Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.[O:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1>[Na].C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:19]3[CH2:20][CH2:21][O:16][CH2:17][CH2:18]3)[CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: O=C1CCOCC1
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na]
Solvent: ClCCl
Product: Clc1ncc2c(n1)N1CCOC[C@H]1CN2C1CCOCC1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x63 using (R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 250 mg, 1.103 mmol), dihydro-2H-pyran-4-(3H)-one (110 mg, 1.103 mmol), titanium(IV) chloride in CH2Cl2 (1M, 2.427 mL, 2.427 mmol) and sodium triacetoxyhydroborate (514 mg, 2.427 mmol) in CH2Cl2 (8 mL) (10 mg, 3%). ESI-MS m/z [M+H]+ calc'd for C14H19ClN4O2, 311.13. found 311.2.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12](I)[S:13][C:6]=12.Br[C:23]1[N:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][CH:24]=1.C[Sn](C)(C)[Sn](C)(C)C>O1CCOCC1>[F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:23]3[CH:24]=[CH:25][C:26]([CH:29]=[O:30])=[CH:27][N:28]=3)[S:13][C:6]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: O=Cc1ccc(Br)nc1
Agent: C[Sn](C)(C)[Sn](C)(C)C
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Temperature: 100 °C
Yield: 50.2 %

Procedure:
To a solution of 7-(2-fluoro-4-nitrophenoxy)-2-iodothieno[3,2-b]pyridine (24) [US 2006/0287343 A1] (6 g, 14.42 mmol) in dioxane (40 mL) were added 6-bromopyridine-3-carbaldehyde (3.22 g, 17.30 mmol), palladium tetrakistriphenylphosphine (0.500 g, 0.433 mmol) and hexamethyldistannane (3.29 mL, 15.86 mmol). The mixture was heated at 100° C. for 20 h. It was then concentrated and adsorbed on silica gel, transferred onto a silica gel column and eluted with DCM/MeOH (100/0, 99/1, 98/2, 97/3) to afford title compound 123 (2.864 g, 50% yield). MS (m/z): 396.1 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[C@@H:5]([NH:13][C:14]1[S:15][C:16](=[CH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:36][CH2:35][C:30]4(OCCO4)[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)[C:17](=[O:19])[N:18]=1)[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].[NH2:38][CH2:39][C@@H:40]([C:42]1[CH:43]=[CH:44][C:45]([OH:53])=[C:46]([NH:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH:47]=1)[OH:41].CNC1SC(=CC2C=CC(N3CCC(=O)CC3)=CC=2)C(=O)N=1.NC[C@@H](C1C=CC=C(Cl)C=1)O>>[CH2:1]([O:3][C:4](=[O:37])[C@@H:5]([NH:13][C:14]1[S:15][C:16](=[CH:20][C:21]2[CH:22]=[CH:23][C:24]([N:27]3[CH2:28][CH2:29][CH:30]([NH:38][CH2:39][C@H:40]([OH:41])[C:42]4[CH:43]=[CH:44][C:45]([OH:53])=[C:46]([NH:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH:47]=4)[CH2:35][CH2:36]3)=[CH:25][CH:26]=2)[C:17](=[O:19])[N:18]=1)[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2]
Reactant: CCOC(=O)CC[C@H](NC1=NC(=O)C(=Cc2ccc(N3CCC4(CC3)OCCO4)cc2)S1)C(=O)OCC
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Agent: CNC1=NC(=O)C(=Cc2ccc(N3CCC(=O)CC3)cc2)S1
Agent: NC[C@H](O)c1cccc(Cl)c1
Product: CCOC(=O)CC[C@H](NC1=NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)S1)C(=O)OCC

