Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[N:18]1[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][C:7](=[O:11])[NH:8]3)=[CH:4][CH:3]=2)[CH:19]=1
Reactant: O=C1Cc2ccc(Br)cc2N1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1Cc2ccc(-c3cccnc3)cc2N1
Temperature: 100 °C
Reaction time: 12 h
Yield: 42 %

Procedure:
To a warm, stirred solution of 6-bromo-2-oxindole (4 g, 26.3 mmol) in 60 mL toluene and 60 mL ethanol was added tetrakis(triphenylphosphine)palladium(0) (2.3 g, 1.9 mmol) followed by 2M aqueous sodium carbonate (50 mL, 100 mmol) and pyridine-3-boronic acid, propanediol ester (5 g, 30.7 mmol). The mixture was stirred at 100° C. in an oil bath for 12 hours. The reaction mixture was cooled, diluted with ethyl acetate (500 mL) and washed with saturated sodium bicarbonate (200 mL), water (200 mL) and brine (200 mL). The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated to afford a brown solid. The solid was triturated with methylene chloride/diethyl ether to give 2.32 g (42%) of 6-pyridin-3-yl-1,3-dihydro-indol-2-one as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([C:10](Cl)([F:12])[F:11])=[N:6][C:5]=1[CH2:14][CH2:15][CH2:16][O:17][CH3:18].[H][H]>CO.C(N(CC)CC)C.[Pd]>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([F:11])[F:12])=[N:6][C:5]=1[CH2:14][CH2:15][CH2:16][O:17][CH3:18]
Reactant: COCCCc1nc(C(F)(F)Cl)ccc1C(=O)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: COCCCc1nc(C(F)F)ccc1C(=O)OC
Yield: 113.4 %

Procedure:
A solution of 194 g of 6-(Chloro-difluoro-methyl)-2-(3-methoxy-propyl)-nicotinic acid methyl ester (prepared according to WO 04/078729) in methanol (ca. 2 liter) and triethylamine (100 ml) is hydrogenated at 1 Atm hydrogen pressure in the presence of 2 g of 5% palladium supported on carbon. After completion of the reduction the reaction mixture is filtered through hyflo, and the filtrate diluted with water and the water/methanol mixture then extracted with ethyl acetate. The combined ethyl acetate extracts are washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and then concentrated in vacuo to give 194.2 g 6-Difluoromethyl-2-(3-methoxy-propyl)-nicotinic acid methyl ester as a pale coloured oil.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([O:16][C:17]([CH2:19][O:20][N:21]=[C:22]([C:62]1[N:63]=[CH:64][S:65][CH:66]=1)[C:23]([NH:25][CH:26]1[C:60](=[O:61])[N:28]2[C:29]([C:44]([O:46][CH:47]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:45])=[C:30]([CH2:33][S:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([CH:41]=[N:42][N:43]=4)[N:40]=3)[CH2:31][S:32][C@H:27]12)=[O:24])=[O:18])([CH3:15])([CH3:14])[CH3:13].C(OC(CON=C(C1N=CSC=1)C(NC1C(=O)N2C(C(OC(C3C=CC=CC=3)C3C=CC=CC=3)=O)C(CSC3C=CC4N(C=NN=4)N=3)=CS[C@H]12)=O)=O)(C)(C)C>C(OCC)(=O)C>[C:12]([O:16][C:17]([CH2:19][O:20][N:21]=[C:22]([C:62]1[N:63]=[CH:64][S:65][CH:66]=1)[C:23]([NH:25][CH:26]1[C:60](=[O:61])[N:28]2[C:29]([C:44]([O:46][CH:47]([C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)=[O:45])=[C:30]([CH2:33][S:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([CH:41]=[N:42][N:43]=4)[N:40]=3)[CH2:31][S:32](=[O:9])[C@H:27]12)=[O:24])=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3ccc4nncn4n3)CS[C@H]12)c1cscn1
Agent: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(CSc3ccc4nncn4n3)=CS[C@H]12)c1cscn1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3ccc4nncn4n3)CS(=O)[C@H]12)c1cscn1
Yield: 91 %

