Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C@H:3]([NH:11][C:12](=[O:25])[NH:13][C:14]1[S:15][C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:17]([CH3:19])[N:18]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH2:4]([C@@H:3]1[CH2:2][N:13]([C:14]2[S:15][C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:17]([CH3:19])[N:18]=2)[C:12](=[O:25])[NH:11]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1sc(NC(=O)N[C@@H](CO)Cc2ccccc2)nc1C
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(N2C[C@@H](Cc3ccccc3)NC2=O)nc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of (R)-ethyl 2-(3-(1-hydroxy-3-phenylpropan-2-yl)ureido)-4-methylthiazole-5-carboxylate (3.20 g, 8.80 mmol) and N,N-diisopropylethylamine (2.70 mL, 115.50 mmol) in tetrahydrofuran (50 mL) was added methanesulfonyl chloride (0.82 mL, 10.50 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 2 hours. To this reaction mixture was added potassium carbonate (1.38 g, 10.00 mmol), and heated to reflux for 17 hours. The solvent was removed in vacuo, the residue was dissolved in ethyl acetate (300 mL) and washed with water and brine. The organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography to afford the title compound in 47% yield (1.43 g): mp 102-103° C.; 1H NMR (300 MHz, acetone-d6) δ 9.38 (s, 1H), 7.37-7.23 (m, 5H), 4.60-4.17 (m, 5H), 3.07-2.95 (m, 2H), 2.44 (s, 3H) 1.26 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, acetone-d6) δ 174.9, 162.1, 161.7, 157.1, 136.9, 129.2, 128.7, 126.8, 113.0, 70.4, 60.1, 56.4, 40.3, 16.6, 13.7; MS (ES+) m/z 346.4 (M+1).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=2[CH:5]=[CH:4]1.[CH2:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)[CH3:17].[Cl-].[NH4+]>CN(C)C=O>[CH2:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([N:3]2[C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=3[CH:5]=[CH:4]2)=[O:23])=[CH:20][CH:19]=1)[CH3:17]
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: CCc1ccc(C(=O)Cl)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCc1ccc(C(=O)n2ccc3c(C(=O)OC)cccc32)cc1
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
Sodium hydride (95%; 0.30 g) was suspended in 10 ml of dimethylformamide and the suspension was stirred while cooling the same at a temperature ranging from 0° to 5° C. To this mixed liquid, there was dropwise added a solution of 2.00 g of methyl indole-4-carboxylate in 5 ml of dimethylformamide over 15 minutes. After the completion of the dropwise addition, the reaction solution was stirred at a temperature ranging from 0° to 5° C. for 30 minutes. To the reaction solution, there was added a solution of 2.09 g of 4-ethylbenzoyl chloride in 5 ml of dimethylformamide, followed by stirring at room temperature for 2 hours. The reaction solution was poured into 200 ml of a 10% ammonium chloride aqueous solution, followed by extraction with ethyl acetate (200 ml×2). The extract was washed with a saturated common salt solution, dried over anhydrous sodium sulfate and the solvent was removed through distillation under reduced pressure to thus give 3.51 g of a residue. The residue was purified by silica gel chromatography (hexane:ethyl acetate=11:1) to give 2.18 g of methyl 1-(4-ethylbenzoyl)indole-4-carboxylate as colorless crystals. The yield thereof was found to be 62%.
Reaction SMILES: CC1CC[C@@H](C(C)=C)CC=1.[Se](=O)=O.[CH3:14][C:15]([CH:17]1[CH2:22][CH:21]=[C:20]([CH:23]=[O:24])[CH2:19][CH2:18]1)=[CH2:16]>[O-2].[O-2].[O-2].[Cr+6]>[CH3:16][C:15]([C@@H:17]1[CH2:18][CH:19]=[C:20]([CH2:23][OH:24])[CH2:21][CH2:22]1)=[CH2:14]
Reactant: C=C(C)C1CC=C(C=O)CC1
Agent: [Cr+6]
Agent: C=C(C)[C@H]1CC=C(C)CC1
Agent: O=[Se]=O
Product: C=C(C)[C@@H]1CC=C(CO)CC1

