Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:11]1[N:12]=[C:13]([NH:16][C:17](=[O:20])[CH2:18][Cl:19])[S:14][CH:15]=1)[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[K+]>C(O)C.O>[CH2:1]([O:3][N:4]=[C:5]([C:11]1[N:12]=[C:13]([NH:16][C:17](=[O:20])[CH2:18][Cl:19])[S:14][CH:15]=1)[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCON=C(C(=O)OCC)c1csc(NC(=O)CCl)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCON=C(C(=O)O)c1csc(NC(=O)CCl)n1
Temperature: 25 °C
Yield: 91 %

Procedure:
1.06 g of ethyl α-ethoxyimino-2-(chloroacetylamino)-thiazol-4-ylacetate is suspended in a solution of 0.94 g of potassium hydroxide in a mixture of 40 ml of ethanol and 2 ml of water and the suspension is stirred at room temperature to make it to be a solution, followed by further stirring for 45 minutes at room temperature. The reaction solution is subjected to the distillation of ethanol under reduced pressure and the residue is adjusted to pH 2.0 with 1N hydrochloric acid under ice-cooling, to precipitate crystals. The crystals are filtered, washed with water and dried. The procedure yields 0.88 g of α-ethoxyimino-2-(chloroacetylamino)thiazol-4-ylacetic acid. Yield 91%.
Reaction SMILES: [OH-].[Ca+2:2].[OH-].[N+:4]([O-:7])([OH:6])=[O:5]>O>[N+:4]([O-:7])([O-:6])=[O:5].[Ca+2:2].[N+:4]([O-:7])([O-:6])=[O:5]
Reactant: O=[N+]([O-])O
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])[O-]

Procedure:
A method of removing dioxide and nitrogen oxides from a gaseous stream where an alkaline earth compound is added, either in a wet scrubbing unit which substantially saturates the gaseous stream with water, or to a gaseous stream to which water has been added, and the gaseous stream then exposed to a coronal discharge, with dry calcium hydroxide added which reacts with nitric acid formed by the coronal discharge to form calcium nitrate. Alkaline earth sulfites or sulfates, formed by reaction of the alkaline earth compound with sulfur dioxide are removed from the gaseous stream and calcium nitrate, formed by reaction of injected dry calcium hydroxide with the nitric acid produced are separated from the gaseous stream and the gaseous stream, with sulfur dioxide and nitrogen oxides removed, is discharged to the atmosphere.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][CH2:5][N:6]([C:21]1[C:26]([N+:27]([O-])=O)=[CH:25][CH:24]=[CH:23][N:22]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O.C>C(O)(=O)C.C(O)(C)C.[Fe]>[CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][CH2:5][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:27][C:26]2[CH:25]=[CH:24][CH:23]=[N:22][C:21]1=2
Reactant: CN(C)CCCN(c1ccccc1C(=O)c1ccccc1)c1ncccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CN(C)CCCN1c2ccccc2C(c2ccccc2)=Nc2cccnc21
Reaction time: 1 h

Procedure:
To a stirred solution of 3.3 g of crude [2-[[3-(dimethylamino)propyl](3-nitro-2-pyridinyl)amino]phenyl]phenylmethanone obtained in Example (8c) in 20 ml of acetic acid at 65° C. was added portionwise 6.6 g of iron powder. The reaction was exothermic at the beginning, the temperature rising to 90° C. Thereafter the temperature was controlled at 85° C. for 1 hr. The mixture was filtered through celite and washed with acetic acid and methanol. The filtrate and washes were combined and evaporated and the residue was dissolved in methanol. The solution was filtered to remove insoluble iron acetate. The filtrate was evaporated and the residue dissolved in water/methylene chloride and made basic with sodium hydroxide and potassium carbonate. The mixture was mixed with celite and filtered through celite. The aqueous layer of the filtrate was extracted twice with methylene chloride which had been used to wash the cake. The combined methylene chloride solution was washed once with NaCl solution, dried and treated with charcoal, filtered and evaporated to give a black foam weighing 1.63 g (46%). The foam was dissolved in isopropyl alcohol. The solution was treated with charcoal and the mixture was filtered into a solution of 0.7 g fumaric acid in isopropyl alcohol. This solution was again treated with charcoal and filtered. Chemical ionization mass spectral analysis and thin-layer chromatography confirmed the presence of the title compound.
Reaction SMILES: [N:1]([CH:4]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[C:8]2[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:7]1=2)=[N+]=[N-].[Cl-].[NH4+]>C(O)C.O.[Zn]>[CH3:21][N:18]1[CH2:17][CH2:16][C:8]2[C:9]3[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][C:14]=3[N:6]([CH2:5][CH:4]([C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)[NH2:1])[C:7]=2[CH2:20][CH2:19]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(N=[N+]=[N-])c2ccncc2)CCN(C)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(c1)c1c(n2CC(N)c2ccncc2)CCN(C)CC1
Temperature: 85 °C
Reaction time: 0.75 h
Yield: 25.8 %

