Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=CC(C2ON=[C:13]3[C:16]4[C:21]([CH2:22][CH2:23][C:12]=23)=[CH:20][C:19]([CH:24]=[O:25])=[CH:18][CH:17]=4)=CC=1C(F)(F)F)C(C)C.[CH2:30]([C:35]1[S:36]C2C3C(=CC(C=C)=CC=3)CCC=2[N:39]=1)[CH2:31][CH2:32][CH2:33][CH3:34]>>[CH2:30]([C:35]1[S:36][C:13]2[C:16]3[C:21](=[CH:20][C:19]([CH:24]=[O:25])=[CH:18][CH:17]=3)[CH2:22][CH2:23][C:12]=2[N:39]=1)[CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: C=Cc1ccc2c(c1)CCc1nc(CCCCC)sc1-2
Reactant: CC(C)Cc1ccc(-c2onc3c2CCc2cc(C=O)ccc2-3)cc1C(F)(F)F
Product: CCCCCc1nc2c(s1)-c1ccc(C=O)cc1CC2

Procedure:
This compound was prepared according to the procedure described for Preparation 23D, employing 192 mgs of 2-pentyl-7-vinyl-4,5-dihydronaphtho[2,1-d]thiazole (86C). Yield: (190 mgs, 98%). LC/MS M+1=286.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.Br[CH2:18][CH2:19][C:20]([O:22]CC)=[O:21].C(=O)(O)[O-].[Na+]>C(O)C>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
The reaction mixture of 1-(3-trifluoromethylphenyl)piperazine (510 mg, 2.2 mmol), ethyl 3-bromopropionate (500 mg, 2.7 mmol), sodium bicarbonate (300 mg, 3.5 mmol) and ethanol (15 ml) was refluxed for 3 h till the amine disappeared completely. After the mixture was filtered, the resulting solid was dissolved in 5 ml dioxane and 14 ml 5% sodium hydroxide solution. The mixture was stirred at room temperature overnight, then it was acidified with concentrated hydrogen chloride. Solid was filtered and washed with water, and then dried to give 500 mg 3-[4-(3-trifluoromethylphenyl)-1-piperazinyl]propionic acid as a white solid, mp 228-230° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]1=[O:13].FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C1C(=O)N([I:41])C(=O)C1>>[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([F:12])([F:10])[F:11])=[C:4]([I:41])[C:3]1=[O:13]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc(C(F)(F)F)cc(=O)n1C
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(F)(F)F)c(I)c(=O)n1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 61.8 %

Procedure:
A mixture containing 1,6-dimethyl-4-(trifluoromethyl)-2-pyridone (2.1 g, 10.98 mmol), trifluoroacetic acid (18 mL) and trifluoroacetic anhydride (3.5 mL) was refluxed for 5 min. Then, NIS (3.15 g, 14 mmol) was added and the reaction mixture was stirred for 15 h. The reaction mixture was cooled to room temperature and the solvent was removed under vacuum. The residue was diluted with ethyl acetate (100 mL), was washed with saturated sodium bicarbonate solution (2×100 mL) and brine solution (100 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave a crude product, which was purified by silica gel chromatography on a Biotage (40m) column to afford 2.15 g (62% yield) of 1,6-dimethyl-3-iodo-4-(trifluoromethyl)-2-pyridone as an amorphous white solid. EI-HRMS m/e calcd for C8H7F3INO (M+) 316.9524, found 316.9527.
Reaction SMILES: [C:1]([Si:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[OH:19][CH2:20][C@H:21]([CH3:27])[CH2:22][C:23]([O:25][CH3:26])=[O:24].N1C=CN=C1.O>C(Cl)Cl>[Si:5]([O:19][CH2:20][C@H:21]([CH3:27])[CH2:22][C:23]([O:25][CH3:26])=[O:24])([C:1]([CH3:4])([CH3:3])[CH3:2])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)C[C@@H](C)CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: COC(=O)C[C@@H](C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.6 %

