Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[C:13]3[N:22]=[C:21]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[S:20][C:14]=3[C:15](=[O:19])[NH:16][CH2:17][CH:18]=2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+].O>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[C:13]3[N:22]=[C:21]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[S:20][C:14]=3[C:15](=[O:19])[NH:16][CH2:17][CH:18]=2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1C1=CCNC(=O)c2sc(N3CCOCC3)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Cl)ccc1C1=CCNC(=O)c2sc(N3CCOCC3)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.7 %

Procedure:
To a solution of methyl 5-chloro-2-[2-(morpholin-4-yl)-4-oxo-5,6-dihydro-4H-[1,3]thiazolo[5,4-c]azepin-8-yl]benzoate (0.125 g, 0.298 mmol) in THF (3.7 mL) and MeOH (1.2 mL) was added a solution of 1M sodium hydroxide in water (3.66 mL, 3.66 mmol). The solution was stirred at room temperature for 16 hours. The solvents were evaporated and the residue was diluted with water and then added 1N hydrogen chloride aqueous solution until pH 7 was reached. Extracted twice with EA and the combined organic layer was then washed with brine then dried over anhydrous sodium sulfate and concentrated to give the product (0.100 g, 83%) which was used directly in the next step. LCMS: (AA) ES+ 406, 408. 1H NMR (400 MHz, d6-DMSO) δ: 12.79 (s, 1H), 7.86 (t, J=4.9 Hz, 1H), 7.68 (d, J=2.4 Hz, 1H), 7.57 (dd, J=8.2, 2.4 Hz, 1H), 7.32 (d, J=8.2 Hz, 1H), 6.21 (t, J=6.9 Hz, 1H), 3.65-3.55 (m, 6H), 3.30-3.26 (m, 4H).
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[S:23](=[O:30])(=[O:29])[NH:24]C(C)(C)C)=[CH:13][C:12]=2[F:31])=[C:8]([C:32]#[N:33])[N:7]([C:34]2[CH:39]=[C:38]([NH:40][C:41](=[O:44])[CH2:42][CH3:43])[CH:37]=[CH:36][C:35]=2[Cl:45])[N:6]=1)[CH2:2][CH2:3][CH3:4].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[S:23](=[O:30])(=[O:29])[NH2:24])=[CH:13][C:12]=2[F:31])=[C:8]([C:32]#[N:33])[N:7]([C:34]2[CH:39]=[C:38]([NH:40][C:41](=[O:44])[CH2:42][CH3:43])[CH:37]=[CH:36][C:35]=2[Cl:45])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2cc(NC(=O)CC)ccc2Cl)c(C#N)c1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2Cl)c(C#N)c1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
A mixture of 142 mg (0.218 mmol) of 3-n-butyl-4-[[2'-(N-t-butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-1-[2-chloro-5-(propionylamino)phenyl]-1H-pyrazole-5-carbonitrile (from Step J), 237 μL (236 mg, 2.18 mmol) of anisole, and 675 μL of trifluoroacetic acid (TFA) was stirred at room temperature overnight in a stoppered flask. The mixture was evaporated under a stream of N2, and the residue was flash chromatographed on silica gel (elution with 1% and then 3% MeOH in CH2Cl2), yielding 126 mg (97%) of the title compound as a slightly yellow, stiff foam; nearly homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 594 (M+1)+. 400 MHz 1H NMR (CDCl3) δ0.93 (t, J=7.3 Hz, 3H), 1.20 (t, J=7.5 Hz, 3H), 1.40 (m, 2H), 1.67 (m, 2H), 2.37 (q, J=7.5 Hz, 2H), 2.69 (t, J=7.8 Hz, 2H), 4.02 (s, 2H), 4.52 (s, 2H), 7.2-7.6 (m, 8H), 7.81 (d, J=2.5 Hz, 1H), 8.15 (dd, J=8.0, 1.3 Hz, 1H).
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[CH3:29][O:30][C:31]1[N:36]=[N:35][C:34]([NH2:37])=[C:33]([CH3:38])[C:32]=1[CH3:39].C(N(CC)C(C)C)(C)C>C(#N)CCC>[CH3:29][O:30][C:31]1[C:32]([CH3:39])=[C:33]([CH3:38])[C:34]2[N:35]([C:2]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:3]([C:5]3[CH:6]=[CH:7][C:8]([C:11]4([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:19])[CH3:20])[CH2:12][CH2:13][CH2:14]4)=[CH:9][CH:10]=3)[N:37]=2)[N:36]=1
Reactant: COc1nnc(N)c(C)c1C
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Solvent: CCCC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1nn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c(C)c1C
Temperature: 120 °C
Yield: 28 %

