Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl[C:17]1[C:18]2[C:25]([I:26])=[CH:24][N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:19]=2[N:20]=[CH:21][N:22]=1>C(O)CCC>[I:26][C:25]1[C:18]2[C:17]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[N:22][CH:21]=[N:20][C:19]=2[N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:24]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[Si](C)(C)CCOCn1cc(I)c2c(N3CCOCC3)ncnc21

Procedure:
Morpholine (2.45 g, 28.1 mmol) and N,N-diisopropylethylamine (6.63 g, 51.3 mmol) were added to a solution of 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (C1) (10.5 g, 25.6 mmol) in n-butanol (300 mL), and the reaction mixture was heated at reflux for 18 hours, then concentrated under reduced pressure. Aqueous hydrochloric acid (0.1 M, 100 mL) was added and the resulting solid was collected by filtration, washed with water (20 mL) and dried under vacuum to provide the product as a yellow solid. Yield: 8.0 g, 17 mmol, 66%. LCMS m/z 461.2 [M+H+]. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.81 (s, 1H), 5.52 (s, 2H), 3.80-3.86 (m, 4H), 3.46-3.53 (m, 6H), 0.77-0.84 (m, 2H), −0.10 (s, 9H).
Reaction SMILES: C(O)(=O)C.[C:5]([O:9][C:10]([N:12]1[CH2:17][C@H:16]([CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][C@H:20]2[CH3:25])[N:15](CC2C=CC=CC=2)[CH2:14][C@H:13]1[CH3:33])=[O:11])([CH3:8])([CH3:7])[CH3:6]>CCO.[Pd]>[C:5]([O:9][C:10]([N:12]1[CH2:17][C@H:16]([CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][C@H:20]2[CH3:25])[NH:15][CH2:14][C@H:13]1[CH3:33])=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.4 %

Procedure:
Pd/C (33 g) and acetic acid (220 mL) were added to a solution of (2R,5S)-4-benzyl-2-methyl-5-((R)-3-methyl-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (41.3 g, 102 mmol) in EtOH (300 mL). The mixture was stirred under H2 (1 atmosphere) at room temperature for 18 h. The reaction mixture was then filtered through a pad of Celilte to remove the catalyst and the solvent was removed in vacuo. The crude material was partitioned between saturated aqueous NaHCO3 and DCM and the product extracted with DCM (3×). The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give the title compound (30.5 g) as a pale yellow oil. 1H NMR (CDCl3): 4.43-3.87 (1H, m), 3.78 (1H, d), 3.73-3.55 (3H, m), 3.32 (1H, dd), 3.22 (1H, dd), 3.16-2.93 (3H, m), 2.93-2.72 (1H, m), 2.55-2.35 (2H, m), 2.35-2.15 (2H, m), 1.89 (1H, dd), 1.45 (9H, s), 1.26 (3H, d), 0.96 (3H, d).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[H-].[Na+].[Cl:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=1[S:31](Cl)(=[O:33])=[O:32])[C:24]([O:26]C)=[O:25].O>C1COCC1>[Cl:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=1[S:31]([N:6]([CH2:5][C:4]1[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=1[O:2][CH3:1])[C:7]1[S:8][CH:9]=[CH:10][N:11]=1)(=[O:33])=[O:32])[C:24]([OH:26])=[O:25]
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(C(=O)O)cc2Cl)c(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice cooled solution of N-(2,4-dimethoxybenzyl)-1,3-thiazol-2-amine (Preparation 6, 8.4 g, 33.4 mmol, 1 eq) in THF (80 ml) was added 60% sodium hydride (2.0 g, 50.2 mmol, 1.5 eq) portionwise. The mixture was stirred for 15 minutes before the addition of methyl 3-chloro-4-(chlorosulfonyl)benzoate (Preparation 5, 9 g, 33.4 mmol, 1 eq) then stirred for a further 30 minutes. The reaction mixture was added to water (20 ml) and the THF evaporated in vacuo. The residue was diluted with water (200 ml), extracted with ethyl acetate (2×200 ml) and DCM (100 ml). The combined organics were dried over sodium sulphate, filtered and evaporated in vacuo to yield the title compound.
Reaction SMILES: [Mg].[CH2:2]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C:29]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:10][CH:11]=2)([OH:32])[CH2:28][CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCCCCOc1ccc(Br)cc1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCOc1ccc(C2(O)CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
To a suspension of magnesium turnings (0.48 g) in tetrahydrofuran (10 ml) was added dropwise a solution of 4-hexyloxybromobenzene (5 g) in tetrahydrofuran (70 ml) and stirred for 1 hour at ambient temperature. Then to the reaction mixture was added 1-benzyloxycarbonyl-4-piperidone (4.12 g) and stirred for 2 hours under ice-cooling. The reaction was quenched with saturated NH4Cl aq. and extracted with ethyl acetate. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and filtrate was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with (hexane/ethyl acetate)=(3/1). The fractions containing the object compound were collected and evaporated under reduced pressure to give 1-benzyloxycarbonyl-4-(4-hexyloxyphenyl)-4-hydroxypiperidine (3.44 g).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([C:8]1[CH:26]=[CH:25][C:11]([O:12][CH2:13][CH:14]([OH:24])[CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:10][CH:9]=1)#[N:7].O.C(Cl)Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:1][S:2]([O:24][CH:14]([CH2:13][O:12][C:11]1[CH:10]=[CH:9][C:8]([C:6]#[N:7])=[CH:26][CH:25]=1)[CH2:15][NH:16][C:17]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:23])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC(O)COc1ccc(C#N)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(COc1ccc(C#N)cc1)OS(C)(=O)=O
Yield: 103.9 %

