Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]1([CH2:8][OH:9])[C@@H:4]([CH2:5][CH2:6][CH3:7])[O:3]1.CCN(C(C)C)C(C)C.[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21].P([O-])([O-])([O-])=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:23]([O:9][CH2:8][C@:2]1([CH3:1])[C@@H:4]([CH2:5][CH2:6][CH3:7])[O:3]1)([C:20]([CH3:22])([CH3:21])[CH3:19])([CH3:25])[CH3:24]
Reactant: CCC[C@H]1O[C@]1(C)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC[C@H]1O[C@]1(C)CO[Si](C)(C)C(C)(C)C
Yield: 89.6 %

Procedure:
Alcohol 3 (51.1 mg, 0.3925 mmol) in 3 ml of CH2Cl2 was treated successively with DIPEA (102 μl, 0.5888 mmol, 1.5 eq), DMAP (1 crystal), and TBSCl (77 mg, 0.5103 mmol, 1.3 eq) and refluxed for 12 h. The solution was poured onto 20 ml of 0.2M pH 7 phosphate buffer and 30 ml of low boiling petroleum ether, shaken, and separated. The aqueous phase was extracted with petroleum ether (3×10 ml), washed with pH 7 buffer (1×10 ml), H2O (1×5 ml), brine (1×5 ml), dried over MgSO4, and concentrated to give 86.0 mg of 4 as a clear oil (89.6%). 1H NMR (CDCl3, 360.134 MHz) δ:3.57 (1H, d, J=11.15 Hz), 3.53 (1H, d, J=11.17 Hz), 2.82 (1H, t, J=5.70 Hz), 1.6-1.4 (4H, m), 1.25 (3H,s), 0.95 (3H, t, J=7.13 Hz), 0.87 (9H, s), 0.04 (3H, s), and (3H, s). 13C NMR (CDCl3, 90.55 MHz) δ:68.0, 61.0, 60.8, 30.2, 25.8, 19.7, 18.3, 14.1, 13.9, and -5.4. IR (thin film): 2959 (s), 2930 (s), 2859 (s), 1473 (m), 1464 (m), 1382 (w), 1362 (w), 1253 (m), 1103 (s), 838 (s), 778 (s), and 667 (w) cm-1. [δ]D=+4.9° (c=2.62, CH2Cl2).
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C@H:8]2[N:9]3[CH2:11][CH2:12][C:13]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]=4[C@@:7]2([C:22]([O:24][CH3:25])=[O:23])[CH2:6][C@@H:5]([CH2:10]3)[CH:4]=1.[CH3:26][CH2:27][C:28]12[C@@H:46]([O:47][C:48]([CH3:50])=[O:49])[C@:45]([OH:55])([C:51]([O:53][CH3:54])=[O:52])[C@H:44]3[C@@:34]4([C:37]5[CH:38]=[CH:39][C:40]([O:57][CH3:58])=[CH:41][C:42]=5[N:43]3[CH3:56])[CH2:35][CH2:36][N:32]([C@@H:33]14)[CH2:31][CH:30]=[CH:29]2>>[CH3:1][CH2:2][C:3]1[CH2:8][N:9]2[CH2:10][C@@H:5]([CH2:6][C@:7]([C:22]([O:24][CH3:25])=[O:23])([C:39]3[CH:38]=[C:37]4[C@@:34]56[C@@H:44]([N:43]([CH3:56])[C:42]4=[CH:41][C:40]=3[O:57][CH3:58])[C@@:45]([OH:55])([C:51]([O:53][CH3:54])=[O:52])[C@H:46]([O:47][C:48]([CH3:50])=[O:49])[C@:28]3([CH2:27][CH3:26])[CH:29]=[CH:30][CH2:31][N:32]([C@H:33]53)[CH2:36][CH2:35]6)[C:14]3[NH:15][C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:13]=3[CH2:12][CH2:11]2)[CH:4]=1
Reactant: CCC12C=CCN3CC[C@@]4(c5ccc(OC)cc5N(C)[C@H]4[C@@](O)(C(=O)OC)[C@@H]1OC(C)=O)[C@@H]32
Reactant: CCC1=C[C@@H]2CN3CCc4c([nH]c5ccccc45)[C@@](C(=O)OC)(C2)[C@@H]13
Product: CCC1=C[C@H]2CN(CCc3c([nH]c4ccccc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@H]3[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]5(CC)C=CCN6CC[C@]43[C@@H]65)C2)C1