Procedure:
The title compound was prepared from (2S)-2-{5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-pentanedioic acid diethyl ester (which was obtained in Intermediate 34) and N-[5-(2-amino-(1R)-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Intermediate 10) according to the procedures of Intermediate 18 and Example 1 as a yellowish solid; mp>130° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ1.19(t, J=7.0 Hz, 3 H), 1.22(t, J=7.0 Hz, 3 H), 1.70-3.00 (m,14 H), 2.92(s, 3 H), 3.50-3.90 (m, 2 H), 4.05(q, J=7.0 Hz, 2 H), 4.14(q, J=7.0 Hz, 2 H), 4.48(dd, J=8.0, 4.3 Hz, 1 H), 4.68(dd, J=8.7, 5.4 Hz, 1 H), 6.82(d, J=8.2 Hz, 1 H), 7.02(dd, J=8.2, 2.0 Hz, 1 H), 7.05(d, J=8.9 Hz, 2 H), 7.18(d, J=2.0 Hz, 1 H), 7.40(d, J=8.9 Hz, 2 H), 7.50 (s, 1 H), MS (ES) m/z: 359.5 ((M+2H)2+, 100%); 718.2 (MH+, 20%); HRMS Calcd. for C33H44N6O9S2 (MH+): 718.2575. Found: 718.2581.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:9])[CH:6]([CH3:8])[CH3:7])=[O:3].[CH3:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20].N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH3:10])[O:4][CH:5]([Cl:9])[CH:6]([CH3:8])[CH3:7]
Reactant: COCCOCCOCCO
Reactant: CC(C)C(Cl)OC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCOCCOCCOC(=O)OC(Cl)C(C)C

Procedure:
In a manner similar to the method described in Example 3, 1-chloro-2-methylpropyl chloroformate (Aldrich) was reacted with 2-(2-(2-methoxyethoxy)ethoxy)ethanol (TCI) and pyridine in methylene chloride at −78° C. for 3 h to give 1-chloro-2-methylpropyl 2-(2-(2-methoxyethoxy)-ethoxy)ethyl carbonate. This material was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid in the presence of cesium carbonate in dimethylformamide overnight to give, after flash chromatography purification (hexane/ethyl acetate, 80/20 to 20/80), 15-methyl-12-oxo-2,5,8,11,13-pentaoxahexadecan-14-yl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white solid. MS (ES+) m/z calcd. for C43H52Cl2F2N3O10: [(M+H)+]: 878, found: 878.
Reaction SMILES: Cl[CH2:2][CH:3]1[C:8]2[CH:9]=[CH:10][S:11][C:7]=2[CH2:6][CH2:5][O:4]1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[Na+].[I-].Cl>CN(C=O)C.O>[S:11]1[C:7]2[CH2:6][CH2:5][O:4][CH:3]([CH2:2][N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:8]=2[CH:9]=[CH:10]1
Reactant: ClCC1OCCc2sccc21
Reactant: C1CCNC1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1cc2c(s1)CCOC2CN1CCCC1
Temperature: 130 °C
Reaction time: 6 h

Procedure:
A mixture of 4-(chloromethyl)-6,7-dihydro-4H-thieno[3,2-c]pyran (1 g, 5.305 mmol, 1 eq), pyrrolidine (11.3 g, 159.1 mmol, 30 eq) and NaI (50 mg) in DMF (50 mL) in a sealed tube was stirred at 130° C. for 6 hr. The reaction mixture was cooled and poured into H2O and the pH was adjusted to ˜2 with 2N HCl. The resulting solution was washed with EtOAc. The aqueous layer was then adjusted to pH 9-10 and extracted with EtOAc. The EtOAc layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting crude product was purified by preparative HPLC. After removal of organic volatiles of the collected HPLC fractions, the pH of remaining aqueous phase was adjusted to ˜8 with saturated Na2CO3 solution. The aqueous solution was extracted with EtOAc (3 times). The combined EtOAc extract was washed with brine, dried with Na2SO4, and concentrated to give the desired product.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[C:8](=[O:24])[CH:7]=1.[Cl:30]N1C(=O)CCC1=O.ClC(Cl)C(O)=O>CC(O)C>[Cl:30][C:7]1[C:8](=[O:24])[N:9]([C:13]2[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[C:10]([CH3:12])=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:2]=1[F:1]
Reactant: COC(=O)c1cc(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c(C)cn1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(O)C(Cl)Cl
Solvent: CC(C)O
Product: COC(=O)c1cc(-n2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)c(C)cn1
Temperature: 60 °C
Yield: 92 %

