Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[O:7][C:8]1[N:16]=[CH:15][C:14]([F:17])=[CH:13][C:9]=1[C:10]([OH:12])=O)[CH3:2].C(N(CC)CC)C.[NH2:28][C@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[OH:35].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[NH3:16].[CH2:1]([S:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[O:7][C:8]1[N:16]=[CH:15][C:14]([F:17])=[CH:13][C:9]=1[C:10]([NH:28][C@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[OH:35])=[O:12])[CH3:2]
Reactant: CCSc1cccc(Oc2ncc(F)cc2C(=O)O)c1
Reactant: N[C@H]1CCCC[C@H]1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CCCC[C@H]2O)c1
Product: N
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.3 %

Procedure:
2-[3-(Ethylsulfanyl)phenoxy]-5-fluoronicotinic acid (250 mg, 0.85 mmol) was dissolved in dimethylformamide (5 ml) and triethylamine (475 μl, 3.41 mmol) was added followed by (1R,2S)-2-aminocyclohexanol hydroformate (144 mg, 0.89 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (180 mg, 0.94 mmol) and 1-hydroxybenzotriazole (127 mg, 0.94 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between water (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography using dichloromethane:methanol:0.880 ammonia (98:2:0.2) as eluant to give 2-[3-(ethylsulfanyl)phenoxy]-5-fluoro-N-[(1S,2R)-2-hydroxycyclohexyl]nicotinamide (57 mg) as a colourless oil.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([C:31]([F:34])([F:33])[F:32])[C:24]([N:26]([CH:28]([CH3:30])[CH3:29])[CH3:27])=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1.S(Cl)(Cl)=O.[Cl-].[CH:40]([NH2:43])([CH3:42])[CH3:41]>ClCCl.CN(C=O)C>[CH:40]([NH:43][CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([C:31]([F:34])([F:33])[F:32])[C:24]([N:26]([CH:28]([CH3:30])[CH3:29])[CH3:27])=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1)([CH3:42])[CH3:41]
Reactant: CC(C)N(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Reactant: CC(C)N
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)NCc1cnnn1-c1cccc(C2=Nc3cc(N(C)C(C)C)c(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from 4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isopropyl-methyl-amino)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 119) (236 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with isopropylamine in DMF according to the method described in Example 45. Obtained as a light yellow solid (100 mg, 39%).
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](/[CH:33]=[CH:34]/[C:35](O)=[O:36])[CH:28]=1>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:35](=[O:36])/[CH:34]=[CH:33]/[C:29]1[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)/C=C/c1cccnc1
Product: CC(C)CN([C@@H](CCCCNC(=O)/C=C/c1cccnc1)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 60 %

Procedure:
Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine was reacted with trans-3-(3-pyridyl)acrylic acid under the conditions described in example 86 to yield 60% of the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12](=[O:13])[C:11]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][NH:9]2)[CH:3]=1.[CH3:20][O:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C1COCC1>[ClH:1].[ClH:1].[CH3:20][O:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([N:8]3[C:12](=[O:13])[C:11]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)=[CH:10][NH:9]3)[CH:3]=2)[CH2:26][CH2:25]1
Reactant: O=c1c(-c2cccnc2)c[nH]n1-c1cc(Cl)ncn1
Reactant: COCCN1CCNCC1
Solvent: C1CCOC1
Product: COCCN1CCN(c2cc(-n3[nH]cc(-c4cccnc4)c3=O)ncn2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
100 mg (0.4 mmol) of the compound from Example 23 and 113 mg (0.7 mmol) of N-(methoxy-ethyl)piperazine are initially charged in 3 ml of THF. The reaction mixture is reacted in a single-mode microwave oven (Emrys Optimizer) at 120° C. for 20 min. The cooled reaction solution is then concentrated on a rotary evaporator, and the residue is chromatographed by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid). 1 ml of a 4 N solution of hydrogen chloride in dioxane is added to the resulting formate salt of the target compound, and the mixture is stirred at RT for 30 min. The suspension is then concentrated under reduced pressure, and the residue is dried.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH2:5].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.B(F)(F)F.CCOCC.Cl>C1(C)C=CC=CC=1>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:15]([CH:3]=[CH:4][N:5]=[CH:13]2)=[CH:16][CH:17]=1
Reactant: COc1cccc(C=O)c1
Reactant: COC(CN)OC
Agent: Cl
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Product: COc1ccc2ccncc2c1
Temperature: 5 °C
Reaction time: 72 h
Yield: 84 %