Procedure:
In J. Am. Chem. Soc./98:22/Oct. 27, 1976, Langlois et al describe a process in which the monomers catharanthine and vindoline are coupled to form AVLB. The coupling is performed using a peracid to generate first the N-oxide of catharanthine, followed by Polonovski-type fragmentation of the N-oxide initiated with addition of trifluoroacetic anhydride to form a dimer. A reducing agent such as sodium borohydride is then added to generate AVLB which can be isolated e.g. chromatographically.
Reaction SMILES: [C:1]([C@H:4]1[C@@H:9]([C:10](=[O:12])[NH2:11])[N:8]([CH2:13][C:14](OC)=[O:15])[CH2:7][CH2:6][N:5]1[CH2:18][C:19]([O:21]C)=O)(=[O:3])[NH2:2].C[O-].[Na+]>CO>[C:1]1(=[O:3])[C@@H:4]2[C@H:9]3[C:10](=[O:12])[NH:11][C:14](=[O:15])[CH2:13][N:8]3[CH2:7][CH2:6][N:5]2[CH2:18][C:19](=[O:21])[NH:2]1
Reactant: COC(=O)CN1CCN(CC(=O)OC)[C@@H](C(N)=O)[C@H]1C(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CN2CCN3CC(=O)NC(=O)[C@@H]3[C@H]2C(=O)N1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
Method A. To a suspension of diester diamide 10 (1.0 g, 3.16 mmol) in 6 mL of absolute MeOH was slowly added (~10 min) 1.8 mL of NaOMe (25% solution in absolute MeOH, 7.9 mmol) under argon at room temperature. The resulting colorless solution was heated at 60° C. for 4 hours and stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, and the residual white solid was dissolved in 3 mL of H2O. The aqueous solution was acidified (concentrated HCl, pH ~2), and the colorless solid was filtered, washed with 5 mL of cold H2O followed by 5 mL EtOH, and dried; yield 0.54 g, (67%); mp 284°-285° C. dec; Anal. (C10H12N4O4) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][C:7]1([CH3:17])[CH3:16].[C:19](OC(=O)C)(=[O:21])C>C(O)=O>[CH3:1][O:2][C:3](=[O:18])[CH2:4][N:5]([CH:19]=[O:21])[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][C:7]1([CH3:16])[CH3:17]
Reactant: COC(=O)CNC1c2ccccc2CCC1(C)C
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: COC(=O)CN(C=O)C1c2ccccc2CCC1(C)C
Reaction time: 70 h

Procedure:
The complete yield of N-(2,2-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)glycine methyl ester of the process a) is added dropwise with cooling to 5° C. to 67.8 ml of formic acid. Additionally 24.9 ml of acetic anhydride are added, and the mixture is kept at room temperature for 70 hours. Destillation under vacuum affords 35.2 g of N-formyl-N-(2,2-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)glycine methyl ester having a melting point of 74°-75° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:23]2[CH2:27][CH2:26][CH:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)[CH2:24]2)=[C:6]([CH:22]=1)[C:7]([NH:9][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8].O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:23]2[CH2:27][CH2:26][CH:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:33][CH:34]=3)[CH2:24]2)=[C:6]([CH:22]=1)[C:7]([NH:9][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2N2CCC(Oc3ccc(C(F)(F)F)cc3)C2)cc1
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](NC(=O)c1cc(Cl)cnc1N1CCC(Oc2ccc(C(F)(F)F)cc2)C1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.3 %

