Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([Si:14]([CH3:17])([CH3:16])[CH3:15])=[C:9]([F:18])[CH:8]=1.[CH:19](N1CCOCC1)=[O:20]>C1COCC1>[Cl:6][C:7]1[C:8]([CH:19]=[O:20])=[C:9]([F:18])[C:10]([Si:14]([CH3:15])([CH3:17])[CH3:16])=[C:11]([F:13])[CH:12]=1
Reactant: C[Si](C)(C)c1c(F)cc(Cl)cc1F
Reactant: O=CN1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)c1c(F)cc(Cl)c(C=O)c1F
Temperature: -70 °C
Yield: 108.2 %

Procedure:
A solution of 2.5M n-BuLi in hexanes (60 ml, 0.15 mol) was added drop-wise to a solution of (4-chloro-2,6-difluorophenyl)trimethylsilane (assumed 0.13 mol) in THF (180 mL) cooled to −70° C. under Ar. After the addition was complete, the mixture was stirred for 1 h before a solution of N-formylmorpholine (20 mL, 0.2 mol) in THF (25 mL) was added dropwise. The reaction was allowed to warm to rt with stirring and then cooled to 0° C. and quenched with H2O. Ether was added, the phases were separated, the aqueous phase was re-extracted with ether and the combined organics washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound (35 g) as an orange oil which was used without further purification.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[OH:53])[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si:65]([C:68]([CH3:71])([CH3:70])[CH3:69])([CH3:67])[CH3:66])[CH2:5][C:4]1=[O:72])[CH3:2].OS(C(F)(F)F)(=O)=O.C(=O)(O)[O-].[Na+]>C1CCCCC1.ClCCl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[O:53][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si:65]([C:68]([CH3:69])([CH3:70])[CH3:71])([CH3:67])[CH3:66])[CH2:5][C:4]1=[O:72])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(O)c4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(OCc4ccccc4)c4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 101.1 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-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 (40 mg) in cyclohexane (0.8 ml) and dichloromethane (0.4 ml) was added 2,2,2-benzyltrichloroacetimidate at 0° C. followed by triflic acid. The reaction was allowed to warm to room temperature and stir for 1.5 hours after which time it was poured into saturated aqueous sodium bicarbonate solution and extracted into ethyl acetate. The organic extracts were dried (MgSO4) and concentrated and the crude material was purified by column chromatography on silica gel eluting with 65% hexane:35% ethyl acetate to give the desired product (22 mg).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]4[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=4[CH3:20])[C:5]=3[C:4]=2[CH:3]=1.[F:25][C:26]1[C:27]([NH:41][CH3:42])=[N:28][CH:29]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>>[F:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]5[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=5[CH3:20])[C:5]=4[C:4]=3[CH:3]=2)[CH:29]=[N:28][C:27]=1[NH:41][CH3:42]
Reactant: CNc1ncc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: Cc1nn(C)c(C)c1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: CNc1ncc(-c2ccc3ncc4c(c3c2)n(-c2c(C)nn(C)c2C)c(=O)n4C)cc1F

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate H) and [3-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-methyl-amine (stage 141.1.1) to give the title compound as a yellow foam. (HPLC: tR 2.15 min (Method A); M+H=432 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.92 (s, 1H), 8.05-7.99 (m, 2H), 7.89-7.84 (m, 1H), 7.41-7.36 (m, 1H), 7.35-7.33 (m, 1H), 6.92-6.86 (m, 1H), 3.83 (s, 3H), 3.58 (s, 3H), 2.88 (d, 3H), 2.07 (s, 3H), 1.91 (s, 3H))
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:26][C:27]2[CH:32]=[C:31]([CH3:33])[C:30](=[O:34])[N:29]([CH3:35])[CH:28]=2)[C:9]2[C:10]([C:23]([OH:25])=O)=[N:11][N:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:13]=2)=[CH:4][CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9]3[C:10](=[N:11][N:12]([CH2:14][C:15]4[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH:13]=3)[C:23](=[O:25])[N:26]2[C:27]2[CH:32]=[C:31]([CH3:33])[C:30](=[O:34])[N:29]([CH3:35])[CH:28]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(Cn2cc(C(Nc3cc(C)c(=O)n(C)c3)c3ccc(Cl)cc3)c(C(=O)O)n2)cc1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(Cn2cc3c(n2)C(=O)N(c2cc(C)c(=O)n(C)c2)C3c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((4-chlorophenyl)((1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)amino)methyl)-1-(4-methoxy-benzyl)-1H-pyrazole-3-carboxylic acid (Step 26.2). tR: 4.40 min (HPLC 1); tR: 1.00 min (LC-MS 2); ESI-MS: 475 [M+H]+ (LC-MS 2); Rf=0.38 (CH2Cl2/MeOH 9:1).
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH3:10][O:11][C:12](=[O:23])/[C:13](/I)=[CH:14]\[CH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:44]1[CH:49]=[CH:48][C:47]([S:50]([CH3:53])(=[O:52])=[O:51])=[C:46]([C:54]([F:57])([F:56])[F:55])[CH:45]=1.[Cl-].[NH4+]>O1CCCC1.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:10][O:11][C:12](=[O:23])/[C:13](/[C:44]1[CH:49]=[CH:48][C:47]([S:50]([CH3:53])(=[O:51])=[O:52])=[C:46]([C:54]([F:56])([F:57])[F:55])[CH:45]=1)=[CH:14]/[CH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)/C(I)=C\C1CCCCCC1
Reactant: CS(=O)(=O)c1ccc(Br)cc1C(F)(F)F
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COC(=O)/C(=C/C1CCCCCC1)c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.7 %

