Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH3:13])=[N:7][N:6]2[C:14]=1[S:15]([NH2:18])(=[O:17])=[O:16])[CH3:2].[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)[N:22]=1.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C.O>[CH3:28][O:27][C:25]1[CH:26]=[C:21]([O:20][CH3:19])[N:22]=[C:23]([NH:29][C:30]([NH:18][S:15]([C:14]2[N:6]3[N:7]=[C:8]([S:11][CH2:12][CH3:13])[CH:9]=[CH:10][C:5]3=[N:4][C:3]=2[CH2:1][CH3:2])(=[O:16])=[O:17])=[O:31])[N:24]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: CCSc1ccc2nc(CC)c(S(N)(=O)=O)n2n1
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCSc1ccc2nc(CC)c(S(=O)(=O)NC(=O)Nc3nc(OC)cc(OC)n3)n2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
As shown in the above reaction scheme, 2-ethyl-6-ethylthioimidazo[1,2-b]pyridazin-3-ylsulfonamide (0.19 g, 0.66 mmol) and phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate (0.20 g, 0.73 mmol) were suspended in acetonitrile (5 ml) and stirred at room temperature, during which DBU (0.11 g, 0.73 mmol) was added thereto. After the mixture was stirred at room temperature for 2 hours, the reaction solution was poured into water (50 ml) and adjusted to pH 2 with dilute hydrochloric acid. The precipitated crystals were collected by filtration, and washed with water and ether in this order. The crystals were dried under reduced pressure to give the title compound as colorless crystals. The yield was 0.18 g (58%), and the melting point was 160 to 165° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH2:13][CH2:14][N:15]=[N+]=[N-])[CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH2:13][CH2:14][NH2:15])[CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2
Reactant: [N-]=[N+]=NCCOc1cc(F)cc2c1OCCC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCCOc1cc(F)cc2c1OCCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.1 %

Procedure:
A solution of 2-(6-fluorochroman-8-yloxy)ethylazide (4.12 g, 0.017 mol) and triphenylphosphine (6.83 g, 0.026 mol) in tetrahydrofuran (80 ml) and water (1.5 ml) was allowed to stir for 18 hours at room temperature. The solvent was removed under vacuum. Chromatography (ethyl acetate) removed triphenylphosphine and triphenylphosphine oxide (40% methanol-methylene chloride plus ammonium hydroxide) to afford 3.45 g (94%) of product as a white solid: mp 68-70° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:10]=1)[C:5]([OH:7])=O.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:49][C:50]1[N:55]=[CH:54][C:53]([CH2:56][NH2:57])=[CH:52][N:51]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:10]=1)[C:5]([NH:57][CH2:56][C:53]1[CH:52]=[N:51][C:50]([CH3:49])=[N:55][CH:54]=1)=[O:7]
Reactant: Cc1ncc(CN)cn1
Reactant: O=C(O)c1cc(Br)cc(C(=O)N2CCCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ncc(CNC(=O)c2cc(Br)cc(C(=O)N3CCCC3)c2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a round-bottom flask were charged 3-bromo-5-(pyrrolidine-1-carbonyl)benzoic acid (340 mg, 1.0 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.39 g, 2.0 mmol), 1-hydroxybenzotriazole (0.30 g, 2.2 mmol), N,N-diisopropylethylamine (0.2 g, 1.5 mmol), methylene chloride (10 mL), 4-dimethylaminopyridine (5 mg, 0.04 mmol), and (2-methylpyrimidin-5-yl)methanamine (240 mg, 1.5 mmol). The mixture was stirred at room temperature overnight, and then diluted with CH2Cl2. The separated organic phase was washed with aq. Na2HPO4, brine, and dried over Na2SO4, and concentrated. The residue was purified via flash chromatography to afford the desired product as an oil. LC-MS: 404.8 [M+1]+; 1H NMR (400 MHz, CDCl3): 8.68 (s, 2H), 7.95 (t, J=1.6 Hz, 1H), 7.76 (t, J=1.3 Hz, 1H), 7.74-7.71 (m, 1H), 7.61 (t, J=1.5 Hz, 1H), 4.57 (d, J=5.8 Hz, 2H), 3.56 (t, J=6.8 Hz, 2H), 3.37 (t, J=6.4 Hz, 2H), 2.73 (s, 3H), 1.96-1.89 (m, 4H).