Procedure:
To a solution of methyl 4-((1S)-1-(5-chloro-2-(3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)nicotinamido)ethyl)benzoate (D191) (50 mg, 0.091 mmol) in 1,4-dioxane (3 ml) and water (1 ml) lithium hydroxide monohydrate (5.8 mg, 0.14 mmol) was added and the resulting mixture was stirred at room temperature for 2 days. Solvents were evaporated in vacuo. The residue was diluted with water (5 ml) and 1M HCl (15 ml) and extracted with ethylacetate (3×20 ml). Collected organics, after solvent evaporation, afforded the title compound (E57) (40 mg).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8](=[O:10])[CH3:9])[C:4]([O:6][CH3:7])=[O:5].[C:11](Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C(Cl)Cl>[O:10]=[C:8]([CH3:9])[CH:3]([NH:2][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)C(N)C(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(NC(=O)C(C)(C)C)C(C)=O
Temperature: 25 °C
Yield: 74.3 %

Procedure:
A solution of methyl 2-amino-3-oxobutanoate hydrochloride (0.50 g, 3.0 mmol) in CH2Cl2 (30 mL) was cooled in an ice bath. Pivaloyl chloride (0.37 mL, 3.0 mmol) and triethylamine (0.84 mL, 6.0 mmol) were slowly added, and the reaction was allowed to slowly warm to room temperature overnight. The reaction was washed with water, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel chromatography (0%-3% MeOH—CH2Cl2) to obtain methyl 3-oxo-2-(pivalamido)butanoate (0.48 g, 74% yield). 1H NMR (400 MHz, CDCl3) δ 6.82 (bs, 1H), 5.21 (d, J=6.1 Hz, 1H), 3.82 (s, 3H), 2.39 (s, 3H), 1.24 (s, 9H) ppm. LC/MS: m/z 216.5 (M+H)+ at 1.98 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>>[F:19][C:16]([F:18])([F:17])[C:13]1[N:11]2[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:26][C:25]4[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:30])[F:31])=[CH:29][CH:28]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)cn12
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4c3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine with 4-(trifluoromethyl)benzaldehyde was carried out according to General Synthetic Method 9. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 3-(trifluoromethyl)-6-[4-[[4-(trifluoromethyl)phenyl]methyl]piperazin-1-yl]-[1,2,4]triazolo[4,3-a]pyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[O:6][CH2:7][C:8]1[O:12][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2C(OC(C)(C)C)=O)=[N:10][CH:9]=1.Cl.CCOC(C)=O.[OH-].[Na+]>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[O:6][CH2:7][C:8]1[O:12][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)=[N:10][CH:9]=1
Reactant: COc1ccc(OCc2cnc([C@@H]3CCCN3C(=O)OC(C)(C)C)o2)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1ccc(OCc2cnc([C@@H]3CCCN3)o2)cc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 71 %