Procedure:
A solution of m-chloroperbenzoic acid (0.4 g) (purity: 80%) in ethyl acetate (5 ml) was added to a solution of a mixture (1.4 g) of benzhydryl 7-[2-t-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamido]-3-(1,2,4-triazolo[4,3-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer) and benzhydryl 7-[2-t-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamido]-3-(1,2,4-triazolo[4,3-b]pyridazin-6-yl)thiomethyl-2-cephem-4-carboxylate (syn isomer) in ethyl acetate (10 ml) under ice-cooling and the resultant mixture was stirred for 1 hour at the same temperature. The resulting solution was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, successively. The organic layer was dried over magnesium sulfate and evaporated to give benzhydryl 7-[2-t-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamido]-3-(1,2,4-triazolo[4,3-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylate-1-oxide (syn isomer) (1.3 g).
Reaction SMILES: [C@@H:1]12[O:9][CH2:8][C@@H:6]([O:7]1)[CH:5]=[CH:4][C@@H:2]2[OH:3].[S:10](Cl)([CH3:13])(=[O:12])=[O:11].Cl>N1C=CC=CC=1>[S:10]([O:3][C@H:2]1[CH:4]=[CH:5][C@H:6]2[CH2:8][O:9][C@@H:1]1[O:7]2)([CH3:13])(=[O:12])=[O:11]
Reactant: O[C@H]1C=C[C@H]2CO[C@@H]1O2
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)O[C@H]1C=C[C@H]2CO[C@@H]1O2
Yield: 63.7 %

Procedure:
0.25 g (1.98 mmol) of 1,6-anhydro-3,4-dideoxy-β-D-threo-hex-3-enopyranose were dissolved in 2 ml of pyridine, and 0.34 g (3.00 mmol) of mesyl chloride were dropped in this mixture under ice-water cooled conditions. The resultant solution was stirred at 0° C. for 3.5 hours and then stored in a refrigerator overnight. This reaction solution was added to 1N hydrochloric acid under ice-water cooled conditions, and extraction was performed using diethyl ether. The resultant diethyl ether solution was washed with an aqueous sodium hydrogencarbonate solution and then with an aqueous sodium chloride solution. The washed solution was dried using magnesium sulfate. The solvent was distilled at a reduced pressure, and the residue was recrystallized using a solvent mixture of hexane, diethyl ether, and ethyl acetate (a mixing ratio of 5:5:2), thereby obtaining 0.26 g (yield: 62.6%) of 1,6-anhydro-3,4-dideoxy-2-O-mesyl-β-D-threo-hex-3-enopyranose.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].O.C[C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH:15]=O)=O)=[CH:9][CH:8]=1.[OH-].[K+].[CH2:19]([OH:21])C>>[CH3:19][O:21][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:15]=[N:4][CH:1]=[CH:2][N:3]=2)=[CH:11][CH:12]=1
Reactant: Cc1ccc(C(=O)C=O)cc1
Reactant: CCO
Reactant: NCCN
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(-c2cnccn2)cc1
Yield: 37 %

