Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:45][CH:46]([CH3:48])[CH3:47])[CH2:14][C@@H:15]([OH:44])[C@@H:16]([NH:32][C:33](=[O:43])[O:34][C@@H:35]3[C@H:42]4[C@H:38]([O:39][CH2:40][CH2:41]4)[O:37][CH2:36]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24]CC4C=CC=CC=4)=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1>C1COCC1.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:45][CH:46]([CH3:48])[CH3:47])[CH2:14][C@@H:15]([OH:44])[C@@H:16]([NH:32][C:33](=[O:43])[O:34][C@@H:35]3[C@H:42]4[C@H:38]([O:39][CH2:40][CH2:41]4)[O:37][CH2:36]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2

Procedure:
A solution of 8.00 g (11.7 mmol) of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-1-[4-(benzyloxy)benzyl]-2-hydroxypropylcarbamate in 200 mL of THF was subjected to hydrogenation at 50 psi in the presence of 8.0 g of 10% palladium on carbon (Degussa type). After 18 hours the reaction vessel was purged with nitrogen, catalyst removed by filtration through celite, and the filtrate concentrated at reduced pressure to a volume of 30 mL. The solution was rapidly stirred with addition of 30 mL of EtOAc followed by 250 mL of hexane. A white suspension resulted which was stirred at RT for 1 hour. The solid was collected by vacuum filtration and dried in vacuo to afford 6.83 g (98%) of (the desired compound as a white powder. 1H NMR (DMSO-d6): 9.00 (s, 1H), 7.25 (d, 1H), 7.17 (s, 1H), 7.12 (d, 1H), 7.01 (d, 1H), 6.92 (d, 2H), 6.52 (d, 2H), 6.12 (S, 2H), 5.46 (d, 1H), 4.93 (d, 1H), 4.80 (q, 1H), 3.80 (dd, 1H), 3.70 (t, 1H), 3.52 (m, 3H), 3.40 (m, 1H), 3.25 (m, 1H), 3.01-2.62 (m, 5H), 2.28 (t, 1H), 1.89 (m, 1H), 1.38 (m, 1H), 1.22 (m, 1H), 0.80 (d, 3H), 0.72 (d, 3H). MS(ESI): 593(M+H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:16]([C:18]2[CH:23]=[C:22]([C:24]3([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)[O:28][CH2:27][CH2:26][O:25]3)[CH:21]=[CH:20][C:19]=2[NH2:36])=[O:17])[CH:13]=[CH:14][CH:15]=1>C1(C)C=CC=CC=1>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[C:16]([C:18]1[CH:23]=[C:22]([C:24]2([C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)[O:28][CH2:27][CH2:26][O:25]2)[CH:21]=[CH:20][C:19]=1[NH:36][C:1](=[O:3])[CH3:2])=[O:17]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc(C(=O)c2cc(C3(c4ccc(Cl)cc4)OCCO3)ccc2N)c1
Solvent: Cc1ccccc1
Product: COc1cccc(C(=O)c2cc(C3(c4ccc(Cl)cc4)OCCO3)ccc2NC(C)=O)c1
Yield: 100 %

Procedure:
Acetic anhydride (13.9 ml) was added to a solution of interm. (7-c) (31.2 g) in toluene (300 ml) and the mixture was stirred and refluxed for 2 hours. The mixture was evaporated till dryness and the product was used without further purification, yielding 36.4 g (100%) of N-[2-(3-methoxybenzoyl)-4-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]phenyl]acetamide (interm. 7-d).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[CH2:9][N:8]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:35])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[CH3:34])=[CH:22][CH:21]=3)=[O:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1>O1CCCC1.CCOCC>[CH:3]1[C:13]2[CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[CH2:9][N:8]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([N:26]([CH2:7][N:8]([CH3:18])[CH3:9])[C:27](=[O:35])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[CH3:34])=[CH:22][CH:21]=3)=[O:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)N(CN(C)C)c1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reaction time: 1 h
Yield: 176.7 %