Procedure:
To a solution of 6-(2-azido-2-(pyridin-4-yl)ethyl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (188 mg, 0.522 mmol) in ethanol-water (9 mL: 1 mL), zinc dust (135 mg, 2.08 mmol) and ammonium chloride (110 mg, 2.08 mmol) were added and the reaction mixture was stirred at 85° C. for 45 min. The reaction mixture was filtered and the filtrate concentrated. The residue was basified with aqueous ammonia and extracted with EtOAc (2×50 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by reverse phase HPLC to yield 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(pyridin-4-yl)ethanamine (45 mg). The racemate can be further separated into the optically active forms by chiral preparative HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.6 (d, 2H), 7.6 (d, 2H), 7.22 (s, 1H), 7.0 (s, 1H), 6.9 (s, 1H), 4.9 (m, 3H), 4.8 (m, 1H), 4.7 (m, 1H), 3.8-3.6 (m, 2H), 3.2 (m, 2H), 3.18-2.97 (m, 4H), 2.8 (bs, 1H), 2.38 (s, 3H).
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][PH:8]([CH2:10][OH:11])=[O:9])[C:3]([OH:5])=[O:4].[C:12]([NH2:15])(=[O:14])[CH3:13]>O>[C:12]([NH:15][C:2](=[CH:6][CH2:7][PH:8]([CH2:10][OH:11])=[O:9])[C:3]([OH:5])=[O:4])(=[O:14])[CH3:13]
Reactant: CC(N)=O
Reactant: O=C(O)C(=O)CC[PH](=O)CO
Solvent: O
Product: CC(=O)NC(=CC[PH](=O)CO)C(=O)O

Procedure:
A finely divided mixture of 2-oxo-4-(hydroxymethylphosphinyl)butanoic acid (1.80 g, 10 mmol) and acetamide (1.18 g, 20 mmol) were heated at 100° for 5 hours at 20 mm Hg. The mixture melted with evolution of water vapour. The final product was a yellow glass-like solid which was evacuated at 0.1 mm Hg at 100° for one hour to remove excess acetamide.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].C(NC(C)C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[CH3:9][N:8]([CH3:10])[C:6](=[O:7])[C:5]1[CH:11]=[CH:12][C:2]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])=[CH:3][CH:4]=1
Reactant: CN(C)C(=O)c1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CN(C)C(=O)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 57 °C

Procedure:
To a mixture under Ar of 4-Iodo-N,N-dimethyl-benzamide (237 mg), trimethylsilylacetylene (169 mg), [PdCl2(PPh3)2] (30 mg) and copper(i) iodide (15 mg) is added a degassed mixture of THF (4.5 ml) and diisopropylamine (4.5 ml). After stirring over night at 57° C. and aqueous work up, the organic layer is dried over Na2SO4 and the solvent is evaporated. Flash chromatography (silica gel, CH2Cl2/MeOH/25% NH4OH 97:3:0.3) yields N,N-Dimethyl-4-trimethylsilanylethynyl-benzamide as a brown oil, 1H-NMR (300 MHz): 0.25 (s, 3H); 2.96 (s, 3H); 3.10 (s, 3H); 7.35 (d, J=8.5, 2H); 7.49 (d, J=8.5, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(I)cccc2c1N
Reactant: OB(O)c1ccc(F)cc1
Product: CCCNC(=O)c1nnc2c(-c3ccc(F)cc3)cccc2c1N
Yield: 46.9 %