Procedure:
A mixture of methyl 4-[(2,4-difluorobenzyl)oxy]-5′,6-dimethyl-2-oxo-2H-1,4′-bipyridine-2′-carboxylate (0.15 g, 0.375 mmol), N-chlorosuccinimide (0.06 g, 0.43 mmol) in 2-propanol (3.0 mL) containing dichloroacetic acid (0.05 mL) was heated at 60° C. under nitrogen for 2 h. The reaction mixture was concentrated, and the residue was purified by silica-gel flash chromatography using 4% methanol in ethyl acetate. Appropriate fractions were combined and concentrated under reduced pressure to give 0.15 g of the title compound. ES-MS, m/z=435 (M+H).
Reaction SMILES: [F:1][C:2]([F:35])([CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:3][CH2:4][C@H:5]1[C@H:9]([O:10]C2CCCCO2)[CH2:8][C:7](=[O:17])[C@@H:6]1[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]>C(O)(=O)C.O.C1COCC1>[F:1][C:2]([F:35])([CH2:27][O:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:3][CH2:4][C@H:5]1[C@H:9]([OH:10])[CH2:8][C:7](=[O:17])[C@@H:6]1[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]
Reactant: O=C(O)CCC/C=C\C[C@H]1C(=O)C[C@@H](OC2CCCCO2)[C@@H]1CCC(F)(F)COc1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CCC/C=C\C[C@H]1C(=O)C[C@@H](O)[C@@H]1CCC(F)(F)COc1ccccc1
Temperature: 25 °C

Procedure:
(Z)-7-((1R,2R,3R)-2-(3,3-Difluoro-4-phenoxybutyl)-5-oxo-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoic acid, prepared in Step H, is dissolved in a (4:2:1) solution of acetic acid-water-THF (0.5 M). The solution is stirred for several days at room temperature until the reaction is complete, as judged by TLC. The crude product is purified by flash chromatography on regular silica gel using ethyl acetate-hexane-acetic acid as eluent to afford the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1>CN(C=O)C>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[N:8]([CH2:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=3)[CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCN2
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN2CCOc3cc([N+](=O)[O-])ccc32)cc1
Yield: 90.5 %

Procedure:
The same operation as in Example (90a) was performed using 7-nitro-2,3-dihydro-4H-1,4-benzoxazine (described in Higuchi, Robert I.; Arienti, Kristen L.; Lopez, Francisco J.; Mani, Neelakhanda S.; Mais, Dale E.; Caferro, Thomas R.; Long, Yun Oliver; Jones, Todd K.; Edwards, James P.; Zhi, Lin; Schrader, William T.; et al.; J. Med. Chem.; 50; 10; 2007; 2486-2496, 0.6 g, 3.3 mmol), sodium hydride (55% content, 145 mg, 3.3 mmol), methyl 4-bromomethylbenzoate (0.76 g, 3.3 mmol) and DMF (20 mL). The resulting solid was washed with ethyl acetate/hexane=1/1 to obtain 0.98 g of the title compound as a yellow solid (90%).
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[H-].[Na+].[CH2:11](I)[CH3:12]>C1COCC1>[CH2:11]([O:8][CH2:7][C@@H:2]([NH2:1])[CH2:3][CH:4]([CH3:6])[CH3:5])[CH3:12]
Reactant: CC(C)C[C@H](N)CO
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC[C@@H](N)CC(C)C
Reaction time: 20 h