Procedure:
Perillyl alcohol can be produced by reacting limonene with selenium dioxide (that is toxic) and other oxidants (that are difficult to work with i.e., anhydrous chromium trioxide) to yield various oxidation products, including a small amount of perillaldehyde. Once isolated, perillaldehyde is reduced to afford perillyl alcohol. While this two-step process is conceptually attractive, the oxidation of limonene to give perillyl alcohol proceeds in a low overall yield.
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=O)[CH2:5][C:6]([CH3:10])([CH3:9])[CH2:7][CH2:8]\1.[NH2:12][NH2:13]>CO>[CH3:9][C:6]1([CH3:10])[CH2:5][C:4]2[NH:13][N:12]=[CH:2][C:3]=2[CH2:8][CH2:7]1
Reactant: CC1(C)CC/C(=C/O)C(=O)C1
Reactant: NN
Solvent: CO
Product: CC1(C)CCc2cn[nH]c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
To a solution of 2-[1-hydroxy-meth-(Z)-ylidene]-5,5-dimethyl-cyclohexanone (1.64 g, 10.6 mmol) in MeOH (10 mL) was added hydrazine (0.33 mL, 10.6 mmol) dropwise. The exothermic reaction was controlled by intermitant use of an ice bath. The yellow reaction mixture was stirred at room temperature for 30 min then concentrated. The residue was dissolved in CH2Cl2 and washed with water. The organic layer was dried over MgSO4 and concentrated to afford 1.53 g (96%) of 6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole as a yellow solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.32 (s, 1H), 2.55 (t, J=6.4 Hz, 2H), 2.44 (s, 2H), 1.53 (t, J=6.4 Hz, 2H), 1.01 (s, 6H).
Reaction SMILES: [N:1]([O-])=O.[Na+].Cl.[CH2:6]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[NH:17][C:18](=[O:24])[C:19]([NH2:23])=[C:20]([NH2:22])[N:21]=1)[CH:7]=[CH2:8]>O>[CH2:6]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:21]=[C:20]2[C:19](=[N:23][N:1]=[N:22]2)[C:18](=[O:24])[N:17]=1)[CH:7]=[CH2:8]
Reactant: O=N[O-]
Reactant: C=CCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: C=CCOc1ccccc1C1=NC(=O)C2=NN=NC2=N1
Yield: 32.2 %

Procedure:
Sodium nitrite (3 g.) was added slowly with stirring to a solution of concentrated hydrochloric acid (100 ml.) in water (100 ml.) maintained at between -5° and 0° C. by means of an ice/salt bath. 2-(2-Allyloxyphenyl)-4,5-diaminopyrimid-6-one (5.1 g.) was then added in portions during 30 minutes with stirring at between -5° and 0° C. The cooling bath was removed, and the mixture stirred at room temperature overnight. The solid which separated was filtered off and dissolved in a solution of concentrated ammonium hydroxide (10 ml.) in water (100 ml.). The solution was heated with charcoal, filtered, and the filtrate acidified with glacial acetic acid. The solid which separated was filtered off and recrystallised from methanol to give 2-(2-allyloxyphenyl)-8-azapurin-6-one (1.7 g.), m.p. 173°-175° C.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=2[CH3:20])[CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9].[I:21]I.CCCCCON=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:8]([C:7]1[CH:6]=[CH:5][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=2[CH3:20])=[CH:3][C:2]=1[I:21])[CH3:9]
Reactant: CCc1ccc(-c2ccc(C(=O)OC)cc2C)cc1N
Reactant: II
Agent: CCCCCON=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCc1ccc(-c2ccc(C(=O)OC)cc2C)cc1I
Temperature: 80 °C

