Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:27][C:15]3[N:16]=[C:17](Cl)[N:18]=[C:19]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)=[O:4].CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1>>[NH2:43][C:40]1[N:41]=[CH:42][C:37]([C:17]2[N:18]=[C:19]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:14]3[CH:13]=[C:12]([CH2:11][N:8]4[CH2:9][CH2:10][N:5]([C:3]([N:2]([CH3:28])[CH3:1])=[O:4])[CH2:6][CH2:7]4)[S:27][C:15]=3[N:16]=2)=[CH:38][N:39]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CN(C)C(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: CN(C)C(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3s2)CC1

Procedure:
4-(2-Chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidin-6-ylmethyl)-piperazine-1-carboxylic acid dimethylamide was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine in General Procedure A. Purification on silica yielded 128. NMR (CDCl3): 2.55 (m, 4H, 2×CH2), 2.84 (s, 6H, 2×CH3), 3.32 (m, 4H, 2×CH2), 3.79 (s, 2H, CH2), 3.89-3.91 (m, 4H, 2×CH2), 3.95-3.97 (m, 4H, 2×CH2), 5.24 (sbr, 2H, NH2), 7.14 (s, H, ArH), 9.30 (s, 2H, 2×ArH). MS: (ESI+): MH+=484.31
Reaction SMILES: C(OC(C1C=NN(C2N=C3C(N=CN3[C@@H]3C[C@H](NC(=O)CC)[C@@H](O)[C@H]3O)=C(NC(C3C=CC(OC)=CC=3)C3C=CC(OC)=CC=3)N=2)C=1)=O)C.[C:50]1([CH:56]([C:82]2[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=2)[CH2:57][NH:58][C:59]2[N:67]=[C:66]([NH:68][NH2:69])[N:65]=[C:64]3[C:60]=2[N:61]=[CH:62][N:63]3[C@@H:70]2[CH2:74][C@H:73]([NH:75][C:76](=[O:79])[CH2:77][OH:78])[C@@H:72]([OH:80])[C@H:71]2[OH:81])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.[N+:88]([CH:91]([CH:94]=O)[CH:92]=O)([O-:90])=[O:89].[Na]>>[C:82]1([CH:56]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH2:57][NH:58][C:59]2[N:67]=[C:66]([N:68]3[CH:94]=[C:91]([N+:88]([O-:90])=[O:89])[CH:92]=[N:69]3)[N:65]=[C:64]3[C:60]=2[N:61]=[CH:62][N:63]3[C@@H:70]2[CH2:74][C@H:73]([NH:75][C:76](=[O:79])[CH2:77][OH:78])[C@@H:72]([OH:80])[C@H:71]2[OH:81])[CH:83]=[CH:84][CH:85]=[CH:86][CH:87]=1
Reactant: NNc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](NC(=O)CO)[C@@H](O)[C@H]3O)c2n1
Reactant: O=CC(C=O)[N+](=O)[O-]
Agent: CCOC(=O)c1cnn(-c2nc(NC(c3ccc(OC)cc3)c3ccc(OC)cc3)c3ncn([C@@H]4C[C@H](NC(=O)CC)[C@@H](O)[C@H]4O)c3n2)c1
Agent: [Na]
Product: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cc([N+](=O)[O-])cn4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to 1-[6-{[bis-(4-methoxy-phenyl)-methyl]-amino}-9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-9H-purin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (example 168, step 3), by reaction of N-{(1S,2R,3S,4R)-4-[6-(2,2-diphenyl-ethylamino)-2-hydrazino-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate ZP1) and sodium nitromalonaldehyde (prepared as described by Fanta P. E. Org. Syntheses, Coll. Vol. 4 (1963), pp 844-845).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@@H:4]([NH:23]C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][N:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][N:14]=2)=[CH:8][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3](=[O:31])[C@@H:4]([NH2:23])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][N:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][N:14]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(Nc2nccc3cnccc23)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](N)Cc1ccc(Nc2nccc3cnccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
A solution of (S)-2-tert-butoxycarbonylamino-3-[4-([2,6]naphthyridin-1-ylamino)phenyl] propionic acid methyl ester (405 mg, 0.96 mmol) in dichloromethane (11.5 ml) was, treated with trifluoroacetic acid (11.5 ml) and stirred at room temperature for 2 h. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (80 ml) and saturated aqueous NaHCO3 (30 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (3×30 ml). The combined organic extracts were dried (MgSO4) and evaporated in vacuo to afford the title compound (308 mg, 100%) as a dark viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn](CCCC)(CCCC)CCCC)[S:10][C:3]=12.ClC1C=CN=C2C=C(C3SC=CN=3)SC=12.BrC1SC=CN=1.Br[C:46]1[N:47]([CH3:55])[C:48]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][N:50]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:46]3[N:47]([CH3:55])[C:48]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][N:50]=3)[S:10][C:3]=12
Reactant: COC(=O)c1cnc(Br)n1C
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2nccc(Cl)c2s1
Agent: Brc1nccs1
Agent: Clc1ccnc2cc(-c3nccs3)sc12
Product: COC(=O)c1cnc(-c2cc3nccc(Cl)c3s2)n1C