Procedure:
Aminoacetaldehyde dimethyl acetal (81.9 mL) was added to a solution of 60.8 mL of 3-methoxy-benzaldehyde in 600 mL of toluene. The mixture was refluxed for 5 h using a Dean-Stark trap and subsequently cooled to 5° C. In a nitrogene atmosphere trifluoroacetic acid anhydride (209 mL) and borontrifluoride etherate (185 mL) were added in succession at such a rate, that the internal temperature was kept below 10° C. After stirring for 3 days at room temperature the the reaction mixture was poured on ice, 250 mL 2 N hydrochloric acid added and the organic layer extracted with 1 N hydrochloric acid. The pH value of the combined aqueous extracts was adjusted to pH 9 by adding concentrated aqueous ammonia. Extraction with ethyl acetate, followed by drying and removal of the solvent in vacuo gave 66.9 g (84%) of the title compound as a light brownish oil. EI-MS: 159 (M+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](I)[C:3]=1[C:4]#[N:5].[S:11]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12]1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:13]2[CH:14]=[CH:15][S:11][CH:12]=2)[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(F)cccc1I
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1c(F)cccc1-c1ccsc1
Temperature: 25 °C
Yield: 36.5 %

Procedure:
In a dry round bottom flask were added 2-fluoro-6-iodobenzonitrile (500 mg; 2.02 mmol), 3-thiophene boronic acid (311 mg; 2.43 mmol), sodium carbonate (2.32 g; 21.86 mmol), tetrakis(triphenylphosphine)palladium(0) (77 mg; 0.07 mmol), DME (20 mL) and water (20 mL) and heated to reflux for 5 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (3×), washed with brine (1×) and water (1×). Organic layers were combined and dried over sodium sulfate and then filtered and solvent removed to yield crude material which was purified by column chromatography (4% ethyl acetate/hexane) to obtain 150 milligrams of 2-fluoro-6-thiophen-3-yl-benzonitrile.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=O)=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][NH2:32].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(C)=O.O>[O:24]=[C:22]([NH:32][O:31][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][O:25]1)/[CH:21]=[CH:20]/[C:17]1[CH:16]=[CH:15][C:14]([NH:13][C@@H:10]2[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)=[N:19][CH:18]=1
Reactant: NOC1CCCCO1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ccc(/C=C/C(=O)O)cn2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ccc(/C=C/C(=O)NOC3CCCCO3)cn2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.1 %

Procedure:
A mixture of (2E)-3-(6-{[(3R)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid (450 mg), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (174 mg), HOBt (191 mg) and EDCI (220 mg) in DMF (20 ml) was stirred at ambient temperature for 15 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (95:5). The eluted fractions containing the desired product were collected and evaporated in vacuo to give tert-butyl (3R)-3-[(5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridinyl)amino]-1-pyrrolidinecarboxylate (450 mg).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C@H:17]3[CH2:26][CH2:25][C@@:19]4([NH:23][C:22](=[O:24])[O:21][CH2:20]4)[CH2:18]3)[CH:13]=2)[CH:8]=1)(=O)=O.CN1C(=O)CCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:46]([Mg]Br)[CH2:47][CH2:48][CH2:49][CH2:50][CH3:51].CCOCC>C1COCC1>[CH2:46]([C:7]1[CH2:16][CH2:15][C:14]2[CH:13]=[C:12]([C@H:17]3[CH2:26][CH2:25][C@@:19]4([NH:23][C:22](=[O:24])[O:21][CH2:20]4)[CH2:18]3)[CH:11]=[CH:10][C:9]=2[CH:8]=1)[CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]
Reactant: CCCCCC[Mg]Br
Reactant: O=C1N[C@@]2(CC[C@H](c3ccc4c(c3)CCC(OS(=O)(=O)C(F)(F)F)=C4)C2)CO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCC1=Cc2ccc([C@H]3CC[C@]4(COC(=O)N4)C3)cc2CC1
Reaction time: 0.25 h