Procedure:
tert-Butyl(chloro)diphenylsilane (26.5 g) was added dropwise to a solution of methyl (R)-4-hydroxy-3-methyl-butyrate (11.0 g) and imidazole (8.5 g) in methylene chloride (200 mL) under ice cooling, and the mixture was then stirred at room temperature for 24 hours. Water was added thereto to separate an organic layer. The organic layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: hexane→hexane/ethyl acetate=97/3) to obtain the title compound (29.8 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH3:7])[CH:3]1[OH:8].[C:9]([O:13][C:14]([NH:16][C:17]1([C:20](O)=[O:21])[CH2:19][CH2:18]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:9]([O:13][C:14]([NH:16][C:17]1([C:20]([O:8][CH:3]2[CH:4]([CH3:7])[CH2:5][CH2:6][CH:2]2[CH3:1])=[O:21])[CH2:19][CH2:18]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC1CCC(C)C1O
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1CCC(C)C1OC(=O)C1(NC(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
To a solution of 2,5-dimethylcyclopentanol (0.55 g), compound 1 (0.97 g), and 4-(dimethylamino)pyridine (0.06 g) in methylene chloride (100 ml) was added dicyclohexylcarbodiimide (1.09 g), and the resulting mixture was stirred overnight. The precipitated dicyclohexylurea was removed by filtration, and the filtrate was evaporated. Ethyl acetate was then added to the residue, and the mixture was filtered again. The filtrate was washed with 1M hydrochloric acid, saturated aqueous sodium bicarbonate, and water, dried over magnesium sulfate, and the solvent was evaporated to a colorless oil (1.18 g. 83%). The product was purified by column chromotography on silica gel, 4:1 hexane:ethyl acetate, eluent. NMR (CDCl3): δ0.92 (t, 6H, 2CH3), 1.05-2.10 (m, 10H, cyclopentyl, cyclopropyl), 1.40 (s, 9H, t-Bu), 4.60 (dd., 1H, CO2CH), 5.05 (br. s, 1H, NH).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][C@@H:9]2[CH:16]3[CH2:17][N:12]4[CH2:13][CH:14]([CH2:18][CH:10]2[CH2:11]4)[CH2:15]3)=[N:6][CH:7]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1B(O)O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=C(C2SC(O[C@@H]3C4CN5CC(CC3C5)C4)=NN=2)C=N1.N>>[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:2]1[CH:3]=[CH:4][C:5]([O:8][C@@H:9]2[CH:16]3[CH2:17][N:12]4[CH2:13][CH:14]([CH2:18][CH:10]2[CH2:11]4)[CH2:15]3)=[N:6][CH:7]=1
Reactant: Brc1ccc(OC2C3CC4CC2CN(C4)C3)nc1
Reactant: OB(O)c1cccs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Agent: c1n[nH]cc1-c1nnc(OC2C3CC4CC2CN(C4)C3)s1
Product: c1csc(-c2ccc(OC3C4CC5CC3CN(C5)C4)nc2)c1

Procedure:
The free base of the title compound was prepared from the product of Example 10C (50 mg, 0.16 mmol) and 2-thiophene boronic acid (29 mg, 0.23 mmol; Aldrich) according to Method G, and converted to the p-toluenesulfonate salt using the procedure of Method H: 1H NMR (300 MHz, methanol-D4) δ ppm 1.92 (d, J=13.6 Hz, 2H), 2.19 (s, 1H), 2.32-2.46 (m, 6H), 2.55 (s, 2H), 3.57 (s, 2H), 3.68 (s, 4H), 5.46 (s, 1H), 6.93 (d, J=8.5 Hz, 1H), 7.10 (dd, J=5.1, 3.4 Hz, 1H), 7.22 (d, J=8.5 Hz, 2H), 7.37 (dd, J=15.3, 4.4 Hz, 2H), 7.70 (d, J=8.1 Hz, 2H), 7.97 (dd, J=8.6, 2.5 Hz, 1H), 8.38 (d, J=2.7 Hz, 1H). MS (DCI/NH3) m/z=313 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[C:11]1[CH2:24][CH2:25][CH2:26][CH3:27].[CH3:28][S:29](Cl)(=[O:31])=[O:30]>>[NH2:23][C:14]1[C:13]2[N:12]=[C:11]([CH2:24][CH2:25][CH2:26][CH3:27])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:29]([CH3:28])(=[O:31])=[O:30])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCN
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCNS(C)(=O)=O
Yield: 48.2 %

