Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C:8]([NH:10][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][N:14]=2)[CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH:27]1(B(O)O)[CH2:29][CH2:28]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CO>[CH:27]1([C:2]2[CH:26]=[CH:25][C:5]([O:6][CH2:7][C:8]([NH:10][C@@H:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][N:14]=3)[CH3:12])=[O:9])=[CH:4][CH:3]=2)[CH2:29][CH2:28]1
Reactant: OB(O)C1CC1
Reactant: C[C@@H](NC(=O)COc1ccc(Br)cc1)c1ccc(OCC(F)(F)F)cn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@H](NC(=O)COc1ccc(C2CC2)cc1)c1ccc(OCC(F)(F)F)cn1
Temperature: 120 °C
Yield: 7 %

Procedure:
To a solution of (R)-2-(4-bromophenoxy)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acetamide (100 mg, 0.23 mmol) and cyclopropylboronic acid (26 mg, 0.30 mmol) in dioxane (2 mL) were added 1.27 M potassium phosphate (0.36 mL) and tetrakistriphenyl phosphine palladium (13 mg, 0.012 mmol) at room temperature. The mixture was stirred at 120° C. using microwave oven for 2 hours. The mixture was dried over magnesium sulfate. After the filtration to separate solvent and magnesium sulfate, the solvent was removed under reduced pressure to give the residue. The residue was diluted with methanol and applied onto a strong cation exchange cartridge (BondElute(registered trademark) SCX, 1 g/6 mL, Varian Inc.), and the solid phase matrix was rinsed with methanol (6 mL). The crude mixture was eluted in a collection tube with 1 mol/L ammonia in methanol (6 mL) and concentrated in vacuo. The residue was purified by preparative LC-MS to give 6.5 mg, (7% yield) of the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:12])[CH3:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[BH4-].[Na+].CC(=O)OCC>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:12])[CH3:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(=O)c1ccc2c(c1)OCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(O)c1ccc2c(c1)OCO2
Yield: 86.3 %

Procedure:
To a solution of 1-benzo[1,3]dioxol-5-yl-ethanone (2.5 gm; 15.2 mmol) in methanol (50 mL) is added sodium borohydride (634 mg; 16.7 mmol) in portions allowing for gas evolution. The reaction is stirred at room temperature for 3 hours before additional sodium borohydride is added to give a complete reaction by TLC (20% EA/Hex). The reaction is quenched with saturated ammonium chloride and extracted with ethyl acetate. The organics are separated, washed with water, dried over magnesium sulfate, and the solvent is removed to give 2.18 grams of 1-benzo[1,3]dioxol-5-yl-ethanol.
Reaction SMILES: [ClH:1].[CH3:2][S:3]([NH:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)(=[O:5])=[O:4].[CH3:21][C:22]1[N:27]=[C:26]([CH:28]=[CH2:29])[CH:25]=[CH:24][CH:23]=1.C([O-])(=O)C.[Na+].CO>O>[ClH:1].[ClH:1].[CH3:21][C:22]1[N:27]=[C:26]([CH2:28][CH2:29][N:16]2[CH2:17][CH2:18][CH:13]([C:11](=[O:12])[C:10]3[CH:9]=[CH:8][C:7]([NH:6][S:3]([CH3:2])(=[O:4])=[O:5])=[CH:20][CH:19]=3)[CH2:14][CH2:15]2)[CH:25]=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)C2CCNCC2)cc1
Reactant: C=Cc1cccc(C)n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cccc(CCN2CCC(C(=O)c3ccc(NS(C)(=O)=O)cc3)CC2)n1
Yield: 150.7 %