Procedure:
A mixture of zinc dust (390 mg, 6 mmol, Aldrich, −325 mesh) and dry tetrahydrofuran (1 mL) under argon was treated with 1,2-dibromoethane (94 mg, 0.5 mmol). The zinc suspension was then heated with a heat gun to ebullition, allowed to cool, and heated again. This process was repeated three times to make sure the zinc dust was activated. The activated zinc dust suspension was then treated with trimethylsilyl chloride (55 mg, 0.5 mmol), and the suspension was stirred for 15 min at 25° C. The reaction mixture was then treated dropwise with a solution of (E)-3-cycloheptyl-2-iodo-acrylic acid methyl ester (prepared in Example 5, 616 mg, 2 mmol) in dry tetrahydrofuran (2 mL). After the addition, the reaction mixture was stirred for 1 h at 40-45° C. and then stirred overnight at 25° C. The reaction mixture was then diluted with dry tetrahydroftiran (2 mL), and the stirring was stopped to allow the excess zinc dust to settle down (˜2 h). In a separate reaction flask, bis(dibenzylideneacetone)palladium(0) (27 mg, 0.05 mmol) and triphenylphosphine (52 mg, 0.2 mmol) in dry tetrahydrofuran (4 mL) was stirred at 25° C. under argon for 10 min and then treated with 4-bromo-1-methanesulfonyl-2-trifluoromethyl-benzene (prepared in Example 12, 303 mg, 1 mmol) and the freshly prepared zinc compound in tetrahydrofuran. The resulting brick red solution was heated at 40-45° C. for 24 h. The reaction mixture was cooled to 25° C. and then poured into a saturated aqueous ammonium chloride solution (30 mL), and the organic compound was extracted into ethyl acetate (3×25 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 4/1 hexanes/ethyl acetate) afforded (E)-3-cycloheptyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-acrylic acid methyl ester (387 mg, 95%) as a viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:16]=[C:15]3[NH:40][C:41](=[O:61])[C:42]2[CH:47]=[CH:46][C:45]([N:48]([CH3:57])[CH2:49][CH2:50][N:51]3[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]3)=[CH:44][C:43]=2[N+:58]([O-:60])=[O:59])(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[ClH:62]>O1CCOCC1>[ClH:62].[F:8][C:6]1[CH:5]=[C:4]([S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[C:15]3[NH:40][C:41](=[O:61])[C:42]2[CH:47]=[CH:46][C:45]([N:48]([CH3:57])[CH2:49][CH2:50][N:51]3[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56]3)=[CH:44][C:43]=2[N+:58]([O-:60])=[O:59])(=[O:11])=[O:10])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CN(CCN1CCCCC1)c1ccc(C(=O)Nc2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(S(=O)(=O)c4cc(F)cc(F)c4)cc23)c([N+](=O)[O-])c1
Agent: Cl
Solvent: C1COCCO1
Product: CN(CCN1CCCCC1)c1ccc(C(=O)Nc2n[nH]c3ccc(S(=O)(=O)c4cc(F)cc(F)c4)cc23)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A solution of N-[5-(3,5-difluoro-benzenesulfonyl)-1-trityl-1H-indazol-3-yl]-4-[methyl-(2-piperidin-1-yl-ethyl)-amino]-2-nitro-benzamide (1.86 g, 2.21 mmol) in 1,4-dioxane (50 mL) was treated with 4N HCl in 1,4-dioxane (4.42 mL, 17.68 mmol). The mixture was stirred at room temperature for 30 hours then the volatiles were removed under reduced pressure. The residue was suspended in diethylether (100 mL), stirred for 1 hour, filtered, washed with diethylether and dried in oven at 40° C. affording the title compound as orange solid (1.29 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[N+:5]([O-:18])=[CH:4][CH:3]=1.[OH-:19].[K+]>>[OH:19][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[N+:5]([O-:18])=[CH:4][CH:3]=1
Reactant: [O-][n+]1ccc(Cl)c2ccc(-c3ccccc3)cc21
Reactant: [OH-]
Agent: [K+]
Product: [O-][n+]1ccc(O)c2ccc(-c3ccccc3)cc21