Procedure:
Starting from the compound 98 (scheme 19) and following the procedure described above for the synthesis of compound 10 (example 12, scheme 2) but substituting 2-bromothiazole in the step 2 for the bromide 118, title compound 119 was obtained as a white solid (580 mg, 100% yield). MS (m/z) 308.1/310.0 (M+H).
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:12])[C:9]=1[CH2:10]2.Cl(O)(=O)(=O)=[O:14]>O1CCCC1>[C:8]1([OH:12])[C:9]2[CH2:10][C@@H:11]([OH:1])[C@H:2]([OH:14])[CH2:3][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc2c1CC1OC1C2
Reactant: [O-][Cl+3]([O-])([O-])O
Solvent: C1CCOC1
Product: Oc1cccc2c1C[C@@H](O)[C@H](O)C2

Procedure:
and reacting the 5,6,7,8-tetrahydro-6,7-epoxy-1-naphthol in tetrahydrofuran with aqueous perchloric acid at a temperature within the range of from about 0° to about 60°C., to form trans-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol XXV which can be converted to the 2,3-trans-1,2,3,4-tetrahydro-5-[2,3-(epoxy)propoxy]-2,3-naphthalenediol XXVI which in turn can be converted to the 2,3-trans-1,2,3,4-tetrahydro-5-[2-hydroxy-3-(substituted amino)propoxy]-2,3-naphthalenediol XXVII in a manner similar to that described hereinbefore.
Reaction SMILES: OC(COC1C=CC=CC=1)CC(O)=O.OC(CCCOC1C=CC=CC=1)CC(O)=O.O[CH:32]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:33][C:34]([OH:36])=[O:35]>>[O:42]([CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(O)CC(O)CCCCCOc1ccccc1
Agent: O=C(O)CC(O)CCCOc1ccccc1
Agent: O=C(O)CC(O)COc1ccccc1
Product: O=C(O)CCCCCCCOc1ccccc1

Procedure:
Result indicates that PHA copolymer containing three units of 3-hydroxy-4-phenoxybutyric acid (3HPxB), 3-hydroxy-6-phenoxyhexanoic acid (3HPxHx) and 3-hydroxy-8-phenoxyoctanoic acid (3HPxO) can be produced by the strain H45 with a substrate 8-phenoxyoctanoic acid.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][C:4]#[CH:5].[Li][CH2:8][CH2:9][CH2:10]C.ICCC>C1COCC1>[CH3:1][CH:2]([CH2:3][C:4]#[C:5][CH2:8][CH2:9][CH3:10])[CH3:6]
Reactant: [Li]CCCC
Reactant: C#CCC(C)C
Solvent: C1CCOC1
Solvent: CCCI
Product: CCCC#CCC(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
To a solution of 4-methylpent-1-yne (0.588 mL, 5 mmol) in THF at −78° C. was added BuLi, 2.5 M in hexanes (2.200 mL, 5.50 mmol). After stirring 15 minutes at −78° C., the reaction mixture was allowed to warm to room temperature, 1-iodopropane (0.488 mL, 5.00 mmol) was added and the reaction mixture was stirred at rt for 3 days. The reaction mixture was quenched with water (50 mL) and the resulting mixture was transferred to a separatory funnel. The mixture was extracted with ether (75 mL). The organic layer was washed with brine (50 mL), dried (MgSO4) and concentrated to afford 2-methyloct-4-yne (555 mg, 4.47 mmol, 89% yield) as a light yellow liquid. 1H NMR (400 MHz, chloroform-d) δ ppm 0.91-0.99 (m, 9H) 1.45-1.53 (m, 2H) 1.70-1.81 (m, 1H) 2.03 (dt, J=6.5, 2.4 Hz, 2H) 2.12 (tt, J=7.0, 2.4 Hz, 2H).
Reaction SMILES: N[C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7](NC3C=CC(Br)=CC=3)[NH:8][C:4]=2[CH:3]=1.[H-].[Na+].CN(C)C=[O:24]>>[N:6]1[CH:3]=[CH:2][CH:18]=[CH:17][C:5]=1[C:4]([NH:8][CH3:7])=[O:24]
Reactant: CN(C)C=O
Reactant: Nc1ccc2nc(Nc3ccc(Br)cc3)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Product: CNC(=O)c1ccccn1