Procedure:
0.254 g (0.797 mmol) of 4-(4-methylsulfonylaminobenzoyl)piperidine hydrochloride, 0.22 g (1.88 mmol) of 6-methyl-2-vinylpyridine and 0.15 g of sodium acetate were suspended in 3 ml of a mixture of methanol and water (1:1) and the suspension was refluxed for 2 h. The liquid reaction mixture was filtered and the filtrate was concentrated. The obtained residue was purified according to silica gel column chromatography (chloroform:methanol:aqueous ammonia=96:4:0.4). The purified product was converted into its hydrochloride with ethanolic hydrogen chloride and recrystallized from ethanol to obtain 0.285 g (yield: 81%) of the intended compound.
Reaction SMILES: [CH:1]12C[CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12]([NH:14][C:15]([CH3:29])([C:26](O)=[O:27])[CH2:16][C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=1)=[O:13])[CH2:8]2.[CH3:30]N1CCOCC1.ClC(OCC(C)C)=O.[NH2:45][CH2:46][CH2:47][C:48]1[CH:57]=[CH:56][C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[N:49]=1>C1COCC1>[NH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([CH2:16][C:15]([NH:14][C:12](=[O:13])[O:11][CH:2]([CH2:1][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH3:9])[CH3:30])([CH3:29])[C:26]([NH:45][CH2:46][CH2:47][C:48]2[CH:57]=[CH:56][C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[N:49]=2)=[O:27])=[CH:18]1
Reactant: CN1CCOCC1
Reactant: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O
Reactant: NCCc1ccc2ccccc2n1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: CCCCCCCCC(C)OC(=O)NC(C)(Cc1c[nH]c2ccccc12)C(=O)NCCc1ccc2ccccc2n1
Temperature: -22 °C
Reaction time: 1 h
Yield: 17.1 %

Procedure:
To a stirred solution of 2-adamantyloxycarbonyl-α-methyl-DL-tryptophan (1.59 g, 4.0 mmole) in dry THF (50 mL) at -22° C. was added N-methylmorpholine (0.644 g, 6.3 mmole) and isobutyl chloroformate (0.632 g, 4.6 mmole). The mixture was stirred at -22° C. for 1 hour and then a solution of 2-(2-aminoethyl)quinoline (0.690 g, 4.0 mmole) in dry THF (15 mL) was added. After stirring at this temperature 4 hours the reaction mixture was allowed to stir at room temperature 15 hours. The solvent was removed in vacuo and the residue was taken up in EtOAc and washed with 5% citric acid (2×50 mL), water (2×50 mL), 5% NaHCO3 (3×50 mL), water (2×50 mL), and brine (2×50 mL). The organic phase was dried over MgSO4 and the solvent evaporated. The residue was flash chromatographed on silica gel, eluting with EtOAc-n-hexane. The oil obtained was triturated with cold Et2O, yielding the product as an amorphous white solid, (0.38 g, 17%); 1H NMR (CDCl3) δ1.41-1.88 (17H, m), 3.00-3.04 (2H, m), 3.40 (2H, q, J 9.59 Hz), 3.68-3.70 (2H, m), 4.70 (1H, s), 5.43 (1H, br s), 6.90 (1H, d, J 2.23), 6.96-7.22 (4H, m), 7.45-7.55 (2H, m), 7.63-7.70 (2H, m), 7.78 (1H, d, J 8.06), 7.89 (2H, d, J 8.10), 8.03 (1H, d, J 8.46).
Reaction SMILES: C(O[K])(C)(C)C.[CH2:7]([C:9]1[O:13][C:12]([CH:14]=O)=[CH:11][CH:10]=1)[CH3:8].[CH2:16]([O:18][C:19](=[O:27])[CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])[CH3:17]>CC(O)(C)C>[CH2:16]([O:18][C:19](/[C:20](=[CH:14]/[C:12]1[O:13][C:9]([CH2:7][CH3:8])=[CH:10][CH:11]=1)/[CH2:21][C:22]([OH:24])=[O:23])=[O:27])[CH3:17]
Reactant: CCc1ccc(C=O)o1
Reactant: CCOC(=O)CCC(=O)OCC
Agent: CC(C)(C)O[K]
Solvent: CC(C)(C)O
Product: CCOC(=O)/C(=C/c1ccc(CC)o1)CC(=O)O
Temperature: 25 °C
Yield: 100 %