Procedure:
To an AcOEt (1 ml) solution of the compound (0.146 g) obtained in Example 19-(5), 4N HCl-AcOEt (0.5 ml) was added and the mixture was stirred at room temperature for 12 hours. After adding 4N HCl-AcOEt (0.5 ml) and stirring for 3 hours, 4N HCl-AcOEt (0.5 ml) was further added and stirring was continued for an hour. After adding an aqueous solution of 2N NaOH and performing extraction with AcOEt, the organic layer was washed with brine, dried (MgSO4), filtered and concentrated to give the titled compound (0.078 g, pale yellow solid.)
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5]([C@H:7]1[C@@H:13]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([I:21])[CH:15]=2)[CH2:12][C@H:11]2[N:22]([CH3:23])[C@@H:8]1[CH2:9][CH2:10]2)=[O:6].N([O-])=O.[Na+].[N-:28]=[N+:29]=[N-].[Na+].Cl>CC(O)=O.O>[ClH:1].[CH3:3][O:4][C:5]([C@H:7]1[C@@H:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]=[N+:28]=[N-:29])=[C:16]([I:21])[CH:15]=2)[CH2:12][C@H:11]2[N:22]([CH3:23])[C@@H:8]1[CH2:9][CH2:10]2)=[O:6]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@H]1[C@@H](c2ccc(N)c(I)c2)C[C@@H]2CC[C@H]1N2C
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)[C@H]1[C@@H](c2ccc(N=[N+]=[N-])c(I)c2)C[C@@H]2CC[C@H]1N2C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
To a solution of 3β-[3'-iodo-4'-aminophenyl]tropan-2β-carboxylic acid methyl ester dihydrochloride (1a) (90 mg, 0.1902 mmol) in 1 mL of AcOH (3M) was added an aqueous solution of NaNO2 (17.3 mg, 0.2661 mmol, in 0.5 mL of H2O) at 0° C. After 30 min at this temperature NaN3 (19 mg, 0.2754 mmol) in 0.5 mL of H2O was added dropwise to the reaction mixture and stirred for 30 min at 0° C., then 30 min at room temperature. After removal of all solvent by evaporation, the residue was dissolved in CHCl3 and washed with H2O. The organic layer was dried over MgSO4 and concentrated to give an oil which was converted to HCl salt to yield 64 mg (72.7%) of 3β-[3'-iodo-4'-azidophenyl]tropan-2β-carboxylic acid methyl ester hydrochloride (1b) as a yellowish solid: mp 140°-143° C.; [α]25 -97.4° (c 0.115), MeOh); 1HNMR (250MHz, CDCl3) δ1.51-1.73 (m, 3) 2.07-2.16 (m, 2), 2.19 (s, 3, NCH3) 2.47 (m, 1), 2.80-2.93 (m, 2), 3.32 (m, 1, H-5), 3.51 (s, 3, OCH3), 3.54 (m, 1, H-1), 7.01 (d, 1, J-7.7, ArH), 7.28 (dd, 1, J=7.77, J=1, ArH), 7.60 (d, 1, J=1, ArH).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:18]Br>C(Cl)(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][Br:18])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: BrBr
Reactant: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(Oc2ccc(CBr)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a refluxing (250 watt infra-red lamp) and stirred solution of 4-(4-nitrophenoxy)toluene (229.25 g; 1 mol) in CCl4 (2.5 l) under nitrogen, bromine (247.46 g; 1.55 mol) in CCl4 (250 ml) was added dropwise over a period of 4 hours. After refluxing an additional 8 hours, followed by stirring at room temperature overnight, the reaction mixture was washed with 10% sodium bisulphite (1×1 l), saturated sodium bicarbonate (2×2 l) and saturated sodium chloride. The organic layer was dried over magnesium sulphate and evaporated to give a yellow solid which was recrystallised from benzene-hexane (250 ml:350 ml) to yield 4-(4-nitrophenoxy)α-bromotoluene as light yellow crystals. m.p. 68°-70° C. NMR (CDCl3): 8.15 (d,2H), 7.45 (d,2H), 7.0 (d,4H); and 4.49 (s,2H). Analysis: calculated for C13H10BrNO3 : C, 50.67; H, 3.27; N, 4.55; Br, 25.93; found: C, 50.38; H, 3.24; N, 4.58; Br, 26.02.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[O:9][CH2:8][CH2:7][O:6]1.[Cl:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:21]=[C:20]([Cl:30])[C:19]=1[OH:31].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[Cl:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:21]=[C:20]([Cl:30])[C:19]=1[O:31][CH2:2][CH2:3][CH2:4][C:5]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[O:9][CH2:8][CH2:7][O:6]1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: Fc1ccc(C2(CCCCl)OCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccc(C2(CCCOc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)OCCO2)cc1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
2.0 g of 2-(3-chloro-propyl)-2-(4-fluoro-phenyl)-[1,3]dioxolane are added to a suspension of 2.36 g of 2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenol, 1.7 g of potassium carbonate and 120 mg of potassium iodide in 50 ml of acetone. The mixture is then stirred for 48 hours at 60° C. The reaction mixture is concentrated and the residue is taken up in water and extracted with ethyl acetate. After concentration of the organic phase and purification over silica gel, 2-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propyl}-2-(4-fluoro-phenyl)-[1,3]dioxolane is obtained.
Reaction SMILES: [ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:29]I>>[ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH3:29])[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CI
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Agent: Cl
Product: CN1CN(c2ccccc2)C2(CCN(C3CCCCCCCCC3)CC2)C1=O