Procedure:
A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [that was prepared in a manner analgous to that described for Intermediate Example Int-1-A] (391 mg, ˜80% purity, 0.710 mmol, 1.0 eq), 6-methoxy-4,5-dimethylpyridazin-3-amine (that was prepared in a manner analgous to that described for Intermediate Example Int-34, Step 1, 108 mg, 0.710 mmol, 1.0 eq) and N,N-diisopropylethylamine (140 μL, 0.780 mmol, 1.1 eq) in butyronitrile (4.9 mL) was heated for 3 hours at 120° C. On cooling the reaction mixture was concentrated in vacuo. The crude mixture was purified via MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane/EtOAc 9/1→hexane/EtOAc 2/3) to give 105 mg (28% yield) of the title compound.
Reaction SMILES: ClC1C=C2[C:8](=CC=1)[N:7](S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(Cl)(=O)=O.[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](S(C1C=CC=CC=1)(=O)=O)[C:34]([C:48](OCC)=[O:49])=[C:33]2[S:53](Cl)(=[O:55])=[O:54].Cl.CN.Cl.C[NH:62]CCC(OC)=O>>[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:48]([NH2:62])=[O:49])=[C:33]2[S:53]([NH:7][CH3:8])(=[O:55])=[O:54]
Reactant: CNCCC(=O)OC
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Agent: CN
Agent: Cl
Product: CNS(=O)(=O)c1c(C(N)=O)[nH]c2ccc(Br)cc12

Procedure:
Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and methylamine hydrochloride with methyl N-methyl-β-alaninate hydrochloride, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+ MS: 332.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>CO.C(Cl)(Cl)Cl>[CH3:12][O:11][C:3]1[C:2]([NH:1][S:14]([CH3:13])(=[O:16])=[O:15])=[CH:7][CH:6]=[CH:5][C:4]=1[C:8](=[O:10])[CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(N)cccc1C(C)=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1c(NS(C)(=O)=O)cccc1C(C)=O
Reaction time: 12 h

Procedure:
According to the method reported by A. A. Larsenin J. Med. Chem., 10, 462-472 (1967), the above compound was produced from Intermediate 66 (1.59 g) and methanesulfonyl chloride (750 μl). Here, however, the following alteration was incorporated in the purification step from the reaction mixture. Thus, the reaction was terminated with water (50 ml) and the mixture was agitated for 12 hours before extraction with ethyl acetate (once with 50 ml and twice with each 30 ml) with subsequent washing with 1 N hydrochloric acid (twice with each 25 ml) and with saturated aqueous sodium chloride solution, successively, followed by distilling off of the solvent under a reduced pressure, whereby the above-identified compound was obtained (1.93 g). Rf=0.55 (methanol/chloroform of 1/19).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.O1CCCC1.[BH4-].[Na+].O>CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][OH:20])=[CH:21][CH:22]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
To a solution of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzaldehyde (33.42 g) in methanol (150 ml)-tetrahydrofuran (30 ml), sodium borohydride (4.31 g) was added in portions at 0° C. After stirring for 30 minutes at room temperature, water was added to the reaction mixture and the mixture was stirred for 1 hour. The crystals of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylalcohol (32.85 g, yield 98%) were isolated by filtration. Recrystallization from ethyl acetate-diethylether gave pale yellow crystals. m.p. 128-129° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])=[N:4][C:5]([CH3:13])=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][NH:11]C.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:34][C:35]([OH:37])=O)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:34][C:35]([NH:11][CH2:10][CH2:9][NH:8][C:7]2[CH:6]=[C:5]([CH3:13])[N:4]=[C:3]([O:14][C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:2]=2[CH3:1])=[O:37])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: CNCCNc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Reactant: COc1ccc(CC(=O)O)cc1OC
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CC(=O)NCCNc2cc(C)nc(Oc3c(C)cc(C)cc3C)c2C)cc1OC