Procedure:
Using the general method of Example 242, 1-(8-aminooctyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.2 g, 3.26 mmol) was reacted with methanesulfonyl chloride (260 μL, 3.26 mmol) to provide 0.70 g of N-[8-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)octyl]methanesulfonamide as a tan powder, m.p. 121-124° C. Analysis: Calculated for C23H35N5O3S: % C, 61.99: % H, 7.92; % N, 15.72; Found: % C, 62.01; % H, 7.97; % N, 15.75.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:22])=[C:5]2[C:10]=1[C:9]([CH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](O)=[O:16])=[N:8][NH:7][C:6]2=[O:21].[CH3:23][O:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)CC)C>CN(C=O)C>[CH3:23][O:24][CH:25]1[CH2:30][CH2:29][N:28]([C:15]([C:14]2[CH:13]=[C:12]([CH:20]=[CH:19][CH:18]=2)[CH2:11][C:9]2[C:10]3[C:5](=[C:4]([CH3:22])[NH:3][C:2]=3[CH3:1])[C:6](=[O:21])[NH:7][N:8]=2)=[O:16])[CH2:27][CH2:26]1
Reactant: COC1CCNCC1
Reactant: Cc1[nH]c(C)c2c(=O)[nH]nc(Cc3cccc(C(=O)O)c3)c12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC1CCN(C(=O)c2cccc(Cc3n[nH]c(=O)c4c(C)[nH]c(C)c34)c2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.3 %

Procedure:
2-(1H-Benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.179 g, 0.47 mmol) was added to 3-((5,7-dimethyl-1-oxo-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-4-yl)methyl)benzoic acid (51) (0.100 g, 0.34 mmol), 4-methoxypiperidine (0.043 g, 0.37 mmol) and triethylamine (0.117 mL, 0.84 mmol) in DMF (2 mL). The resulting solution was stirred at room temperature for 5 hours. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound (0.054 g, 40.9% yield). 1H NMR (400.132 MHz, DMSO) δ 1.18-1.93 (4H, m), 2.24 (3H, s), 2.51 (3H, s), 3.02-3.19 (2H, m), 3.25 (3H, s), 3.40 (2H, m), 3.76-3.97 (1H, m), 4.09 (2H, s), 7.14 (1H, s), 7.20 (1H, d), 7.27 (1H, d), 7.36 (1H, t), 11.08 (1H, s), 11.92 (1H, s); m/z (LC-MS, ESI+), RT=1.38 min (M+H=395.09).
Reaction SMILES: [CH2:1]([N:3]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]2[O:19][C:20]([CH:23]=[O:24])=[CH:21][CH:22]=2)=[CH:12][CH:11]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]O)[CH3:2].C1CCC(N=C=NC2CCCCC2)CC1.[I:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[CH:43][CH:42]=1.CN(C1C=CC=CN=1)C>O1CCCC1>[CH2:1]([N:3]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]2[O:19][C:20]([CH:23]=[O:24])=[CH:21][CH:22]=2)=[CH:12][CH:11]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:45](=[O:46])[C:44]1[CH:48]=[CH:49][C:41]([I:40])=[CH:42][CH:43]=1)[CH3:2]
Reactant: O=C(O)c1ccc(I)cc1
Reactant: CCN(CCCCCO)c1ccc(C=Cc2ccc(C=O)o2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: CCN(CCCCCC(=O)c1ccc(I)cc1)c1ccc(C=Cc2ccc(C=O)o2)cc1
Reaction time: 8 h