Procedure:
Using method F, 4-amino-8-iodo-N-propyl-cinnoline-3-carboxamide (178 mg, 0.50 mmol) and 4-fluorophenylboronic acid (280 mg, 2.00 mmol) were reacted (reflux 24 hours) to afford the title compound (76 mg, 47% yield) as a white solid. 1H NMR (300 MHz, CDCl3)) δ8.56 (bm, 1H), 7.86 (dd, J=7.7 Hz, 1H), 7.65-7.80 (m, 4H), 7.19 (t, J=8.6 Hz, 2H), 3.45 (apparent q, J=6.6 Hz, 2H), 1.67 (apparent sextet, J=7.4 Hz, 2H), 1.01 (t, J=7.4 Hz, 3H). MS APCI, m/z=325 (M+H) HPLC 1.74 min.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)([CH3:5])[CH:3]=O.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([NH:37][CH2:3][C:2]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=2)[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)([CH3:5])[CH3:1])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)C=O)cn1
Reactant: NCc1ccccc1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CNCc2ccccc2)cn1

Procedure:
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [1-(1,1-dimethyl-2-oxo-ethyl)-1H-imidazol-4-yl]-amide was reacted with benzylamine to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.0, 18.9, 26.4, 26.5, 36.0, 43.1, 53.2, 54.1, 59.0, 59.3, 102.6, 102.9, 103.1, 105.2, 112.4, 112.6, 127.2, 128.2, 128.6, 131.7, 137.8, 138.8, 140.3, 161.9, 164.4, 164.5, 169.2; MS m/z 498.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH:4]=[CH:5][C:6]1[CH:34]=[CH:33][C:9]2[N:10]([CH3:32])[C:11]([CH2:13][NH:14]C(OCC3C4C(=CC=CC=4)C4C3=CC=CC=4)=O)=[N:12][C:8]=2[CH:7]=1.N1CCCCC1>ClCCl>[CH3:1][O:2][C:3](=[O:35])[CH:4]=[CH:5][C:6]1[CH:34]=[CH:33][C:9]2[N:10]([CH3:32])[C:11]([CH2:13][NH2:14])=[N:12][C:8]=2[CH:7]=1
Reactant: COC(=O)C=Cc1ccc2c(c1)nc(CNC(=O)OCC1c3ccccc3-c3ccccc31)n2C
Solvent: C1CCNCC1
Solvent: ClCCl
Product: COC(=O)C=Cc1ccc2c(c1)nc(CN)n2C