Procedure:
Methyl 3′-amino-4′-ethyl-2-methylbiphenyl-4-carboxylate (1.1263 g, 4.18 mmol) and iodine (0.258 ml, 5.02 mmol) were mixed in chloroform (40 mL) and immersed in a preheated oil bath (90° C. when immersed). To this hot mixture was added n-amyl nitrite (0.668 ml, 5.02 mmol). The reaction mixture was heated in an 80° C. oil bath for 2 hours then allowed to cool to ambient temperature overnight. The crude was stirred with a Na2S2O3 solution. Volatiles were removed under reduced pressure. The pot residue was worked up with brine, extracted with ethyl acetate, dried over Na2SO4, filtered and evaporated. The resulting mixture was purified by flash chromatography (SiO2, Isolute Flash Si; 100 g). The column was eluted by an EtOAc/hexane mixture (0% to 30%). Related fractions were pooled and evaporated to afford a light yellow solid as the titled compound. LCMS calc.=380.03. found=381.09 (M+H)+.
Reaction SMILES: Cl.[Cl:2][CH:3]=[CH:4][CH2:5][O:6][NH2:7].C([O-])(=O)C.[Na+].[OH:13][C:14]1[CH2:19][CH:18]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[C:22]([C:28](=[O:32])/[CH:29]=[CH:30]/[CH3:31])[C:21]=2[CH3:33])[CH2:17][C:16](=[O:34])[C:15]=1[C:35](=O)[CH2:36][CH3:37]>C(O)C>[Cl:2][CH:3]=[CH:4][CH2:5][O:6][N:7]=[C:35]([C:15]1[C:14](=[O:13])[CH2:19][CH:18]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[C:22]([C:28](=[O:32])/[CH:29]=[CH:30]/[CH3:31])[C:21]=2[CH3:33])[CH2:17][C:16]=1[OH:34])[CH2:36][CH3:37]
Reactant: NOCC=CCl
Reactant: C/C=C/C(=O)c1c(C)cc(C)c(C2CC(=O)C(C(=O)CC)=C(O)C2)c1C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: C/C=C/C(=O)c1c(C)cc(C)c(C2CC(=O)C(C(CC)=NOCC=CCl)=C(O)C2)c1C
Reaction time: 16 h
Yield: 79.8 %

Procedure:
3-Chloroallyloxyamine hydrochloride (0.3 g) and then anhydrous sodium acetate (0.2 g) were added to a solution of 3-hydroxy-5-(3-crotonyl-2,4,6-trimethylphenyl)-2-propionylcyclohex-2-en-1-one (0.7 g) in anhydrous ethanol (80 ml). The mixture was stirred briefly then allowed to stand at room temperature for 16 hours. The ethanol was removed by evaporation under reduced pressure using a rotary evaporator. The residue was treated with chloroform and the organic phase was washed twice with water (50 ml). The chloroform layer was dried over magnesium sulphate and the solvent was removed by evaporation under reduced pressure to give the product 2-[1-(3-chloroallyloxyimino)propyl]-3-hydroxy-5-(3-crotonyl-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (0.7 g, 85%) as a colourless oil. Proton magnetic spectrum (CDCl3 ; δ in ppm); 1.19 (3H, t); 1.92 (3H, d, J=7 Hz); 2.09 (3H, s); 2.19 (3H, s); 2.39 (3H, s); 2.2-4.0 (7H, m); 4.4-4.8 (2H, m); 5.86.7 (4H, m); 6.86 (1H, s); 15.2 (1 H, bs).
Reaction SMILES: [Cl:1][CH:2]([Cl:18])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:7]([Cl:17])[CH:6]=1)O.S(Cl)([Cl:21])=O>N1C=CC=CC=1>[Cl:1][CH:2]([Cl:18])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:7]([Cl:17])[CH:6]=1)[Cl:21]
Reactant: OC(c1ccc(C2CCCCC2)c(Cl)c1)C(Cl)Cl
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: Clc1cc(C(Cl)C(Cl)Cl)ccc1C1CCCCC1
Reaction time: 12 h