Procedure:
Methanesulfonyl chloride (22.3 g 0.195 mol) was added over the course of 1.5 hours to a cooled (0° C.) solution of tert-butyl 3-(4-cyano-phenoxy)-2-hydroxypropylcarbamate (from step (iii) above; 51.2 g, 0.177 mol) and 4-(dimethylamino)pyridine (1.3 g, 10.6 mmol) in pyridine (250 mL), kept under an inert atmosphere. The reaction mixture was stirred for 2 h at rt before water and DCM were added. The organic layer was separated, washed with water, dried (MgSO4) and concentrated in vacuo to yield 68.1 g (100%) of the sub-title compound.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[N:5]=[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:28][Cl:29].CCCCCC.C([Li])CCC.[Cl-].[NH4+]>O1CCCC1>[Cl:29][CH2:28][C:3](=[O:2])[C@@H:4]([N:5]=[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Reactant: ClCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(CCl)[C@H](Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 99.7 %

Procedure:
N-(diphenylmethylene)-L-phenylalanine methyl ester (3.35 g) and bromochloromethane (0.83 ml) were added to dehydrated tetrahydrofuran (97 ml), and the mixture was cooled to −78° C. Then, a 1.53 M n-butyllithium hexane solution (8.3 ml) was added thereto. The mixture was stirred for 35 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction solution to terminate the reaction. The resulting reaction solution was extracted twice with ethyl acetate at room temperature. The ethyl acetate layer was then washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. After magnesium sulfate was removed, the ethyl acetate solution was concentrated to obtain desired (3S)-1-chloro-3-(diphenylmethylene)amino-4-phenyl-2-butanone (3.52 g) in a yield of 99.7%.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][N:14]=1>C(#N)C>[BrH:1].[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([I:19])=[CH:15][N:14]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(I)cn1
Reactant: O=C(CBr)c1ccc(O)cc1
Solvent: CC#N
Product: Br
Product: Oc1ccc(-c2cn3cc(I)ccc3n2)cc1

Procedure:
First, 2-bromo-4′-hydroxyacetophenone and 2-amino-5-iodopyridine are dissolved in an inactive solvent such as acetonitrile, and are allowed to react with each other at a reflux temperature for 2 to 6 hours to produce 2-(4′-hydroxyphenyl)-6-iodoimidazo[1,2-a]pyridine hydrobromide salt as white precipitates. The solvent used in this instance may be acetonitrile or another solvent that is usually employed in a similar reaction, for example, methanol and acetone. The reaction temperature may be a temperature allowing refluxing, for example, 110° C. when the solvent is acetonitrile. The amount of the solvent to be used may be an amount sufficient to effect the reaction, however, it should be noted that if the solvent is too much, it will become difficult to obtain precipitates of reaction products. For example, when 2-bromo-4′-hydroxyacetophenone in an amount corresponding to 10 mmol is used for the reaction, the amount of a solvent to be used can be about 40 to 80 mL.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([C:14]([NH2:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[C:19](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH3:19])[CH:10]([C:14]([NH2:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNC(C(N)=O)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCN(C(=O)OC(C)(C)C)CC1C(N)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.1 %

