Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O.[CH3:34][O:35][C:36]1[C:37]([CH3:60])=[C:38]([C:51]([O:58][CH3:59])=[C:52]([O:56][CH3:57])[C:53]=1[O:54][CH3:55])[CH2:39][C:40]1[CH:41]=[CH:42][C:43](O)=[C:44]([CH:49]=1)[C:45]([O:47][CH3:48])=[O:46].[OH-].[Na+]>C1C=CC=CC=1>[CH3:34][O:35][C:36]1[C:37]([CH3:60])=[C:38]([C:51]([O:58][CH3:59])=[C:52]([O:56][CH3:57])[C:53]=1[O:54][CH3:55])[CH2:39][C:40]1[CH:41]=[CH:42][C:43]([O:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[C:44]([CH:49]=1)[C:45]([O:47][CH3:48])=[O:46]
Reactant: OCc1cccnc1
Reactant: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1O
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1OCc1cccnc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.4 %

Procedure:
3-Pyridinemethanol (0.084 g, 0.774 mmol), tri-n-butylphosphine (0.156 g, 0.774 mmol) and N,N,N′,N′-tetramethylazodicarboxamide (0.133 g, 0.774 mmol) were added to a benzene solution of methyl 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-hydroxybenzoate (0.194 g, 0.516 mmol) and the solution was stirred at room temperature for 12 hours. The reaction solution was poured into an aqueous 2N sodium hydroxide solution (15 ml) and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=2:3) to obtain the titled compound (0.167 g, 0.358 mmol, 69%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:11]=[CH:10][NH:9][C:7](=O)[C:5]=2[CH:6]=1.C[Si](Br)(C)C.C(Cl)[Cl:18]>>[Cl:18][C:7]1[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[N:11]=[CH:10][N:9]=1
Reactant: O=c1[nH]cnc2ccccc12
Reactant: ClCCl
Agent: C[Si](C)(C)Br
Product: Clc1ncnc2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of the quinazoline 2 (0.168 g, 0.29 mmol) in DCM (1.5 mL) was added TMSBr (0.079 mL, 0.61 mmol) at 0° C. The reaction was stirred for 1 h at 0° C., then for 1 h at RT. The reaction was quenched with water (3 mL) and stirred for 15 min. The aqueous layer was washed with EtOAc (5 mL), and dried with lyophilizer overnight to give desired product 3 as white foam (0.14 g, 100% yield). LC/MS (10-99%) M/Z 406.0 retention time 3.32 min.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7]O[C:9]2=[O:12])=[CH:4][CH:3]=1.[NH2:13][C@@H:14]([CH2:22][CH3:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>>[C:18]([O:17][C:15](=[O:16])[CH:14]([N:13]1[CH:7]([NH:13][CH:14]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:22][CH3:23])[CH2:6][C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]1=[O:12])[CH2:22][CH3:23])([CH3:19])([CH3:21])[CH3:20]
Reactant: CC[C@H](N)C(=O)OC(C)(C)C
Reactant: O=c1occc2ccc(Cl)cc12
Product: CCC(NC1Cc2ccc(Cl)cc2C(=O)N1C(CC)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 85 °C
Yield: 64.2 %

Procedure:
A mixture of 7-Chloro-isochromen-1-one (10 g) and (S)-2-aminobutyric acid, tert-butyl ester (22 g) was heated at 85° C. for 24 hours. The mixture was then cooled and purified by flash chromatography (5-25% ethyl acetate/hexane) to afford the sub-title compound as a yellow oil (17.1 g, 64%): 1H NMR (400 MHz, CDCl3) δ 0.68-1.32 (6H, m), 1.50 (21H, m), 1.92 (1H, m), 2.15 (1H, m), 2.82-3.40 (3H, m), 4.41 (1H, m), 4.68 (1H, m), 7.11 (1H, m),7.35-7.52 (1H, m), 8.05 (1H, m).
Reaction SMILES: Cl.[NH2:2]O.[CH2:4]([O:6][C:7](=[O:36])[C:8](O)=[CH:9][C:10]([C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:14][C:13]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:11])[CH3:5]>C(O)C>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([C:12]2[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:14][C:13]=2[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:11][N:2]=1)=[O:36])[CH3:5]
Reactant: NO
Reactant: CCOC(=O)C(O)=CC(=O)c1cc(Cl)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Temperature: 25 °C