Procedure:
To a suspension of tBuOK (61.4 g, 0.54 mol) in tBuOH (180 mL) was added a suspension of 5-ethyl-2-furaldehyde (22.5 g, 0.18 mol) in succinic acid diethyl ester (142.1 g, 0.82 mol). The reaction mixture was refluxed for 1 h. Then the same amounts of tBuOK, tBuOH and succinic acid diethyl ester were added at the same temperature, and the reaction mixture was stirred at reflux for another 1 h. TLC (petroleum ether/EtOAc 2:1) indicated the complete consumption of the furaldehyde. The reaction mixture was allowed to cool to room temperature, acidified to a pH˜2 by 20% aqueous HCl (200 mL) and extracted with EtOAc (500 mL×3). The organic phase was washed with 10% aqueous Na2CO3 (500 mL×3). The combined aqueous layers was washed with ethyl ether (500 mL) and acidified to a pH˜2 with 20% aqueous HCl (100 mL). The aqueous phase was finally extracted with EtOAc (500 mL×4). The combined organic layers were dried over Na2SO4 and concentrated to give the crude acid (45.4 g, 100%), which was directly used to next step without further purification.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH3:22])([O:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[C:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:37]S(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:22][C:5]([O:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:37][CH2:36][CH2:35][C:33]2[N:34]=[C:30]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:31][C:32]=2[CH3:48])=[CH:9][CH:8]=1)[C:4]([OH:23])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(C)c1
Product: Cc1cccc(OC(C)(Cc2ccc(OCCc3nc(-c4ccccc4)oc3C)cc2)C(=O)O)c1

Procedure:
The title compound was prepared from 3-(4-hydroxy-phenyl)-2-methyl-2-m-tolyloxy-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester using Standard Procedure (B). 1H NMR (400 MHz, CDCl3) δ 8.04-8.01 (m, 2H), 7.47-7.45 (m, 3H), 7.18 (d, 2H, J=8.60 Hz), 7.13 (t, 1H, J=7.82 Hz), 6.87-6.85 (m, 1H), 6.82 (d, 2H, J=8.60 Hz), 6.74-6.67 (m, 2H), 4.23 (t, 2H, J=6.26 Hz), 3.24 (d, 1H, J=13.69 Hz), 3.12 (d, 1H, J=13.69 Hz), 3.06 (t, 2H, J=6.26 Hz), 2.41 (s, 3H), 2.29 (s, 3H), 1.42 (s, 3H); HRMS (ES+) m/z exact mass calcd for C29H30O5 472.2124, found 472.2098.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([S:12][CH3:13])=[CH:7][C:6]=1[CH3:14])=O.[NH2:15][C:16]([NH2:18])=[S:17]>CCO>[CH3:14][C:6]1[CH:7]=[C:8]([S:12][CH3:13])[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:15]=[C:16]([NH2:18])[S:17][CH:2]=1
Reactant: NC(N)=S
Reactant: CSc1cc(C)c(C(=O)CBr)c(C)c1
Solvent: CCO
Product: CSc1cc(C)c(-c2csc(N)n2)c(C)c1
Yield: 44.6 %

Procedure:
A mixture of 2-bromo-1-(2,6-dimethyl-4-(methylthio)phenyl)ethanone (4.64 g, 17.0 mmol) and thiourea (1.29 g, 17.0 mmol) in 95% EtOH (24.3 mL) was heated at reflux for 120 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (4.0 mL). The resultant precipitate was filtered and recrystallized in toluene (30 mL). The solids were filtered and dried under vacuum to give 4-(2,6-dimethyl-4-(methylthio)phenyl)thiazol-2-amine (1.9 g) as light yellow solids in 45% yield: 1H NMR (500 MHz, CDCl3) δ 6.97 (s, 2 H), 6.26 (s, 1 H), 2.47 (s, 3 H), 2.15 (s, 6 H).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([F:8])([F:7])[C:4]([O-])=O.[K+].CN([CH:15]=[O:16])C.[C:17]1(C)[CH:22]=[CH:21]C=[CH:19][CH:18]=1>[Cu]I>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:4]([C:3]([F:8])([F:7])[C:2]([F:10])([F:9])[F:1])=[CH:19][CH:18]=1
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Reactant: CN(C)C=O
Reactant: Cc1ccccc1
Agent: [Cu]I
Agent: [K+]
Product: COc1ccc(C(F)(F)C(F)(F)F)cc1
Temperature: 140 °C