Procedure:
A solution of 6.00 g of 4-(t-butoxycarbonyl)piperazine-2-carboxamide and 3.28 g of a 37% aqueous formaldehyde solution in 60 ml of methanol was ice-cooled, and 16.66 g of sodium triacetoxyborohydride was added, followed by stirring at room temperature for 24 hours after removing an ice bath. The reaction solution was again ice-cooled, 3.28 g of a 37% aqueous formaldehyde solution and 16.66 g of sodium triacetoxyborohydride were added thereto. After stirring at room temperature for 16 hours, the reaction solution was diluted with ice water, alkalified with an aqueous saturated sodium hydrogen carbonate solution, followed by extraction with ethyl acetate three times. The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 5.42 g of the objective compound as colorless crystals.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[SH:11].[CH2:12]([O-])[CH2:13][CH3:14].[Na+].C(O)CC>>[CH2:12]([S:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH2:13][CH3:14]
Reactant: CCC[O-]
Reactant: Sc1ccc2ccccc2c1
Agent: [Na+]
Solvent: CCCO
Product: CCCSc1ccc2ccccc2c1
Reaction time: 10 h
Yield: 93.8 %

Procedure:
50 g (0.31 mole) of naphth-2-yl mercaptan were introduced into a solution of 29.5 g (0.36 mole) of sodium n-propanolate and 800 ml (10.6 moles) of n-propanol, and the mixture was heated from 25° to 150° C. in the course of 60 minutes under a carbon monoxide pressure of 300 bar in a 1.2 liter stirred autoclave, and then kept at this temperature for 10 hours. The mixture which emerged from the reactor was distilled to give 58.8 g (95% of theory) of naphth-2-yl n-propyl thioether of boiling point 115°-120° C./0.6 mbar.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:30])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:25](O)=[O:26])([CH3:24])[CH3:23])[CH:16]=1)[C:11]([CH3:29])([CH3:28])[CH2:10]2)=[O:4].Cl.[CH3:32][N:33](C)CCCN=C=NCC.CN.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.O1CCCC1.ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:30])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([CH3:24])([C:25](=[O:26])[NH:33][CH3:32])[CH3:23])[CH:16]=1)[C:11]([CH3:28])([CH3:29])[CH2:10]2)=[O:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(NC(C)(C)C(=O)O)c1)C(C)(C)C2
Agent: CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)C(C)(C)Nc1cccc(C2Nc3c(cc(Cl)cc3C(=O)OC)CC2(C)C)c1
Reaction time: 48 h
Yield: 99.4 %

Procedure:
A mixture of 2-[3-(1-carboxy-1-methyl-ethylamino)-phenyl]-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (73 mg, 0.17 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (65 mg, 0.34 mmol), 4-dimethylaminopyridine (41.5 mg, 0.34 mmol), methaneamine (0.26 mL, 0.52 mmol) in tetrahydrofuran and triethylamine (34 mg, 0.34 mmol) in dichloromethane (10 mL) was stirred for 48 hours. Removal of the solvent to afford the crude product 6-chloro-3,3-dimethyl-2-[3-(1-methyl-1-methylcarbamoyl-ethylamino)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (75 mg, 100%) which was used in next step without purification: LC/MS m/e calcd for C24H30ClN3O3 (M+H)+: 444.98, observed: 444.1.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[Cl:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1>>[ClH:21].[CH3:30][O:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[CH2:22][O:14][C:13]1[C:8]([NH:7][C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]=2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(CCl)c1
Reactant: Cc1csc(Nc2ncccc2O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cccc(COc2cccnc2Nc2nc(C)cs2)c1
Product: Cl
Yield: 41.8 %

Procedure:
2-(4-Methylthiazol-2-ylamino)pyridin-3-ol (prepared according to Example 3, Step A) (0.150 g, 0.724 mmol), K2CO3 (0.225 g, 1.63 mmol), and 1-(chloromethyl)-3-methoxybenzene (0.113 g, 0.724 mmol) were reacted according to Example 3, Step B, to provide 3-(3-methoxybenzyloxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine hydrochloride (0.110 g, 46.4% yield). 1H NMR (CDCl3) δ 12.34 (bs, 1H), 7.93 (dd, 1H), 7.28 (d, 1H), 7.20 (m, 1H), 7.12 (m, 2H), 6.97 (m, 1H), 6.84 (m, 1H), 6.38 (s, 1H), 5.34 (s, 2H), 3.84 (s, 3H), 2.47 (s, 3H). Mass spectrum (apci) m/z=328.1 (M+H-HCl). Analysis calculated for C17H18N3O2ClS.0.54DCM: C, 56.29; H, 5.14; N, 11.23. found: C, 56.29; H, 5.23; N, 11.01.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1.Cl.Cl.[C:17]12([CH2:24][N:25]3[CH2:29][CH2:28][C@@H:27]([NH2:30])[CH2:26]3)[O:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][CH2:18]2.CCN(CC)CC.O>CC(N(C)C)=O>[C:17]12([CH2:24][N:25]3[CH2:29][CH2:28][C@@H:27]([NH:30][C:2]4[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=4)[CH2:26]3)[O:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][CH2:18]2
Reactant: N[C@@H]1CCN(CC23CCC(CC2)O3)C1
Reactant: CCOC(=O)/C=C/c1cnc(Cl)cn1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(CC34CCC(CC3)O4)C2)cn1
Temperature: 100 °C
Reaction time: 24 h
Yield: 99.9 %