Procedure:
The title compound, white solid, m.p. 248° C. (dec.) and MS: m/e=384.3 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4 ,5]decan-4-one hydrochloride and methyl iodide.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[N:17][CH:18]=2)[N:15]([C:19]([NH2:21])=[O:20])[CH2:14][CH2:13][CH2:12]3)O1.Br[C:24]1[CH:25]=[C:26]([C:30]2([OH:36])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:27]=[N:28][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].O>CCOC(C)=O.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[OH:36][C:30]1([C:26]2[CH:25]=[C:24]([C:9]3[CH:10]=[C:11]4[C:16](=[N:17][CH:18]=3)[N:15]([C:19]([NH2:21])=[O:20])[CH2:14][CH2:13][CH2:12]4)[CH:29]=[N:28][CH:27]=2)[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1
Reactant: CC1(C)OB(c2cnc3c(c2)CCCN3C(N)=O)OC1(C)C
Reactant: OC1(c2cncc(Br)c2)CCOCC1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: NC(=O)N1CCCc2cc(-c3cncc(C4(O)CCOCC4)c3)cnc21
Temperature: 80 °C

Procedure:
To the crude 6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (0.21 mmol, which is prepared according to the procedure for Step 3 of Example 16) is added 4-(5-bromo-pyridin-3-yl)-tetrahydro-pyran-4-ol (65.9 mg, 0.26 mmol), PdCl2(DPPF) (7.8 mg, 0.01 mmol) and Na2CO3 (45.1 mg, 0.43 mmol). 0.1 mL of H2O is added and the mixture is heated for 2 hrs at 80° C. The mixture is diluted with 50 mL EtOAc, quenched with 20 mL of saturated aqueous NH4Cl, washed with 2×20 mL of H2O and 1×20 mL of brine. The organic phase is dried with MgSO4, filtered and concentrated. The crude material is applied to a silica preparative TLC plate, and eluted (5% MeOH/CH2Cl2) to give 73 mg of 6-[5-(4-Hydroxy-tetrahydro-pyran-4-yl)-pyridin-3-yl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide.
Reaction SMILES: [CH:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27](Cl)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C2C=CC([C:42]([N:44]3[C:50]4C=CC=C[C:49]=4[CH2:48][N:47]4C(C(O)=O)=CC=[C:46]4[CH2:45]3)=O)=CC=2)CCCCC1.C(N(CC)C(C)C)(C)C.CN1CCCNCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27]([N:47]5[CH2:48][CH2:49][CH2:50][N:44]([CH3:42])[CH2:45][CH2:46]5)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Reactant: O=C(Cl)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Agent: CN(C)c1ccncc1
Agent: CN1CCCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCCN(C(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(C4CCCCC4)cc2)C3)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude 10-(4-cyclohexyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carbonyl chloride (prepared from 2.5 g of the corresponding acid of Example 22, in the manner of Example 23) was added to a stirred mixture of N,N-diisopropylethyl amine (1.73 g), 4-(dimethylamino)pyridine (0.1 g) and N-methyl homopiperazine (1.52 g) in dichloromethane (25 mL). After stirring overnight at room temperature the reaction mixture was washed with water and saturated aqueous sodium bicarbonate, and dried over anhydrous sodium sulfate. The solution was filtered through a short column of Magnesol® and the eluate refluxed with the slow addition of hexane to provide the title compound as off-white crystals (0.46 g), m.p. 133–136° C.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([SH:14])=[CH:8][C:7]=1[CH3:15].Br[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1>>[Cl:25][C:20]1[CH:19]=[C:18]([C:10]2[CH:9]=[CH:8][C:7]([CH2:15][S:14][C:9]3[C:10]([O:12][CH3:13])=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:16])=[C:7]([CH3:15])[CH:8]=3)=[CH:6][CH:11]=2)[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: Clc1ccc(Br)cc1Cl
Reactant: COC(=O)COc1cc(OC)c(S)cc1C
Product: COc1cc(OCC(=O)O)c(C)cc1SCc1ccc(-c2ccc(Cl)c(Cl)c2)cc1