Reaction SMILES: CN[C@@H]1CCCC[C@H]1NC.CN[C@@H]1CCCC[C@H]1NC.I[C:22]1[C:23](=[O:48])[NH:24][C:25](=[O:47])[N:26]([CH2:28][CH2:29][CH2:30][N:31]2[CH2:36][C@H:35]3[C@:33]([C:37]4[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=4)([CH2:34]3)[CH2:32]2)[CH:27]=1.C([O-])([O-])=O.[K+].[K+].[CH3:55][C:56]1[CH:60]=[CH:59][NH:58][N:57]=1.[N-]=C=O>C1(C)C=CC=CC=1.C(Cl)Cl.[Cu](I)I>[CH3:55][C:56]1[CH:60]=[CH:59][N:58]([C:22]2[C:23](=[O:48])[NH:24][C:25](=[O:47])[N:26]([CH2:28][CH2:29][CH2:30][N:31]3[CH2:36][C@H:35]4[C@:33]([C:37]5[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=5)([CH2:34]4)[CH2:32]3)[CH:27]=2)[N:57]=1
Reactant: Cc1cc[nH]n1
Reactant: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)cc1I
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1ccn(-c2cn(CCCN3C[C@@H]4C[C@]4(c4ccc(C(F)(F)F)cc4)C3)c(=O)[nH]c2=O)n1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
Copper iodide (56.5 mg, 0.297 mmol), (1R,2R)—N,N′-dimethyl-1,2-cyclohexanediamine methyl[(1R,2R)-2-(methylamino)cyclohexyl]amine (169 mg, 1.187 mmol), 5-iodo-1-(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-2,4(1H,3H)-pyrimidinedione (Prep10, 150 mg, 0.297 mmol) and K2CO3 (86 mg, 0.623 mmol) were dissolved in Toluene (1.5 ml) to give a blue suspension with a white precipitate. 3-methyl-1H-pyrazole (commercially available from ABCR, 0.029 ml, 0.356 mmol) was added thereto. After shaking at 110° C. for 18 h, the reaction mixture was filtered and the solvent evaporated. The obtained crude was dissolved in 20 mL of DCM and 500 mg of PS-thiol resin and 2.0 g of MP-isocyanate resin were added to blue solution. The obtained suspension was shaken for 2 h at 35° C., then filtered and the solvent evaporated. The resulting mixture was iteratively purified (two times) by preparative LC-MS. Obtained 51.8 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11]>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.[Cu]I.C1COCC1>[CH3:9][Si:10]([C:13]#[C:14][C:2]1[CH:7]=[CH:6][C:5]([C:14]#[C:13][Si:10]([CH3:12])([CH3:11])[CH3:9])=[CH:4][CH:3]=1)([CH3:12])[CH3:11]
Reactant: Brc1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(C#C[Si](C)(C)C)cc1
Temperature: 45 °C
Yield: 92 %

Procedure:
40 mL THF was transferred to a flame-dried Schlenk flask. 1,4-dibromobenzene (2.5 mmol, 0.060 g), Pd(PPh3)4 (0.1 mmol 0.12 g), and CuI (0.2 mmol, 0.004 g) were added. Trimethylsilylacetylene (6 mmol, 0.87 mL) and 10 mL DIPA was added via syringe. The mixture was heated to 45° C. for 24 hrs. under nitrogen. The resulting suspension was filtered and filtrate was concentrated under reduced pressure. The residual solid was dissolved in dichloromethane and washed with an aqueous ammonium chloride solution. The organic layer was concentrated and crude product was subjected to column chromatography (silica, hexanes) to afford a white solid (2.3 mmol, 0.61 g, 90% yield). 1H NMR (400 MHz, CDCl3) δ: 7.37 (s, 4H), 0.22 (s, 18H).