Procedure:
To a mixture of ethyl (2E)-3-(5-chloropyrazin-2-yl)acrylate (242.8 mg) in DMA (1.9 mL) was added (3R)-1-(7-oxabicyclo[2.2.1]hept-1-ylmethyl)pyrrolidin-3-amine dihydrochloride (370 mg) and Et3N (796 uL), which was stirred at 100° C. for 24 hours. To the resultant was added H2O, which was extracted with AcOEt. The organic phase was washed with brine, dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(5-{[(3R)-1-(7-oxabicyclo[2.2.1]hept-1-ylmethyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate (425 mg) as a brown solid.
Reaction SMILES: C([NH:7][C:8]1[NH:13][C:12]2=[N:14][CH:15]=[CH:16][C:11]2=[CH:10][N:9]=1)(=O)C(C)(C)C.C(Cl)Cl>CCO.[Cl-].[Cl-].[Zn+2]>[NH2:7][C:8]1[NH:13][C:12]2=[N:14][CH:15]=[CH:16][C:11]2=[CH:10][N:9]=1
Reactant: CC(C)(C)C(=O)Nc1ncc2ccnc-2[nH]1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Solvent: ClCCl
Product: Nc1ncc2ccnc-2[nH]1

Procedure:
A suspension of 2-(pivaloylamino)-pyrrolo[2,3-d]pyrimidine and ZnCl2 (3-20 equiv.) in wet EtOH (5 vol % water) was heated to 80 AC, and monitored by HPLC. When the reaction reached completion, DCM was added, and the organic layer was washed with sat. aq. NaHCO3 and brine. Drying (Na2SO4) and concentration afforded the desired 2-amino-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:33][C:32]([CH3:34])=[CH:31][C@@H:30]([CH2:35][CH:36]=[CH2:37])[C:28](=[O:29])[CH2:27][C@H:26]([OH:38])[C@@H:25]([CH3:39])[C@@H:24](/[C:40](/[CH3:51])=[CH:41]/[C@H:42]2[CH2:47][C@@H:46]([O:48][CH3:49])[C@H:45]([OH:50])[CH2:44][CH2:43]2)[O:23][C:21](=[O:22])[C@H:20]2[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[C:13](=[O:14])[C:11](=[O:12])[C@:9]2([OH:52])[O:10][C@@H:5]([C@@H:6]([O:54][CH3:55])[CH2:7][C@H:8]2[CH3:53])[C@@H:4]([O:56][CH3:57])[CH2:3]1.[N+:58]([C:61]1[CH:69]=[CH:68][C:64]([C:65](Cl)=[O:66])=[CH:63][CH:62]=1)([O-:60])=[O:59]>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:35]([CH:30]1[CH:31]=[C:32]([CH3:34])[CH2:33][CH:2]([CH3:1])[CH2:3][CH:4]([O:56][CH3:57])[CH:5]2[O:10][C:9]([OH:52])([CH:8]([CH3:53])[CH2:7][CH:6]2[O:54][CH3:55])[C:11](=[O:12])[C:13](=[O:14])[N:15]2[CH:20]([CH2:19][CH2:18][CH2:17][CH2:16]2)[C:21](=[O:22])[O:23][CH:24]([C:40]([CH3:51])=[CH:41][CH:42]2[CH2:43][CH2:44][CH:45]([O:50][C:65](=[O:66])[C:64]3[CH:63]=[CH:62][C:61]([N+:58]([O-:60])=[O:59])=[CH:69][CH:68]=3)[CH:46]([O:48][CH3:49])[CH2:47]2)[CH:25]([CH3:39])[CH:26]([OH:38])[CH2:27][C:28]1=[O:29])[CH:36]=[CH2:37]
Reactant: C=CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC(=O)c4ccc([N+](=O)[O-])cc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the FR-900506 substance (30.5 mg) in pyridine (1 ml) was added p-nitrobenzoyl chloride (ca. 100 mg), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, and washed with a saturated aqueous sodium hydrogen carbonate, water, 1N-hydrochloric acid, water, a saturated aqueous sodium hydrogen carbonate, water and an aqueous sodium chloride, successively, and then dried. The resulting solution was concentrated under reduced pressure, and the residue was purified on silica gel column chromatography to give 17-allyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-12-[2-(4-(p-nitrobenzoyloxy)-3-methoxycyclohexyl]-1-methylvinyl]-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone (37.7 mg).
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)S(O[C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23])(=O)=O.C(N(CC)CC)C>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:8]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:20]2[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=2[C:22]([O:24][CH3:25])=[O:23])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: COC(=O)c1ccccc1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1ccccc1P(c1ccccc1)c1ccccc1