Procedure:
8.3 g of potassium pentafluoropropionate and 9.8 g of CuI are introduced, under an inert atmosphere, into a 500 mL three-necked flasked equipped with Dean-Stark apparatus and a condenser. 90 mL of DMF and 110 mL of toluene are added. The medium is heated to 140° C. under nitrogen, and 80 mL of toluene are distilled off. The medium is then cooled to RT and then deoxygenated by sparging with nitrogen. 6 g of iodoanisole are then added and the mixture is then heated at 155° C. for 20 hours. After cooling to RT, the medium is diluted with 200 mL of a water/ethyl ether mixture. The medium is then filtered through Celite®. The organic phase is washed 3 times with water, dried over MgSO4 and then evaporated to give 4.3 g of a brown oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([F:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][C@@H:33]([CH3:35])[N:32](C(=O)C(F)(F)F)[CH2:31][C:30]2=[O:42])[CH:26]=[CH:27][CH:28]=1>Cl>[F:21][C:5]1[C:6]([NH:8][C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[N:7][C:2]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]3[CH2:34][C@@H:33]([CH3:35])[NH:32][CH2:31][C:30]3=[O:42])[CH:24]=2)=[N:3][CH:4]=1
Reactant: CC(C)NC(=O)c1ccccc1Nc1nc(Cl)ncc1F
Reactant: C[C@@H]1CN(c2cccc(N)c2)C(=O)CN1C(=O)C(F)(F)F
Agent: Cl
Product: CC(C)NC(=O)c1ccccc1Nc1nc(Nc2cccc(N3C[C@@H](C)NCC3=O)c2)ncc1F
Temperature: 95 °C
Yield: 55 %

Procedure:
To the suspension solution of 2-[(2-chloro-5-fluoro-4-pyrimidinyl)amino]-N-(1-methylethyl)benzamide (100 mg, 0.32 mmol) and (5R)-1-(3-aminophenyl)-5-methyl-4-(trifluoroacetyl)-2-piperazinone (147 mg, 0.48 mmol) was added 2 drops of 12N HCl. The reaction mixture was then sealed and heated in a 95° C. oil bath for 16 h. The reaction was followed by LC/MS. The reaction was evaporated to dryness. The residue was then dissolved in THF (10 mL) with LiOH (1.0 M solution 0.64 mL). The reaction mixture was heated at 50° C. for 3 h. Then the solvent was evaporated to dryness on high vacuum and the residue was loaded on silica gel column and eluted with 2.0 to 9.0% MeOH (with 0.1% NH4OH) in CH2Cl2. Oil was then recrystalized from hot EtOH to yield the pure title compound (84 mg, 55%). MS: M(C25H28FN7O2)=477.54 (M+H)+=478.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([NH:16][C@@H:17]([C:28]([OH:30])=[O:29])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([O:26][CH3:27])[CH:20]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[CH2:1]([O:30][C:28](=[O:29])[C@H:17]([NH:16][C:14]([O:13][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:15])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([O:26][CH3:27])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)ccc1O
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Benzyl bromide (2.34 ml, 19.8 ml) was added to a solution of N-tert-butyloxycarbonyl-4-hydroxy-3-methoxy-D-phenylalanine (3.44 g) and N,N-diisopropylethylamine (3.85 ml) in N,N-dimethylformamide (20 ml). After being stirred at room temperature for 6 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of hexane and ethyl acetate (4:1) to give (2R)-2-(tert-butyloxycarbonylamino)-3-(4-hydroxy-3-methoxyphenyl)propionic acid benzyl ester (2.98 g) as colorless powders.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C@@H:5]([CH3:16])[NH:4]1.C(N(CC)CC)C.[C:24](=[S:26])=[S:25].[CH3:27]I>CO.C(O)C>[OH:1][CH2:2][C@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C@@H:5]([CH3:16])[N:4]1[C:24]([S:26][CH3:27])=[S:25]
Reactant: CI
Reactant: S=C=S
Reactant: C[C@H]1N[C@@H](CO)Cc2c1[nH]c1ccccc21
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCO
Product: CSC(=S)N1[C@@H](CO)Cc2c([nH]c3ccccc23)[C@H]1C
Yield: 68.9 %

Procedure:
In the same manner as described in Example 13 by using (1R, 3R)-3-hydroxymethyl-1-methyl-1,2,3,4-tetrahydro-β-carboline (4.32 g), triethylamine (4.04 g), CS2 (3.04 g), methyl iodide (5.68 g) and 80% ethanol (150 ml), there is prepared the title compound (4.22 g, 69%) as white powder, [α]D20 -205.4° (c=1.0, methanol). NMR (CDCl3, δ): 1.66 (d, J=6.7 Hz, 3H, C1 --CH3), 2.70 (s, 3H, CSSCH3), Mass m/e: 306 (M+), 258 (M+ --CH3SH).
Reaction SMILES: C([NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)CCC.Cl.O>C1COCC1>[CH2:6]([C:12]1[CH:11]=[C:10]([Cl:13])[CH:9]=[CH:8][C:7]=1[CH2:6][NH2:5])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCNC(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1cc(Cl)ccc1CN
Temperature: 0 °C
Yield: 164.6 %