Procedure:
Hydroxylamine hydrochloride (0.89 g; 12.8 mmol) was added to a suspension of 4-(2,4-bis-benzyloxy-5-chlorophenyl)-2-hydroxy-4-oxo-but-2-enoic acid ethyl ester (5.00 g; 10.7 mmol) in absolute ethanol (100 ml). The reaction mixture was heated at reflux for four hours then allowed to cool to ambient temperature (during this time the mixture remains heterogeneous but becomes lighter yellow in colour). The mixture was filtered and the filtered solid was washed with water (2×20 ml), ethanol (2×20 ml) and dried in vacuo at 45° C. This affords 5-(2,4-bis-benzyloxy-5-chlorophenyl)-isoxazole-3-carboxylic acid ethyl ester as a fluffy yellow solid, 4.49 g (91%) LCMS: [M+H]+ 466, 464 (37Cl; 35Cl).). 1H NMR (400 MHz, CDCl3) δ 1.42 (t, 3H), 4.42 (q, 2H), 5.13 (s, 2H), 5.14 (s, 2H), 6.62 (s, 1H), 7.01 (s, 1H), 7.35-7.43 (m, 10H), 8.00 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10](O)=[O:11].[BH4-].[Na+].II>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH2:10][OH:11]
Reactant: O=C(O)CNc1ccccc1F
Agent: II
Agent: [BH4-]
Agent: [Na+]
Product: OCCNc1ccccc1F

Procedure:
Similar procedure as described in example 31a) was used, starting from 2-fluorophenylglycine, sodium borohydride and iodine to give 2-fluoro-Phenylglycinol. LC-MS m/e 156 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([CH2:22][CH3:23])[C:16](=[O:21])[CH:17]=[C:18](Cl)[N:19]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[C:32]#[N:33].C([O-])([O-])=O.[Na+].[Na+]>CC#N>[C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([CH2:22][CH3:23])[C:16](=[O:21])[CH:17]=[C:18]([C:28]3[CH:29]=[CH:30][C:31]([C:32]#[N:33])=[C:26]([F:25])[CH:27]=3)[N:19]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(Cl)cc1=O
Reactant: N#Cc1ccc(B(O)O)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(-c2ccc(C#N)c(F)c2)cc1=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
A mixture of [1-(4-chloro-1-ethyl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester (210 mg, 0.59 mmol) in CH3CN (10 mL), 3-fluoro-4-cyanophenylboronic acid (126 mg, 0.77 mmol), Pd(PPh)4 (14 mg, 0.012 mmol) and 0.4 M Na2CO3 (4.5 mL, 1.77 mmol) was stirred at 90° C. overnight under N2 atmosphere. The organic was concentrated in vacuo, and the aqueous extracted with DCM (2×). The combined organics were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by silica chromatography (1:2, EA:PE) to give 185 mg (64%) of the title compound as a yellow solid. [M+H] Calc'd for C23H28FN5O3, 442. Found, 442.
Reaction SMILES: [NH:1]([C:3]1[CH2:4][N:5]=[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:7]2[CH:12]=[C:11]([CH2:13][CH3:14])[S:10][C:8]=2[N:9]=1)[NH2:2].[N:22]([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>Cl.O>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:6]1[C:7]2[CH:12]=[C:11]([CH2:13][CH3:14])[S:10][C:8]=2[N:9]2[N:22]=[N:2][N:1]=[C:3]2[CH2:4][N:5]=1
Reactant: O=N[O-]
Reactant: CCc1cc2c(s1)N=C(NN)CN=C2c1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCc1cc2c(s1)-n1nnnc1CN=C2c1ccccc1Cl
Yield: 79.3 %