Procedure:
A solution of 4-chloro-7-phenylquinoline-1-oxide (1.9 g) and potassium hydroxide (4.2 g) in industrial methylated spirit (70 ml) was heated under reflux for 3 hours. The solvent was removed by distillation and water (200 ml) was added. The mixture was filtered and the filtrate neutralised with glacial acetic acid (5 ml). The precipitate was collected by filtration and purified by crystallisation from industrial methylated spirit (100 ml) to give the novel compound '4-hydroxy-7-phenylquinoline-1-oxide, m.p. 244°-250° decomp.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](O)=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[BH4-].[Na+]>C1COCC1.C(OCC)(=O)C.CCCCCCC>[OH:18][CH2:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCC(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)Nc1ccc(CCCO)cc1
Reaction time: 0.17 h
Yield: 48.9 %

Procedure:
3-{4-[(tert-Butoxycarbonyl)amino]phenyl}propanoic acid (1.33 g, 5.013 mmol) and BOP reagent (2.882 g, 6.517 mmol) were mixed in THF (30 ml). DIPEA (907 mg, 7.018 mmol) was added. The mixture was stirred for 10 minutes. Sodium borohydride (246 mg, 6.517 mmol) was added. The mixture was stirred for 30 minutes more and then evaporated to dryness. Ethyl acetate and water were added into the residue. The organic phase was washed with water and brine and dried with magnesium sulfate. The solvent was evaporated and an oil mixture was obtained. Column chromatography of the oil on silica gel using ethyl acetate/heptane (10:90, then 25:75) as eluant gave the desired oil product (616 mg), yield 49%.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:14]3[C:21]([CH3:22])=[C:20]([C:23]([NH2:25])=[O:24])[S:19][C:15]=3[N:16]=[CH:17][N:18]=2)=[C:8]([O:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]2)[CH:7]=1.C(N(CC)CC)C.CN(C=O)C>CO.CCOC(C)=O>[C:1]([CH2:2][CH2:3][N:29]1[CH2:30][CH2:31][CH2:32][C@@H:27]([O:26][C:8]2[CH:7]=[C:6]([F:5])[CH:11]=[CH:10][C:9]=2[NH:12][C:13]2[C:14]3[C:21]([CH3:22])=[C:20]([C:23]([NH2:25])=[O:24])[S:19][C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:28]1)#[N:4]
Reactant: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCCNC3)c12
Reactant: C=CC#N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCCN(CCC#N)C3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acrylonitrile (20 μl) was added to a suspension of 4-[4-fluoro-2-((R)-piperidin-3-yloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid amide (60 mg) and triethylamine (42 μl), in methanol (1 ml). After 1 h DMF (0.5 ml) was added. The reaction mixture was stirred at room temperature overnight. The reaction was diluted with EtOAc and washed with water and brine. The organic phase was passed through a hydrophobic frit and evaporated. The residue was triturated with diethylether.
Reaction SMILES: CC1(C)N([O])C(C)(C)CCC1.[OH:12][CH2:13][CH2:14][C:15]1([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[CH:13]([CH2:14][C:15]1([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)=[O:12]
Reactant: OCCC1(CCN2CCOCC2)CCCCC1
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: O=CCC1(CCN2CCOCC2)CCCCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 143.5 %

