Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)O[C@H:6]1[CH2:10][C@@H:9]([N:11]2[CH:19]=[N:18][C:17]3[C:12]2=[N:13][C:14]([Cl:21])=[N:15][C:16]=3[Cl:20])[CH:8]=[CH:7]1)C.ClC1N=C2C(N=CN2[C@@H]2C[C@H](O)C=C2)=C(Cl)N=1.[C:40]([O:44][C:45](=[O:51])[NH:46][C:47](=[O:50])[CH2:48][CH3:49])([CH3:43])([CH3:42])[CH3:41].C(N(C(OC(C)(C)C)=O)[C@H]1C[C@@H](N2C=NC3C2=NC(Cl)=NC=3Cl)C=C1)(OC(C)(C)C)=O>>[C:40]([O:44][C:45](=[O:51])[N:46]([C@H:6]1[CH2:10][C@@H:9]([N:11]2[CH:19]=[N:18][C:17]3[C:12]2=[N:13][C:14]([Cl:21])=[N:15][C:16]=3[Cl:20])[CH:8]=[CH:7]1)[C:47](=[O:50])[CH2:48][CH3:49])([CH3:42])([CH3:41])[CH3:43]
Reactant: CCC(=O)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Agent: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Agent: O[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Product: CCC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1

Procedure:
The title compound is prepared from carbonic acid (1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl ester ethyl ester (an intermediate for preparing the compound of Example 4) and propionyl-carbamic acid tert-butyl ester (see preparation of intermediates) using a procedure analogous to that of di-Boc-[(1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl]-amine (another intermediate for preparing the compound of Example 4). 1H nmr (CDCl3, 400 MHz); 8.70(s, 1H), 6.15(m, 1H), 5.85(m, 1H), 5.80(m, 1H), 5.60(m, 1H), 3.15(m, 1H), 2.75(q, 2H), 2.10(m, 1H), 1.55(s, 9H), 1.15(t, 3H), MS (ES+) m/e 426 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:11](O)[CH3:12].CCN(C(C)C)C(C)C>S(Cl)(Cl)=O>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnccc1Cl
Reactant: CCO
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
A suspension of 4-chloro-nicotinic acid (3.0 g, 19.0 mmol) in thionyl chloride (50 ml) was heated under reflux for 90 minutes. After cooling to ambient temperature, the solution was concentrated to dryness and then azeotroped with toluene (2×50 ml) to afford a solid. The resultant solid was added in portions to a cooled (0° C.) solution of ethanol (25 ml) and DIPEA (15 ml). The reaction was stirred at room temperature for 4 hours then concentrated in vacuo before water (75 ml) was added. The solution was extracted with ethyl acetate (2×75 ml) and the combined organic phases were dried over sodium sulfate, then concentrated to give the title compound as a brown oil (3.3 g, 94%). 1H NMR (CDCl3, 400 MHz) 9.03 (s, 1H), 7.58 (d, J=5.4 Hz, 1H), 7.41 (dd, J=5.4 Hz, 0.5 Hz, 1H), 4.45 (q, J=7.3 Hz, 2H), 1.43 (t, J=7.3 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18]Br.FC(F)(F)C1C=CC(C2(C#N)CCCC2)=CC=1>>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[C:5]([C:9]2([C:10]#[N:11])[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:6]=[CH:7][CH:8]=1
Reactant: N#CCc1cccc(C(F)(F)F)c1
Reactant: BrCCCCBr
Agent: N#CC1(c2ccc(C(F)(F)F)cc2)CCCC1
Product: N#CC1(c2cccc(C(F)(F)F)c2)CCCC1

Procedure:
1-(3-(Trifluoromethyl)phenyl)cyclopentanecarbonitrile (468) was synthesized from 2-(3-(trifluoromethyl)phenyl)acetonitrile (467) and 1,4-dibromobutane following the procedure described for 1-(4-trifluoromethyl-phenyl)-cyclopentanecarbonitrile (237).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:12](OC)(=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[SH:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]2[S:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[C:12](=[O:20])[N:9]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccccc1S
Reactant: CC(=O)c1ccc(C#N)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(-c2nc(=O)c3ccccc3s2)cc1
Yield: 1.8 %