Procedure:
To a solution of ((5-aminobenzimidazol-2-yl)(4-bromophenylamine (1 eq) in N,N-dimethylformamide was added sodium hydride (2 eq) and the mixture was microwaved for 8 mins at 220° C. The reaction mixture was partitioned between ethyl acetate and water and the organic layer was dried with sodium sulfate and concentrated. Preparative chromatography yielded [4-({2-[(4-bromophenyl)amino}benzimidazol-5-yl}amino)(2-pyridyl-N-methylcarboxamide. MS: MH+=437.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:28]=[CH:27][N:14]3[C:15](=[O:26])[C:16]([O:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:17][N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.CO.O>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:28]=[CH:27][N:14]3[C:15](=[O:26])[C:16]([O:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)COc1cnc2cc(CCc3nc(C(C)C)cs3)ccn2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1csc(CCc2ccn3c(=O)c(OCC(=O)O)cnc3c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The ethyl 2-{8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-4-oxo-4H-pyrido[1,2-a]-pyrimidin-3-yloxy}acetate (41 mg) obtained in (A) was dissolved in tetrahydrofuran (1 ml) and methanol (300 ml), added with a solution of lithium hydroxide (5 mg) dissolved in water (300 ml), and then the mixture was stirred at room temperature for 1 hour, and the solvent was concentrated under reduced pressure. The residue was distributed between ether and water, and the aqueous layer was separated and made pH 3 with hydrochloric acid, and then extracted with ethyl acetate. The organic layer was dried over sodium sulfate. After the solvent was evaporated, the residue was purified by silica gel column chromatography to obtain the title compound (quantitative).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:11]=[CH:10][NH:9][N:8]=2)[CH2:3][CH2:2]1.C1C(=O)N([Cl:19])C(=O)C1>O1CCCC1>[Cl:19][C:11]1[C:7]([CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[N:8][NH:9][CH:10]=1
Reactant: c1cc(C2CCOCC2)n[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: Clc1c[nH]nc1C1CCOCC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (compound 294.2, 3.5 g, 23.0 mmol) in tetrahydrofuran (20 mL) was added NCS (3.4 g, 25.4 mmol). The reaction mixture was stirred overnight at 40° C. The resulting mixture was concentrated under reduced pressure. This resulted in 4.75 g (crude) of the title compound as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(N(CC)CC)C.Br[CH2:18][C:19]1[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=1[Cl:26]>C(O)C>[Cl:26][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Cl:25])[C:19]=1[CH2:18][S:8][C:6]1[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Clc1cncc(Cl)c1CBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2c(Cl)cncc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.7 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (134 mg, 940 μmol) was dissolved in absolute ethanol (10 mL), then triethylamine (200 μL, 1.4 mmol) and 4-(bromomethyl)-3,5-dichloropyridine (250 mg, 1.0 mmol) were added. The mixture was stirred for 2 hours at room temperature. The solid was removed by filtration, and filtrate was evaporated. The residue was triturated in diethyl ether, filtered, washed with water plus diethyl ether, and then dried in vacuo to afford to 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (56 mg, 20% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.23 (s, 3H), 4.69 (s, 2H), 6.10 (bs, 1H), 8.66 (s, 2H); LRMS (ES+) m/z 302 (100%, M+1), 304 (70%, M+3).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[CH3:16][C@@H:17](O)[CH2:18][CH:19]=[CH2:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OCC)=O)=N/C(OCC)=O>C1COCC1>[CH3:20][C@H:19]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13])[CH2:18][CH:17]=[CH2:16]
Reactant: COC(=O)c1ccc2ccccc2c1O
Reactant: C=CC[C@@H](C)O
Agent: CCOC(=O)/N=N\C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC[C@H](C)Oc1c(C(=O)OC)ccc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.8 %