Procedure:
The title compound was prepared in the manner analogous to Example 5A using 1D and 4-bromo-1,2-dichloro-benzene. MS m/z 479 (M+2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([C:15]([OH:17])=[O:16])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[Si](C)(C)C.[C:30]([CH2:32][C:33](Cl)=[O:34])#[N:31]>ClCCl>[C:30]([CH2:32][C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([C:15]([OH:17])=[O:16])=[CH:10][N:9]=2)=[CH:6][CH:7]=1)=[O:34])#[N:31]
Reactant: Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Reactant: N#CCC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCC(=O)Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1

Procedure:
Using the method for the preparation of the side chain acid in Example 1, 9.2 g (40 mmol) of 2-(4-aminophenyl)-4-hydroxy-5-pyrimidine carboxylic acid, 16.8 ml (120 mmol) of triethylamine, 16 ml (126 mmol) of chlorotrimethylsilane, 400 ml of dichloromethane, and 5.0 (45 mmol) of cyanoacetyl chloride [Org. Syn. Col. Vol. V, p. 171] gives 12.3 g of 2-[4-(cyanoacetylamino)phenyl]-4-hydroxy-5-pyrimidine carboxylic acid as the monohydrate; mp>280°.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:12]([F:13])=[CH:11][C:10]([N:14]3[CH2:18][C@@H:17]([CH2:19]CO)[O:16][C:15]3=[O:22])=[CH:9][C:8]=2[F:23])[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:43][C:44]1[NH:48][N:47]=[N:46][N:45]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>ClCCl.C(OCC)(=O)C.CO>[S:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:12]([F:13])=[CH:11][C:10]([N:14]3[CH2:18][C@H:17]([CH2:19][N:46]4[N:47]=[N:48][C:44]([CH3:43])=[N:45]4)[O:16][C:15]3=[O:22])=[CH:9][C:8]=2[F:23])[CH2:3][CH2:2]1
Reactant: Cc1nnn[nH]1
Reactant: O=C1O[C@H](CCO)CN1c1cc(F)c(C2CCSCC2)c(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: Cc1nnn(C[C@H]2CN(c3cc(F)c(C4CCSCC4)c(F)c3)C(=O)O2)n1
Yield: 52.1 %

Procedure:
(5R)-3-[4-(Tetrahydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-[(hydroxymethyl)methyl]oxazolidin-2-one (Intermediate 47) (0.66 g, 2 mmol), triphenylphosphine (0.786 g, 3 mmol), 5-methyl tetrazole (0.303 g, 3.6 mmol) and diisopropylazodicarboxylate (0.59 ml, 3 mmol) were reacted as described for Example 28. Chromatography on silica gel with 0.2-0.5% methanol in dichloromethane followed by 40% ethyl acetate in hexanes gave the title product (0.412 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]2[N:29]=[N:30][NH:31][C:26]2=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[N:28]=[C:27]3[N:29]=[N:30][NH:31][C:26]3=[CH:25][CH:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: Clc1ccc2[nH]nnc2n1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc4[nH]nnc4n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1, Step 5 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (70 mg, 0.22 mmol) and 5-chloro-1H-[1,2,3]triazolo[4,5-b]pyridine (35 mg, 0.22 mmol) as starting materials.