Procedure:
[f] 10 g of 2-hydrazino-5-o-chlorophenyl-7-ethyl-3H-thieno[2,3-e][1,4]diazepine prepared in the above example [d] is suspended in 54 ml of 2N hydrochloric acid. A solution of 2.4 g of sodium nitrite in 20 ml of water is added to the suspension at -5°C with stirring. The mixture is stirred at room temperature for 30 minutes, and then alkalified with sodium carbonate. The precipitated crystals are filtered off and dissolved in chloroform, and the solution is washed with water. The chloroform layer is dried over anhydrous magnesium sulfate, and the chloroform is distilled off under reduced pressure. The reddish brown jellylike residue thus obtained is crystallized from a mixture of ligroin and ethanol to give 8.2 g of 6-o-chlorophenyl-8-ethyl-4H-tetrazolo[5,1-c]thieno[2,3-e] [1,4]diazepine as white crystals. The product, when recrystallized from ethanol, melts at 135° - 136°C.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[C:9]([Cl:18])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:19][C:20]1[CH:21]=[C:22]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1>>[F:19][C:20]1[CH:21]=[C:22]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:23][N:24]1[CH2:25][CH2:26][CH:27]([NH:30][C:2]2[C:3]3[C:10]([C:11]4[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=4)=[C:9]([Cl:18])[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:28][CH2:29]1
Reactant: Fc1ccc(-c2c(Cl)sc3ncnc(Cl)c23)cc1
Reactant: NC1CCN(Cc2cc(F)cc(F)c2)CC1
Product: Fc1ccc(-c2c(Cl)sc3ncnc(NC4CCN(Cc5cc(F)cc(F)c5)CC4)c23)cc1

Procedure:
The title compound was prepared (140 mg, 49%) from 4,6-dichloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidine (175 mg, 0.59 mmol) and 1-(3,5-difluorobenzyl)piperidin-4-amine (170 mg, 0.7 mmol) by following the general procedure described for Preparation 6. 1H NMR (400 MHz, CDCl3): δ 8.45 (s, 1H), 7.45 (m, 2H), 7.30 (m, 2H), 6.85 (m, 2H), 6.65 (m, 1H), 4.65 (m, 1H), 4.05 (bs, 1H), 3.40 (s, 2H), 2.40 (m, 2H), 2.15 (m, 2H), 1.85 (m, 2H), 1.15 (m, 1H). MS (ESI) m/z: Calculated: 488.1; Observed: 489.2 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[C:11]1[CH:16]=[CH:15]C(F)=[CH:13][C:12]=1O[C@H](CC=C)C>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][C@H:16]([CH2:11][CH:12]=[CH2:13])[CH3:15]
Reactant: Oc1ccc(F)cc1Br
Reactant: C=CC[C@H](C)Oc1cc(F)ccc1Br
Product: C=CC[C@H](C)Oc1ccc(F)cc1Br
Yield: 88 %