Procedure:
A mixture of 4-acetylbenzonitrile (2.00 g, 14 mmol), methyl thiosalicylate (4.63 g, 28 mmol), triethylamine (2.79 g, 28 mmol) and toluene (10 ml) was heated and refluxed for 72 hours under a nitrogen flow. The reaction solution was concentrated under reduced pressure and the residue was applied to column chromatography using silica gel (100 g). Fractions eluted with hexane-ethyl acetate (3:1, v/v) were concentrated under reduced pressure. The residue was recrystallized from isopropyl ether to give the title compound (0.07 g, 2%) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[NH:12][NH2:13]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[N:13][NH:12][C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: COc1cccc(C=O)c1
Reactant: CC(C)(C)OC(=O)NN
Solvent: C1CCOC1
Product: COc1cccc(C=NNC(=O)OC(C)(C)C)c1
Yield: 103.1 %

Procedure:
A solution of 3-methoxybenzaldehyde (27.0 g) and t-butyl carbazate (25.0 g) in tetrahydrofuran (350 ml) was refluxed for 4 hours. The reaction mixture was concentrated to dryness giving t-butyl 3-methoxybenzylidenecarbazate (48.8 g) as an oil, which was used without further purification.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:36]=[CH:35][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:54][C:55]1[CH:60]=[CH:59][C:58]([O:61][CH2:62][CH:63]2[CH2:65][O:64]2)=[CH:57][CH:56]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[C:29]1([CH:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:21][NH:20][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:65][C@H:63]([OH:64])[CH2:62][O:61][C:58]4[CH:59]=[CH:60][C:55]([OH:54])=[CH:56][CH:57]=4)=[CH:36][CH:35]=3)[CH2:13][CH2:14]2)=[O:19])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1ccc(NC2CCN(C(=O)NCC(c3ccccc3)c3ccccc3)CC2)cc1
Solvent: ClC(Cl)Cl
Solvent: O=CO
Solvent: CO
Product: O=C(NCC(c1ccccc1)c1ccccc1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 19.7 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(2,2-diphenylethyl)-1-piperidinecarboxamide formate (0.60 g, 1.2 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.496 g, 1.2 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.20 g, 0.236 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:4]=1[CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:10]=2[NH:9][C:8](=O)[CH2:7]1.CN(C)C1C=CC(C)=CC=1.[Cl-:37].[P+]=O>C1(C)C=CC=CC=1>[Cl:37][C:8]1[CH2:7][N:6]([CH2:5][C:4]2[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:3]=2[O:2][CH3:1])[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:10]=2[N:9]=1
Reactant: COc1ccc(CN2CC(=O)Nc3ccc(OC)cc3C2=O)c(OC)c1
Reactant: [Cl-]
Agent: O=[P+]
Solvent: Cc1ccccc1
Solvent: Cc1ccc(N(C)C)cc1
Product: COc1ccc(CN2CC(Cl)=Nc3ccc(OC)cc3C2=O)c(OC)c1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
4-(2,4-Dimethoxy-benzyl)-7-methoxy-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (23.7 g, 67 mmol) and N,N-dimethyl-p-toluidine (19.2 mL, 133 mmol) were mixed in toluene (200 mL) and heated to 100° C. Then phosphorous oxide chloride (6.7 mL, 73 mmol) was added dropwise and heating at 100° C. was continued for 2.5 h. The resulting dark red solution was evaporated to dryness and the residue redissolved in THF (150 mL) and used directly in the subsequent step.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[N+:12]([CH:15]=[C:16](SC)[S:17][CH3:18])([O-:14])=[O:13]>C(O)C>[N+:12]([CH:15]=[C:16]([S:17][CH3:18])[NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)([O-:14])=[O:13]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCSCc1ccccn1
Solvent: CCO
Product: CSC(=C[N+](=O)[O-])NCCSCc1ccccn1
Yield: 29.4 %