Procedure:
Diphenylphosphine (0.94 mL, 5.40 mmol, 1 eq) was added to a stirred solution of methyl 2-trifluoromethanesulfonyloxybenzoate (1.531 g, 5.39 mmol, 1 eq), triethylamine (0.85 mL, 6.1 mmol, 1.1 eq) and palladium acetate (0.005 g, 0.02 mmol, 0.004 eq) in degassed MeCN (10 mL) instantly giving a red coloration. The solution was heated at reflux under nitrogen for 17 hours. The blood-red solution was allowed to cool and an aliquot taken for NMR analysis.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6](C(O)=O)[N:5]=[C:4]2[N:20]([CH3:23])[CH:21]=[N:22][C:3]=12.C([N:26]([CH2:29]C)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:38])C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]2[N:22]=[CH:21][N:20]([CH3:23])[C:4]=2[N:5]=[C:6]2[NH:26][C:29](=[O:38])[N:8]([C:9]3[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=3[F:16])[C:7]=12
Reactant: CCN(CC)CC
Reactant: Cn1cnc2c(Cl)c(Nc3ccc(I)cc3F)c(C(=O)O)nc21
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: Cn1cnc2c(Cl)c3c(nc21)[nH]c(=O)n3-c1ccc(I)cc1F
Temperature: 25 °C

Procedure:
To a suspension of 7-chloro-6-(2-fluoro-4-iodophenylamino)-3-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (2.75 g, 6.16 mmol) in toluene (80 ml) is added triethylamine (2.57 ml, 18.5 mmol) and diphenylphosphoryl azide (1.56 ml, 7.7 mmol). The reaction is heated at reflux for 4 h. The mixture is cooled to room temperature and concentrated to dryness. Silica gel chromatography yields the title compound.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[F:16][C:17]1[CH:18]=[C:19]2[C:29](=[CH:30][CH:31]=1)[C:22]([CH2:23][CH:24]([C:26]([OH:28])=[O:27])[NH2:25])=[CH:21][NH:20]2>>[C:26]([CH:24]([NH:25][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:23][C:22]1[C:29]2[C:19](=[CH:18][C:17]([F:16])=[CH:31][CH:30]=2)[NH:20][CH:21]=1)([OH:28])=[O:27]
Reactant: NC(Cc1c[nH]c2cc(F)ccc12)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1c[nH]c2cc(F)ccc12)C(=O)O
Yield: 42 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 6-fluoro-DL-tryptophan to provide the title compound in 42% yield as yellow needles (recrystallization from MeOH).
Reaction SMILES: [CH2:1]([S:11][CH2:12][CH2:13][OH:14])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[H-].[Na+].CCCCCC.Br[CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH:29]([CH3:31])[CH3:30]>COCCOC.CCOCC>[CH:29]([O:28][CH2:27][CH2:26][CH2:25][CH2:24][O:14][CH2:13][CH2:12][S:11][CH2:1][C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1)([CH3:31])[CH3:30]
Reactant: OCCSCc1ccc2c(c1)OCO2
Reactant: CC(C)OCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)OCCCCOCCSCc1ccc2c(c1)OCO2
Reaction time: 3 h

Procedure:
2.12 g (0.01 mol) of 2-piperonylthioethanol are added at room temperature over the course of 10 minutes, to a suspension of 0.48 g (0.01 mol) of 50% sodium hydride dispersion, which had been freed from the mineral oil with hexane, in 40 cc of 1,2-dimethoxy ethane. The mixture is stirred at 50° for 3 hours and a solution of 1.95 g (0.01 mol) of 1-bromo-4-isopropoxybutane in 30 cc of 1,2-dimethoxy ethane is subsequently added. The mixture is stirred at 60° over the course of 48 hours. After cooling to 20°, 100 cc of ether are added to the reaction mixture. The ether solution is extracted with saturated sodium chloride solution, dried over sodium sulphate and evaporated. The residue is purified by chromatography on silica gel with hexane/ethyl acetate (5:1), whereupon [2-(4-isopropoxy-butyloxy)-ethyl]-piperonylthioether is obtained as a slightly yellow, clear oil.