Procedure:
To a mixture of 6-((5R,7S)-2-oxo-3-oxa-1-azaspiro[4.4]nonan-7-yl)-3,4-dihydronaphthalen-2-yl trifluoromethanesulfonate (Int. 6, 1 g, 2.396 mmol) and NMP (2.306 mL, 23.96 mmol) in THF (20 mL) at −40° C. was added a solution of lithium bis(trimethylsilyl)amide in THF (2.396 mL, 2.396 mmol). The reaction mixture was stirred for 15 minutes, and then ferric acetylacetonate (0.042 g, 0.120 mmol) and hexylmagnesium bromide in ether (2.396 mL, 4.79 mmol) were added. The reaction mixture was stirred for 30 minutes and quenched with water. The reaction mixture was diluted with ethyl acetate and washed with 1M HCl. The organic layer was dried with MgSO4, filtered and concentrated. The crude material was purified on a silica gel cartridge (40 g) using an EtOAc/hexane gradient (0-100% EtOAc over 12 CV) to afford 662 mg of (5R,7S)-7-(6-hexyl-7,8-dihydronaphthalen-2-yl)-3-oxa-1-azaspiro[4.4]nonan-2-one as a white solid. HPLC retention time=1.28 min (Condition G); LC/MS M+1=354: 1H NMR (400 MHz, chloroform-d) δ 7.03-6.88 (m, 3H), 6.21 (s, 1H), 5.16 (br. s., 1H), 4.44-4.15 (m, 2H), 3.13-2.96 (m, 1H), 2.80 (t, J=8.0 Hz, 2H), 2.47-2.08 (m, 6H), 2.05-1.93 (m, 2H), 1.90-1.73 (m, 1H), 1.68-1.43 (m, 4H), 1.41-1.22 (m, 5H), 1.01-0.83 (m, 3H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[N:17]1([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(OCC)C>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:29][CH:28]=1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(CN2CCCCC2)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a solution of 0.2 g (0.60 mmol) of (4E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione in 2 mL of N,N′-dimethylformamide is added 4-piperidin-1-ylmethyl-phenylamine (0.127 mL, 0.67 mmol). The reaction mixture is heated at 120° C. under N2 for 1.5 h. After cooling, ethyl ether is added and left in refrigerator overnight to give dark brown crystal. The crystal is collected and dissolved in 4 mL of dimethyl sulfoxide, followed by addition of 6 mL of 65% MeOH/H2O solution to give a precipitate. The solid is collected and washed thoroughly with water, MeOH, Et2O and hexane, and air-dried to give 0.143 g (48.3% yield) of tan solid: mp 202-203° C., MS (ESI) m/z 488.1 (M+H)+1
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:18])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:2]2[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[CH:3]=2)=[C:13]([F:18])[CH:12]=1
Reactant: Cc1cc(Br)cc(C)n1
Reactant: Oc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2ccc(Br)cc2F)cc(C)n1
Temperature: 150 °C

Procedure:
A mixture of 4-bromo-2,6-dimethyl-pyridine (1 g, 5.4 mmol), 4-bromo-2-fluoro-phenol (0.59 g, 5.4 mmol) and potassium carbonate (0.89 g, 6.4 mmol) in xylenes (2 ml) was heated at 150° C. (oil bath temperature) into a sealed tube for 48 hours. After cooling to room temperature the mixture was diluted with EtOAc and filtered through a diatomaceous earth pad. The filtrate was evaporated till dryness and the crude product thus obtained was purified by column chromatography (silica gel; DCM to DCM/EtOAc up to 10% as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate D22 (1.28 g, 80%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:6]([C:7](=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C@H:5]([CH:15]=[O:16])[CH2:4][O:3]1.[CH3:18][CH2:19][Mg+].[Br-]>CCOCC>[CH2:18]([CH:15]([C@@H:5]1[CH2:4][O:3][C:2]([CH3:1])([CH3:17])[N:6]1[C:7](=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[OH:16])[CH3:19]
Reactant: CC[Mg+]
Reactant: CCCCCCC(=O)N1[C@H](C=O)COC1(C)C
Agent: [Br-]
Solvent: CCOCC
Product: CCCCCCC(=O)N1[C@H](C(O)CC)COC1(C)C
Reaction time: 1.5 h