Procedure:
A solution of 2-[(2-aminoethyl)thiomethyl]pyridine (5.0 g) and 1-nitro-2,2-bis-methylthioethylene (5.28 g) in ethanol was heated under reflux for 3 hours. Concentration and chromatographic purification of the product on a column of silica gel with elution by iso-propyl alcohol-ethylacetate (1:5) gave 1-nitro-2-methylthio-2-[2-(2-pyridylmethylthio)ethylamino]-ethylene (2.49 g), m.p. 95.5° - 96.5°.
Reaction SMILES: [Na].Cl.[NH2:3][OH:4].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([NH:17][C:18]([CH2:20][C:21](OCC)=[O:22])=[O:19])[CH:10]=[C:11]([O:15][CH3:16])[C:12]=1[O:13][CH3:14]>CO>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([OH:4])[CH:10]=[C:11]([O:15][CH3:16])[C:12]=1[O:13][CH3:14].[C:18]([CH2:20][C:21]([NH:3][OH:4])=[O:22])(=[O:19])[NH2:17]
Reactant: NO
Reactant: CCOC(=O)CC(=O)Nc1cc(OC)c(OC)c(OC)c1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COc1cc(O)cc(OC)c1OC
Product: NC(=O)CC(=O)NO
Reaction time: 8 h

Procedure:
4.15 g (0.18 gram atom) of sodium are added in small pieces to 100 ml of anhydrous methanol and this cold solution is then poured into a solution of 7 g (0.1 mol) of hydroxylamine hydrochloride in 100 ml of methanol; the sodium chloride is filtered off and 23.8 g (0.08 mol) of ethyl 3,4,5-trimethoxyphenylcarbamoylacetate are added to the filtrate. The reactants are left in contact overnight, the mixture is evaporated to dryness in vacuo, the residue is taken up in water, the solution is acidified with 3 N HCl and the product is filtered off and washed with cold water and with diisopropyl ether. recrystallisation from methanol gives CRL 40,509. Melting point=195°-196° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][CH:19]=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:20].C([O-])(=O)C.[Na+].[I:26]Cl>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([I:26])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:20]
Reactant: Cc1cc(-c2cc(C(F)F)n3nccc3n2)ccc1Cl
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(-c2cc(C(F)F)n3ncc(I)c3n2)ccc1Cl
Temperature: 25 °C
Reaction time: 19 h
Yield: 96.3 %