Procedure:
(S)-leucinol (6.4 mL, 5 mmol) was added over 30 minutes to a well stirred slurry of 6% sodium hydride (2.2 g, 55 mmol) in THF (50 mL) at room temperature under N2. After all of the sodium hydride had reacted, a solution of ethyl iodide (4 mL, 50 mmol) in THF (50 mL) was added and the reaction stirred at 20°-25° C. for 20 hours. THF was removed under reduced pressure and the residue partitioned between diethyl ether and brine. The ether extract was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was flash chromatographed over silica gel and pure aminoether eluted with a mixture of 10% isopropanol and 90% chloroform.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.CC(C)([O-])C.[K+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]([NH2:25])=[O:24])[CH:18]=1>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]([NH2:25])=[O:24])[CH:18]=2)=[C:4]([F:9])[CH:3]=1
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Oc2ccc(N)cc2F)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
A solution of 4-amino-2-fluorophenol (0.81 g, 6.4 mmol, 1.0 eq) in DMF (6.5 mL) was treated with potassium tert-butoxide (0.79 g, 7.1 mmol, 1.1 eq) at room temperature and the reaction mixture was stirred for 1 h. 4-Chloropicolinamide (1.0 g, 6.4 mmol, 1.0 eq) was added and the reaction mixture was heated to 110 IC for 8 h. The reaction was cooled to room temperature and the reaction mixture quenched with water. The resulting heterogeneous solution was filtered and the solid material was washed with water. The solid was triturated with a small amount of MeOH followed by Et2O. The solid was filtered and dried in vacuo to afford the product (1.3 g, 82%) as a solid. 1H NMR (DMSO-d6) δ 8.49-8.50 (m, 1H), 8.12 (br s, 1H), 7.71 (br s, 1H), 7.35-7.36 (m, 1H), 7.14-7.16 (m, 1H), 7.01-7.06 (m, 1H), 6.44-6.47 (m, 2H), 5.53 (s, 2H); MS (ESI+) m/z 248 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[CH2:12][CH2:13][OH:14]>[Pt].C1COCC1>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[C:4]([CH2:12][CH2:13][OH:14])[CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CO)c(CCO)c1
Agent: [Pt]
Solvent: C1CCOC1
Product: Nc1ccc(CO)c(CCO)c1

Procedure:
Pt-C (50% water wet, 200 mg) was added to a THF (40 mL) solution of 2-(2 hydroxymethly-5-nitro-phenyl)-ethanol (1.0 g, 5 mmol) and the reaction hydrogenated at 50 psi for 2 hrs. NMR showed complete reaction to form 2-(5-amino-2-hydroxymethyl-phenyl)-ethanol (compound (9) in Scheme 3);
Reaction SMILES: [CH:1]1[C:18]2[C:5](=[C:6]([C:19]3[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=3[CH2:21][Br:22])[C:7]3[C:16]([CH:17]=2)=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[CH3:27][N:28]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=1)[CH3:29].[PH4+].[AsH4+]>C(#N)C.C(OCC)C>[Br-:22].[C:37]([C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N+:28]([CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[C:6]2[C:7]3[C:16](=[CH:15][C:14]4[C:9]([CH:8]=3)=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH:17]=[C:18]3[C:5]=2[CH:4]=[CH:3][CH:2]=[CH:1]3)([CH3:27])[CH3:29])=[CH:36][CH:35]=1)#[N:38]
Reactant: CN(C)Cc1ccc(C#N)cc1
Reactant: BrCc1ccccc1-c1c2ccccc2cc2cc3ccccc3cc12
Agent: [AsH4+]
Agent: [PH4+]
Solvent: CCOCC
Solvent: CC#N
Product: C[N+](C)(Cc1ccc(C#N)cc1)Cc1ccccc1-c1c2ccccc2cc2cc3ccccc3cc12
Product: [Br-]