Procedure:
Prepared from 2-bromo-4-fluorophenol in 88% yield following the same procedure as (S)-1-bromo-4-fluoro-2-(pent-4-en-2-yloxy)benzene. 1H NMR (400 MHz, CDCl3) δ 7.39-7.33 (m, 1H), 7.30 (dd, J=8.0, 3.0 Hz, 1H), 7.01-6.94 (m, 1H), 6.91-6.85 (m, 1H), 5.90 (ddt, J=17.2, 10.2, 7.0 Hz, 1H), 5.20-5.10 (m, 2H), 4.36 (sxt, J=6.1 Hz, 1H), 2.58-2.49 (m, 1H), 2.45-2.36 (m, 1H), 1.34 (d, J=6.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7](O)=[O:8])=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Br:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[N:47]=[C:48]([C@@H:51]3[CH2:55][C@H:54]([CH3:56])[CH2:53][NH:52]3)[NH:49][CH:50]=2)=[CH:42][CH:41]=1.C(N(CC)C(C)C)(C)C>CC(N(C)C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@H:6]([C:7]([N:52]1[CH2:53][C@@H:54]([CH3:56])[CH2:55][C@H:51]1[C:48]1[NH:49][CH:50]=[C:46]([C:43]2[CH:44]=[CH:45][C:40]([Br:39])=[CH:41][CH:42]=2)[N:47]=1)=[O:8])[CH:10]([CH3:12])[CH3:11]
Reactant: C[C@@H]1CN[C@H](c2nc(-c3ccc(Br)cc3)c[nH]2)C1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
A mixture of (S)-2-methoxycarbonylamino-3-methyl-butyric acid (103 mg, 0.59 mmol, Preparation 3) and HATU (270 mg, 0.71 mmol) were stirred in DMA (2 mL) for 10 min and then 4-(4-Bromo-phenyl)-2-((2S,4S)-4-methyl-pyrrolidin-2-yl)-1H-imidazole 2 HCl (224 mg, 0.59 mmol, Preparation 4) and N,N-diisopropylethylamine (0.31 mL, 1.8 mmol) were added. The resulting mixture was stirred at RT overnight, diluted with ethyl acetate (50 mL), and washed with water (2×5 mL). The organic layer was dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography (0-100% EtOAc/hexanes)). Fractions with desired product were combined and concentrated to give the title compound (183 mg, 66% yield) (m/z): [M+H]+ calcd for C21H27BrN4O3 463.13; 465.12. found 465.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[S:8](=[O:17])(=[O:16])[CH2:7][C:6]=2[CH:18]=1.[H-].[Na+].[N:21]1([CH2:27][CH2:28][CH2:29]Cl)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(O)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[S:8](=[O:16])(=[O:17])[CH:7]([CH2:29][CH2:28][CH2:27][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:6]=2[CH:18]=1
Reactant: ClCCCN1CCCCC1
Reactant: O=S1(=O)Cc2cc(Cl)ccc2Oc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: O=S1(=O)c2ccccc2Oc2ccc(Cl)cc2C1CCCN1CCCCC1
Temperature: 70 °C
Reaction time: 4.5 h

Procedure:
A solution of 4.18 g 2-chloro-11H-dibenz (b,f)-1,4-oxathiepin 10,10-dioxide in 40 ml of dimethylformamide was treated with 0.65 g of sodium hydride and the mixture stirred for 4.5 hours at 70° C. Thereafter, 10 ml of 3-piperidinopropyl chloride were added and the mixture stirred for 3.5 hours at 70° C. It was then decomposed by dropwise addition of 4 ml of ethanol and diluted with 700 ml of water and extracted with benzene. From the benzene solution the base was extracted with 100 ml of 3M-HCl. The separated acid aqueous solution was made alkaline with aqueous ammonia and the base extracted with chloroform. The extract was dried with potassium carbonate and evaporated. The residue was chromatographed on a column of 400 g of neutral aluminum oxide (activity II). The less polar impurities were eluted with benzene and 4.37 g of homogeneous oily base were eluted with benzene and 4.37 g of homogeneous oily base were eluted with chloroform. Neutralization with hydrogen chloride in a mixture of ethanol and ether yielded the hydrochloride. By crystallization from a mixture of ethanol and ether the pure product was obtained, m.p. 177°-179° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[Cl:45])[O:11][C:12]1[CH:16]=[C:15]([N:17]2[C:25]3[CH:24]=[C:23]([CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[N:22]=[CH:21][C:20]=3[N:19]=[CH:18]2)[S:14][C:13]=1[C:35]([O:37]C)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:46]>CO>[Si:1]([O:8][CH2:9][C@@H:10]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[Cl:45])[O:11][C:12]1[CH:16]=[C:15]([N:17]2[C:25]3[CH:24]=[C:23]([CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[N:22]=[CH:21][C:20]=3[N:19]=[CH:18]2)[S:14][C:13]=1[C:35]([NH2:46])=[O:37])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O[C@@H](CO[Si](C)(C)C(C)(C)C)c1ccccc1Cl
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCc1cc2c(cn1)ncn2-c1cc(O[C@@H](CO[Si](C)(C)C(C)(C)C)c2ccccc2Cl)c(C(N)=O)s1