Procedure:
3-[2-(N-Fmoc-aminomethyl)-1-methyl-1H-benzimidazol-5-yl]-acrylic acid methyl ester (43 mg, 0.176 mmol, prepared according to Example 42, step 1-3 by using appropriate starting materials) was dissolved in 10 mL of dichloromethane. The resulting solution was treated with 2.0 mL of piperidine. Removed all the solvent and piperidine under vacuum gave 3-(2-aminomethyl-1-methyl-1H-benzimidazol-5-yl)-acrylic acid methyl ester. MS(m/z): 246 [MH]+.
Reaction SMILES: ClC1C(C)=C([CH2:8][NH:9][C:10]2[N:11]=[C:12]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:13][C:14]=2[C:15]([NH2:17])=[O:16])C=CC=1.CSCC(Cl)=O>COCCOC>[N:18]1([C:12]2[S:13][C:14]3[C:15](=[O:16])[N:17]=[CH:8][NH:9][C:10]=3[N:11]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: Cc1c(Cl)cccc1CNc1nc(N2CCOCC2)sc1C(N)=O
Agent: CSCC(=O)Cl
Solvent: COCCOC
Product: O=c1nc[nH]c2nc(N3CCOCC3)sc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-{[(3-chloro-2-methylphenyl)methyl]amino}-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide (100 mg, 0.273 mmol) in 1,2-Dimethoxyethane (DME) (1000 μl) was added (methylthio)acetyl chloride (67.9 mg, 0.545 mmol) in 1,2-Dimethoxyethane (DME) (400 μl). The mixture was stirred at room temperature for 3 h, then irradiated (uwave) at 90° C. for 15 min. After quenching with methanol, the mixture was concentrated and purified by reversed-phase HPLC to provide 4-[(3-chloro-2-methylphenyl)methyl]-5-[(methylthio)methylthio)methyl]-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one. (28 mg, 24%); LC/MS: MS (ES+) m/e 437 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.11 (s, 3H), 2.43 (s, 3H), 3.51 (m, 4H), 3.62 (s, 2H), 3.64-3.71 (m, 4H), 5.59 (s, 2H), 6.53 (d, J=7.8 Hz, 1H), 7.15 (m, 1H), 7.38 (d, J=8.01 Hz, 1H).
Reaction SMILES: N#N.[NH:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[N:3]1([CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: OCCOCCCl
Reactant: C1CCNC1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: OCCOCCN1CCCC1

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of pyrrolidine (0.35 mL, 4.22 mmol) and 2-(2-chloroethoxy)ethanol (0.45 mL, 4.22 mmol) in dry toluene (7 mL) was added K2CO3 (3.21 g, 23.20 mmol) at rt followed by KI (70 mg, 0.42 mmol). The reaction mixture was stirred at reflux for 15 h. The mixture was filtered and the filtrate concentrated under reduced pressure to give crude 2-(2-(pyrrolidin-1-yl)ethoxy)ethanol as a yellow oil. TLC:rf (90:10:0.5 CH2Cl2-MeOH—NH4OH)=0.17.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH2:7]1>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.C(OCC)C.CO>[N:19]1([CH2:18][CH2:17][CH2:16][O:15][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:13]=2[CH2:14][NH:6][CH2:7]3)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: COc1ccc(CN2Cc3cccc(OCCCN4CCOCC4)c3C2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CCOCC
Product: c1cc2c(c(OCCCN3CCOCC3)c1)CNC2
Yield: 236.9 %

Procedure:
A solution of 2-(2,4-dimethoxy-benzyl)-4-(3-morpholin-4-yl-propoxy)-2,3-dihydro-1H-isoindole (233 mg, 0.56 mmol) in trifluoroacetic acid (1.0 mL) and anisole (0.5 mL) was heated at 150° C. under microwave irradiation for 10 minutes. The mixture was diluted with diethyl ether and extracted twice with water. The combined aqueous extracts were concentrated to give an oil which was dissolved in methanol and concentrated in vacuo to afford the title compound as a brown oil (348 mg, including residual TFA and/or water). 1H NMR (methanol-d4) 7.40 (1H, t), 7.03 (1H, d), 6.99 (1H, d), 4.63 (2H, s), 4.59 (2H, s), 4.21 (2H, t), 4.14-4.04 (2H, m), 3.85-3.73 (2H, m), 3.61-3.52 (2H, m), 3.41-3.36 (2H, m), 3.25-3.13 (2H, m), 2.32-2.25 (2H, m). MS: [M+H]+ 263.
Reaction SMILES: [Na].CCO.[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=O)[CH2:11][CH2:10]2.S([CH2:27][N+:28]#[C-])(C1C=CC(C)=CC=1)(=O)=O>COCCOC>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH:12]([C:27]#[N:28])[CH2:11][CH2:10]2
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [Na]
Solvent: CCO
Solvent: COCCOC
Product: COc1ccc2c(c1)CCC2C#N
Temperature: -5 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
Dissolve sodium metal (1.51 g, 66.0 mmol) in abs. EtOH (50 ml) and DME (100 ml) and add the resulting solution drop-wise to a mixture of 5-methoxy-1-indanone (3.57 g, 22.0 mmol), tosylmethyl isocyanide (6.45 g, 33.0 mmol) and DME (150 ml) cooled to −5° C. under nitrogen. After addition is complete (ca. one hour), allow mixture to slowly obtain ambient temperature and stir overnight. After cooling to 0° C., carefully quench with water and extract with EtOAc (2×). Wash the combined extracts with water and brine, dry (MgSO4) and concentrate. Purify on silica gel (toluene) to give 5-methoxy-indan-1-carbonitrile (2.55 g) as a yellow oil. 1HNMR (CDCl3): 7.31 (d, 1H), 6.80 (m, 2H), 4.05 (t, 1H), 3.80 (s, 3H), 3.07 (m, 1H), 2.93 (m, 1H), 2.56 (m, 1H), 2.39 (m, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH2:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=2)[CH2:7][CH2:6]1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:50])=CC=1>>[CH3:1][CH:2]([CH2:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=2)[CH2:7][CH2:6]1)=[S:50]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(CN1CCN(c2ccc(C(F)(F)F)cc2)CC1)C(=O)N1CCC(Nc2ccc(C#N)c(C(F)(F)F)c2)CC1
Product: CC(CN1CCN(c2ccc(C(F)(F)F)cc2)CC1)C(=S)N1CCC(Nc2ccc(C#N)c(C(F)(F)F)c2)CC1