Procedure:
To a suspension of 14 mg of 60% sodium hydride in oil, in 2 ml of tetrahydrofuran is added 0.13 g of N-[4-[(6,11-dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]phenyl]-2-methylbenzamide. The reactants are stirred for 1 hour and 62 mg of N,N-dimethyl-15 methylene ammonium iodide added followed by stirring for 2 hours. The mixture is diluted with 10 ml of ether and filtered. The filtrate is evaporated in vacuo to a residue which is stirred with hexanes to give 0.13 g of the desired product as a white solid, m.p. 131°-133° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.C(N(CC)CC)C.[NH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:26][CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([S:35]([NH2:38])(=[O:36])=[O:37])=[CH:33][CH:34]=3)[N:3]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Reactant: CP(C)(=O)c1ccc(Nc2ncnc(Cl)n2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CP(C)(=O)c1ccc(Nc2ncnc(NCCc3ccc(S(N)(=O)=O)cc3)n2)cc1

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added 50 L of triethylamine and 4-(2-aminoethyl)benzene-sulfonamide (23 mg, 0.12 mmol). The mixture can be microwaved at 120 degrees until formation of the desired compound. The reaction mixture is filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[CH2:3]/[CH:4]=[CH:5]/[CH2:6][OH:7].[OH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][N:12]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CN(C)C=O>[OH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([O:7][CH2:6]/[CH:5]=[CH:4]/[CH2:3][Si:2]([CH3:9])([CH3:8])[CH3:1])=[O:16])=[CH:13][N:12]=1
Reactant: C[Si](C)(C)C/C=C/CO
Reactant: O=C(O)c1ccc(O)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: C[Si](C)(C)C/C=C/COC(=O)c1ccc(O)nc1
Yield: 38 %

Procedure:
1.3 g of 4-trimethylsilyl-(E)-but-2-en-1-ol (synthesis described in J. Org. Chem. 1984, 49, 4092), 1.08 g of 6-hydroxy-nicotinic acid and 178 mg of 4-dimethylaminopyridine were placed in succession in 30 ml of abs. dimethylformamide. 1.77 g (1.1 eq.) of dicyclohexylcarbodiimide were added thereto at 0° and the mixture was left to react at room temperature overnight. The separated urea was filtered off, the filtrate was extracted with ethyl acetate, washed twice with H2O, dried over Na2SO4 and the solvent was removed under reduced pressure. Flash chromatography on SiO2 (hexane/ethyl acetate=1/1) yielded 782 mg of 4-trimethylsilanyl-(E)-but-2-enyl 6-hydroxy-nicotinate as white crystals of m.p. 107-110° (dec.).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=[O:7])[CH2:5][C:4]([CH3:9])([CH3:8])[O:3]1.C[O-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]3[CH2:29][CH2:28]3)=[C:23]([CH:30]=O)[CH:22]=2)=[C:17]([F:32])[CH:16]=1>COCCOC.C(OCC)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]3[CH2:28][CH2:29]3)=[C:23]([CH:30]=[C:5]3[C:4]([CH3:9])([CH3:8])[O:3][C:2]([CH3:10])([CH3:1])[C:6]3=[O:7])[CH:22]=2)=[C:17]([F:32])[CH:16]=1
Reactant: O=Cc1cc(-c2ccc(Cl)cc2F)ccc1C1CC1
Reactant: CC1(C)CC(=O)C(C)(C)O1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: CC1(C)OC(C)(C)C(=Cc2cc(-c3ccc(Cl)cc3F)ccc2C2CC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91920 %