Procedure:
The procedure of Example 1 was repeated, using 10.68 g (0.178 mol) of ethylenediamine, 27.0 g (0.148 mol) of 4-methylphenylglyoxal monohydrate, 200 ml of ethanol and 9.01 g of potassium hydroxide. 10.1 g of the titled compound was produced (yield: 37%).
Reaction SMILES: [C:1](Cl)(=[O:3])C.[CH3:5][C:6]1[S:7][CH:8]=[C:9]([CH:11]([O:14][Si](C)(C)C)[C:12]#N)[N:10]=1.C[OH:20]>>[OH:14][CH:11]([C:9]1[N:10]=[C:6]([CH3:5])[S:7][CH:8]=1)[C:12]([O:3][CH3:1])=[O:20]
Reactant: CO
Reactant: Cc1nc(C(C#N)O[Si](C)(C)C)cs1
Reactant: CC(=O)Cl
Product: COC(=O)C(O)c1csc(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Acetyl chloride 725 μL, 10.2 mmol) was dropped at 0° C. in methanol (10 mL). After 30 minutes, a solution of 2-(2-methyl-1,3-thiazol-4-yl)-2-[(trimethylsilyl)oxy]acetonitrile (15a) (3.93 mmol) in methanol (30 mL) was added at 0° C. to the reaction. The mixture was then warmed at room temperature for 20 hours and concentrated under vacuum. A saturated aqueous solution of sodium bicarbonate (20 mL) was added to the residue and extracted with dichloromethane (2×20 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (dichloromethane/ethyl acetate 80/20) to afford the desired hydroxyl-ester (15b) as a yellow oil (560 mg, 2.99 mmol, 90%).
Reaction SMILES: Cl.Cl[C:3]1C=CC=C[C:4]=1C(OC1CNC1)C1C=CC=CC=1Cl.[N-]=C=O.[Cl:25][C:26]1[CH:51]=[CH:50][CH:49]=[CH:48][C:27]=1[CH:28]([O:36][CH:37]1[CH2:40][N:39]([C:41]([NH:43][C:44]([CH3:47])([CH3:46])C)=[O:42])[CH2:38]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35]>>[Cl:25][C:26]1[CH:51]=[CH:50][CH:49]=[CH:48][C:27]=1[CH:28]([O:36][CH:37]1[CH2:40][N:39]([C:41]([NH:43][CH:44]2[CH2:46][CH2:4][CH2:3][CH2:47]2)=[O:42])[CH2:38]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35]
Reactant: Clc1ccccc1C(OC1CNC1)c1ccccc1Cl
Reactant: CC(C)(C)NC(=O)N1CC(OC(c2ccccc2Cl)c2ccccc2Cl)C1
Agent: Cl
Agent: [N-]=C=O
Product: O=C(NC1CCCC1)N1CC(OC(c2ccccc2Cl)c2ccccc2Cl)C1

Procedure:
This material was prepared from 3-(2,2′-dichlorobenzhydryloxy)azetidine hydrochloride (68) and the corresponding commercially available isocyanate using the procedure described for compound (69).
Reaction SMILES: [C:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[CH:15]=[N:16][C:17]([C:18](OCC)=[O:19])=[C:7]2[C:6]1=[O:23])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27].[H-].[Na+].C(O)(=O)C>O1CCCC1>[C:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[CH:15]=[N:16][C:17]([C:18](=[O:19])[CH2:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[C:7]2[C:6]1=[O:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ncn2c1c(=O)n(C(C)(C)C)c1ccccc12
Reactant: CC(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)CC(=O)c1ncn2c1c(=O)n(C(C)(C)C)c1ccccc12

Procedure:
To a stirred mixture of ethyl 5-tert-butyl-4,5-dihydro-4-oxo-imidazo[1,5-a]quinoxaline-3-carboxylate (1.6 g, 5 mmol) and pinacolone (1.25 ml, 10 mmol) in dry tetrahydrofuran (THF) (30 ml) was added sodium hydride (200 mg, 80% in mineral oil, 6.9 mmol). The mixture was brought to reflux for 2 h, then cooled to room temperature and neutralized with acetic acid. After evaporation of the solvent the residue was partitioned between sat. aqueous NaHCO3 (10 ml) and methylene chloride (30 ml). The organic phase was dried over Na2SO4 and evaporated to give the title compound as yellow crystals. M.p. 190°-191 ° C. (Compound 1).
Reaction SMILES: C.C1C(Br)=C(Br)[NH:4]C=1C(O)=O.N([O-])=O.[Na+].[CH2:16]([C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].[N+:37]([O-:40])([OH:39])=[O:38]>O.CC(C)=O>[N+:37]([O-:40])([O-:39])=[O:38].[CH2:16]([C:30]1[CH:31]=[CH:32][C:33]([N+:34]#[N:4])=[CH:35][CH:36]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCCCc1ccc(N)cc1
Reactant: O=C(O)c1cc(Br)c(Br)[nH]1
Reactant: O=[N+]([O-])O
Agent: C
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCc1ccc([N+]#N)cc1
Product: O=[N+]([O-])[O-]