Procedure:
In a 200 mL flask, 5 (7.63 g, 23.3 mmol), DCC (4.81 g, 23.3 mmol), 4-iodobenzoic acid (5.79 g, 23.3 mmol), and dimethylamino pyridine (0.85 g, 7.0 mmol) were dissolved in tetrahydrofuran (20 vol., 150 mL, freshly distilled from sodium and benzophenone) at room temperature and stirred overnight under Ar. The reaction mixture was filtered and the filtrate was added to a separatory funnel containing ether and water. The ether layer was rinsed several times with water, followed by dilute K2CO3, and then with dilute aqueous brine. The organic layer was evaporated onto silica gel and subsequently purified on silica gel with 3:1 hexane:ethyl acetate. Product 6A was a red viscous liquid (100% trans).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[C:10]2[C:11](=[O:15])[NH:12][CH:13]=[CH:14][C:9]=2[S:8][C:7]=1[CH3:16]>S(=O)(=O)(O)O>[Br:5][C:6]1[C:10]2[C:11](=[O:15])[NH:12][CH:13]=[C:14]([N+:1]([O-:4])=[O:2])[C:9]=2[S:8][C:7]=1[CH3:16]
Reactant: O=[N+]([O-])O
Reactant: Cc1sc2cc[nH]c(=O)c2c1Br
Agent: O=S(=O)(O)O
Product: Cc1sc2c([N+](=O)[O-])c[nH]c(=O)c2c1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
A solution of nitric acid (1.68 mL, 70%, 26.8 mmol) in sulfuric acid (5 mL) was added dropwise to a 0° C. solution of Example 66A (3.27 g, 13.4 mmol) in sulfuric acid (15 mL). The resulting mixture was stirred at 0° C. for 1 hour, warmed to room temperature overnight, and poured into ice water. The resulting precipitate was collected by filtration, washed with water, and dried in a vacuum oven to provide 2.47 g (64% yield) of the desired product. MS (ESI(+)) m/e 290 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[F:12][C:13]([F:28])([F:27])[C:14]1[CH:15]=[C:16]([N:24]=[C:25]=[O:26])[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1>>[F:12][C:13]([F:27])([F:28])[C:14]1[CH:15]=[C:16]([NH:24][C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[CH:5]3)=[O:26])[CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:19]=1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Nc1ccc2ncccc2c1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Nc1ccc2ncccc2c1

Procedure:
Prepared from 6-aminoquinoline and 3,5-bis(trifluoromethyl)phenyl isocyanate. m/z (ES+) 400 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][N:24]([CH3:31])[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:23][N:24]([CH3:31])[CH:25]1[CH2:30][CH2:29][N:28]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:27][CH2:26]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: CN(C)C1CCNCC1
Product: CN(C)C1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with N,N-dimethylpiperidin-4-amine (1.2 equiv) to give 175 (17.9 mg, M+1 424.1)
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[N:17]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]3=[N:15][N:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:22][C:19]1[CH:20]=[CH:21][C:16]2[N:17]([C:13]([C@@H:10]3[CH2:11][CH2:12][NH:8][CH2:9]3)=[N:14][N:15]=2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2nnc3ccc(F)cn23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc2nnc([C@@H]3CCNC3)n2c1

Procedure:
A mixture of Intermediate 90b (335 mg, 1.09 mmol) and TFA (0.812 mL, 10.9 mmol) in DCM (5 mL) was stirred at reflux for 45 min. The cooled solution was concentrated in vacuo, redissolved in MeOH (2 mL), applied to an SCX-2 cartridge (10 g) and washed with MeOH (50 mL). The product was eluted with 2M NH3 in MeOH; concentration in vacuo left the title compound as a pale yellow solid (225 mg, >99%). LCMS (Method 3): Rt 0.44 min, m/z 207 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:6]=[N:7][C:8]([CH2:14][CH3:15])=[C:9]([CH2:11][CH:12]=C)[CH:10]=1.[O:17]=[O+][O-].CSC>CO.ClCCl>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:6]=[N:7][C:8]([CH2:14][CH3:15])=[C:9]([CH2:11][CH:12]=[O:17])[CH:10]=1
Reactant: C=CCc1cc(CC(=O)OC)cnc1CC
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Solvent: CSC
Product: CCc1ncc(CC(=O)OC)cc1CC=O
Reaction time: 8 h
Yield: 78 %