Procedure:
To an ice-cold solution of dihydro-2,2,5,5-tetramethylfuran-3-one (8.40 g, 0.059 mol) in anhydrous 1,2-dimethoxyethane (75 ml) is added sodium methoxide (3.60 g, 0.066 mol) in one portion, and the mixture is stirred at this temperature for 30 minutes. A solution of 4′-chloro-4-cyclopropyl-2′-fluorobiphenyl-3-carbaldehyde (14.80 g, 0.054 mmol) is then added dropwise over 20 minutes, maintaining temperature below 10° C. The reaction mixture is stirred at this temperature for 1 hour, then allowed to warm to room temperature before diluting with diethyl ether and distilled water. The two phases are separated, and the aqueous phase is extracted again with diethyl ether (×2). Organic fractions are combined, washed with brine, then dried over magnesium sulfate. The suspension is filtered and the filtrate concentrated in vacuo to afford 4-[1-(4′-chloro-4-cyclopropyl-2′-fluorobiphenyl-3-yl)methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (19.80 g) which is of sufficient purity to use directly in the next step.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH2:13]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCCc1ccccc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: c1ccc(CCn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under an atmosphere of N2, a mixture of imidazole (788 mg, 11.57 mmol, 2.1 equiv) and potassium carbonate (370 mg, 2.68 mmol, 1 equiv) in dry THF (18 mL) was stirred at rt for 10 min. To this was added a solution of (2-bromoethyl)benzene (1.00 g, 5.40 mmol, 1 equiv) in THF (1 mL) and the mixture was heated at reflux temperature for 14 h. The mixture was filtered and the filtrate was concentrated to a clear oil. The oil was dissolved in CH2Cl2 and the organic phase was washed with water (2×). The CH2Cl2 layer was then extracted with dilute aqueous HCl (3×). The aqueous extract was then neutralized with solid NaHCO3, and the free base extracted using CH12Cl2 (3×). The combined organic extracts were dried Na2SO4) and concentrated. High-vacuum drying gave QC-207 (420 mg, 2.44 mmol, 45%) as a clear oil: 1H NMR (400 MHz, CDCl3): δ 3.05 (t, J=7.0 Hz, 2H), 4.17 (t, J=7.0 Hz, 2H), 6.83 (s, 1H), 7.01-7.09 (m, 3H), 7.22-7.34 (m, 4H); 13C NMR (100 Adz, CDCl3): δ 38.0, 48.6, 118.9, 127.1, 128.7, 128.9, 129.6, 137.2, 137.6.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:7][N:8]=1)[NH2:2].[CH:16]([O-])([O-])OCC>CCCCCC>[F:15][C:12]1[CH:11]=[CH:10][C:9]([C:6]2[CH:7]=[N:8][C:3]3[N:4]([CH:16]=[N:2][N:1]=3)[N:5]=2)=[CH:14][CH:13]=1
Reactant: CCOC([O-])[O-]
Reactant: NNc1ncc(-c2ccc(F)cc2)nn1
Solvent: CCCCCC
Product: Fc1ccc(-c2cnc3nncn3n2)cc1

Procedure:
A mixture of 3.09 g. of 3-hydrazino-6-(p-fluorophenyl)-1,2,4-triazine and 35 ml. of ethyl orthoformate is refluxed for 2 hours, cooled and poured into hexane. The solid is collected and washed with ethanol giving the desired product as a brown solid, m.p. 231°-235° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[C:9](/[CH3:16])=[CH:10]/[C:11](OCC)=[O:12])[CH:5]=[C:6]([Br:8])[CH:7]=1.CC(C[AlH]CC(C)C)C>>[Br:1][C:2]1[CH:3]=[C:4](/[C:9](/[CH3:16])=[CH:10]/[CH2:11][OH:12])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: CCOC(=O)/C=C(\C)c1cc(Br)cc(Br)c1
Agent: CC(C)C[AlH]CC(C)C
Product: C/C(=C\CO)c1cc(Br)cc(Br)c1

Procedure:
(E)-Ethyl 3-(3,5-dibromophenyl)-but-2-enoate was reduced with DIBAL-H by a procedure analogous to that described in example 50b, to give the colourless oil (E)-3-(3,5-dibromophenyl)-but-2-en-1-ol.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=O.[CH:10]([OH:13])(C)C>>[CH:10]([NH:1][C@@H:2]1[C:7](=[O:8])[O:9][C:4](=[O:6])[CH2:3]1)=[O:13]
Reactant: CC(C)O
Reactant: N[C@@H](CC(=O)O)C(=O)O
Product: O=CN[C@H]1CC(=O)OC1=O