Procedure:
After adding 2,2,6,6-tetramethylpiperidine 1-oxyl free radical (32 mg, 0.20 mmol) to a solution of 4-[2-[1-(2-hydroxyethyl)cyclohexyl]ethyl]morpholine (439 mg, 1.82 mmol) and iodobenzene diacetate (644 mg, 2.00 mmol) in methylene chloride (10 mL), the mixture was stirred at room temperature for 14 hours. The reaction mixture was washed with saturated aqueous sodium hydrogencarbonate and saturated brine in that order and dried (anhydrous sodium sulfate), and then the solvent was distilled off under reduced pressure to obtain the title compound as a brown oil (625 mg). This was used without purification for the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][N:10]2[CH:14]=[CH:13][CH:12]=[C:11]2[C:15]([O:17]C)=O)=[CH:4][CH:3]=1.[CH2:20]([NH2:24])[CH2:21][CH2:22][NH2:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[CH2:9][N:10]4[CH:14]=[CH:13][CH:12]=[C:11]4[C:15](=[O:17])[N:23]2[CH2:22][CH2:21][CH2:20][NH:24]3)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccn1CC(=O)c1ccc(Cl)cc1
Reactant: NCCCN
Product: O=C1c2cccn2CC2(c3ccc(Cl)cc3)NCCCN12
Temperature: 180 °C
Yield: 10.6 %

Procedure:
Methyl 1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylate (100 mg, 0.36 mmol) was mixed with propane-1,3-diamine (0.9 g, 12.14 mmol) in xylenes (2 mL) and the mixture heated in the microwave at 180° C. for 1 hour (monitored by LCMS). The mixture was concentrated in vacuo and purified by flash chromatography using 2 to 10% MeOH in CH2Cl2, to give 11a-(4-chlorophenyl)-1,2,3,4,11,11a-hexahydro-6H-pyrrolo[1′,2′:4,5]pyrazino[1,2-a]pyrimidin-6-one (123) (11.5 mg, yield 10%).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([N:24]1[C@H:29]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[C@@H:28]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[CH2:27][C@@:26]([CH2:45][C:46]([OH:48])=[O:47])([CH3:44])[C:25]1=[O:49])[CH:21]1[CH2:23][CH2:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:50][Si](C=[N+]=[N-])(C)C>CO.C1C=CC=CC=1>[Si:1]([O:18][CH2:19][C@@H:20]([N:24]1[C@H:29]([C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)[C@@H:28]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[CH2:27][C@@:26]([CH2:45][C:46]([O:48][CH3:50])=[O:47])([CH3:44])[C:25]1=[O:49])[CH:21]1[CH2:22][CH2:23]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)[Si](OC[C@H](C1CC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)C[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C2CC2)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-((3R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (1400 mg, 1.96 mmol; Example 263, Step A) in a mixture of MeOH (3.1 mL) and benzene (12.5 mL) was added 2.0 M (trimethylsilyl)diazomethane in hexanes (1.96 mL, 3.92 mmol) at 0° C. dropwise. After being stirred at 0° C. for 1 h, the reaction was concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (40 g SiO2, 10%, and 20% EtOAc/Hex) provided the title compound as a pale yellow foam.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][C:14]3=[O:19])=[CH:9][CH:8]=2)[CH2:5][C@H:4]([CH2:20][NH:21][CH:22]=[O:23])[O:3]1.[Cl:24][C:25]1[S:29][C:28](C(Cl)=O)=[CH:27][CH:26]=1.C(OCC)(=O)C.O>O1CCCC1.[H-].[Na+].CO.C(O)(=O)C>[CH:11]1[C:10]([N:13]2[C:14](=[O:19])[CH2:15][O:16][CH2:17][CH2:18]2)=[CH:9][CH:8]=[C:7]([N:6]2[C:2](=[O:1])[O:3][C@@H:4]([CH2:20][NH:21][C:22]([C:28]3[S:29][C:25]([Cl:24])=[CH:26][CH:27]=3)=[O:23])[CH2:5]2)[CH:12]=1
Reactant: O=CNC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Reactant: O=C(Cl)c1ccc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1