Procedure:
A carbon black with a surface area of 58 m2 /g and a DBPA of 46 ml/100 g was used. A suspension of 50 g of this carbon black was prepared by stirring it into 450 g of water. A solution of 0.85 g of NaNO2 in 4 g of cold water was slowly added to a dispersion of 2.98 g of 4-tetradecylaniline, 1.98 g of concentrated nitric acid and 4 ml of acetone in 15 g of water that was cooled in an ice bath. 4-Tetradecylbenzenediazonium nitrate was formed. After 15 minutes of stirring, the mixture was added to the stirring carbon black suspension. Bubbles were released. After 30 minutes, the product was collected by filtration, washed with water and tetrahydrofuran (THF) and dried in an oven at 125° C. The carbon black product had attached p-C6 H4C14H29 groups.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([N:30]2[CH2:40][C:39]([CH3:42])([CH3:41])[C:38](=[O:43])[N:37]([CH3:44])[C:36]3[C:31]2=[N:32][C:33]([NH:45][C:46]2[CH:54]=[CH:53][C:49]([C:50]([OH:52])=O)=[CH:48][C:47]=2[O:55][CH3:56])=[N:34][CH:35]=3)[CH2:29][CH2:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.Cl.Cl.[NH2:68][CH:69]1[CH2:74][CH2:73][CH2:72][N:71]([CH3:75])[CH2:70]1>CC(N(C)C)=O>[CH:25]1([N:30]2[CH2:40][C:39]([CH3:41])([CH3:42])[C:38](=[O:43])[N:37]([CH3:44])[C:36]3[C:31]2=[N:32][C:33]([NH:45][C:46]2[CH:54]=[CH:53][C:49]([C:50]([NH:68][CH:69]4[CH2:74][CH2:73][CH2:72][N:71]([CH3:75])[CH2:70]4)=[O:52])=[CH:48][C:47]=2[O:55][CH3:56])=[N:34][CH:35]=3)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Reactant: CN1CCCC(N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc(C(=O)NC2CCCN(C)C2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.4 %

Procedure:
A solution of HATU (126 mg, 0.33 mmol) in DMA (5 mL) was added to a mixture of the 4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-3-methoxy-benzoic acid (Example 242 132 mg, 0.3 mmol), DIPEA (261 uL, 1.5 mmol) and 3-amino N-methylpiperidine dihydrochloride (71 mg, 0.375 mmol) in DMA (5 mL). The resulting mixture was stirred at room temperature for 2 hours, then partially purified by SCX. The compound was eluted from the SCX column using 7N ammonia in methanol, then concentrated in vacuo, and further purified by column chromatography, eluting with 0-10% ammonia (7N in methanol) in DCM. The pure material was recovered as an orange oil, which foamed and solidified under high vacuum. Trituration under ether gave the title compound as a pale yellow amorphous solid (65 mg, 41%)
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:31]1([CH2:37][C:38](Cl)=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl>[C:31]1([CH2:37][C:38]([NH:23][CH2:22][C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 12.4 %