Procedure:
β,β-Dichloro-α-(3-chloro-4-cyclohexylphenyl)ethanol (67.5 g.; 0.22 moles) is heated with thionyl chloride (110 ml) containing 1 drop of pyridine until solution is obtained. The heating is discontinued and the reaction is allowed to proceed at room temperature for 12 hours. The reaction mixture is heated for an additional hour and the thionyl chloride removed, chased by benzene several times and distilled to give β,β,α,3-tetrachloro-4-cyclohexylphenylethane.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:18])([CH3:17])[CH:15]=O)[CH:11]=[CH:10][C:9]=2[NH:19][C:20]([C:22]2[NH:23][CH:24]=[C:25]([C:27]#[N:28])[N:26]=2)=[O:21])=[CH:4][CH2:3]1.[CH3:30][C:31]1([CH3:39])[O:38][CH:34]2[CH2:35][NH:36][CH2:37][CH:33]2[O:32]1>CO.C(Cl)Cl>[CH3:1][C:2]1([CH3:29])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:15])([CH3:17])[CH2:18][N:36]3[CH2:37][CH:33]4[O:32][C:31]([CH3:39])([CH3:30])[O:38][CH:34]4[CH2:35]3)[CH:11]=[CH:10][C:9]=2[NH:19][C:20]([C:22]2[NH:23][CH:24]=[C:25]([C:27]#[N:28])[N:26]=2)=[O:21])=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2cc(C(C)(C)C=O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: CC1(C)OC2CNCC2O1
Solvent: CO
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(C(C)(C)CN3CC4OC(C)(C)OC4C3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Yield: 61.8 %

Procedure:
The title compound was prepared by the procedure of Example 138, step (i) using 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1,1-dimethyl-2-oxo-ethyl)-phenyl]-amide (as prepared in Example 138, step (h), 60.0 mg, 0.154 mmol) and 2,2-dimethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole (Couturier, M. et at, Organic Process Research & Development, 2002, 6, 42-48, 132 mg, 0.924 mmol). Silica gel chromatography (1-3% MeOH/DCM) afforded the title compound (49.3 mg, 63%) as a white solid. 1H-NMR (1:1 CD3OD; 400 MHz): 8.13 (d, 1H, J=8.6 Hz), 7.98 (s, 1H), 7.32 (dd, 1H, J=8.6, 2.3 Hz), 7.21 (d, 1H, J=2.3 Hz), 5.73 (m, 1H), 4.48 (m, 2H), 2.70 (d, 2H, J=11.4 Hz), 2.59 (s, 2H), 2.31 (m, 2H), 2.08 (m, 2H), 1.98-2.04 (m, 2H), 1.59 (t, 2H, J=6.3 Hz), 1.44 (s, 3H), 1.34 (s, 6H), 1.23 (s, 3H), 1.09 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C30H39N5O3, 518.3 (M+H). found 518.3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[Cl:14][C:15]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:16]=1[CH2:17][NH2:18].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:18][CH2:17][C:16]3[CH:19]=[C:20]([C:23]([F:24])([F:25])[F:26])[CH:21]=[CH:22][C:15]=3[Cl:14])[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: NCc1cc(C(F)(F)F)ccc1Cl
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(Cl)c2cc(NCc3cc(C(F)(F)F)ccc3Cl)ccc12

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.58 mmol), 2-chloro-5-trifluoromethyl-benzylamine (135 mg, 0.64 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), rac-BINAP (132 mg, 0.17 mmol) and NaOt-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 80° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(2-chloro-5-trifluoromethyl-benzylamino)-2H-phthalazin-1-one: 18 mg (8.0%): m/z (M+H)=388. 1H-NMR (DMSO-d6) δ: 12.39 (s, 1H), 7.96 (d, 1H), 7.80 (m, 1H), 7.75 (m, 1H), 7.70 (m, 2H), 7.18 (dd, 1H), 6.84 (s, 1H), 4.59 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:7]2[S:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:24])=[CH:12][C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:14][C:4]=2[O:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[ClH:41].[CH2:42]([N:44]([CH2:51][CH3:52])[CH2:45][CH2:46][CH2:47][C:48](O)=[O:49])[CH3:43]>C(Cl)Cl>[ClH:41].[CH2:42]([N:44]([CH2:51][CH3:52])[CH2:45][CH2:46][CH2:47][C:48]([O:24][C:11]1[C:5]2[C:6]3[CH2:10][CH2:9][S:8][C:7]=3[C:2]([CH3:1])([CH3:25])[O:3][C:4]=2[CH:14]=[C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])[CH:12]=1)=[O:49])[CH3:43]
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCS1
Reactant: CCN(CC)CCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN(CC)CC)c2c(c1)OC(C)(C)C1=C2CCS1
Yield: 53 %