Procedure:
formylating L-aspartic acid in a first reaction mixture of formic acid, acetic anhydride and isopropyl alcohol to yield N-formyl aspartic anhydride;
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([O:14]C)=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].COB([C:20]1[CH:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22][CH:21]=1)O.C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[C:2]1([C:20]2[CH:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22][CH:21]=2)[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[CH:5]=[C:6]([C:7]([OH:9])=[O:8])[CH:11]=1
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Reactant: COB(O)c1ccc(C(=O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)c1ccc(-c2cc(C(=O)O)cc(C(=O)O)c2)cc1
Temperature: 25 °C
Yield: 60.2 %

Procedure:
Dimethyl 5-bromoisophthalate (8.15 g, 29.9 mmol), methyl 4-carboxyphenylboronic acid (5.91 g, 32.8 mmol), K2CO3 (8.29 g, 60.0 mmol), toluene (60 mL), ethanol (30 mL) and water (30 mL) are added into a 200 mL round-bottomed flask equipped with a magnetic stir bar and water jacketed condenser. The resulting suspension is degassed for 15 min by sparging with nitrogen gas. Pd(PPh3)4 (0.862 g, 0.746 mmol) is added, and the mixture is heated to reflux overnight under a nitrogen atmosphere. After cooling to room temperature both layers are separated, the organic layer is dried over anhydrous Na2SO4, filtered and the solvent is removed under reduced pressure. The residue is filtered on a short silica plug using acetone as eluent and the solvent is removed by evaporation. The crude product is dissolved in dioxane (50 mL) and an aqueous KOH solution (9 M, 50 mL) is added. This mixture is heated to reflux for 12 h. The solvent is evaporated then the residue is dissolved in H2O (100 mL). The residual solids are filtered off and the filtrate is acidified with concentrated HCl (20 mL). The target compound is collected by filtration, washed with H2O and acetone and dried under vacuum to yield 5.15 g of biphenyl-3,4′,5-tricarboxylic acid (18.0 mmol as a white powder, 60%): mp>300° C.; 1H NMR (400 MHz, DMSO-d6): δ 13.23 (br s, 3H), 8.41 (d, J=1.0 Hz, 1H), 8.33 (t, J=1.0 Hz, 2H), 7.99 (d, J=8.0 Hz, 2H), 7.77 (d, J=8.0 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): δ 167.4, 166.8, 142.8, 140.3, 132.6, 131.8, 130.8, 130.6, 129.9, 127.4; HRMS (EI) calcd. for C15H10O6 (m/e): 286.0477. found: 286.0485; Anal. Calcd for C15H10O6: C, 62.94; H, 3.52. Found: C, 62.54; H, 3.57.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]([C:6]1[O:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)=[CH:9][CH:10]=1)=[O:5]>CO>[Cl:18][C:13]1[CH:12]=[C:11]([C:8]2[O:7][C:6]([CH:4]([OH:5])[CH3:3])=[CH:10][CH:9]=2)[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: CC(=O)c1ccc(-c2ccc(Cl)c(Cl)c2)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccc(-c2ccc(Cl)c(Cl)c2)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
Sodium Borohydride (1.5 g, 0.04 mole) was added in portions to a stirred mixture of 15 g (0.059 mole) of 5-(3,4-dichlorophenyl)-2-furyl methyl ketone and 125 ml of MeOH at 15°-20° over 30 minutes. The mixture was stirred at ambient temperature for 3 hours. Some insoluble material was removed by filtration and set aside. The filtrate was poured into 300 ml of ice-H2O mixture and made acidic with dilute HCl. The oil which was deposited solidified and was collected by filtration. Recrystallization from n-hexane gave 11 g (73%) of title compound, m.p. 82.5°-83.5°.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[OH:14][CH2:15][C:16]1[N:17]=[C:18]([CH:21]([CH3:23])[CH3:22])[S:19][CH:20]=1.CN1CCOCC1>C(Cl)Cl>[CH:21]([C:18]1[S:19][CH:20]=[C:16]([CH2:15][O:14][C:2]([O:4][C:5]2[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=2)=[O:3])[N:17]=1)([CH3:23])[CH3:22]
Reactant: CC(C)c1nc(CO)cs1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)c1nc(COC(=O)Oc2ccc([N+](=O)[O-])cc2)cs1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1.12 g (5.56 mmol) of 4-nitrophenyl chloroformate in 20 ml of CH2Cl2 was cooled to 0° C. and treated sequentially with 0.8 g (5.1 mmol) of 4-(hydroxymethyl)-2-isopropylthiazole and 0.6 ml (5.6 mmol) of 4-methylmorpholine. The resulting solution was stirred at 0° C. for 1 h, diluted with CH2Cl2, washed with three portions of aqueous NaHCO3, dried over Na2SO4, and concentrated in vacuo to give crude 2-isopropyl-4-(p-nitrophenyloxycarbonyloxymethyl)thiazole. A portion (0.53 g, 1.65 mmol) of the residue was taken up in 20 ml of chloroform, treated with 0.23 g (1.67 mmol) of L-alanine methyl ester hydrochloride and 0.36 ml (3.3 mmol) of 4-methylmorpholine, and heated at reflux for 16 h. After being allowed to cool, the solven was removed in vacuo, and the residue was purified by silica gel chromatography using 2% methanol in chloroform to provide 0.45 g (94%) of the desired compound, Rf 0.43 (5% methanol in CH2Cl2). 1H NMR (DMSO-d6) δ 1.26 (d, J=8 Hz, 3H), 1.32 (d, J=7 Hz, 6H), 3.27 (heptet, J=7 Hz, 1H), 3.63 (s, 3H), 4.10 (p, J=8 Hz, 1H), 5.02 (s, 2H), 7.47 (s, 1H), 7.81 (d, J=8 Hz, 1H). Mass spectrum: (M+H)+=287.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[C:18]([C:25]#[C:26][CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH:16]=[N:15][N:14]=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:13]1[C:22]2[C:17](=[C:18]([C:25]#[C:26][CH2:27][CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH:16]=[N:15][N:14]=1
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COc1ccc2c(Cl)nncc2c1C#CCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1C#CCCCc1ccccc1
Reaction time: 1 h
Yield: 51.5 %