Procedure:
A mixture of (B) and N,N-dimethyl-4-cyano benzylamine in acetonitrile was refluxed for 2 hours. The reaction mixture was then poured into diethyl ether, and the crude product was collected by filtration. The crude product was recrystallized from ethanol. The same reaction can be used to prepare the corresponding phosphonium and arsonium salts.
Reaction SMILES: [C:1]1([CH:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([NH:19][NH2:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@@H:21]2[CH2:25][C@H:24]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[C@@H:23]([OH:31])[C@H:22]2[OH:32])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:39]1([CH:45]=O)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>CO>[CH:39]1([CH:45]=[N:20][NH:19][C:17]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[C@@H:21]3[CH2:25][C@H:24]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[C@@H:23]([OH:31])[C@H:22]3[OH:32])=[C:10]([NH:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:18]=2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: O=CC1CCCCC1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(NN)nc32)[C@H](O)[C@@H]1O
Solvent: CO
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(NN=CC4CCCCC4)nc32)[C@H](O)[C@@H]1O

Procedure:
To a solution of N-{4-[6-(2,2-diphenyl-ethylamino)-2-hydrazino-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (step 1) (0.1 g, 0.19 mmol) in dry methanol (5 ml) is added cyclohexane carboxaldehyde (0.026 g, 0.23 mmol). The reaction mixture is heated at reflux for 12 h. The reaction mixture is concentrated in vacuo purification by preparative TLC affords the title compound. LC-MS (0.1% formic acid, acetonitrile): (MH+ 611.45)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.O>CS(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([O:8][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:4][CH2:3]1
Reactant: Fc1ccccn1
Reactant: CN1CCC(O)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CN1CCC(Oc2ccccn2)(c2ccccc2)CC1
Reaction time: 1 h
Yield: 37.3 %

Procedure:
A solution of 1-methyl-4-phenyl-4-piperidinol (prepared by reaction of 1-methyl-4-piperidone with phenyl lithium; 3.83 g, 20 mM) in dry DMSO (50 ml) was treated with sodium hydride (960 mg of 50% dispersion in oil, 20 mM), stirred for 1 hour then treated with 2-fluoro-pyridine (1.94 g, 20 mM). After 48 hours the reaction was poured on to water (200 ml) and extracted with ether (3×200 ml). The organic extract was washed with brine, dried and the solvent removed under reduced pressure. Recrystallisation of the residue from cyclohexane gave the title compound (2.0 g,) m.p. 95°-6° C.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:14][CH3:15])[CH2:6][C@H:5]1[OH:16])=[N+]=[N-].[H][H]>[Pd].C(O)C>[NH2:1][C@@H:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:14][CH3:15])[CH2:6][C@H:5]1[OH:16]
Reactant: [H][H]
Reactant: COc1cccc2c1C[C@@H](N=[N+]=[N-])[C@H](O)C2
Agent: [Pd]
Solvent: CCO
Product: COc1cccc2c1C[C@@H](N)[C@H](O)C2
Reaction time: 0.83 h

Procedure:
4.0 g of palladium on charcoal (10%) are coated with 100 ml of ethanol. 8.76 g (0.040M) of trans-3-azido-1,2,3,4-tetrahydro-5-methoxy-2-naphthalinol are dissolved in 100 ml of ethanol, and the solution is added to the catalyst suspension. The mixture is subsequently hydrogenated at 20° at 1.2 bar hydrogen pressure. Every 10 minutes for 50 minutes, the reaction vessel is emptied and rinsed with hydrogen. The reaction mixture is then filtered through a G 4 Hyflo suction filter. The catalyst is washed with methylene chloride and the filtrate concentrated by evaporation. Trans-3-amino-1,2,3,4-tetrahydro-5-methoxy-2-naphthalinol is obtained (m.p. 130°-132° after purification by column chromatography, silica gel, methylene chloride and 10% methanol).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([NH2:11])=[CH:8][C:6]=2[N:7]=1.[C:18]([CH2:22][C:23](Cl)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([NH:11][C:23](=[O:24])[CH2:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:8][C:6]=2[N:7]=1
Reactant: Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC(C)(C)CC(=O)Cl
Product: CC(C)(C)CC(=O)Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1