Procedure:
A solution of N-butyl-4-chlorobenzamide (2.26 g; 0.011 mol) in dry THF (25 ml) was added slowly to an ice-cooled solution of 1.0M B2H6 -THF complex (45 ml; 0.045 mol) under a nitrogen blanket. When addition was complete, the mixture was stirred and heated to reflux for 3 hours, cooled and decomposed by dropwise addition of 1:1 conc aq HCl-water (10 ml). The mixture was then evaporated on a rotary evaporator at 60° for 1/2 hour to decompose the boron-amine complexes. The residue was taken up in water, strongly basified with aq NaOH and extracted with CH2Cl2 (3×25 ml). The combined extracts were washed with water, dried (MgSO4), filtered and evaporated to give n-butyl-4-chlorobenzenemethanamine (1.79 g) as an oil. The oil was converted to the hydrochloride salt of the title compound (1.98 g) by crystallising from ethanolic HCl and ethyl acetate, mp 250°-252° after melting and resolidifying at 203°-207° .
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[C:4]2[CH:5]=[N:6][N:7]([CH3:13])[C:8]=2[C:9](=[O:12])[C:10]=1[Cl:11].[CH:15]1([NH2:18])[CH2:17][CH2:16]1>C(O)C>[Cl:11][C:10]1[C:9](=[O:12])[C:8]2[N:7]([CH3:13])[N:6]=[CH:5][C:4]=2[C:3](=[O:14])[C:2]=1[NH:18][CH:15]1[CH2:17][CH2:16]1
Reactant: Cn1ncc2c1C(=O)C(Cl)=C(Cl)C2=O
Reactant: NC1CC1
Solvent: CCO
Product: Cn1ncc2c1C(=O)C(Cl)=C(NC1CC1)C2=O

Procedure:
5,6-Dichloro-1-methyl-1H-indazole-4,7-dione (10 grams prepared as in Example I) and cyclopropylamine (10 grams) in ethanol (50 milliliters) were stirred together at room temperature for 30 minutes. The precipitate formed was filtered off and dried to yield the desired product as a red solid having a melting point of 175°-176° C.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([CH2:23][S:24]([C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:15]=2)[CH2:9]1)C1C=CC=CC=1.[CH2:37]([O:44][C:45](Cl)=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[OH-].[Na+]>C1C=CC=CC=1>[CH2:37]([O:44][C:45]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([CH2:23][S:24]([C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:15]=2)[CH2:9]1)=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(OC2CCN(Cc3ccccc3)C2)cc1CS(=O)(=O)c1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: O=C(OCc1ccccc1)N1CCC(Oc2ccc([N+](=O)[O-])c(CS(=O)(=O)c3cccc4ccccc34)c2)C1
Reaction time: 3 h
Yield: 70 %