Procedure:
N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)formamide (1 g) taken in a mixture of tetrahydrofuran (10 ml) and sodium hydride (0.11 g) stirred reaction mass at 25 to 30° C. for 30 minutes. To this mixture added 5-chlorothiophene carbonyl chloride (0.86 g). Obtained reaction mass then stirred for 1 to 2 h at 25 to 30° C. After completion of reaction, added ethyl acetate and water. Separated organic layer and concentrated under reduced pressure to obtain residue. Added acetic acid and methanol to residue stirred for 30 minutes and obtained solid is filtered off. Washed solid with methanol
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[Cl:11][C:12]1(Cl)[CH2:17][O:16][CH2:15][CH2:14][O:13]1>>[Cl:11][CH2:12][CH2:17][O:16][CH2:15][C:14]([NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:13]
Reactant: ClC1(Cl)COCCO1
Reactant: Nc1cccc([N+](=O)[O-])c1
Product: O=C(COCCCl)Nc1cccc([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of 1.12 g (8.12 mmol) of 3-nitroaniline and 1.11 g of 2-chlorodioxene (contains 6% of 2,2-dichlorodioxane) is heated at 80° C. with stirring for 24 hours, giving 2.1 g of 2-(2-chloroethoxy)-N-(3-nitrophenyl)acetamide as brownish oil. ESI 259.
Reaction SMILES: CN1C=CN=C1.[CH:7]1([CH2:12][C@H:13]([CH2:24][N:25]([CH:34]=[O:35])[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:14]([N:16]2[C@H:20]([C:21]([OH:23])=O)[CH2:19][CH:18]=[N:17]2)=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]1.S(Cl)(C)(=O)=O.[N:41]1[CH:46]=[CH:45][C:44]([NH2:47])=[N:43][CH:42]=1>CN(C)C=O>[CH:7]1([CH2:12][C@H:13]([CH2:24][N:25]([CH:34]=[O:35])[O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:14]([N:16]2[C@H:20]([C:21]([NH:47][C:44]3[CH:45]=[CH:46][N:41]=[CH:42][N:43]=3)=[O:23])[CH2:19][CH:18]=[N:17]2)=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)O)OCc1ccccc1
Reactant: Nc1ccncn1
Agent: CS(=O)(=O)Cl
Agent: Cn1ccnc1
Solvent: CN(C)C=O
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)Nc1ccncn1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 63.9 %

Procedure:
1-Methylimidazole (39.7 μl, 0.498 mmol) was added into the solution of (55)-1-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-4,5-dihydro-1H-pyrazole-5-carboxylic acid (100 mg, 0.249 mmol) in N,N-dimethylformamide (DMF) (1.8 ml). The resulting solution was cooled to 0° C., and then mesyl chloride (20.24 μl, 0.262 mmol) was added dropwise at 0° C. To the reaction mixture was added 4-pyrimidinamine (26.1 mg, 0.274 mmol). After stirring for 2 h 10 min at ambient temperature, the reaction solution was purified by RP-HPLC to yield (5S)-1-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-N-4-pyrimidinyl-4,5-dihydro-1H-pyrazole-5-carboxamide (76 mg, 0.159 mmol, 64% yield). MS (ES+) m/z 478.8 (MH+).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH2:16])=[N:13][C:12]=1[CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>O1CCCC1.CN(C)C1C=CN=CC=1>[C:23]([NH:16][C:14]1[S:15][C:11]([C:9]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])=[C:12]([CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[N:13]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCN(CC)Cc1nc(N)sc1C(=O)NCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)Cc1nc(NC(=O)c2ccccc2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 31.1 %

Procedure:
To a solution of 2-amino-4-diethylaminomethylthiazole-5-carboxylic acid benzylamide (0.052 g, 0.16 mmol) in tetrahydrofuran (5 mL) at 0° C. were added benzoyl chloride (0.04 mL, 0.34 mmol), 4-dimethylaminopyridine (catalytical amount) and triethylamine (0.3 mL, 2.10 mmol). The reaction mixture was allowed to warm to ambient temperature over 18 h then concentrated in vacuo. The crude product was purified by flash column chromatography eluting with methanol/dichloromethane (1/40 to 20/80) to afford the title compound (0.021 g); MS (ES+) m/z 423 (M+1).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:22][NH:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][NH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-:23].[Mn+2:24].[Cl-:25]>CO>[Cl:23][C:8]1([CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:22][NH:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][N:9]1[Cl:25].[Mn+2:24]
Reactant: C1CCC(CC2CNCCNCCNCCNCCN2)CC1
Reactant: [Cl-]
Agent: [Mn+2]
Solvent: CO
Product: ClN1CCNCCNCCNCCNCC1(Cl)CC1CCCCC1
Temperature: 0 °C
Yield: 65 %

Procedure:
A solution of 2-cyclohexylmethyl-1,4,7,10,13-pentaazacyclopentadecane prepared as in Example 7A (0.43 g, 1.4 mmole) and anhydrous manganese(II) chloride (0.17 g, 1.4 mmole) in anhydrous methanol (30 ml) was refluxed under a dry nitrogen atmosphere overnight. The solution was filtered and concentrated in vacuo to a volume of 3 ml. Ethyl ether (20 ml) was added. Upon cooling to 0° C., 0.39 g (65% yield) of the product was obtained as a white solid: FAB mass spectrum (NBA) m/z (relative intensity) 401/403 [(M-Cl)+, 100/33]: Anal. Calcd. for C17H37Cl2MnN5 : C, 46.69; H, 8.53; N, 16.09. Found: C, 45.87; H, 8.40; N, 15.55.