Procedure:
4-(1-{2-Methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-propionyl}-piperidin-4-ylamino)-2-trifluoromethyl-benzonitrile (15 mg; 0.026 mmol, prepared in accordance with Example 92) is reacted with Lawesson's reagent (5 mg; 0.013 mmol) according to the general conditions described in Example 109. The desired product is obtained following purification by preparative HPLC (9 mg; 0.015 mmol). The structure was confirmed using Protocol I-B. Calculated mass=584; observed mass=584; HPLC retention time=4.68 min
Reaction SMILES: [C:1](=[O:6])([O:4][CH3:5])OC.C[O-].[Na+].[NH2:10][C:11]1[CH:15]=[C:14]([CH3:16])[O:13][N:12]=1.Cl>C(OCC)(=O)C.O>[CH3:16][C:14]1[O:13][N:12]=[C:11]([NH:10][C:1](=[O:6])[O:4][CH3:5])[CH:15]=1
Reactant: COC(=O)OC
Reactant: Cc1cc(N)no1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)Nc1cc(C)on1

Procedure:
Dimethyl carbonate (2.38 g) and sodium methoxide (0.30 g) are added to 3-amino-5-methylisoxazole (0.49 g), and the resultant mixture is stirred at 100° C. for 3 hours. After cooling, the reaction mixture is combined with water (15 ml), adjusted to pH 1 with a small amount of c. hydrochloric acid and shaken twice with ethyl acetate. The organic layer is washed with water, dried over anhydrous sodium sulfate and evaporated to remove the solvent. The resulting light yellow crystals (0.52 g) are chromatographed on a column of silica gel, whereby methyl N-(5-methyl-3-isoxazolyl)carbamate is obtained as crystals melting at 136.0° to 137.0° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:16]3=[CH:17][C:18]4[O:22][CH2:21][O:20][C:19]=4[CH:23]=[C:15]3[O:14][CH2:13]1)[C:5](=[O:12])[N:6]2[CH3:11].BrC1C=CC=C2C=1C1(COC3C=C4C(=CC1=3)CCO4)C(=O)N2C[C:35]1[O:36][C:37](C(F)(F)F)=[CH:38][CH:39]=1.O1C=CC(B(O)O)=C1.N1C=C(B(O)O)C=NC=1>>[O:36]1[CH:37]=[CH:38][C:39]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([C:16]4=[CH:17][C:18]5[O:22][CH2:21][O:20][C:19]=5[CH:23]=[C:15]4[O:14][CH2:13]2)[C:5](=[O:12])[N:6]3[CH3:11])=[CH:35]1
Reactant: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cccc(Br)c2C12COc1cc3c(cc12)CCO3
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Agent: OB(O)c1ccoc1
Agent: OB(O)c1cncnc1
Product: CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(-c3ccoc3)cccc21