Procedure:
In a similar manner as described for example A5, 500 mg of methyl 3-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(2-chlorophenyl)ethoxy]-5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]thiophene-2-carboxylate and 40 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:33][C:32]([CH3:34])=[CH:31][C@@H:30](CC=C)[C:28](=[O:29])[CH2:27][C@H:26](O)[C@@H:25]([CH3:39])[C@@H:24](/C(/C)=C/[C@H]2C[C@@H](OC)[C@H](O)CC2)[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(O)[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.IC1C=CC(S(Cl)(=O)=O)=CC=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:57][O:56][CH:4]1[CH:5]2[O:10][CH:9]([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][CH2:24][CH:25]([CH3:39])[CH2:26][CH2:27][C:28](=[O:29])[CH2:30][CH:31]=[C:32]([CH3:34])[CH2:33][CH:2]([CH3:1])[CH2:3]1
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
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
Agent: O=S(=O)(Cl)c1ccc(I)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC1CC(C)CC(C)=CCC(=O)CCC(C)COC(=O)C2CCCCN2C(=O)C(=O)C2OC1C(OC)CC2C
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of the FR-900506 substance (100.7 mg) in pyridine (3 ml) was added p-iodobenzenesulfonyl chloride (500 mg), and the mixture was stirred at room temperature for 36 hours. The solution was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogen carbonate, water and an aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure The residue was chromatographed on silica gel (developing solvent diethyl ether and hexane, 3:1 v/v) to give 17-allyl-1,14-dihydroxy-12-2-[4-(p-iodobenzenesulfonyloxy)-3-methoxycyclohexyl]-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (61 mg) and 17-allyl-1-hydroxy-12-[2-[4-(piodobenzenesulfonyloxy)-3-methoxycyclohexyl]-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacosa-14,18-diene-2,3,10,16-tetraone (12 mg), respectively.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:26]([N:28]=[C:29]=[O:30])[CH3:27]>>[N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH:23][C:29]([NH:28][CH2:26][CH3:27])=[O:30])=[CH:21][CH:20]=3)[N:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: CCN=C=O
Product: CCNC(=O)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1

Procedure:
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.130 g 0.38 mmoles) and ethyl isocyanate (260 mg, 10 fold excess) the title compound was isolated as a white solid. Yield; 38 mg (25%); (M+H)=414.4
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]([CH3:11])[C:8]3[CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1>C(O)CO.[Pd]=O>[F:1][C:2]1[C:10]2[N:9]([CH3:11])[C:8]3[CH:12]=[CH:13][NH:14][C:15](=[O:16])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c2c(c3cccc(F)c31)C(=O)NCC2
Agent: O=[Pd]
Solvent: OCCO
Product: Cn1c2cc[nH]c(=O)c2c2cccc(F)c21
Yield: 100.9 %

Procedure:
A mixture of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one (300 mg) and 10% palladium oxide on carbon catalyst (50% aqueous paste; 150 mg) in ethylene glycol (30 ml) was heated at reflux under nitrogen for 24 h. The cooled mixture was filtered and evaporated to give a solid (ca. 300 mg) which was purified by FCC eluting with System A (200:10:1) to give a solid (100 mg). A sample of this solid was further purified by HPLC on a Spherisorb 55W column, eluting with System A (95:5:0.5) at a flow rate of 15 ml/min to give the title compound, m.p. 294°-296°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[N:5]([CH3:7])[CH3:6].[N:14]1C=CC=C[CH:15]=1.C([Cu])#N.N>O>[CH3:6][N:5]([CH3:7])[C:4]1[CH:3]=[C:2]([CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=1)[C:15]#[N:14]
Reactant: c1ccncc1
Reactant: CN(C)c1cc(Br)cc([N+](=O)[O-])c1
Agent: N#C[Cu]
Agent: N
Solvent: O
Product: CN(C)c1cc(C#N)cc([N+](=O)[O-])c1
Temperature: 220 °C
Reaction time: 3.5 h
Yield: 33 %

