The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 62.1 mg (23.0%) of the desired product as a solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[N:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[S:15][C:14]=1[NH2:22].[CH3:23][CH:24](O)[CH3:25]>>[CH:24]([O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:22][C:14]1[S:15][C:16]2[C:21]([N:13]=1)=[CH:20][CH:19]=[CH:18][N:17]=2)([CH3:25])[CH3:23]
Reactant: Nc1nc2cccnc2s1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: CC(C)O
Product: CC(C)Oc1ccc2ncnc(Nc3nc4cccnc4s3)c2c1

Procedure:
The compound of Example 24 was manufactured by the same method as in Example 22, by a similar method thereto or by a combination of such a method with a conventional method using 4-chloro-6-hydroxy-quinazoline, 2-propanol and thiazolo[5,4-b]pyridin-2-yl-amine.
Reaction SMILES: C(OC1N=C2C(NC=N2)=C(N)N=1)CCCCCCC.[C:20]([NH:28][C:29]1[C:30]2[N:31]=[CH:32][N:33]([C:45]=2[N:46]=[C:47](C)[N:48]=1)[C@@H:34]1[O:41][C@H:38]([CH2:39][OH:40])[C@@H:36]([OH:37])[C:35]1=S(=O)=O)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)C(C)C)C.C(N)(=O)CCCCCCC>CN(C=O)C>[C:20]([NH:28][C:29]1[C:30]2[N:31]=[CH:32][N:33]([C:45]=2[N:46]=[CH:47][N:48]=1)[C@@H:34]1[O:41][C@H:38]([CH2:39][OH:40])[C@@H:36]([OH:37])[CH2:35]1)(=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1nc(NC(=O)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)C3=S(=O)=O)c2n1
Agent: CCCCCCCC(N)=O
Agent: CCCCCCCCOc1nc(N)c2[nH]cnc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1)c1ccccc1

Procedure:
Synthesis of 5LO sequence 5′-GAA GTC ACT GGA ACG-3′ (SEQ ID NO:21) containing 2-octanoxyadenine at specific positions is described. A solution of N6-benzoyl-2′-deoxy-2-methyl-sulfonyladenosine, ethyl diisopropylamine, octanoylamine, and DMF is heated to 100° C. for 30 min and evaporated to dryness under reduced pressure. Recrystallization of the residue affords N6-benzoyl-2′-deoxyadenosine with the carbon chain in the 2-position. This material is converted by procedures of examples 107 and 108 above into its 5′-DMT-3′-β-cyanoethyldiisopropylphosphoramidite derivative which is inserted into the 5LO-sequence 5′-GAA GTC ACT GGA ACG (SEQ ID NO:21) via automated, solid phase DNA synthesis.
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4.[CH:18]([C:20]1[CH:21]=[N:22][CH:23]=[N:24][CH:25]=1)=[CH2:19].S([O-])([O-])(=O)=O.[Mg+2]>>[N:22]1[CH:21]=[C:20](/[CH:18]=[CH:19]/[C:2]2[C:10]3[NH:9][C:8]4[CH:11]5[CH2:17][CH2:16][N:14]([CH2:15][C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]5)[CH:25]=[N:24][CH:23]=1
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Reactant: C=Cc1cncnc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: C(=C/c1cccc2c3c([nH]c12)C1CCN(CC1)C3)\c1cncnc1