Procedure:
0.5 g. (1.39 mmole) of 1,2-dihydro-4,4-dimethyl-9-hydroxy-7-(3-methyl-2-octyl)-4H-thieno[2,3-c][1]benzopyran, 0.31 g. (1.50 mmole; Aldrich Chemical Co.) of dicyclohexylcarbodiimide and 0.272 g. (1.39 mmole) of 4-diethylaminobutyric acid hydrochloride (F. F. Blicke, W. B. Wright, Jr., and M. R. Zienty, J. Amer. Chem. Soc., 63 2488 (1941)) were combined in 30 ml. of methylene chloride and stirred at room temperature for 4 hours. The insoluble by-product of dicyclohexylurea was separated by filtration and the methylene chloride was removed on a rotary evaporator. Attempts to crystallize the material were unsuccessful and 400 mg. (53%) of dark brown residue was obtained. The structure was confirmed by the IR and NMR spectra; and TLC gave Rf 0.5 in 5% MeOH/CHCl3. The acid addition salt may be converted to the free base form by methods well known in the art, and the resulting free base form may then be reacted with another suitable acid to form a different acid addition salt.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][C:9]([C:11]1[S:12][C:13]2[C:19]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:18][CH:17]=[C:16]([O:26][CH3:27])[C:14]=2[N:15]=1)=O.FC(F)(F)C([O-])=O.[NH4+:35]>O>[CH3:27][O:26][C:16]1[C:14]2[N:15]=[C:11]([C:9]3[NH:35][C:2]4[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=4[N:8]=3)[S:12][C:13]=2[C:19]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[CH:18][CH:17]=1
Reactant: [NH4+]
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)NC3CCCCC3=O)nc12
Agent: O=C([O-])C(F)(F)F
Solvent: O
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCCC4)nc12
Temperature: 25 °C
Yield: 42.1 %

Procedure:
A mixture of 0.10 g 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid (2-oxo-cyclohexyl)-amide and 0.34 g ammonium triflouroacetate was melted at 165° C. for 50 minutes and, after cooling to room temperature, suspended in water. Extraction with dichloromethane and chromatography on silicagel with ethylacetate/hexane 6:4 gave 0.04 g (39%) 4-methoxy-7-morpholin-4-yl-2-(4,5,6,7-tetrahydro-1H-benzoimidazol-2-yl)-benzothiazole as light brown solid; MS (ISP): m/e=371 (M+H+).
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:6][CH2:5]1)=[O:3].[O-:7][CH2:8][CH3:9].[Na+]>C(OCC)(=O)C.C(O)C>[CH:4]1([C:2](=[O:3])[CH2:1][C:8](=[O:7])[CH3:9])[CH2:6][CH2:5]1
Reactant: CC[O-]
Reactant: CC(=O)C1CC1
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)C1CC1
Reaction time: 3 h

Procedure:
To a stirred solution of 8.4 g (0.1 mol) of cyclopropyl methyl ketone in 100 mL of ethyl acetate under nitrogen was added dropwise 39 mL (0.1 mol) of a 21 wt % solution of sodium ethoxide in absolute ethanol. The flask was fitted with a condenser and Dean-Stark trap and was heated. The ethanol was removed by azeotropic distillation. Additional ethyl acetate was added to the flask as needed. After three hours the temperature of the distillate had reached 75° C. and the reaction was allowed to cool and stand overnight. The white solid which precipitated out was collected by filtration and the filtrate was set aside. The solid was dissolved in water and this solution was acidified at 0° C. with 10% aqueous hydrochloric acid. This solution was extracted three times with ethyl ether. The ethyl acetate filtrate was washed with water three times, acidified with 10% aqueous hydrochloric acid, and extracted with ethyl ether. The ether extracts from both extractions were combined, dried over magnesium sulfate, and filtered. Removal of solvents gave 3.5 g of 1-cyclopropyl-1,3-butanedione as an oil. Analysis by GC showed 75% purity. This intermediate was used without further purification.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([O:30]CC)=O)[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43][NH2:44]>>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([NH:44][CH3:43])=[O:30])[C:24]=2[CH:33]=1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Product: CNC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12

Procedure:
Starting materials: Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and methylamine (2M in THF)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CS[C:9]1[N:10]=[N:11][CH:12]=[CH:13][N:14]=1.C(N(CC)CC)C.C(OCC)(=O)C>C(O)CCC>[N:1]1([C:9]2[N:10]=[N:11][CH:12]=[CH:13][N:14]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: CSc1nccnn1
Reactant: C1CNCCN1
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: c1cnc(N2CCNCC2)nn1
Temperature: 120 °C
Yield: 68.7 %