Procedure:
Following the procedure as described in EXAMPLE 4.14, and making non-critical variations using 4′-bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-{[5-(trifluoromethyl)-2-furyl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 3-furanboronic acid to replace pyrimidine-5-boronic acid, the title compound was obtained (81%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.40-7.28 (m, 2H), 7.05-6.95 (m, 1H), 6.90-6.78 (m, 2H), 6.45-6.38 (m, 1H), 6.23-6.16 (m, 1H), 6.07-5.97 (m, 1H), 5.97-5.80 (m, 2H), 4.75-4.50 (m, 2H), 3.30-3.22 (m, 3H); MS (ES+) m/z 362.4 (M+1).
Reaction SMILES: [CH3:1][CH:2]([O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH:5]([CH3:9])[CH:6]([CH3:8])[CH3:7].[CH2:20](Br)[C:21]#[CH:22]>>[CH2:22]([O:16][C:15](=[O:17])[C:14]1[CH:18]=[CH:19][C:11]([O:10][CH:2]([CH3:1])[CH2:3][CH2:4][CH:5]([CH3:9])[CH:6]([CH3:7])[CH3:8])=[CH:12][CH:13]=1)[C:21]#[CH:20]
Reactant: CC(CCC(C)C(C)C)Oc1ccc(C(=O)O)cc1
Reactant: C#CCBr
Product: C#CCOC(=O)c1ccc(OC(C)CCC(C)C(C)C)cc1

Procedure:
By utilizing the procedure of Example 8, by reacting p-[(1,4,5-trimethylhexyl)oxy]benzoic acid with propargyl bromide, there is obtained p-[(1,4,5-trimethylhexyl)oxy]benzoic acid propargyl ester; nD22 = 1.5050.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:28])[C@@H:13]([NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14][CH:15]=[CH2:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[OH2:29].C[N+]1([O-])CCOCC1.OS([O-])=O.[Na+].CC(C)=O.[OH2:47]>O=[Os](=O)(=O)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:28])[C@@H:13]([NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14][CH:15]([OH:47])[CH2:16][OH:29])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O
Reactant: C=CC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCN(C(=O)OCC)CC1
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Agent: O=S([O-])O
Solvent: CC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(O)CO)NC(=O)OCc2ccccc2)CC1
Reaction time: 0.08 h

Procedure:
To a solution of 640 mg 4-((S)-2-Benzyloxycarbonylamino-pent-4-enoyl)-piperazine-1-carboxylic acid ethyl ester in 10 ml acetone/water (4/1) were added 2.1 ml OsO4 (2.5 w/w in t-BuOH) and 567 mg 4-Methylmorpholine-N-oxide monohydrate at 0° C. After 1 h solid NaHSO3 was added, the suspension stirred for 5 minutes, filtered and the filtrate concentrated. The residue was redissolved in dichloromethane and washed with aqueous NaHSO3 (5%) and brine. The crude product obtained after evaporation of the solvent was directly used in the next reaction step. Yield: 755 mg.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4]1.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14].C([O-])(O)=O.[Na+].O>CN(C=O)C>[O:14]=[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12][NH:2][C:3]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4]1
Reactant: CCOC(=O)C1(N)CC1
Reactant: O=C(CBr)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NCC(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of ethyl 1-aminocyclopropanecarboxylate hydrochloride (1.0 g, 7.74 mmol), 2-bromoacetophenone (3.08 g, 15.5 mmol), and NaHCO3 (1.30 g, 15.5 mmol) in DMF (20 mL) was stirred at ambient temperature for 18 h. H2O (20 mL) was added and the mixture was extracted with EtOAc (2×75 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. The product-containing fractions were combined, adjusted to pH 10 by addition of saturated aqueous Na2CO3 and extracted with EtOAc (2×75 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound. MS: m/z=248 (M+1).