Procedure:
Stir a solution of [3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-4-pyridyl][2-(methylamino)ethyl]amine (68 mg, 0.23 mmol), 3,4-dimethoxyphenylacetic acid (59 mg, 0.3 mmol), EDC (59 mg, 0.3 mmol) and HOBT (41 mg, 0.3 mmol) in DMF (1.0 mL) for 12 h. Dilute the reaction mixture with EtOAc (10 mL) and wash with saturated aq NaHCO3 (2×10 mL) and saturated aq brine (2×10 mL), dry and concentrate in vacuo to obtain the title compound as an oily residue. M+1: 478.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C([O-])(O)=O.[Na+].[CH3:15][O:16][C:17](=[O:21])[CH:18](Br)[CH3:19].C(=O)=O>>[CH3:15][O:16][C:17](=[O:21])[CH:18]([NH:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1])[CH3:19]
Reactant: COC(=O)C(C)Br
Reactant: Cc1cccc(C)c1N
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Product: COC(=O)C(C)Nc1c(C)cccc1C
Reaction time: 1 h

Procedure:
6 g-moles of 2,6-dimethylaniline, 6.6 g-moles of NaHCO3 and 18.0 g-moles of α-bromopropionic acid methyl ester are placed together and heated slowly, with stirring, for 1 hour upto 120°-125° C. bath temperature. As CO2 is evolved, stirring of the mixture at this temperature is continued for 18 hours. The mixture is subsequently cooled, the inorganic constituents are filtered off, and the filtrate distilled in a water-jet vacuum (ca. 10- 12 Torr). After removal of the excess α-bromopropionic acid methyl ester, the resulting yield is 990.3 g (79.6% of theory) of final product, which boils at 133°-134° (12 Torr).
Reaction SMILES: C[C@@:2]1([C:27]([O-:29])=[O:28])[CH2:6][C@@H:5]([O:7][C:8]([N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3Br)[CH2:11]2)=[O:9])[CH2:4][N:3]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[CH3:30][C:31]([CH3:46])([CH3:45])[C@@H:32]([C:42]([OH:44])=[O:43])[NH:33][C:34]([O:36][CH2:37][CH2:38][CH2:39][C:40]#[CH:41])=[O:35].[C:47]([O-])(O)=O.[Na+].CCOC(C)=O>C1COCC1.N1CCCC1.[Cu](I)I.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>[C:23]([O:22][C:20]([N:3]1[C@H:2]([C:27]([O:29][CH3:47])=[O:28])[CH2:6][C@@H:5]([O:7][C:8]([N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:41]#[C:40][CH2:39][CH2:38][CH2:37][O:36][C:34]([NH:33][C@H:32]([C:42]([OH:44])=[O:43])[C:31]([CH3:46])([CH3:45])[CH3:30])=[O:35])[CH2:11]2)=[O:9])[CH2:4]1)=[O:21])([CH3:25])([CH3:24])[CH3:26]
Reactant: C#CCCCOC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: CC(C)(C)OC(=O)N1C[C@H](OC(=O)N2Cc3cccc(Br)c3C2)C[C@@]1(C)C(=O)[O-]
Reactant: O=C([O-])O
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1CCNC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(C#CCCCOC(=O)N[C@H](C(=O)O)C(C)(C)C)c3C2)CN1C(=O)OC(C)(C)C
Temperature: 70 °C
Yield: 99 %

Procedure:
A solution of 1-tert-butyl 2-methyl-(2S,4R)-4-{[(4-bromo-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate (100 mg, 0.21 mmol) and 3-methyl-N-[(pent-4-yn-1-yloxy)carbonyl]-L-valine (103 mg, 0.43 mmol) in THF (1 mL) and pyrrolidine (1 mL) was purged with nitrogen. Copper iodide (4 mg, 0.02 mmol) and Pd(PPh3)4 (25 mg, 0.02 mmol) were added and the reaction mixture was heated for 30 min at 70° C. under nitrogen. The resulting mixture was poured into saturated aqueous NaHCO3 and EtOAc, the organic layer separated and washed twice with 10% citric acid solution, then brine and dried over Na2SO4. The residue was purified by column chromatography on silica gel (eluting with 90:10:1 DCM:MeOH:NH4OH) and concentrated to give N-[({5-[2-({[(3R,5S)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidin-3-yl]oxy}carbonyl)-2,3-dihydro-1H-isoindol-4-yl]pent-4-yn-1-yl}oxy)carbonyl]-3-methyl-L-valine (131 mg, 99% yield) as colorless oil. LRMS (ESI) m/z 530.5 [(M+H)+; calcd for C27H36N3O8: 530.6].
Reaction SMILES: [CH3:1][N:2]([C:6](Cl)=[O:7])[C:3](Cl)=[O:4].I.[CH3:10][S:11][C:12](=[NH:18])[NH:13][N:14]=[C:15]([CH3:17])[CH3:16].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][N:2]1[C:6](=[O:7])[NH:18][CH:12]([S:11][CH3:10])[N:13]([N:14]=[C:15]([CH3:17])[CH3:16])[C:3]1=[O:4]
Reactant: CN(C(=O)Cl)C(=O)Cl
Reactant: CSC(=N)NN=C(C)C
Agent: I
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CSC1NC(=O)N(C)C(=O)N1N=C(C)C
Yield: 75.1 %

Procedure:
15.6 g (0.1 mole) of N-methyl-bis-(chlorocarbonyl)-amine were dissolved in 100 ml of benzene and added dropwise, whilst stirring, to 27.3 g (0.1 mole) of acetone-S-methyliso-thio-semicarbazone hydroiodide suspended in 100 ml of benzene. Thereafter, 30.3 g (0.3 mole) of triethylamine in 50 ml of benzene were slowly added dropwise. The mixture was stirred for a further hour and the precipitate was filtered off. The precipitate was introduced into 100 ml of chloroform and 100 ml of water and extracted by shaking. The chloroform phase was separated off, dried over calcium chloride and evaporated in vacuo, together with the benzene filtrate. The resudue was recrystallized from isopropanol. 17.3 g (76%) of 1-methyl-3-isopropylideneamino-4-methylmercapto-tetrahydro-1,3,5-triazine-2,6-dione were obtained as a colorless powder; melting point 130-132° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[F:11][CH:12]([F:25])[CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.C([O:28][C:29]([CH2:31][C:32](O)=[O:33])=O)C.C(=O)(OC)OC(C)(C)C[N+]#[C-].CC(C)([O-])C.[Na+]>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:21]([C:20]4[CH:23]=[CH:24][C:17]([O:16][CH2:15][CH2:14][CH2:13][CH:12]([F:25])[F:11])=[CH:18][CH:19]=4)[C:29](=[O:28])[CH2:31][C:32]3=[O:33])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=Cc1ccc(OCCCC(F)F)cc1
Reactant: Nc1ccc2[nH]cnc2c1
Reactant: CCOC(=O)CC(=O)O
Agent: CC(C)(C)[O-]
Agent: [C-]#[N+]CC(C)(C)OC(=O)OC
Agent: [Na+]
Product: O=C1CC(=O)N(c2ccc3[nH]cnc3c2)C1c1ccc(OCCCC(F)F)cc1

Procedure:
The compound was synthesized starting from 1H-benzo[d]imidazol-5-amine (0.620 g, 4.6 mmol), 4-(4,4-difluorobutoxy)benzaldehyde (1.0 g, 4.6 mmol), 2-(ethoxycarbonyl)acetic acid (0.61 g, 4.6 mmol), 1-isocyano-2-methylpropan-2-yl methyl carbonate (0.72 g, 4.6 mmol) and sodium tert.-butoxide (0.620 g, 5.5 mmol) according to method 3.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH2:12][OH:13])[C:9]2[CH:14]=[C:15]([Br:20])[C:16]([O:18][CH3:19])=[CH:17][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.[Cl-].[Na+].O>[Br:20][C:15]1[C:16]([O:18][CH3:19])=[CH:17][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH2:12][OH:13])[C:9]=2[CH:14]=1
Reactant: COc1cc2c(cc1Br)C(CO)CN(C(=O)C(F)(F)F)CC2
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1Br)C(CO)CNCC2
Reaction time: 1 h
Yield: 87.4 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-1-hydroxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.009 g, 0.024 mmol) in methanol (1 mL) was treated with 15% aqueous NaOH (1 mL), and stirred for 1 hour at 50 C. The product mixture was diluted with brine (5 mL), extracted twice with EtOAc (5 mL), dried with MgSO4, and concentrated to give 0.006 g clear oil. 1H NMR (400 MHz, CD3OD) d 7.28 (s, 1H), 6.79 (s, 1H), 3.84 (m, 2H), 3.0-2.8 (m, 7H). MS calculated for C12H16BrNO2+H: 286, observed: 286.
Reaction SMILES: CC[O:3][CH2:4][CH3:5].[Br:6][C:7]1[CH:14]=[CH:13][C:10](C=O)=[CH:9][CH:8]=1.[CH2:15]1[CH2:19]O[CH2:17][CH2:16]1>>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([CH:4]([OH:3])[CH2:5][CH2:19][CH2:15][CH2:16][CH3:17])=[CH:13][CH:14]=1
Reactant: CCOCC
Reactant: C1CCOC1
Reactant: O=Cc1ccc(Br)cc1
Product: CCCCCC(O)c1ccc(Br)cc1
Reaction time: 1 h
Yield: 76 %

Procedure:
n-PentylMgBr (29 mL, 58 mmol, 2 M/ether) was added to a 0° C. solution of 4-bromobenzaldehyde (9.953 g, 54 mmol) in THF (100 mL). After 1 h, the reaction was quenched by addition of 200 mL saturated ammonium chloride solution. The resulting mixture was extracted with ethyl acetate (3×100 mL) and the combined ethyl acetate solution was dried (Na2SO4), filtered and evaporated. Purification of the residue by flash chromatography on silica gel gave 4 (10.501 g, 76%).
Reaction SMILES: [O:1]1[CH2:17][CH:2]1[CH2:3][O:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8]([CH:15]=[O:16])=[CH:7][CH:6]=1.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([NH:22][CH2:17][CH:2]([OH:1])[CH2:3][O:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8]([CH:15]=[O:16])=[CH:7][CH:6]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)N
Reactant: O=Cc1ccc(OCC2CO2)c2c1CCCC2
Product: CC(C)(C)NCC(O)COc1ccc(C=O)c2c1CCCC2
Temperature: 45 °C

Procedure:
To 4-(2,3-epoxypropoxy)-5,6,7,8-tetrahydronaphthaldehyde (2.4 gms) is added tert.-butylamine (15 ml.). The resulting solution is heated at 45° C. for 15 hours. The excess tert.-butylamine is removed at reduced pressure (20 mm). To the residue is added 30 ml. 6N hydrochloric acid, and the resulting mixture is refluxed for three hours. The acidic mixture i poured into a saturated solution of sodium carbonate which is heated on a steam bath with nitrogen bubbling through it. The basic mixture is extracted with chloroform, which is dried over anhydrous sodium sulfate, filtered and concentrated to give 2.3 g of 4-(3-tert.butylamino-2-hydroxypropoxy)-5,6,7,8-tetrahydronapthaldehyde as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]([CH2:7][N:8]2[C:12]([C:13]([OH:15])=[O:14])=[C:11]([C:16](=[O:30])[C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[CH:19][C:18]=3[N+:27]([O-])=O)[N:10]=[N:9]2)=[CH:5][CH:4]=1.C(O)C.C(OCC)(=O)C.[H][H]>[C].[Pd].C(Cl)Cl>[NH2:27][C:18]1[CH:19]=[C:20]([O:25][CH3:26])[C:21]([O:23][CH3:24])=[CH:22][C:17]=1[C:16]([C:11]1[N:10]=[N:9][N:8]([CH2:7][C:6]2[CH:31]=[CH:32][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:12]=1[C:13]([OH:15])=[O:14])=[O:30]
Reactant: COc1ccc(Cn2nnc(C(=O)c3cc(OC)c(OC)cc3[N+](=O)[O-])c2C(=O)O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(Cn2nnc(C(=O)c3cc(OC)c(OC)cc3N)c2C(=O)O)cc1
Yield: 100 %