Procedure:
A solution of 9a (108 mg, 0.44 mmol) in ether (1 mL) is added dropwise to a cold (5° ) solution of EtMgBr (3M in ether, 0.36 mL). The cold bath is removed, a crystal of iodine is added to the mixture and stirring is continued for 1.5 h at room temperature. The resulting mixture is diluted with EtOAc and washed with saturated aqueous NH4Cl solution. The aqueous phase is reextracted and the combined organic solution dried and evaporated to yield crude 10a: NMR δ0.88 (m, 3H), 1.05 (m, 3H), 1.30 (m, 6H), 1.45 (m, 2H), 1.57 (s, 3H), 1.50-1.75 (m, 5H), 2.10-2.60 (m, 2H), 3.50-4.50 (m, 4H); MS (EI) m/z 271 (M).
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([CH:46]=[CH:47][CH:48]=1)[CH2:6][N:7]1[C:15]2[C:10](=[N:11][C:12]([N:16](C(OC(C)(C)C)=O)[NH:17][C:18](OC(C)(C)C)=O)=[CH:13][CH:14]=2)[CH:9]=C1C(OCC1C=CC=C(C(F)(F)F)C=1)=O.[OH-].[Na+].[CH3:53]O.[C:55]([OH:58])(=[O:57])[CH3:56]>>[CH3:53][C:18]1[N:11]2[C:10]3[CH:9]=[C:56]([C:55]([OH:58])=[O:57])[N:7]([CH2:6][C:5]4[CH:46]=[CH:47][CH:48]=[C:3]([C:2]([F:50])([F:49])[F:1])[CH:4]=4)[C:15]=3[CH:14]=[CH:13][C:12]2=[N:16][N:17]=1
Reactant: CO
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(C(=O)OCc3cccc(C(F)(F)F)c3)n2Cc2cccc(C(F)(F)F)c2)n1
Agent: [Na+]
Agent: [OH-]
Product: Cc1nnc2ccc3c(cc(C(=O)O)n3Cc3cccc(C(F)(F)F)c3)n12
Reaction time: 0.33 h

Procedure:
Di-tert-butyl 1-[1-[3-(trifluoromethyl)benzyl]-2-({[3-(trifluoromethyl)benzyl]oxy}carbonyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]hydrazine-1,2-dicarboxylate (0.28 g, 0.40 mmol, from Step 2) in acetic acid (10 mL) was heated to 180° C. in the microwave for 5 minutes. The acetic acid was then removed in vacuo. The residue was dissolved in THF (10 mL) and 1.0 M NaOH (10 mL, 10 mmol) was added. After stirring for 20 minutes, MeOH was added to make the mixture monophasic and the product was purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: 45 mg, 30%.
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.Cl.[NH2:21][CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1.C(N(CC)CC)C>C(O)C.CO>[CH2:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30][CH:22]1[NH:21][C:5]1[C:4]2[N:8]=[CH:9][N:10]([C:3]=2[N:2]=[CH:1][N:6]=1)[C@@H:11]1[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]1[OH:19]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NC1Cc2ccccc2C1
Agent: Cl
Solvent: CCO
Solvent: CO
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2cnc3c(NC4Cc5ccccc5C4)ncnc32)[C@H](O)[C@@H]1O
Yield: 72.9 %

Procedure:
Two grams 6-chloropurine riboside, 1.48 grams 2-aminoindane hydrochloride and 1.74 g triethylamine are refluxed in ethanol under nitrogen for 20 hours. Upon cooling, solid material crystallizes. The reaction mixture is diluted with 70 ml ethanol, filtered and washed with ethanol. Solid thus obtained is suspended in approximately 25 to 30 ml methanol, filtered, and washed with methanol and dried affording 1.95 g (73%) N(6)-(2-indanyl)adenosine having a melting point of 166°-168° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.[NH:20]1[C:24]([CH2:25][C:26](O)=[O:27])=[N:23][N:22]=[N:21]1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.O>C(OCC)(=O)C>[C:14]1([C:12]2[C:3]3[C:2](=[CH:7][CH:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:4]=3)[NH:1][C:26](=[O:27])[C:25]=2[C:24]2[NH:23][N:22]=[N:21][N:20]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)c1ccccc1
Reactant: O=C(O)Cc1nnn[nH]1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1[nH]c2ccc(C(F)(F)F)cc2c(-c2ccccc2)c1-c1nnn[nH]1
Temperature: 50 °C
Yield: 94.1 %