Procedure:
To a stirred solution of 5-(4-chloro-3-methyl-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine (5.1 g, 17.4 mmol) in acetic acid (25 mL) was added at room temperature sodium acetate (1.61 g, 19.6 mmol) and drop wise a solution of iodine monochloride (3.19 g, 19.6 mmol) in acetic acid (10 mL). The reaction mixture was stirred at room temperature for 19 h, diluted slowly with water (300 mL), stirred at room temperature for 30 min, the precipitate was filtered off, washed with water and dried to give 5-(4-chloro-3-methyl-phenyl)-3-iodo-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine (7.03 g, 96%) as a yellow solid. MS (EI) 419.9 [(M)+]; mp 144° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)C2(C3=CC4OCOC=4C=C3OC2)C1=O.[F:44][C:45]([F:55])([F:54])[C:46]1[CH:47]=[C:48]([CH:51]=[CH:52][CH:53]=1)[CH2:49]Cl.COC1C=CC(CCl)=CC=1>>[F:44][C:45]([F:54])([F:55])[C:46]1[CH:47]=[C:48]([CH:51]=[CH:52][CH:53]=1)[CH2:49][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: COc1ccc(CCl)cc1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Product: O=C1N(Cc2cccc(C(F)(F)F)c2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 7 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 3-(trifluoromethyl)benzyl chloride to replace 4-methoxybenzyl chloride, 1′-[3-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (92%) as a colorless solid: mp 131-134° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ7.62-7.43 (m, 4H), 7.25-7.18 (m, 2H), 7.05 (dd, J=7.5, 7.5 Hz, 1H), 6.75 (d, J=7.5 Hz, 1H), 6.52 (s, 1H), 6.23 (s, 1H), 5.14 (d, J=15.9 Hz, 1H), 4.95 (d, J=9.0 Hz, 1H), 4.88 (d, J=15.9 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.23-4.18 (m, 2H), 4.15-4.11 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.8, 155.4, 144.8, 141.8, 138.5, 137.0, 132.3, 131.4 (q, J=32.4 Hz), 130.7, 129.7, 129.0, 124.9 (q, J=3.7 Hz), 124.25, 124.22 (q, J=3.7 Hz), 124.0 (q, J=272.4 Hz), 123.8, 120.9, 111.6, 109.1, 99.6, 80.2, 64.7, 64.0, 58.2, 43.8; MS (ES+) m/z 453.9 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:8])[CH:5]=[CH:6][CH:7]=1.C([Li])(C)(C)C.CCCCC.[C:19]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)#N.[OH-:27].[Na+]>CCOCC.O>[F:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:19]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[O:27]
Reactant: [OH-]
Reactant: N#Cc1cccnc1
Reactant: Fc1cccc(Br)c1
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CCCCC
Product: O=C(c1cccnc1)c1cccc(F)c1
Temperature: 15 °C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
A solution of 3-bromofluorobenzene (25.0, 0.143 mol) in ether (250 ml) was cooled to -78° C. and stirred during the dropwise addition of a 2.3 M solution of tert-butyllithium in pentane (62 ml, 0.143 mol). After the addition was completed, stirring was continued for 15 minutes and a solution of 3-cyanopyridine (14.9 g, 0.143 mol) in ether (125 ml) was added dropwise. The resulting mixture was allowed to warm to 15° C. and a solution of 12 N HC1 (36 ml) in H2O (90 ml) was added dropwise. After the resulting light yellow solution had stirred for 30 minutes, 10% NaOH was added to give a pH of 10, and the ether layer was separated. The aqueous phase was extracted twice with ether, the combined ether extracts were concentrated and the residue was distilled to yield 21.3 g (74%) of 3-(3-fluorobenzoyl)pyridine bp: 112°-128° C./59.99 Nm-2.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[CH:8]=1)[CH3:2].[Br:15]Br.O>C(O)(=O)C>[CH2:1]([O:3][CH2:4][CH2:5][S:6][C:7]1[CH:8]=[C:9]([CH3:14])[C:10]([Br:15])=[C:11]([CH3:13])[CH:12]=1)[CH3:2]
Reactant: BrBr
Reactant: CCOCCSc1cc(C)cc(C)c1
Solvent: CC(=O)O
Solvent: O
Product: CCOCCSc1cc(C)c(Br)c(C)c1
Temperature: 25 °C
Yield: 65.1 %

Procedure:
To a solution of 2-[(3,5-dimethylphenyl)thio]ethyl ethyl ether (2.69 g, 12.8 mmol) in acetic acid (60 mL) was slowly added dropwise a solution of bromine (0.68 mL, 13.2 mmol) in acetic acid (30 mL) under stirring at room temperature. The reaction mixture was stirred at the same temperature for 2 hr, poured into cold water, and the mixture was extracted with diethyl ether. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane/ethyl acetate=20/1) to give the title compound (2.41 g, yield 65%) as a pale-yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[C:24]3[CH:25]=[CH:26][NH:27][C:23]=3[CH:22]=[CH:21][N:20]=2)[CH2:15][CH2:14]1.CN(C)[CH:30]=[O:31].[NH4+].[Cl-]>O1CCCC1.CCCCCC>[NH:27]1[C:23]2[CH:22]=[CH:21][N:20]=[C:19]([N:16]3[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][C:5]4[C:4]5[C:8](=[CH:9][CH:10]=[C:2]([CH:30]=[O:31])[CH:3]=5)[NH:7][CH:6]=4)[CH2:14][CH2:15]3)[C:24]=2[CH:25]=[CH:26]1
Reactant: Brc1ccc2[nH]cc(CCN3CCN(c4nccc5[nH]ccc45)CC3)c2c1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1ccc2[nH]cc(CCN3CCN(c4nccc5[nH]ccc45)CC3)c2c1
Reaction time: 1 h