Procedure:
A mixture of methyl 1-hydroxy-2-naphthoate (500 mg, 2.473 mmol), (R)-pent-4-en-2-ol (0.382 mL, 3.71 mmol), triphenylphosphine (1297 mg, 4.95 mmol) and (Z)-diethyl diazene-1,2-dicarboxylate (0.836 mL, 4.95 mmol) in THF (20 mL) was stirred at rt for 3 h. It was then concentrated and the residue was purified by biotage, eluting with 10% EtOAc/hexane to isolate (S)-methyl 1-(pent-4-en-2-yloxy)-2-naphthoate (500 mg, 74.8%) as an oil. 1H NMR (400 MHz, CDCl3) δ 8.41-8.27 (m, 1H), 7.96-7.81 (m, 2H), 7.69-7.45 (m, 3H), 5.89 (ddt, J=17.2, 10.1, 7.1 Hz, 1H), 5.22-5.04 (m, 2H), 4.49-4.29 (m, 1H), 3.99 (s, 3H), 2.66-2.57 (m, 1H), 2.55-2.46 (m, 1H), 1.28 (d, J=6.4 Hz, 3H).
Reaction SMILES: P(Br)(Br)[Br:2].[C:5]([C:9]1[CH:10]=[C:11]([CH:38]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:40]=1)[CH:12]=[CH:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH:22]=[CH:23][C:24]2[CH:29]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:27]=[C:26]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:25]=2)[CH:21]=1)[CH2:17]O)([CH3:8])([CH3:7])[CH3:6].CC(O)C>ClCCl>[C:5]([C:9]1[CH:10]=[C:11]([CH:38]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:40]=1)[CH:12]=[CH:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH:22]=[CH:23][C:24]2[CH:29]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:27]=[C:26]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:25]=2)[CH:21]=1)[CH2:17][Br:2])([CH3:8])([CH3:7])[CH3:6]
Reactant: BrP(Br)Br
Reactant: CC(C)(C)c1cc(C=Cc2cc(C=Cc3cc(C(C)(C)C)cc(C(C)(C)C)c3)cc(CO)c2)cc(C(C)(C)C)c1
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)(C)c1cc(C=Cc2cc(C=Cc3cc(C(C)(C)C)cc(C(C)(C)C)c3)cc(CBr)c2)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.5 %

Procedure:
Phosphorus tribromide (2.8 cm3, 30 mmol) was added to a solution of 3,5-bis(3′,5′-di-tert-butylstyryl)benzyl alcohol (1.60 g, 3.0 mmol) in dichloromethane (50 cm3) and the mixture stirred at room temperature for 3 h. Propan-2-ol (14 cm3) was added slowly and the solvent was completely removed. The residue was purified by column chromatography over silica, eluting with dichloromethane-light petroleum (40-60) (1:9), giving 3,5-bis(3′,5′-di-tert-butylstyryl)benzyl bromide (1.52 g, 85%). A sample for analysis was recrystallised from a dichloromethane-light petroleum (60-80) mixture, mp 222-223° C. (Found: C, 77.75; H, 8.72. C39H51Br requires C, 78.11; H, 8.57%); νmax(CHCl3)/cm−1 1596s (C═C) and 964s (C═C—H trans); λmax(CHCl3)/nm (log ε) 315 (4.82); δH(400 MHz, CDCl3) 1.38 (36 H, s, t-Bu), 4.55 (2 H, s, CH2), 7.12 and 7.24 (4 H, d, J 16, 7′,8′-H), 7.39 (2 H, dd, J 1.5, 4′-H), 7.41 (4 H, d, J 1.5, 2′,6′-H), 7.47 (2 H, d, J 1, 2,6-H) and 7.63 (1 H, m, 4-H); m/z (APCI+) 521 ((M-Br)+, 100%) and 599 (M+, 40%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[C:11]([O:15][C:16](=[O:31])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16](=[O:31])[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]=[C:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: CCCCCCCC(=O)NCCCCC(=O)OC(C)(C)C
Product: CCCCCCCc1nc2ccccc2n1CCCCC(=O)OC(C)(C)C
Yield: 21.5 %