Procedure:
3.45 g (40.1 mmoles) of piperazine is placed in the presence of 1.7 g (13.4 mmoles) of intermediate 2a in 1-butanol. 6.5 ml (47 mmoles) of triethylamine is added and the mixture is heated for 24 hours at 120° C. After concentrating the reaction medium, the residue obtained is taken up with ethyl acetate and washed with water. After drying on MgSC4, the organic phase is concentrated to dryness. The residue obtained is purified by flash chromatography (CH2Cl2-MeOH-NH4OH gradient: 100-0-0 to 90-9-1). 1.52 g of intermediate 5a is obtained in brown oil form (yield: 69%).
Reaction SMILES: [CH2:1]([C:3]1[NH:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:5][CH:4]=1)[CH3:2].C1C(=O)N([I:20])C(=O)C1>>[CH2:1]([C:3]1[NH:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:5][C:4]=1[I:20])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)c1ncc(CC)[nH]1
Product: CCOC(=O)c1nc(I)c(CC)[nH]1
Yield: 100 %

Procedure:
The same operation as in Example (1c) was performed using ethyl 5-ethyl-1H-imidazole-2-carboxylate obtained by the method described in Example (1b) (0.20 g, 1.19 mmol) and NIS (0.29 g, 1.31 mmol), to obtain 0.35 g of the title compound as a pale yellow solid (100%).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][N:9]([CH2:33][CH2:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[C:10]([CH:12]([CH2:19][S:20]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)(=[O:22])=[O:21])[CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:35]1([CH2:34][CH2:33][N:9]([CH2:8][CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:10]([CH:12]([CH2:19][S:20]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)(=[O:21])=[O:22])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:11])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: COC(=O)CCC(CS(=O)(=O)c1ccc2ccccc2c1)C(=O)N(CCC1CCCCC1)CCC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCC(CS(=O)(=O)c1ccc2ccccc2c1)C(=O)N(CCC1CCCCC1)CCC1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.8 %

Procedure:
To a solution of methyl 4-[N,N-bis(2-cyclohexylethyl)carbamoyl]-5-(2-naphthylsulfonyl)pentanoate (150 mg) in ethanol (3 ml) was added a 1N sodium hydroxide solution (0.26 ml), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo, acidified with a dilute hydrochloric acid, extracted with ethyl acetate. The organic layer was washed with water, dried over MgSO4, and evaporated at reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give 86 mg of 4-[N,N-bis(2-cyclohexylethyl)carbamoyl]-5-(2-naphthylsulfonyl)pentanoic acid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C:9]#[CH:10])=[O:4].I[C@@:14]1([N:23]2[CH:30]=[CH:29][C:27](=[O:28])[NH:26][C:24]2=[O:25])[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17](O)[C@H:15]1O.CO>ClCCl>[F:1][C:2]([F:11])([F:12])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C:9]#[C:10][C:29]1[C:27](=[O:28])[NH:26][C:24](=[O:25])[N:23]([CH:30]=1)[C@@H:14]1[O:22][C@H:19]([CH2:20][OH:21])[CH2:17][CH2:15]1)=[O:4]
Reactant: C#CCCCNC(=O)C(F)(F)F
Reactant: O=c1ccn([C@]2(I)O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Solvent: ClCCl
Solvent: CO
Product: O=C(NCCCC#Cc1cn([C@H]2CC[C@@H](CO)O2)c(=O)[nH]c1=O)C(F)(F)F

Procedure:
5-Trifluroacetamido-1-pentyne (59) was coupled for 4 h to 5-iodo-2',3'-dideoxyuridine (47, prepared as described in Example 2A) according to the general procedure described in EXAMPLE 1C. Chromatography on silica gel (100 g) with a 0-5% methanol in dichloromethane gradient afforded 647.7 mg of alkynylamino nucleoside 58 as a light tan foam. This material was homogeneous by TLC and NMR except for the presence of about 16 mole % of dimethylformamide. Correcting for the presence of dimethylformamide, the yield of desired product was 80%.