Procedure:
(2-Amino-5-(trifluoromethyl)phenyl)(phenyl)methanone (300 mg, 1.13 mmol) and 2-(1H-tetrazol-5-yl)acetic acid (145 mg, 1.13 mmol) were suspended in ethyl acetate (10 ml). Then 1-propanephosphonic acid cyclic anhydride (2.02 g, 1.89 ml, 50% solution in EtOAc, 3.18 mmol) was added and the mixture was heated to 50° C. overnight. Then water was added at room temperature and the resulting precipitate was filtered, washed with water and heptane and dried at 50° C. and 15 mbar to afford the title compound (380 mg, 94%) as yellow solid. MS (ESI): 356.5 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)[CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1>ClC(Cl)C.C(N)C1C=CC=CC=1.C(O)C>[CH2:6]([NH:7][CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:6]2[C:5]3[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH:10]=1)[C:5]1[CH:20]=[CH:21][CH:2]=[CH:3][CH:4]=1
Reactant: Fc1ccc2c(-c3cccc(OC[C@H]4CO4)c3)noc2c1
Solvent: CC(Cl)Cl
Solvent: CCO
Solvent: NCc1ccccc1
Product: O[C@H](CNCc1ccccc1)COc1cccc(-c2noc3cc(F)ccc23)c1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(3-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dichloroethane, benzylamine and ethanol, essentially as described above in Example 57. Purity by LC/MS=88%, [M+H]+=393.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[O:12][C@@H:11]([N:23]2[C:33]3[N:32]=[C:30]([NH2:31])[NH:29][C:27](=[O:28])[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[Si](Cl)(C)C.ClC([O:42][C:43]1C=CC=CC=1)=O.CO.[CH3:51][NH2:52]>N1C=CC=CC=1>[Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:17])[CH3:18])[O:12][C@@H:11]([N:23]2[C:33]3[N:32]=[C:30]([NH:31][C:43](=[O:42])[NH:52][CH3:51])[NH:29][C:27](=[O:28])[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: C[Si](C)(C)Cl
Solvent: CO
Solvent: c1ccncc1
Product: CNC(=O)Nc1nc2c(ncn2[C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
3′,5′-Bis-O-(tert-butyldimethylsilyl)deoxyguanosine (1.5 g, 3.02 mmol) was azeotroped with anhydrous pyridine three times and then dissolved in anhydrous pyridine (15 mL), and trimethylsilyl chloride (576 μL, 4.53 mmol) was added thereto. The mixture was stirred at room temperature for 1 hour, and then phenyl chloroformate (569 μL, 3.93 mmol) was added thereto. The mixture was stirred at room temperature for 4 hours. A 40% methylamine methanol solution (1.8 mL, 15.1 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate (200 mL)/water (150 mL) once and then with ethyl acetate (200 mL)/brine (150 mL) twice. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography with methanol/50% to 80% chloroform to give 3′,5′-bis-O-(tert-butyldimethylsilyl)-2-N-methylcarbamoyldeoxyguanosine (1.38 g, 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]2.[S:17]1[C:21]([CH2:22][C:23](O)=O)=[CH:20][C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]1=2>>[S:17]1[C:21]([CH2:22][CH2:23][N:13]([CH:10]2[CH2:9][CH2:8][C:7]3[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=3)[CH2:11]2)[CH2:14][CH2:15][CH3:16])=[CH:20][C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]1=2
Reactant: O=C(O)Cc1cc2ccccc2s1
Reactant: CCCNC1CCc2cccc(OC)c2C1
Product: CCCN(CCc1cc2ccccc2s1)C1CCc2cccc(OC)c2C1

Procedure:
Synthesis works according to the preparation of A4-1 or A4-4 when using N-(8-methoxytetralin-2-yl)-N-propylamine (A2-1: R═OMe) and 2-benzo[b]thienyl acetic acid (A3-10: R═OMe, Cy=2-benzo[b]thienyl) (purchasable from Rare Chemicals, Kiel (Germany); order number: GT HW 0344) and subsequent reaction according to the synthesis of A5-1.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][OH:15])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H-].[Na+].Cl[C:21]1[N:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=1.O>CS(C)=O>[C:1]([NH:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][C:21]2[N:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(OCCOCCO)cc1
Reactant: Clc1cnc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Nc1ccc(OCCOCCOc2ncc(Cl)cn2)cc1
Yield: 63.5 %

Procedure:
2-[2-(4-Acetamidophenoxy)ethoxy]ethanol (9 g) was dissolved in dry dimethylsulfoxide (60 ml) and granular sodium hydride (0.9 g) was added portionwise to the solution. 2,5-Dichloropyrimidine (5.6 g) was slowly added to the cooled stirred solution and on completion of the addition the mixture was stirred at room temperature for 1 hour. The mixture was poured into water (200 ml) and the solid was collected by filtration. The product was recrystallised from ethanol/water to give 2-{2-[2(4-acetamidophenoxy)ethoxy]ethoxy}-5-chloropyrimidine (8.4 g), m.p. 110° C.