Procedure:
2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-amine (40 mg) was reacted with 41 μL of tert-butylacetyl chloride via General Procedure G to give N-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-3,3-dimethylbutanamide.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=2)[NH2:13])=[CH:6][C:5]=1[OH:19])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:27]([CH2:31][CH2:32][C:33](Cl)=[O:34])([O:29][CH3:30])=[O:28].Cl>O1CCCC1>[C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:13][C:33](=[O:34])[CH2:32][CH2:31][C:27]([O:29][CH3:30])=[O:28])[CH:14]=[CH:15][CH:16]=2)=[CH:6][C:5]=1[OH:19])(=[O:3])[CH3:2]
Reactant: COC(=O)CCC(=O)Cl
Reactant: CC(=O)c1ccc(OCc2cccc(N)c2)cc1O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CCC(=O)Nc1cccc(COc2ccc(C(C)=O)c(O)c2)c1
Temperature: 25 °C
Yield: 53 %

Procedure:
A solution of 3-[(4-acetyl-3-hydroxyphenoxy)methyl]aniline (3.4 g prepared as in Example 1B) and triethylamine (1.62 g) in tetrahydrofuran (40 ml) is cooled to -78° C. under nitrogen. To this solution is added 3-carbomethoxypropanoyl chloride (2 g, neat), dropwise. The reaction is left to warm to room temperature overnight, then poured onto 10% HCl and extracted with ether. The extracts are washed with saturated brine, and then dried over MgSO4, and concentrated on a rotary evaporator. The residue is dissolved in a minimum amount of acetone, to which several drops of ether are added and then stored at 0° C. Filtration gives 2.6 g (53% yield) of product, m.p. 121°-123° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[Br:16]C1C=C(C=CC=1)CBr.[Mg].C(OCC)(=O)C(OCC)=O>>[Br:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(=O)Cc1ccccc1F
Reactant: BrCc1cccc(Br)c1
Agent: [Mg]
Solvent: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(=O)Cc1ccccc1Br
Yield: 80 %

Procedure:
The title compound was prepared as described for B4 using 3-bromobenzyl bromide (1.250 g, 5.00 mmol), magnesium (0.134 g, 5.50 mmol) and diethyl oxalate (1.462 g, 10.00 mmol). The product was isolated in the form of colorless oil in 80% yield and use instantly in next step.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[Cl:14]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].Cl>CC#N.O>[Cl:14][C:7]1[C:6]2[C:10](=[C:2]([CH3:1])[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=2)[NH:9][N:8]=1
Reactant: Cc1cc(C(=O)O)cc2cn[nH]c12
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(C(=O)O)cc2c(Cl)n[nH]c12
Yield: 97.8 %

Procedure:
To a suspension of 7-methyl-1H-indazole-5-carboxylic acid (180 mg, 1.01 mmol) in CH3CN (10 mL) was added N-chlorosuccinimide (150 mg, 1.12 mmol). The mixture was heated at reflux overnight before concentration. The solid was suspended in water and aqueous sodium thiosulfate solution, acidified with 1 N HCl and the solids were isolated by filtration. The solids were then washed with water and dried to provide the title compound as a tan solid (208 mg, 98%).
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[C:13]1[C:18]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[C:15]([CH3:34])[N:14]=1.[CH2:35]([O:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1)[CH3:36]>O>[CH2:35]([O:37][C:38]1[CH:43]=[C:42]([C:13]2[C:18]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:17][CH:16]=[C:15]([CH3:34])[N:14]=2)[CH:41]=[CH:40][CH:39]=1)[CH3:36]
Reactant: CCOc1cccc(B(O)O)c1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cccc(-c2nc(C)ccc2Oc2ccnc3cc(OC)c(OC)cc23)c1
Temperature: 70 °C
Reaction time: 5 h
Yield: 87.2 %

Procedure:
N,N-Dimethylformamide (1 ml) and a 2 M aqueous potassium carbonate solution (1 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and 3-ethoxyphenylboronic acid (59 mg) under an argon atmosphere, and the mixture was stirred at 70° C. for 5 hr. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (43 mg, yield 87%).