Procedure:
To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (200 mg, 0.63 mmol) and triethylamine (93 μL, 0.66 mmol) in anhydrous dichloromethane (8 mL) under nitrogen atmosphere at 0° C. was added dropwise a solution of phenylacetyl chloride (93 μL, 0.66 mmol) in anhydrous dichloromethane (2 mL). After stirring for 3 h at 0° C., the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with water then dried over magnesium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with DCM:MeOH (98:2) to give the title compound (34 mg, 12%). 1H NMR (400 MHz, CDCl3) δ7.32-7.31 (m, 3H), 7.12-7.10 (m, 2H), 6.89-6.87 (d, 2H), 6.76-6.74 (d, 2H), 4.91 (t, 1H), 4.02 (t, 2H), 3.79-3.74 (m, 2H), 3.53-3.51 (m, 2H), 3.47 (s, 2H), 3.37-3.35 (d, 2H), 2.62 (m, 6H), 2.08-2.06 (m, 2H), 1.93-1.85 (m, 6H), 1.76-1.74 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:20][C:21]([NH:23][N:24]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[C:25]2[C:30]([N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:37])=[O:22])=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:17]=1)[C:7]([O:9]N1C(=O)CCC1=O)=O.[CH3:46][NH:47][CH3:48]>C1COCC1>[Br:1][C:2]1[C:3]([CH2:20][C:21]([NH:23][N:24]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[C:25]2[C:30]([N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:37])=[O:22])=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:17]=1)[C:7]([N:47]([CH3:48])[CH3:46])=[O:9]
Reactant: COc1ccc(N(NC(=O)Cc2cc(OC)c(C(=O)ON3C(=O)CCC3=O)cc2Br)c2c(C)cccc2N2CCCCC2)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: COc1ccc(N(NC(=O)Cc2cc(OC)c(C(=O)N(C)C)cc2Br)c2c(C)cccc2N2CCCCC2)cc1
Reaction time: 2 h
Yield: 53 %

Procedure:
To a solution of 85 mg of the compound obtained in stage 8 of Example 1 in 500 μL of THF are added at room temperature 2 mL (29 equivalents) of a 2 M dimethylamine solution in THF. The reaction medium is then stirred for 2 hours before being dry evaporated. The obtained white solid is taken up in 10 mL of ethyl acetate. The resulting organic phase is washed several times with water and then with a saturated NaCl solution, dried on sodium sulphate, dry evaporated. The raw product is chromatographed on silica gel (dichloromethane/methanol:98/2) in order to provide 45 mg of the expected compound as a white solid.
Reaction SMILES: [N+:1]([O-:31])([O:3][C@@H:4]1[CH:21]2[C@:16]([CH3:22])([CH2:17][CH2:18][CH2:19][CH2:20]2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10]24OCCO[C:9]2(OCC[O:23]4)[CH2:8]3)[CH2:5]1)=[O:2].CC1C=CC(S(O)(=O)=[O:40])=CC=1.O.C([O-])(O)=O.[Na+]>CC(C)=O>[N+:1]([O-:31])([O:3][C@@H:4]1[CH:21]2[C@:16]([CH3:22])([CH2:17][CH2:18][C:19](=[O:40])[CH2:20]2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:23])[CH2:9][CH2:8]3)[CH2:5]1)=[O:2]
Reactant: C[C@]12CCCCC1[C@@H](O[N+](=O)[O-])C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C[C@]12CCC(=O)CC1[C@@H](O[N+](=O)[O-])C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
A solution of 3,3:17,17-bis(ethylendioxy)androstane-6α-yl nitrate (2.50 g) and pTSA.H2O (6.05 g) in acetone (150 mL) was stirred at room temperature for 1.5 h. The solution was neutralized by addition of 5% aqueous NaHCO3, and acetone was evaporated. The aqueous phase was extracted with CH2Cl2 (3×50 mL). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2, cyclohexane/Acetone/CH2Cl2 70/15/15) to give the title compound II-ab as a white solid (1.66 g, 75%). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 5.09 (1H, ddd), 2.60-0.95 (17H, m), 1.25 (3H, s), 0.90 (3H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])/[CH:5]=[C:6](\[NH:8][CH2:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1[F:17])/[CH3:7])[CH3:2].CC1(C)[O:25][C:24](=O)[CH:23]=[C:22]([CH3:27])O1>C1(C)C=CC=CC=1>[F:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([F:17])[C:10]=1[CH2:9][N:8]1[C:22]([CH3:27])=[CH:23][C:24](=[O:25])[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:18])=[C:6]1[CH3:7]
Reactant: CCOC(=O)/C=C(/C)NCc1c(F)cccc1F
Reactant: CC1=CC(=O)OC(C)(C)O1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)n(Cc2c(F)cccc2F)c(C)cc1=O
Yield: 43 %