Procedure:
Method A applied to 1-iodo-2-nitrobenzene (125 mg, 0.5 mmol) and 5-octanoylamino-pentanoic acid tert-butyl ester (180 mg, 0.6 mmol) yielded the title compound as yellowy oil (40 mg, 38%). 1H NMR (DMSO) δ 0.86 (t, J=6.8Hz, 3H), 1.22-1.86 (m, 23H), 2.27 (t, J=7.3, 2H), 3.14 (t, J=7.8Hz, 2H), 4.43 (t, J=7.2Hz), 7.49-7.54 (m, 2H), 7.77 (d, J=8.8Hz, 1H), 7.93 (d, J=8.8Hz).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5](=[O:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+].[OH:14][C:15]1[CH:16]=[CH:17][C:18]2[N:40]([CH:41]=1)[C:21]1[N:22]([C:31]3[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=3)[C:23](=[O:30])[C:24]3[C:29]([C:20]=1[N:19]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3>CN(C=O)C>[N+:37]([C:34]1[CH:33]=[CH:32][C:31]([N:22]2[C:21]3[N:40]4[CH:41]=[C:15]([O:14][CH2:6][C:5]([O:4][CH2:3][CH3:2])=[O:7])[CH:16]=[CH:17][C:18]4=[N:19][C:20]=3[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:30])=[CH:36][CH:35]=1)([O-:39])=[O:38]
Reactant: CC(=O)OCCBr
Reactant: O=c1c2ccccc2c2nc3ccc(O)cn3c2n1-c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2nc3c4ccccc4c(=O)n(-c4ccc([N+](=O)[O-])cc4)c3n2c1
Yield: 94.9 %

Procedure:
Bromoethylacetate (1.2 equiv., 1.128 mmol, 0.188 g) and potassium carbonate (3.0 equiv., 2.820 mmol, 0.390 g) were added to a solution of 10 (1.0 equiv., 0.940 mmol, 0.350 g) in DMF (10 ml). The mixture was heated at reflux for 2 h. The reaction product was precipitated by the addition of water, filtered off and washed with isopropanol and isopropyl ether successively to give ethyl 2-[[5,6-dihydro-6-(4-nitrophenyl)-5-oxo-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-9-yl]oxy]-acetate (13) (0.409 g, yield=95%, purity (LC)=92%) as a light red powder.
Reaction SMILES: C[N:2]1[CH2:15][CH2:14][C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[C:7]2[CH2:16][CH2:17][CH2:18][C:6]=2[N:5]3[CH2:4][CH2:3]1.ClC(OC(Cl)C)=O>ClC(Cl)C>[CH2:4]1[N:5]2[C:13]3[C:8]([C:7]4[CH2:16][CH2:17][CH2:18][C:6]=42)=[CH:9][CH:10]=[CH:11][C:12]=3[CH2:14][CH2:15][NH:2][CH2:3]1
Reactant: CN1CCc2cccc3c4c(n(c23)CC1)CCC4
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: c1cc2c3c(c1)c1c(n3CCNCC2)CCC1
Temperature: 25 °C
Yield: 33.1 %

Procedure:
To a solution of 3-methyl-2,3,4,5,10,11-hexahydro-1H,9H-cyclopenta[b][1,4]diazocino[7,8,1-hi]indole (90 mg, 0.36 mmole) in dichloroethane (10 mL) was added 1-chloroethyl chloroformate (0.15 mL, 1.3 mmole) and the solution refluxed for 24 hours under nitrogen. The reaction mixture was cooled to room temperature and the solvent removed in vacuo and replaced with methanol (25 mL) and refluxed for another 3 hours under nitrogen. The solvent was removed in vacuo and the residue purified by flash column chromatography (silica gel, 1.5% methanol in dichloromethane) to provide 27 mg of the title compound as a light yellow oil. The oil was further treated with one equivalent of fumaric acid in ethanol to form a fumarate salt, mp 180-183° C., which contained a slight excess of fumaric acid. MS (ESI) m/z 227 ([M+H]+).
Reaction SMILES: Cl[C:2]1[C:3](C)=[N+:4]([O-])[CH:5]=[CH:6][CH:7]=1.[N+:10]([O-])([OH:12])=[O:11]>>[N+:10]([C:7]1[CH:6]=[CH:5][N:4]=[CH:3][CH:2]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: Cc1c(Cl)ccc[n+]1[O-]
Product: O=[N+]([O-])c1ccncc1

Procedure:
3-Chloro-2-methylpyridine N-oxide may be nitrated with a mixture of nitric acid and sulphuric acids, and the 4-nitropyridine produced successively treated with sodium methoxide, heated in acetic anhydride, purified and deacetylated to give 2-hydroxymethyl-3-chloro-4-methoxypyridine, which may be substituted for 2-hydroxy-3-methoxypyridine in the procedure of Example 1(ii)-(v) to prepare N-cyano-N'-methyl-N"-[2-((3-chloro-4-methoxy-2-pyridyl)methylthio)ethyl]guanidine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:14]3[O:13][CH:12]([CH2:15][NH2:16])[CH2:11][C:10]=3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.C(N(C(C)C)CC)(C)C.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>>[CH2:30]([O:29][C:27](=[O:28])[NH:16][CH2:15][CH:12]1[CH2:11][C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)[C:14]=2[O:13]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NCC1Cc2cccc(-c3ccsc3)c2O1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cccc(-c3ccsc3)c2O1)OCc1ccccc1
Yield: 70.7 %