Procedure:
A solution under N2 of 3,5-dichloro-4-methyl-pyridine (1.28 g, 7.9 mmoles) in dry DMF (15 ml) was added under stirring at room temperature with 60% NaH (316 mg, 7.9 mmoles). The mixture was stirred for 1 hour, then dropwise added with 1-chloro-6-methoxy-5-(5phenyl-pent-1-ynyl)-phthalazine (1.33 g, 3.95 mmoles), prepared as described in example 65, in dry DMF (20 ml). After 3 hours the mixture was poured into water, extracted with ethyl acetate, washed with water, anhydrified over Na2SO4 and brought to dryness. The residue was flash chromatographed (eluent: petrolatum/ethyl acetate 1:1). The separated product was taken up in ethanol (10 ml) and crystallised. The resultant product was filtered and dried under vacuum at 40° C. to give 940 mg of the title compound (yield: 51%). m.p.: 130-132° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)=[CH:10][C:9]([Cl:26])=[CH:8][CH:7]=2.[CH2:40]([O:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH2:54][S:55](Cl)(=[O:57])=[O:56])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[CH2:40]([O:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH2:54][S:55]([NH:1][CH2:2][CH2:3][C:4]1[N:5]([CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)=[CH:10][C:9]([Cl:26])=[CH:8][CH:7]=2)(=[O:56])=[O:57])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1OCc1ccccc1
Reactant: COC(=O)c1ccc(CCCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: COC(=O)c1ccc(CCCc2c(CCNS(=O)(=O)Cc3ccccc3OCc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 70.4 %