Procedure:
A solution at −78° C. of 1.5 mmol of the compound obtained in Step 3 in tetrahydrofuran is treated with 9 mmol of tert-butylithium (1.8M in hexane). After stirring the mixture for 1 hour, 12 mmol of dimethylformamide are added and the mixture is brought to ambient temperature. After reaction for 4 hours, the solution is hydrolysed by a saturated solution of NH4Cl and then extracted with dichloromethane. After treating the organic phase in conventional manner, chromatography of the residue on silica gel enables the expected product to be isolated.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][C:12]1[O:16][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14][C:13]=1[CH2:23][CH2:24][OH:25].[H-].[Na+].O>C1COCC1>[CH3:11][C:12]1[O:16][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14][C:13]=1[CH2:23][CH2:24][O:25][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 49.5 %

Procedure:
To a stirred solution of 2-chloro-5-nitropyridine (25 g), 2-(5-methyl-2-phenyl-4-oxazolyl)ethanol (32.1 g) in THF (250 ml) was added portionwise, under ice-cooling, sodium hydride (60% in oil, 6.92 g). The reaction mixture was stirred for further 15 hours at room temperature, which was poured into water, followed by extraction with ethyl acetate. The ethyl acetate was washed with water and dried (MgSO4), then the solvent was distilled off under reduced pressure. The residual crystals were collected by filtration. Recrystallization from ethanol gave 2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-nitropyridine (25.4 g, 49%) as yellowish brown crystals, m.p.l10.5-111.5° C.
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]2[C:13]([O:15][C:16](=[O:17])[C@H:11]2[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([OH:28])C.[CH:29]1[CH:34]=CC=CC=1>>[CH2:1]([N:8]1[C@H:12]([C:13]([O:14][CH2:34][CH3:29])=[O:28])[C@H:11]([C:16]([OH:15])=[O:17])[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C1OC(=O)[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Reactant: c1ccccc1
Product: CCOC(=O)[C@@H]1[C@H](C(=O)O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Reaction time: 8 h

Procedure:
A mixture of cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid anhydride (70.0 g), 99.5% ethanol (16.6 g) and benzene (1000 ml) was heated under reflux for 2 hours. The reaction mixture (about 600 ml) was concentrated under ordinary pressure. The residue was stirred overnight with n-hexane (200 ml). Crystals produced were filtered and dried under reduced pressure to yield racemic cis-1,3-dibenzyl-5-ethoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid (76.2 g), which were recrystallized from toluene. M.P. 110°-111° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl.C(=O)(O)[O-].[Na+].[O:29]1[CH:34]=[CH:33][CH2:32][CH2:31][CH2:30]1>>[Br:1][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][O:29]1)[CH:6]=2
Reactant: O=[N+]([O-])c1cc(Br)cc2[nH]ncc12
Reactant: C1=COCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Br)cc2nn(C3CCCCO3)cc12
Reaction time: 0.17 h

Procedure:
To 6-bromo-4-nitro-1H-indazole (10 g, available from Sinova Ltd) in dihydropyran (100 ml) was added TFA (0.068 ml) and the reaction was heated for 1.5 hours at reflux. After cooling, 180 ml DCM and 50 ml saturated sodium bicarbonate solution was added and stirred for 10 minutes. The DCM was separated from the aqueous which was re-washed with DCM (70 ml). The combined organic layers were passed through a hydrophobic frit and evaporated to dryness. The residual solid was triturated with ether then filtered. The solid material was dissolved in DCM and purified by chromatography on silica on the ISCO Companion, using an isocratic gradient of DCM. Purified fractions were combined and evaporated to dryness to afford the title compound (7.78 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH:10](I)([CH3:12])[CH3:11].C(N(CC)CC)C>CO>[CH:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)([CH3:12])[CH3:11]
Reactant: COc1ccc(N)cc1
Reactant: CC(C)I
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(NC(C)C)cc1