Procedure:
3-Bromo-N,N-dimethyl-5-nitroaniline (1.73 g, 7.06 mmol) (prepared according to the method described in J. Org. Chem. 60: 5091-5103 (2003)), pyridine (24 mL), and CuCN (1.26 g, 2.14 mmol) were added to a dry sealed tube. The mixture was heated at 220° C. with stirring for 3.5 h. The reaction mixture was allowed to cool to 100° C., poured into a flask containing a mixture of aqueous ammonia (100 mL) and water (100 mL), and extracted with EtOAc (2×100 mL). The EtOAc solution was washed with diluted ammonia solution (100 mL), water (100 mL) and brine (100 mL) successively, dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 3-(dimethylamino)-5-nitrobenzonitrile (0.44 g, 33%) as an orange solid. 1H NMR (400 MHz, CDCl3): δ 7.74 (dd, 1H, J=2.0, 1.2 Hz), 7.65 (t, 1H, J=2.2 Hz), 7.11 (dd, 1H, J=2.4, 1.2 Hz), 3.10 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([NH:25][C:26]([C:28]3[N:29]=[C:30]([CH2:33][N:34]4[CH2:39][C@H:38]([CH3:40])[O:37][C@H:36]([CH3:41])[CH2:35]4)[S:31][CH:32]=3)=[O:27])[C:13]3[C:17]([CH:18]=2)=[N:16][N:15]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:14]=3)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].CN1CCOCC1.Cl[CH2:50][CH2:51][S:52](Cl)(=[O:54])=[O:53]>C(Cl)Cl>[CH3:41][C@H:36]1[O:37][C@@H:38]([CH3:40])[CH2:39][N:34]([CH2:33][C:30]2[S:31][CH:32]=[C:28]([C:26]([NH:25][C:12]3[C:13]4[C:17]([CH:18]=[C:10]([C:4]5[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([NH:1][S:52]([CH:51]=[CH2:50])(=[O:54])=[O:53])[CH:3]=5)[CH:11]=3)=[N:16][N:15]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[CH:14]=4)=[O:27])[N:29]=2)[CH2:35]1
Reactant: O=S(=O)(Cl)CCCl
Reactant: COc1ncc(-c2cc(NC(=O)c3csc(CN4C[C@@H](C)O[C@@H](C)C4)n3)c3cn(C4CCCCO4)nc3c2)cc1N
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C=CS(=O)(=O)Nc1cc(-c2cc(NC(=O)c3csc(CN4C[C@@H](C)O[C@@H](C)C4)n3)c3cn(C4CCCCO4)nc3c2)cnc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-[6-[5-Amino-6-(methyloxy)-3-pyridinyl]-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl]-2-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-thiazole-4-carboxamide (250 mg) was dissolved in DCM (6 ml) and N-methylmorpholine (0.143 ml) was added. The reaction was cooled to 0° C. in an ice bath, then 2-chloroethanesulfonyl chloride (0.047 ml) was added dropwise. The reaction was left to warm to RT overnight. Reaction had blown dry, so was redissolved in DCM (6 ml). Further 2-chloroethanesulfonyl chloride (0.047 ml) was added and stirred at RT for 2 hours. Water (6 ml) was added to the reaction. The DCM was separated, passed through a hydrophobic frit, then evaporated to dryness to give crude title compound (250 mg) used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].CN(C)C=O.[H-].[Na+].Cl[C:37]1[CH:42]=[C:41]([CH3:43])[N:40]=[CH:39][N:38]=1>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:16]3[CH2:22][CH2:21][N:20]([C:37]4[CH:42]=[C:41]([CH3:43])[N:40]=[CH:39][N:38]=4)[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: Cc1cc(Cl)ncn1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2cc(C)ncn2)C3)cc1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0499 g, 0.000130 mol) in dry N,N-Dimethylformamide (1.00 mL, 0.0129 mol) was cooled at 0° C. then added sodium hydride, 60% dispension in mineral oil (3:2, Sodium hydride:Mineral Oil, 0.0109 g), warmed to room temperature, stirred for 10 minutes, added 4-Chloro-6-methylpyrimidine (0.0196 g, 0.000152 mol) heated at 60° C. for 3 hours. LC-MS does show some product present but a lot of starting material is still remaining. The reaction mixture was heated at 60° C. and stirred overnight. The reaction mixture was filtered and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 8.44 (s, 1H), 8.21 (d, J=8.8, 2H), 7.49 (d, J=8.8, 2H), 6.86 (s, 1H), 6.16 (t, J=5.6, 1H), 4.69 (s, 2H), 3.87 (s, 2H), 3.79-3.68 (m, 4H), 3.48 (d, J=4.4, 4H), 3.20-3.05 (m, 2H), 2.75 (s, 2H), 2.30 (s, 3H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+475.3 (M+H)+