Procedure:
A solution of 1-benzyl-3-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-pyrrolidine (4.2 g, 8.4 mmol) and benzylchloroformate (12.0 mL, 84 mmol in 2 equal portions) in benzene was heated at reflux temperature, under nitrogen, for 3 hours, cooled to ambient temperatures, poured into 2.5 N sodium hydroxide and extracted with ethyl acetate. The extracts were combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography using 40-50% ethyl acetate in hexane to afford 3-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-pyrrolidine-1-carboxylic acid benzyl ester as a buff foam, 3.2 g (70% yield), Mass spectrum (+EI, [M+H]+) m/z 547. 1HNMR (500 MHz, DMSO-d6): δ8.46 (d, 1H, J=7.44 Hz), 8.27 (d, 1H, J=8.06 Hz), 8.06-8.08 (m, 1H), 7.94-7.99 (m, 2H), 7.57-7.68 (m, 3H), 7.26-7.39 (m, 5H), 7.09 (dd, 1H, J=9.15 Hz and 2.68 Hz), 6.77 (s, 1H), 5.19-5.26 (m, 2H), 5.01-5.10 (m, 2H), 4.90 (s, 1H), 3.42-3.59 (m, 2H), 3.31-3.36 (m, 1H), 1.98-2.10 (m, 1H), 1.79-1.86 ppm (m, 1H).
Reaction SMILES: [NH2:1][C:2]([S:9][CH3:10])=[C:3]([C:7]#[N:8])[C:4](=[S:6])[NH2:5].OO>C(O)C>[NH2:5][C:4]1[S:6][N:1]=[C:2]([S:9][CH3:10])[C:3]=1[C:7]#[N:8]
Reactant: CSC(N)=C(C#N)C(N)=S
Agent: OO
Solvent: CCO
Product: CSc1nsc(N)c1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
A slurry of 18.7 g of 3-amino-2-cyano-3-(methylthio)propenethioamide in 100 ml of ethanol was heated under reflux, as 14 ml (4.1 g) of 30% hydrogen peroxide were added dropwise. The exothermic reaction kept the system under reflux. The solution was heated under reflux for 30 minutes. The reaction mixture was allowed to cool to ambient temperature while it was stirred overnight. The white solid was collected by filtration to give 16.4 g of 5-amino-4-cyano-3-(methylthio)isothiazole; m.p. 188°-189°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)(O)[O-].[Na+]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Cc1ccc([N+](=O)[O-])cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A room temperature solution of 2.53 gms. (4-Nitro-phenyl)-acetic acid in tetrahydrofuran (10 mL) is treated with 2.44 gms. 1′,1′-carbonyl-diimidizole and immediately immersed in an ice bath. The reaction mixture is stirred in the ice bath for 30 minutes then it is allowed to warm to room temperature. Once at room temperature the reaction mixture is treated with 1.21 mL piperidine, and then is stirred overnight at room temperature. The reaction is then made basic with the addition of saturated aqueous sodium bicarbonate, and the resulting mixture is extracted with ethyl acetate. The organics are separated, dried over anhydrous sodium sulfate, filtered, and subsequently evaporated to dryness in vacuo. The crude product residue is then chromatographed by flash silica gel chromatography using 50% ethyl acetate in hexanes as the eluant. Following evaporation of solvent, 2-(4-nitro-phenyl)-1-piperidin-1-yl-ethanone is isolated as a white solid in the amount of 3.18 gms. 2-(4-Nitro-phenyl)-1-piperidin-1-yl-ethanone (1.24 gms.) is then dissolved in tetrahydrofuran (5 mL), and slowly added dropwise to a 0° C., 1.0M solution (35 mL) of Borane in tetrahydrofuran. The reaction mixture is maintained at 0° C. for 20 minutes following the completion of the addition to the Borane/tetrahydrofuran solution. The reaction mixture is then allowed to warm to room temperature, and is subsequently refluxed using an oil bath. The reaction mixture is maintained at refluxing temperature overnight, then cooled to 0° C. and quenched with the addition of concentrated HCl (added until fizzing stops). The quenched reaction mixture is then extracted with ethyl acetate and water. The organic layer is then separated, dried over sodium sulfate and concentrated in vacuo. The solid isolated is then triturated with hexanes and a little ethyl acetate to yield 0.7563 gms. of 1-[2-(4-nitro-phenyl)-ethyl]-piperidine as a white solid following filtration.
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3](=N)[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.OCC[CH2:18][C:19](=[O:21])[CH3:20].FC(F)(F)S(O)(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:5]([O:4][CH2:3][CH2:2][CH2:18][C:19](=[O:21])[CH3:20])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: CC(=O)CCCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)CCCOCc1ccccc1
Reaction time: 8 h
Yield: 64.9 %

Procedure:
Benzyl trichloroacetimidate (1.85 g) was added to a mixed solution of 5-hydroxy-2-pentanone (500 mg, 4.89 mmol) in dichloromethane (20 mL) in an argon atmosphere at room temperature, and then trifluoromethanesulfonic acid (87 μL) was added in an ice bath. The mixture was returned to room temperature and stirred overnight. After completion of the reaction, a saturated sodium bicarbonate solution was added to the reaction solution in an ace bath, and the pH was adjusted to 8. After extraction with chloroform-water, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 610 mg of the title compound (yield: 65%) as a pale yellow oil.