Procedure:
Treatment of (±)-1-(7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methanamine (0.56 g, 2.09 mmol) with diisopropylethylamine (0.406 g, 3.14 mmol) and benzyl chloroformate (0.393 g, 2.30 mmol) generally according to the procedure described for Intermediate 12 provided 0.54 g (71%) of (±)-benzyl(7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate as a colorless oil. Rf=0.49 (silica, ethyl acetate:hexanes 2:8); Anal. calcd. for C21H19NO3S.0.3H2O: C, 68.01; H, 5.33; N, 3.78. Found: C, 67.88; H, 5.18; N, 3.72. Chiral HPLC separation of (±)-benzyl(7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralcel AD, water:methanol 1:9) provided two fractions. Fraction 1 (Rt=13.00 min, (Chiralcel AD, water:methanol 1:9); Fraction 2 (Rt=14.1 min, (Chiralcel AD, water:methanol 1:9).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1.[CH3:20][N:21]([CH3:31])[C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>>[CH3:20][N:21]([CH3:31])[C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:30])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:9][C:10]3([CH3:19])[CH3:18])=[CH:24][CH:23]=1
Reactant: CN(C)c1ccc(N=C=O)cc1
Reactant: CC1(C)CN(Cc2ccccn2)c2ccc(O)cc21
Product: CN(C)c1ccc(NC(=O)Oc2ccc3c(c2)C(C)(C)CN3Cc2ccccn2)cc1

Procedure:
The title compound was synthesized from 1-(2-pyridylmethyl)-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with 4-dimethylaminophenylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (5.2 mg, 16%) having the following characteristics.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:12](=O)([O-])[O-].[K+].[K+].IC.CN(C=O)C>O>[CH3:12][O:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ncccc1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ncccc1OC
Reaction time: 8 h
Yield: 44.5 %

Procedure:
A mixture of methyl 3-hydroxypyridine-2-carboxylate (Intermediate 96, 1.2 g, 7.8 mmol), potassium carbonate (1.2 g, 8.7 mmol), iodomethane (0.63 ml, 1.0 mmol) and DMF (10 ml) was stirred overnight. The mixture was diluted with water (20 ml) and extracted with ethyl acetate (2×20 ml). The combined organic extracts were washed with water and concentrated under vacuum. The residue (0.82 g) was purified by flash column chromatography (5 g silica; heptane-ethyl acetate, 1:0-5:1-2:1) to give the title compound as a clear oil (0.58 g, 45%). Method C HPLC-MS: MH+ requires m/z=168. Found: m/z=168, Rt=0.76 min (100%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11](=[O:28])[CH:12]([C:14]1[N:19]=[C:18]([O:20]C)[CH:17]=[C:16]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:15]=1)[CH3:13].[I-].[K+].C(#N)C.C[Si](C)(C)Cl>C(OCC)(=O)C.O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11](=[O:28])[CH:12]([C:14]1[NH:19][C:18](=[O:20])[CH:17]=[C:16]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[N:15]=1)[CH3:13]
Reactant: COc1cc(N2CCOCC2)nc(C(C)C(=O)N2CCc3c(F)cccc32)n1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CC(C(=O)N1CCc2c(F)cccc21)c1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 80.5 %

Procedure:
210 mg of 1-(4-fluoro-2,3-dihydroindol-1-yl)-2-(4-methoxy-6-morpholin-4-yl-pyrimidin-2-yl)propan-1-one, 270 mg of potassium iodide, 7 ml of acetonitrile and 208 ml of trimethylchlorosilane are added to a microwave tube. After microwave irradiation for one hour at a temperature of 100° C., the reaction medium is diluted with 20 ml of ethyl acetate and 20 ml of water. After settling out, the organic phase is dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue obtained is stirred in the presence of 5 ml of ethyl acetate and 20 ml of petroleum ether. The solid obtained is filtered off and then dried under reduced pressure. 163 mg of 2-[1-(4-fluoro-2,3-dihydro-1H-indol-1-yl)-1-oxopropan-2-yl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are thus obtained in the form of a pale yellow solid, the characteristics of which are the following: