Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:35]([C:37]1[N:38]=[C:39]([CH3:50])[N:40](COCC[Si](C)(C)C)[CH:41]=1)#[CH:36]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:8][C:4]1[CH:3]=[C:2]([C:36]#[C:35][C:37]2[N:38]=[C:39]([CH3:50])[NH:40][CH:41]=2)[CH:7]=[CH:6][N:5]=1
Reactant: C#Cc1cn(COCC[Si](C)(C)C)c(C)n1
Reactant: Cc1cc(Br)ccn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4-Bromo-2-methyl-pyridine (1.92 g, 11.2 mmol) was dissolved in 50 mL dry THF and triethylamine (3.9 mL, 30 mmol) was added. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphin (73 mg, 0.28 mmol) and bis(triphenylphosphin)palladium(II)chloride (327 mg, 0.47 mmol) were added and the reaction mixture was stirred at RT for 20 min. Copper(I)iodide (53 mg, 0.28 mmol) and a mixture of 4-ethynyl-2-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole and 5-ethynyl-2-methyl-1-(2-trimethyl-silanyl-ethoxymethyl)-1H-imidazole (2.2 g, 9.3 mmol) were added. The reaction mixture was then stirred at RT overnight. The solvent was evaporated. The residue was taken up in 50 mL water and extracted three times with ethyl acetate (70 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 80:20 →0:100 gradient ) and the desired compound was obtained as a mixture of 2 isomers (2.86 g, 94%), MS: m/e=327.2 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[S:7][C:8]([C:14]([OH:16])=O)=[CH:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:19][O:20][C:21](=[O:30])[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([NH2:29])[CH:23]=1.N1C=CC=CC=1>O=S(Cl)Cl.C1COCC1>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[S:7][C:8]([C:14]([NH:29][C:24]4[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=4[Cl:28])[C:21]([O:20][CH3:19])=[O:30])=[O:16])=[CH:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc(Cl)c(N)c1
Reactant: O=C(O)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(NC(=O)c2cc3c(s2)-c2ccc(Br)cc2OCC3)c1
Reaction time: 8 h
Yield: 86.7 %

Procedure:
A solution of 8-bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-2-carboxylic acid (25 g, 0.077 mol) in 200 mL of SOCl2 was heated at 80° C. for 3 h. Concentration gave the crude acid chloride. A suspension of the crude acid chloride (ca. 0.077 mol) from above in 1000 mL of THF at 0° C. was treated with a solution of 3-amino-4-chloro-benzoic acid methyl ester (15.7 g, 1.1 eq)/pyridine (30 mL) in 100 mL of THF. The mixture was allowed to reach room temperature overnight. The reaction solution was concentrated to ½ volume, diluted with water. The resulting precipitate was filtered, washed with water and Et2O. The filter cake was dried to a constant weight under vacuum to give methyl 3-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoate (32.9 g, yield 87%). LC-MS: (ESI, m/z)=494 [M+1]+
Reaction SMILES: F[C:2](F)=O.B(F)(F)F.CCO[CH2:12][CH3:13].[C:14]1([CH3:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:18]1[C:19]2[C:14](=[CH:20][CH:2]=[CH:12][CH:13]=2)[CH:15]=[CH:16][CH2:17]1
Reactant: CCOCC
Reactant: Cc1ccccc1
Reactant: O=C(F)F
Agent: FB(F)F
Solvent: C1CCOC1
Product: C1=Cc2ccccc2CC1
Yield: 85 %

Procedure:
The reaction temperature can range from 0° C. to 90° C. In carrying out the reaction, the difluoroketone can be mixed with the entire charge of the fluorinating reagent or the reagent can be added dropwise to a solution of the difluoroketone. Lewis acid catalysts such as boron trifluoride etherate (BF3.Et2O) or HF can be used to accelerate the reaction. The product obtained is usually a mixture of the desired 1,1,2,2-tetrafluoro compound and the corresponding 1,1,2,4-tetrafluoro isomer. We have found that both the yield and the isomer ratio are highly dependent on the solvent used. Toluene is unexpectedly superior to other organic solvents in producing a high yield of the desired isomer. For example, when THF was used as solvent at 60° C., a 65% yield of 1,1,2,2-tetrafluoro-6-trans-4-propylcyclohexyl)-1,2-dihydronaphthalene was obtained (1,1,2,2-tetrafluoro/1,1,2,4-tetrafluoro=51/49), while when toluene was used as solvent at the same temperature, an 85% yield was obtained (1,1,2,2-tetrafluoro/1,1,2,4-tetrafluoro=90/10) under the same reaction conditions.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[CH3:12][N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.N1CCCC1.N>C(O)C.CO>[CH3:12][N:13]1[CH2:14][CH:15]=[C:16]([C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=3)[NH:8][CH:7]=2)[CH2:17][CH2:18]1
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: CN1CCC(=O)CC1
Agent: N
Solvent: CCO
Solvent: CO
Solvent: C1CCNC1
Product: CN1CC=C(c2c[nH]c3ccc(C#N)cc23)CC1
Temperature: 25 °C
Reaction time: 44 h

Procedure:
To an argon-purged round bottom flask fitted with a magnetic stirbar containing an orange solution of 5-cyanoindole (48) (250 mg, 1.76 mmol) dissolved in absolute ethanol (10 mL) were added 1-methyl-4-piperidone (0.43 mL, 3.50 mmol) and pyrrolidine (0.44 mL, 5.27 mmol). The reaction vessel was fitted with a condenser and transferred to an oil bath preheated to 80° C. The reaction was stirred at this temperature for 44 hrs. As no starting material remained (TLC 5% 2M NH3 in methanol/95% CH2Cl2) the reaction was cooled to room temperature followed by additional cooling in the fridge. As no precipitate formed, the reaction was concentrated under reduced pressure to afford an orange oil. The oil was redissolved in ethanol (20 mL) and the solvent removed under reduced pressure. This was repeated once more, and then the final residue was treated with ethanol and left in the fridge for 2 hrs. The precipitate which formed was collected by vacuum filtration and washed with hexanes (205 mg of pale yellow solid, compound 49, 48.7%) 1H NMR (DMSO) δ 11.90 (br s, NH), 8.51 (s, 1H), 7.80 (s, 1H), 7.77-7.74 (d, J=8.7 Hz, 1H), 7.68-7.65 (d, J=8.1 Hz, 1H), 6.41 (s, 1H), 3.53 (s, 2H), 3.27-3.26 (d, J=2.4 Hz, 2H), 2.79-2.77 (d, J=4.5 Hz, 2H), 2.72-2.71 (d, J=1.5 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[C:8]1([C:14]2[O:18][N:17]=[CH:16][C:15]=2[CH2:19][CH2:20][C:21](O)=[O:22])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[NH:1][C:21](=[O:22])[CH2:20][CH2:19][C:15]1[CH:16]=[N:17][O:18][C:14]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Reactant: Nc1cnccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCc1cnoc1-c1ccccc1)Nc1cnccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
A mixture of 2-aminopyrazine (0.26 g), 3-(5-phenyl-4-isoxazolyl)propionic acid (0.58 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.46 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.60 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(2-pyrazinyl)-3-(5-phenyl-4-isoxazolyl)propionamide (0.46 g, yield 58%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 163–164° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8](Br)[C:9]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:5]=[O:6].O[C:21]1C=C(C=CC=1)C=O>>[CH3:21][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: CCCCCCCCOc1c(Br)cc(C=O)cc1Br
Product: CCCCCCCCOc1ccc(C=O)cc1C

Procedure:
The title compound was prepared using a procedure analogous to Aldehyde 3 substituting 3-methyl-4-hydroxybenzaldehyde for 3-hydroxybenzaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[CH2:12][CH2:11][CH2:10][O:9][C:6]2=[N:7][CH:8]=1.[Br:13]N1C(=O)CCC1=O.C(OCC)(=O)C>CN(C)C=O>[Br:13][C:8]1[N:7]=[C:6]2[O:9][CH2:10][CH2:11][CH2:12][C:5]2=[N:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cnc2c(n1)CCCO2
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1nc2c(nc1Br)OCCC2
Temperature: 60 °C

Procedure:
To a solution of 2-methoxy-6,7-dihydro-8H-pyrano[2,3-b]pyrazine (J. Chem. Soc. Perkin Trans. I 1988, 2585-2593; 3.16 g, 19.0 mmol) in N,N-dimethylformamide (95 mL) was added N-bromosuccinimide (5.08 g, 28.5 mmol) at room temperature, and then heated at 60° C. for 5 h. After being cooled to ambient temperature, the reaction mixture was diluted ethyl acetate, washed with 2% aqueous sodium sulfite, water, and saturated brine. The organic layer was dried over sodium sulfate, filtrated and concentrated in vacuo. The crude was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 7:3) to give 3-bromo-2-methoxy-7,8-dihydro-6H-pyrano[2,3-b]pyrazine. MS (APCI): m/z 247 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[N:6]=1.C(=O)([O-])O.[Na+].Cl[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23]>CC(C)=O.C(OCC)C>[N+:13]([C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([NH:1][C:22](=[O:23])[O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])[S:3][CH:4]=2)=[CH:12][CH:11]=1)([O-:15])=[O:14]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: O=C(Nc1nc(-c2ccc([N+](=O)[O-])cc2)cs1)OCC(Cl)(Cl)Cl
Yield: 68.5 %

Procedure:
Into 300 ml of acetone, were added 2.2 g of 2-amino-4-p-nitrophenylthiazole and 3.0 g of sodium hydrogen carbonate. To the resulting mixture, 6.3 g of 2,2,2-trichloroethyl chloroformate in 20 ml of acetone was added dropwise, followed by a stirring for 10 hours at the reflux temperature. Inorganic substances were filtered off and the filtrate was concentrated. Any substances, which were insoluble in diethyl ether, were removed from the concentrate. A crude reaction product resulting from the remaining portion, which was soluble in diethyl ether, was subjected to silica gel column chromatography. It was then eluted with a mixed solvent of chloroform-acetone (10:1) and thereafter recrystallized from chloroform to obtain 2.7 g of 2,2,2-trichloroethyl N-(4-p-nitrophenyl-2-thiazolyl)carbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7]Br)=[CH:4][CH:3]=1.C(Cl)Cl.[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7][C:16]2[NH:15][CH:19]=[CH:18][N:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(Cc1ncc[nH]1)c1ccc(Cl)cc1
Reaction time: 4 h
Yield: 77.1 %

Procedure:
89.2 g 4-chlorophenacyl bromide is dissolved in 170 ml chloroform (or methylene chloride) and the solution is then added dropwise to a solution of 156 g imidazole in 600 ml chloroform (or methylene chloride, as the case may be) while maintaining the reaction mixture at about 0° to 5° C. Thereafter the mixture is continually stirred at this temperature for 4 hours, the solvent is distilled off in a rotation evaporator and the residue is treated with water. After filtering off and drying the precipitate and recrystallizing it in toluene one obtains 65 g p-chlorophenacyl imidazole or 1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)-1-ethanone in the form of colorless crystals having a melting point of 158° to 160° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12](O)=[O:13])[CH:11]=1)[NH:8][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[CH2:23][CH2:22]3)[CH:16]=1)[CH2:6][C:5]2([CH3:35])[CH3:34].[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>CN(C)C1C=CN=CC=1.ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:13])[CH:11]=1)[NH:8][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[CH2:25][CH2:26]3)[CH:16]=1)[CH2:6][C:5]2([CH3:35])[CH3:34]
Reactant: Cc1ccccc1N1CCN(c2cccc(C3CC(C)(C)c4cc(F)cc(C(=O)O)c4N3)c2)CC1
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccccc1N1CCN(c2cccc(C3CC(C)(C)c4cc(F)cc(C(=O)NS(C)(=O)=O)c4N3)c2)CC1
Yield: 29.8 %

Procedure:
A mixture of 6-fluoro-4,4-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (100 mg, 0.21 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (60 mg, 0.31 mmol), 4-dimethylaminopyridine (38 mg, 0.31 mmol), methane sulfonamide (60 mg, 0.63 mmol) in dichloromethane (10 mL) was refluxed for 12 h. Removal of the solvent to afford the oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-{6-fluoro-4,4-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carbonyl}-methanesulfonamide (34.5 mg, 30%) as a light yellow solid: MS (ESI) M+1=551.4.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][OH:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.[C:25]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([N:8]1[CH2:11][CH2:10][CH2:25][C@H:9]1[CH2:12][O:13][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Reactant: Oc1cncc(C(F)(F)F)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(C(F)(F)F)c1

Procedure:
A 333 mg (1.20 mmol) sample of 1-BOC-2-(S)-azetidinemethanol, prepared as in Example 7b above, and 230 mg (1.30 mmol) of 3-hydroxy-5-trifluoromethylpyridine, from step 66b above, were reacted with triphenylphosphine and DEAD (1.2 mmol each) in 5 mL of THF according to the procedure of Example 14a, to give 360 mg of the title compound. MS (DCI/NH3) m/e 347 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.50 (s, 1H), 8.48 (s, 1H), 7.46 (s, 1H), 4.28-3.90 (m, 3H), 3.48-3.84 (m, 2H), 2.12-1.87 (m, 4H).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:26]1(B(O)O)[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[CH:19]1[C:20]2=[C:21]3[C:12](=[CH:13][CH:14]=[C:15]2[C:2]([C:3]2[CH:4]=[CH:5][C:6]([C:27]4[C:28]5=[CH:12][CH:11]=[C:10]6[C:15]([CH:2]=[C:3]7[C:8]([CH:7]=[CH:6][CH:5]=[CH:4]7)=[CH:9]6)=[C:29]5[CH:30]=[CH:31][CH:26]=4)=[CH:7][CH:8]=2)=[CH:17][CH:18]=1)[CH:11]=[C:10]1[C:23]([CH:24]=[CH:25][CH:16]=[CH:9]1)=[CH:22]3
Reactant: Brc1c2ccccc2c(-c2ccc3ccccc3c2)c2ccccc12
Reactant: OB(O)c1ccc(B(O)O)cc1
Product: c1ccc2cc3c(ccc4c(-c5ccc(-c6cccc7c6ccc6cc8ccccc8cc67)cc5)cccc43)cc2c1

Procedure:
Preparation analogous to Example 7. 9-Bromo-10-(2-naphthyl)anthracene is replaced by 4.1 g (25 mmol) of benzene-1,4-diboronic acid. Recrystallisation five times from o-dichlorobenzene (about 20 ml/g); sublimation (p=5×10−5 mbar, T=400° C.). Yield: 11.1 g (21 mmol), 84.0%, purity 99.9% (HPLC).
Reaction SMILES: [C:1]([C:6]1[S:10][C:9]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH2:20]Cl)[CH:15]=2)=[O:13])=[N:8][C:7]=1[C:22]1[O:23][CH:24]=[CH:25][CH:26]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[H-].[Na+].[OH2:29].[CH3:30]O>>[C:1]([C:6]1[S:10][C:9]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH2:20][O:29][CH3:30])[CH:15]=2)=[O:13])=[N:8][C:7]=1[C:22]1[O:23][CH:24]=[CH:25][CH:26]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O
Reactant: CCCC(=O)c1sc(NC(=O)c2ccnc(CCl)c2)nc1-c1ccco1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Product: CCCC(=O)c1sc(NC(=O)c2ccnc(COC)c2)nc1-c1ccco1
Yield: 55 %

Procedure:
Compound 387 (262 mg, 0.671 mmol) was dissolved in methanol (5 mL), and 55% sodium hydride (34.0 mg, 0.775 mmol) was added thereto, followed by stirring under heating and reflux for 4 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=99:1) to afford the entitled Compound 388 (142 mg, 55%).
Reaction SMILES: [NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:19](O)=[O:20])[CH3:18])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN1CCOCC1.[Cl:39][C:40](OCC(C)C)=O.Cl.ClCC(CCl)=O.[NH2:54][C@H:55]([C:60]([OH:62])=O)[CH2:56][CH:57]([CH3:59])[CH3:58]>C1COCC1.CC(C)=O>[NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:19]([NH:54][C@H:55]([C:60]([CH2:40][Cl:39])=[O:62])[CH2:56][CH:57]([CH3:58])[CH3:59])=[O:20])[CH3:18])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)COC(=O)Cl
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Agent: O=C(CCl)CCl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CC(C)=O
Product: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)CCl
Yield: 253.9 %