Procedure:
As outlined in Step 9 Example 1, methyl 4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (Example 7, Step 6, 3.92 g, 7.3 mmol) was reacted with (2-benzyloxy-phenyl)-methanesulfonyl chloride (2.6 g, 8.76 mmol) to afford 4.1 g of methyl 4-{-[2-[2-({[2-(benzyloxy)benzyl]sulfonyl}amino)ethyl]-5-chloro-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoate, a white foam, in 59% yield. 1H NMR (400 MHz, CDCl3) δ 1.80-1.99 (m, 2 H) 2.49-2.78 (m, 6 H) 2.85 (t, J=8.84 Hz, 2 H) 3.89 (s, 3 H) 3.96-4.05 (m, 1 H) 4.26 (s, 2 H) 4.90 (s, 2 H) 6.45 (d, J=8.84 Hz, 1 H) 6.73-6.82 (m, 2 H) 6.83-6.93 (m, 2 H) 6.94-7.08 (m, 4 H) 7.16-7.34 (m, 15 H) 7.39 (d, J=2.02 Hz, 1 H) 7.85-7.98 (m, 2 H).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:29]=[CH:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)[N:26]=2)=[CH:21][CH:20]=1)=[C:17]=[S:18]>>[OH:4][CH2:3][CH:2]([NH:1][C:17]([NH:16][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[N:29]=[CH:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:38])[F:39])=[CH:32][CH:31]=3)[N:26]=2)=[CH:23][CH:24]=1)=[S:18])[C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]([F:13])([F:14])[F:15])=[CH:9][CH:10]=1
Reactant: NC(CO)c1ccc(OC(F)(F)F)cc1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Product: OCC(NC(=S)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)c1ccc(OC(F)(F)F)cc1

Procedure:
The title compound was prepared with 2-amino-2-(4-(trifluoromethoxy)phenyl)ethanol and 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole and isolated as an white solid (1.42 g, 87%) 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.35-8.22 (m, 2H), 7.94 (s, 1H), 7.88-7.71 (m, 2H), 7.51-7.11 (m, 9H), 7.05 (d, J=7.9 Hz, 1H), 5.75 (s, 1H), 4.06 (dd, J=11.2, 3.9 Hz, 1H), 3.94 (dd, J=11.2, 4.7 Hz, 1H); ESIMS m/z 584 ([M+H]+).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:5])[CH3:4].[H-].[Na+].Cl.Cl.[Cl:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([N:24]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:32]=[N:33][N:34]([CH3:37])[C:35]=4[CH3:36])[CH2:26][CH2:25]3)=[N:20][CH:21]=[CH:22][N:23]=2)=[CH:14][CH:13]=1.[I-].[Na+]>CN(C)C=O>[ClH:10].[CH3:37][N:34]1[C:35]([CH3:36])=[C:31]([CH2:30][N:27]2[CH2:28][CH2:29][N:24]([C:19]3[C:18]([C:15]4[CH:16]=[CH:17][C:12]([CH2:11][N:2]([CH3:1])[C:3](=[O:5])[CH3:4])=[CH:13][CH:14]=4)=[N:23][CH:22]=[CH:21][N:20]=3)[CH2:25][CH2:26]2)[CH:32]=[N:33]1
Reactant: CNC(C)=O
Reactant: Cc1c(CN2CCN(c3nccnc3-c3ccc(CCl)cc3)CC2)cnn1C
Agent: Cl
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(=O)N(C)Cc1ccc(-c2nccnc2N2CCN(Cc3cnn(C)c3C)CC2)cc1
Yield: 28.9 %

Procedure:
Dissolve N-methyl acetamide (187 mg, 2.55 mmol) in dry N,N-dimethylformamide (5 mL) at room temperature under nitrogen. Add sodium hydride (60% dispersion in oil, 102 mg, 2.55 mmol), stir for 1 hr., then add 3′-(4-chloromethyl-phenyl)-4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl dihydrochloride (300 mg, 0.64 mmol) and sodium iodide (96 mg, 0.64 mmol). Stir the reaction at 50° C. for 20 hr., the quench with water (10 mL). Extract with DCM (4×10 mL) and pass through an IST Phase Separator Frit®. Purify using SCX-2 chromatography, eluting with 3 M ammonia in methanol and further purify using silica gel chromatography (eluting with 5:95 methanol:DCM). Dissolve the clear oil in acetonitrile, and add 2 M aq. HCl and water then lyophilize to give the title compound as light yellow powder (87 mg, 29%). MS (ES): m/z=434 [M+H].