Procedure:
A solution of 5-allyl-6-ethyl-pyridin-3-yl-acetic acid methyl ester (1.00 g, 4.56 mmol) in 50% methanol in dichloromethane solution (25 mL, 0.2 M) is cooled to −78° C. and treated with ozone. After the solution became blue (30 min), it is purged with nitrogen and treated with dimethyl sulfide (1.7 mL, 23 mmol). After stirring overnight the solvent is removed in vacuo and the product is purified by flash chromatography (50% ethyl acetate in n-heptane) to provide 6-ethyl-5-(2-oxo-ethyl)-pyridin-3-yl-acetic acid methyl ester as a clear oil (0.78 g, 78%): Rf 0.26 (50% ethyl acetate in n-heptane), 1H NMR (CDCl3, 300 MHz) δ 9.77 (s, 1 H), 8.41 (s, 1 H), 7.43 (s, 1 H), 3.76 (s, 2 H), 3.72 (s, 3 H), 3.62 (s, 2 H), 2.77 (q, J=7.5 Hz, 2H), 1.27 (t, J=7.5 Hz, 3H). ESI-LCMS m/z calcd for C12H15NO3: 221.1; found 222.0 (M+1)+.
Reaction SMILES: [OH-].[Na+].Cl.ClCC[NH2:7].F[C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1>O>[C:13]([NH2:7])(=[O:14])[C:12]1[CH:16]=[CH:17][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
In a 1 L round bottom flask, 50.4 g sodium hydroxide (1.26 mol) was dissolved in 500 mL water (˜10% solution). 66.6 g (0.574 mol) 2-chloroethylamine hydrochloride was then added and the solution stirred in an ice bath at 0° C. until the salt was completely dissolved. 100 g (0.631 mol) 4-fluorobenzoyl chloride was then added dropwise via an addition funnel into the vigorously stirred solution. After addition, the solution stirred at 0° C. for 1 hour followed by stirring at room temperature for 1 hour. The cloudy mixture was then filtered to remove the water and the solids washed with ether and then filtered to give 118 g crude (slightly wet) benzamide (Alternatively, the solids could be dissolved in methylene chloride, dried with magnesium sulfate, filtered and evaporated to completely remove water from the solids). These solids were recrystallized from 120 ml EtOAc/200 mL hexanes to give 88.2 g crystalline N-(2-chloroethyl)-4-fluorobenzamide after hexanes wash and drying (an additional 6.22 g benzamide recrystallized from the original water mother liquor). NMR confirmed the structure of this compound (81.4% total yield).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[S:7][C:8]([C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[CH:19])=[O:12])=[CH:9][N:10]=2)[CH2:2]1.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>C(O)C>[C:20]([NH:24][CH2:2][CH:3]([OH:1])[CH2:4][O:5][C:6]1[S:7][C:8]([C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[CH:19])=[O:12])=[CH:9][N:10]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: C#CCCCCNC(=O)c1cnc(OCC2CO2)s1
Reactant: CC(C)(C)N
Solvent: CCO
Product: C#CCCCCNC(=O)c1cnc(OCC(O)CNC(C)(C)C)s1
Temperature: -20 °C
Reaction time: 12 h

Procedure:
This examole illustrates methods for preparing the compounds of the present invention. In this examole a mixture containing 12 g. (0.037 mole) of 1,2-epoxy-3-[5-(hex-5-ynylaminocarbonyl)thiazol-2-yloxy]propane, 12 g. (0.164 mole) of t-butylamine and 20 ml. of ethanol is allowed to stand at room temperature for 12 hours. The mixture is then evaporated under vacuum to remove the ethanol solvent and the resulting residue dissolved in 50 ml. of ethyl acetate and cooled to -20° C, and maintained at this temperature for two hours. The mixture is then filtered and the resulting filter cake washed with cold (about 0° C) ethyl ether and then recrystallized from ethyl acetate affording 1-t-butylamino-3-[5-(hex-5-ynylaminocarbonyl)thiazol-2-yloxy]propan-2-ol, m.p. 140°-148° C.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@H:14]([CH2:15][C:16](=[O:24])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3>C(O)(C)C>[OH:24][C@@H:16]1[CH2:17][CH2:18][C@@:19]2([CH3:20])[C@@H:14]([CH2:13][CH2:12][C@@H:11]3[C@@H:21]2[CH2:22][CH2:23][C@@:6]2([CH3:7])[C@H:8]3[CH2:9][CH2:10][C@@H:5]2[O:4][CH3:3])[CH2:15]1
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1 h

Procedure:
Sodium borohydride (0.37 gms.) is added to a mixture of 17β-methoxy-5α-androstan-3-one (3 gms.) and isopropylalcohol (95%, 35 ml.). The mixture is stirred at 20°-25° for one hour and then is concentrated to dryness. The residue is column chromatographed on a size C prepacked Merck silica gel column. Elution was performed with ethyl acetate:cyclohexane, 10:90. 6 Ml. fractions are collected. The appropriate fractions (TLC) are combined and concentrated to dryness. The residue is recrystallized from isopropyl ether to give 3α-hydroxy-17β-methoxy-5α-androstane, m.p. 164°-167°; IR (mull) 3290, 3220, 1120, 1110, 1005 cm-1 ; NMR (CDCl3) 0.72, 0.76, 0.9-2.0, 3.21, 3.3, and 4.01 δ and 3β-hydroxy-17β-methoxy-5α-androstane, m.p. 150°-152°; NMR (CDCl3) 0.75-2.0, 3.25, 3.37 and 3.6 δ.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Cl[CH2:19][C:20]1[CH:28]=[CH:27][C:23]2[O:24][CH2:25][O:26][C:22]=2[CH:21]=1>>[O:24]1[C:23]2[CH:27]=[CH:28][C:20]([CH2:19][N:16]3[CH:11]([C:4]4[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]3=[O:17])=[CH:21][C:22]=2[O:26][CH2:25]1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Reactant: ClCc1ccc2c(c1)OCO2
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc2c(c1)OCO2