Procedure:
A solution of 4.00 g (9.4 mmol) of Z-Phe-Gly-Ala-OH and 0.95 g of N-methylmorpholine in 100 mL of THF was cooled to -20° under nitrogen, and then 1.28 g of isobutyl chloroformate was added. After 5 minutes a solution of 1.14 g of leucine chloromethyl ketone hydrochloride in dry acetone was added, followed by 0.95 g of N-methylmorpholine. The resulting reaction mixture was stirred and allowed to warm to about 25° over a period of 2 hours. Solvent was evaporated, and the resulting residue was dissolved in ethyl acetate. This solution was washed with ice water, followed by cold 5% citric acid. The resulting solution was dried and then solvent was evaporated to leave 5.63 g of a frothy solid. This material was triturated overnight with 250 mL of ether. The resulting gel-like product was filtered from the ether and washed with additional ether, providing 3.10 g of crude product as a fine white powder. A 2.56 g portion was dissolved in 25 mL of warm ethyl acetate, forming a cloudy solution. This solution was filtered through carbon (Celite) and an additional 200 mL of ether was added. After seeding, 1.15 g of fine needle-like crystals of Z-Phe-Gly-Ala-LeuCH2Cl precipitated and were collected. These crystals melted at 138°-141.8°; δD25 -59° (C=0.45 g/100 mL in acetone).
Reaction SMILES: [O:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([S:10]([NH2:13])(=[O:12])=[O:11])=[C:4]2[S:3][CH2:2]1.C[Al](C)C.C[O:19][C:20](=O)[NH:21][C:22]1[N:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([CH3:30])[N:23]=1.O>C(Cl)Cl.Cl.C(O)(=O)C>[CH3:29][O:28][C:26]1[CH:25]=[C:24]([CH3:30])[N:23]=[C:22]([NH:21][C:20]([NH:13][S:10]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[O:1][CH2:2][S:3][C:4]=23)(=[O:12])=[O:11])=[O:19])[N:27]=1
Reactant: NS(=O)(=O)c1cccc2c1SCO2
Reactant: COC(=O)Nc1nc(C)cc(OC)n1
Agent: C[Al](C)C
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccc3c2SCO3)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2.2 g 1,3-benzoxathiole-4-sulfonamide, prepared in Example 13, in 50 ml methylene chloride at ambient temperature under nitrogen is added 5.5 ml trimethylaluminum (2M in toluene). After stirring 15 minutes at ambient temperature, 2.0 g of methyl[4-methoxy-6-methylpyrimidin-2-yl]carbamate, prepared according to the procedure of Example 3, is added and the reaction mixture is heated at reflux for 16 hours. The reaction mixture is cooled to ambient temperature and 75 ml water, 10 ml glacial acetic acid, and 10 drops hydrochloric acid are sequentially added. The organic phase is separated, dried, and the solvent removed under reduced pressure to give an oil. Crystallization of the oil from n-butyl chloride/ether gives a solid.
Reaction SMILES: [CH3:1][C@@H:2]([NH:14][CH2:15][C@@H:16]([C:18]1[CH:19]=[CH:20][C:21]2[N:22](N=N[N:26]=2)[CH:23]=1)[OH:17])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.O.O.[Cl:29][Sn]Cl>CO>[ClH:29].[ClH:29].[NH2:26][C:21]1[N:22]=[CH:23][C:18]([C@H:16]([CH2:15][NH:14][C@H:2]([CH3:1])[CH2:3][CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)[OH:17])=[CH:19][CH:20]=1.[ClH:29]
Reactant: Cl[Sn]Cl
Reactant: C[C@H](CCc1c[nH]c2ccccc12)NC[C@H](O)c1ccc2nnnn2c1
Solvent: O
Solvent: CO
Product: C[C@H](CCc1c[nH]c2ccccc12)NC[C@H](O)c1ccc(N)nc1
Product: Cl

Procedure:
A solution of 16 g of 1-(1H-indol-3-yl)-3-butanone, 10.3 g of R(+)-1-phenylethylamine and 0.2 g of TsOH.H2O in 80 ml of benzene is heated at reflux with water removal (Dean-Stark trap) for 24 hours. The reaction mixture is concentrated under reduced pressure and the residue redissolved in 80 ml of methanol. To this solution 8 g of Ra(Ni) catalyst is added and the mixture hydrogenated under positive hydrogen pressure for 32 hours. The reaction mixture is filtered through celite and the filtrate concentrated. The residue is chromatographed on silica gel to afford the (R,R,)-diastereomer. This material (6.2 g) is converted into its hydrochloride salt and dissolved in 50 ml of ethanol and hydrogenated over 1.6 g of 5% Pd(C) for 18 hours. The reaction mixture is then filtered and the filtrate concentrated under reduced pressure to dryness. The residue is chromatographed on silica gel to give 1(R)-methyl-3-(1H-indol-3-yl)propyl amine. This amine (650 mg) is condensed with 650 mg of (R)-2-(tetrazolo-[1,5-a]pyrid-6-yl)oxirane in 15 ml of absolute ethanol at reflux for 3 hours. The reaction mixture is concentrated under reduced pressure and the residue purified by chromatography on silica gel to give (R)-α-[[(1(R)-methyl-3-(1H-indol-3-yl)propyl)amino]methyl]tetrazolo[1,5-a]pyridine-6-methanol. This tetrazole (0.6 g) in 15 ml of methanol is treated with 0.6 g of SnCl2.2H2O and the reaction mixture heated at reflux for 18 hours. The reaction solution is partially concentrated under reduced pressure. This concentrated solution is added to a mixture of CH2Cl2 (20 ml) and 12 ml of 2N NaOH solution. The mixture is stirred for twenty minutes and then the layers are separated. The aqueous layer is further extracted with CH2Cl2. The combined organic extracts are backwashed with saturated sodium chloride solution and dried with anhydrous magnesium sulfate. The solution is concentrated and the residue chromatographed on silica gel to give the titled compound after conversion to its hydrochloride salt with ethanolic HCl.