Procedure:
The product of Example 1B (265 mg, 0.91 mmol), the product of Example 29A (193 mg, 1.82 mmol) and magnesium sulfate (55 mg, 0.46 mmol) were combined and processed as described in Example 1D to provide the title compound as the slower eluting compound: 1H NMR (400 MHz, methanol-d4) δ ppm 2.04-2.20 (m, 4 H), 3.04-3.17 (m, 3 H), 3.22-3.30 (m, 2 H), 4.26 (s, 2 H), 7.05 (t, J=7.6 Hz, 1 H), 7.24 (d, J=16.8 Hz, 1 H), 7.31 (dd, J=7.9, 0.9 Hz, 1 H), 7.43-7.47 (m, J=7.3 Hz, 1 H), 7.89 (s, 1 H), 9.02 (d, J=16.1 Hz, 1 H), 9.04 (s, 2 H); MS (APCI) m/z 317 (M+H)+.
Reaction SMILES: [I:1][C:2]1[C:3]([O:22][CH3:23])=[CH:4][C:5]([CH:19]([CH3:21])[CH3:20])=[C:6]([O:8]S(C2C=CC(C)=CC=2)(=O)=O)[CH:7]=1.[OH-].[K+].Cl.CCCCCC>C(O)(C)(C)C.O>[I:1][C:2]1[C:3]([O:22][CH3:23])=[CH:4][C:5]([CH:19]([CH3:21])[CH3:20])=[C:6]([OH:8])[CH:7]=1
Reactant: COc1cc(C(C)C)c(OS(=O)(=O)c2ccc(C)cc2)cc1I
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: O
Solvent: CC(C)(C)O
Product: COc1cc(C(C)C)c(O)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a mixture of 292 grams of toluene-4-sulfonic acid 5-iodo-2-isopropyl-4-methoxy-phenyl ester (0.66 Moles) in 600 mL tert-butyl alcohol was gradually added a solution of 90 g KOH in 400 mL water, and the resultant mixture was stirred overnight at 82 degrees C. The reaction mixture was neutralized with conc. HCl to a pH of 5-6, and then partitioned between 600 mL ethyl acetate and 400 mL water. The organic phase was dried over sodium sulfate, filtered and stripped under vacuum at 65 degrees C. to give a resinous liquid. Hexane (700 mL) was then added and the mixture heated to reflux. The liquid phase was decanted into another flask and stirred overnight at room temperature, during which time a white solid precipitated. The solid was isolated by filtration and vacuum dried to give 162 g of 5-iodo-2-isopropyl-4-methoxy-phenol, representing a yield of 82%: MS (M+H)=293.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]#N)=[N:8][C:9]=2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.[OH-:20].[Na+].Cl.[OH2:23]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:23])=[O:20])=[N:8][C:9]=2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1
Reactant: [OH-]
Reactant: N#Cc1ccc(C2CC2)c(Cc2ccc(F)cc2)n1
Reactant: O
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1
Yield: 70 %

Procedure:
A solution of 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carbonitrile (0.08 g, 0.3 mmol) and NaOH (0.05 g, 1.2 mmol) in H2O (10 mL) was stirred for 2 hours at 90° C. The pH was adjusted to 3 with 1 M HCl. The mixture was extracted with ethyl acetate (3×10 mL), dried over Na2SO4, concentrated under reduced pressure and purified by column chromatography to give the title compound (0.06 g, 70%) as yellow solid; MS (EI): m/e=272.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH2:2][CH3:3].Cl.[C:8]1([CH:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:19][NH2:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.Cl>N1C=CC=CC=1>[C:8]1([CH:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:19][NH:20][C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[O:6])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: CCCN=C=O
Reactant: COC(=O)C(CN)c1cccc2ccccc12
Agent: Cl
Solvent: c1ccncc1
Product: CCCNC(=O)NCC(C(=O)OC)c1cccc2ccccc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
0.011 mol of propyl isocyanate is added dropwise and with magnetic stirring to a suspension of 0.01 mol of 2-(1-naphthyl)-2-(methoxycarbonyl)ethylamine hydrochloride, obtained in stage B of Example 11, in 5 cm3 of pyridine. The reaction medium is stirred for 1 hour at a temperature of 80° C. and then poured into ice-cold water. The mixture is acidified with 1N hydrochloric acid solution. The precipitate formed is drained, washed with water, dried and then recrystallized in a toluene/cyclohexane mixture.