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 5-(chloromethyl)benzo[d][1,3]dioxole. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.71 min.; [M+H]+: 369.68 g/mol.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[O:15][CH:16]([CH3:21])[C:17]([F:20])([F:19])[F:18].[OH-].[Na+]>C1COCC1>[CH3:12][NH:11][S:10]([C:8]1[CH:7]=[CH:6][C:5]([O:15][CH:16]([CH3:21])[C:17]([F:19])([F:18])[F:20])=[C:4]([CH:9]=1)[C:3]([OH:22])=[O:2])(=[O:13])=[O:14]
Reactant: CNS(=O)(=O)c1ccc(OC(C)C(F)(F)F)c(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(OC(C)C(F)(F)F)c(C(=O)O)c1
Temperature: 50 °C

Procedure:
To 1.6 mmol 5-methylsulfamoyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid methyl ester in 10 ml THF was added 20 mmol 2 M aq NaOH, and the mixture was heated at 50° C. for 2 h. The mixture was then cooled to RT and extracted twice with ether. The aqueous phase was acidified with 10% aq citric acid and extracted twice with ethyl acetate. The combined organic phases were dried with Na2SO4. Evaporation in vacuo followed by trituration in ether and hexane afforded the title compound. MS (m/e): 326.2 ([M−H]−, 100%)
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][CH2:7][CH2:8][CH2:9][C:10]1([CH3:17])[NH:14][C:13](=[O:15])[NH:12][C:11]1=[O:16].NCCC[C:22]1(C)[NH:26]C(=O)NC1=O.CSC(=N)[NH2:33]>[OH-].[Ba+2].[OH-]>[NH2:33][N:26]=[CH:22][NH:6][CH2:7][CH2:8][CH2:9][C:10]1([CH3:17])[NH:14][C:13](=[O:15])[NH:12][C:11]1=[O:16]
Reactant: CSC(=N)N
Reactant: CC1(CCCN)NC(=O)NC1=O
Agent: O=S(=O)(O)O
Agent: [Ba+2]
Agent: [OH-]
Product: CC1(CCCNC=NN)NC(=O)NC1=O
Reaction time: 4 h

Procedure:
The compound 5-(3-aminopropyl)-5-methyl-2,4-imidazolidinedione hemisulfate (229 mg, 1 mmol) was dissolved in 0.418 N aqueous barium hydroxide (3.5 ml.) and S-methylisothiourea (153.1 mg, 1.1 mol) was added. The suspension was shaken at room temperature for 6 1/4 hours and 0.418 N aqueous barium hydroxide (1 ml.) was added, followed by another 0.5 ml. of the aforementioned barium hydroxide solution 18 hours later. After 4 hours, S-methylisothiourea (70 mg., 0.5 mmol) was added and shaking of the suspension was continued for 66 hours. At that time only traces of 5-(3-aminopropyl)-5-methyl-2,4-imidazolidinedione hemisulfate could be detected. Barium sulfate was filtered off and washed with water, filtrate and washings were applied to a column containing 5 ml. of sulfonated polystyrene ion exchange resin, the column was washed consecutively with water (50 ml.) 10% by volume aqueous pyridine (25 ml.) and 2.5 M aqueous ammonium hydroxide solution (25 ml). Concentration of the ammoniacal effluent gave a colorless syrup from which crystalline 5-(3-[(aminoiminomethyl) amino]propyl)-5-methyl-2,4-imidazolidinedione was deposited on standing (207 mg., 0.97 mmol, 97%). Recrystallization from water afforded 5-(3-[(amino-iminomethyl)amino]propyl)-5-methyl-2,4-imidazolidienedione as fine needles, m.p. 294°-295° C.