Procedure:
A mixture of ethyl-3-(2,6-difluorobenzylamino)crotonate (2.55 g, 10.0 mmol) and 2,2,6-trimethyl-1,3-dioxin-4-one (1.85 g, 13.0 mmol) in toluene (100 mL) was heated at reflux for 3 hours. The reaction progress was monitored by LC/MS. An additional aliquot of 2,2,6-trimethyl-1,3-dioxin-4-one (2.0 mL) was added and the reaction mixture was refluxed for another 2 hours. LC/MS indicated complete conversion to product. The mixture was cooled down and the solvent was removed in vacuo. The solid residue was triturated with diethyl ether to yield the product as a tan solid (1.37 g, 4.3 mmol, 43%). 1H NMR (CDCl3, 300 MHz): 7.40-7.30 (m, 1H), 7.00-6.91 (m, 2H), 6.30 (s, 1H), 5.20 (s, 2H), 4.37 (q, J=6.9 Hz, 2H), 2.37 (s, 3H), 2.31 (s, 3H), 1.35 (t, J=6.9 Hz, 3H); LRMS m/z 322.1 (M++1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[F:12])[CH2:7][OH:8].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.[Na+].[Cl-]>C1COCC1>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([O:8][CH2:7][C:6]2[CH:9]=[CH:10][C:11]([F:12])=[C:4]([Cl:3])[CH:5]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCc1ccc(F)c(Cl)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCc2ccc(F)c(Cl)c2)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (0.33 g) was added to a solution of the alcohol from Step 3 (2.0 g) in THF (50 mL) at 0° C. under N2. Stirring was continued for 5 minutes at 0° C. followed by 25 min at 25° C. The mixture was then cooled to 0° C. and p-toluenesulfonyl chloride (2.5 g) was added. Stirring was continued for 40 minutes at 0° C. followed by 2 hours at 25° C. The precipitated NaCl was allowed to settle and the supernatant solution (4.0 mL) of the title compound was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH:6][C:2]1=[N:1][S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: Nc1nc2ccccc2s1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)N=c2[nH]c3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93 %

Procedure:
To a solution of 2-aminobenzothiazole (1.018 g, 6.78 mmol) in dry pyridine (4 mL) was added portion wise, p-toluene sulfonyl chloride (1.42 g, 7.48 mmol). The solution turned yellow upon addition. After 5 minutes of stirring at rt, the mixture was heated (70-80° C.) for 5 minutes. The mixture was poured on a bed of ice and the resulting precipitate was filtered off and dried overnight in a dessicator under vacuum to give a yellow powder in 93% yield: mp 246-249° C.; 1H-NMR (DMSO-d6) 2.36 (s, 3H), 7.26, (dt, 1H), 7.30 (d, 1H), 7.37 (d, 2H), 7.40 (dt, 1H), 7.75 (d, 2H), 7.81 (d, 1H); Anal. (C14H12N2O2S2) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>C(#N)C.C(O)C>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]4[CH2:4][C:3]5[C:28](=[CH:29][CH:30]=[CH:20][CH:2]=5)[CH2:27]4)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NCCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: Fc1ccc2c(C3CCN(CCCN4Cc5ccccc5C4)CC3)noc2c1

Procedure:
A stirred mixture of 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl amine (3.46 g, 12.5 mmol), K2CO3 (4 g, 29 mmol) and αα-dibromo-o-xylene (3.3 g, 12.5 mmol) in acetonitrile (300 ml) was heated at reflux for 3.5 hours. The mixture was cooled and the ink solubles were filtered. The dark red solution was concentrated down to a dark oil. This oil was purified by flash chromatography over a silica gel column (SiO2, 45 g; eluted with dichloromethane and MeOH in dichloromethane). The product thus obtained weighed 1.95 g as an oil. This oil was dissolved in ethanol and was treated with a solution of fumaric acid (600 mg) in ethanol. The resulting crystals were collected as an off white solid and weighed 1.44 gm, m.p. 206°-209° C.