Procedure:
A 1 N aqueous sodium hydroxide solution (13 ml) was added to a solution of ethyl 1-(4-methoxybenzyl)-4-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-5-carboxylate (b-1) (3.04 g, 6.46 mmol), prepared in step (b), in tetrahydrofuran (40 ml). The mixture was stirred at room temperature for 3.5 hr. The reaction solution was diluted with ether, and water was added thereto. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate, followed by washing with water and saturated brine solution. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 1-(4-methoxybenzyl)-4-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-5-carboxyic acid as light yellow oil (c-1′: LP) (2.55 g, 89%). The resultant 1-(4-methoxybenzyl)-4-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-5-carboxylic acid (c-1′: LP) (1.07 g, 2.42 mmol) was dissolved in a mixed solvent composed of ethanol (50 ml) and ethyl acetate (50 ml). 10% palladium-carbon (129 mg) was added thereto. The mixture was stirred in a hydrogen atmosphere at room temperature for 4 hr. Methylene chloride was added to the reaction solution to dissolve the precipitated crystal, followed by filtration through Celite. The filtrate was concentrated under reduced pressure to give 4-(2-amino-4,5-dimethoxybenzoyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-carboxylic acid (c-1: LP) (1.06 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]([C:18]2[NH:22][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:20][CH:19]=2)[CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1SC.O1CCC[CH2:30]1.O.O[O:36][S:37]([O-:39])=O.[K+]>C(OCC)(=O)C.CO>[F:1][C:2]1[CH:3]=[C:4]([CH:10]([C:18]2[NH:22][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:20][CH:19]=2)[CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[S:37]([CH3:30])(=[O:39])=[O:36]
Reactant: C1CCOC1
Reactant: CSc1ccc(C(CC2CCOCC2)c2ccc(-c3ccccn3)[nH]2)cc1F
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3ccccn3)[nH]2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 41 %

Procedure:
To a mixture of 2-(5-[1-[3-fluoro-4-(methylsulfanyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl]-1H-pyrrol-2-yl)pyridine (97.8 mg), tetrahydrofuran (2 mL), water (2 mL) and methanol (2 mL) was added Oxone (registered trademark) (159 mg), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (41.2 mg, yield 41%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio). MS: 429 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](O)=[O:19])[CH2:11][CH2:10]1.C(N(CC)CC)C.O=C1N(N(N2CCOC2=O)P(Cl)(Cl)=O)CCO1.[CH3:51][CH2:52][C:53]([NH2:58])([C:56]#[CH:57])[CH2:54][CH3:55]>C(Cl)Cl>[CH2:54]([C:53]([NH:58][C:18](=[O:19])[CH:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1)([CH2:56][CH3:57])[C:52]#[CH:51])[CH3:55]
Reactant: C#CC(N)(CC)CC
Reactant: COc1ccccc1N1CCN(CCC(C(=O)O)c2ccccc2)CC1
Agent: O=C1OCCN1N(N1CCOC1=O)P(=O)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CC(CC)(CC)NC(=O)C(CCN1CCN(c2ccccc2OC)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.8 %

Procedure:
A mixture of 4-[4-(2-methoxyphenyl)piperazin-1-yl]-2-phenylbutanoic acid (1.772 g, 5 mmole), triethylamine (1.518 g, 15 mmole), and N,N-bis(2-oxo-3-oxazolidinyl)phosphoramidic chloride (1.527 g, 6 mmole) was stirred in methylene chloride (80 mL) under exclusion of moisture at ambient temperature for 30 minutes, after which 1,1-diethylpropargylamine (0.668 g, 6 mmole) was added at once at 0° C. The reaction mixture was stirred at room temperature overnight, washed with water (2×100 mL), dried over magnesium sulfate, filtered, and evaporated to dryness in vacuo. Chromatography on silica gel with methanol/chloroform as eluant, followed by trituration from diethyl ether with addition of ethanolic hydrochloric acid gave 0.6 g of the title compound as the trihydrochloride hemihydrate, m.p. 110°-12° C.