Procedure:
A solution of 5 g (40.6 mmol) p-anisidin, 4.1 ml (40.6 mmol) isopropyl iodide and 5.7 ml (40.6 mmol) triethylamine in 40 ml methanol is refluxed for 18 h. The reaction mixture is extracted with diethyl ether/water and the organic layers are evaporated. The crude product is purified by flash chromatography using dichloromethane/MeOH (98:2) as eluent to yield isopropyl-(4-methoxy-phenyl)-amine.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]2[CH2:13][CH:12]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:11][CH2:10][C:9]=2[C:8]([Br:20])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[N+:21]([O-])([OH:23])=[O:22].CCOC(C)=O.CO>FC(F)(F)C(O)=O>[C:1]([NH:4][C:5]1[C:14]2[CH2:13][CH:12]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:11][CH2:10][C:9]=2[C:8]([Br:20])=[CH:7][C:6]=1[N+:21]([O-:23])=[O:22])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(Br)c2c1CC(N1CCCC1)CC2
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1c([N+](=O)[O-])cc(Br)c2c1CC(N1CCCC1)CC2
Reaction time: 4 h

Procedure:
A mixture of 1-acetamido-4-bromo-7-pyrrolidin-1-yl-5,6,7,8-tetrahydronaphthalene (0.3 g) in trifluoroacetic acid (10 mL) was cooled in an icebath and treated with fuming nitric acid (0.5 mL). After stirring for 4 h, the solvent was evaporated and the residue taken up in methylene chloride:water. The mixture was basified with 12.5% NaOH, and the aqueous layer back extracted. The combined organic layers were dried over sodium sulfate, filtered and evaporated to give a solid. Preparative thin layer chromatography (7:3 EtOAc:MeOH) was used to obtain the purified product (0.12 g).
Reaction SMILES: C[C@H]1CO[C@@]2([O:9][C@H]3C[C@H]4[C@@H]5CC=C6C[C@@H](O)CC[C@]6(C)[C@H]5CC[C@]4(C)[C@H]3[C@@H]2C)CC1.[OH-].[K+].[CH2:33]([O:37][CH2:38][CH2:39][CH2:40]CCCCCCCCC)[CH:34]1[O:36][CH2:35]1>C1(C)C=CC=CC=1>[CH2:38]([O:37][CH2:33][CH:34]1[O:36][CH2:35]1)[CH:39]1[O:9][CH2:40]1
Reactant: CCCCCCCCCCCCOCC1CO1
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC=C5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C(OCC1CO1)C1CO1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
In a 250 mL, round bottom 3-neck flask equipped with a condenser, a nitrogen in/out let, a mechanical stirrer, a thermo-watch, and a heating mantle, a mixture of 30 g of 10,000 Mw PEG and toluene (80 mL) was heated to 60° C. At this temperature, KOH (2.19 g, 0.04 mol, in 2 g of water) was added and the reaction mixture was stirred for 1 hour. Dodecyl glycidyl ether (8.71 g, 0.04 mole) was added and the reaction temperature was kept at 110° C. for 5 hours. After the reaction mass was cooled to 60° C., toluene (80 mL) was further added. The solution was precipitated into 300 mL of hexane. After filtration and washing with ethyl acetate (100 mL×3×) and drying in vaccuo, a white polymer (33 g) was obtained. 1H NMR showed 11% hydrophobe incorporation. The Brookfield viscosity of a 5% aqueous solution of this oligomer was >200,000 cps (BF LV, S-63, 0.3 rpm at 25° C.). Paint performance: SG10 M (standard formulation). The material was not soluble in this paint. For UCAR 379 G, TE %=0.52, VLT=−6 KU.