Reaction SMILES: Cl[C:2]([CH3:10])([CH2:4][CH2:5][C:6](Cl)([CH3:8])[CH3:7])[CH3:3].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18].ClCCCl.[Cl-].[Al+3].[Cl-].[Cl-]>O>[Br:11][C:12]1[CH:17]=[C:16]2[C:15](=[CH:14][C:13]=1[CH3:18])[C:6]([CH3:8])([CH3:7])[CH2:5][CH2:4][C:2]2([CH3:10])[CH3:3]
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: Cc1ccccc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Product: Cc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Temperature: 25 °C

Procedure:
18.31 g (100.0 mmol) of 2,5-dichloro-2,5-dimethylhexane, 17.10 g (100.0 mmol) of 2-bromotoluene and 200 ml of 1,2-dichloroethane are introduced into a three-necked flask under an argon atmosphere. 1.33 g (10.0 mmol) of aluminium chloride are added rapidly in a single portion and the reaction medium is stirred for thirty minutes at room temperature. The reaction medium is poured into water, extracted with dichloromethane and washed with water, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. After recrystallization of the residue from methanol, 17.78 g (63%) of the expected compound are collected in the form of fine white crystals with a melting point of 73° C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([OH:18])=O)[CH:15]=2)[NH:12][CH:11]=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C[N:21](C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.N>C(Cl)Cl.C1COCC1>[C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:21])=[O:18])[CH:15]=2)[NH:12][CH:11]=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cc(-c2ccccc2)cc2cc[nH]c12
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1cc(-c2ccccc2)cc2cc[nH]c12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-phenyl-1H-indole-7-carboxylic acid (10.0 g, 42.0 mmol) in a mixture of CH2Cl2 (100 mL) and THF (100 mL) at room temperature, N-(3-Dimethylaminopropy)-N′-ethylcarbodiimide hydrochloride (9.66 g, 50.4 mmol), 1-Hydroxybenzotriazole hydrate (6.81 g, 50.4 mmol) and ammonia (2 M in methanol, 168 mmol, 84 mL) were added. The reaction mixture was stirred at room temperature for 24 hours. All solvent were evaporated and the reaction mixture was partitioned between ethyl acetate (200 mL) and water (200 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (×2). The combined organic phase washed with brine, dried over Mg2SO4 and concentration to give the product which is pure enough for next reaction (10 g, 100%).
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH2:13][C@H:12]3[C@@H:7]([CH:8]=[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][N:11]3[CH2:14][CH2:15][CH3:16])[CH2:6][C:5]=2[N:22]=1.N([O-])=O.[Na+].O.[PH2](O)=O>P(=O)(O)(O)O>[CH2:14]([N:11]1[C@@H:12]2[C@H:7]([CH2:6][C:5]3[N:22]=[CH:2][S:3][C:4]=3[CH2:13]2)[CH:8]=[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10]1)[CH2:15][CH3:16]
Reactant: CCCN1CC(C(=O)OCC)=C[C@H]2Cc3nc(N)sc3C[C@@H]21
Agent: O=N[O-]
Agent: O=P(O)(O)O
Agent: O=[PH2]O
Solvent: O
Product: CCCN1CC(C(=O)OCC)=C[C@H]2Cc3ncsc3C[C@@H]21
Temperature: 25 °C
Yield: 100.1 %

Procedure:
A solution of 0.5 g (1.5 mmole) of ethyl 2-amino-5-propyl-trans-4,4a,5,6,8a,9-hexahydrothiazolo-[4,5-g]quinoline-7-carboxylate (Example 3) in 50 ml of 85% phosphoric acid was cooled to 0° C. Then 110 mg (1.8 mmole) of sodium nitrite dissolved in as small an amount of water as possible was slowly added under the surface of the reaction mixture. The resulting mixture was added dropwise to 50 ml of 50% hypophosphorous acid (H3PO2) at 0° C. The mixture was stirred at room temperature until gas evolution ceased. This took about 1 hour. The mixture was poured onto ice, and the hydrogen ion concentration of the mixture was adjusted to pH 11. Water was added to dissolve the precipitate that formed; then the product was extracted into a solution of CHCl3 /i-PrOH (3:1). This solution was dried using sodium sulfate and evaporated to give 0.46 g of the title product.
Reaction SMILES: [Cl:1][C:2]1[CH2:3][N:4]=[CH:5][C:6]2([CH3:21])[CH:17]([CH3:18])[CH:15]3[CH2:16][C:10]4=[C:11]([N:14]3[C:19]#N)[CH2:12][CH2:13][C:7]2=[C:8]4[CH:9]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:28](OCC)(=O)C.[OH-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[CH2:3][N:4]=[CH:5][C:6]2([CH3:21])[CH:17]([CH3:18])[CH:15]3[CH2:16][C:10]4=[C:11]([N:14]3[CH2:19][CH3:28])[CH2:12][CH2:13][C:7]2=[C:8]4[CH:9]=1
Reactant: CC1C2CC3=C(CCC4=C3C=C(Cl)CN=CC41C)N2C#N
Reactant: CCOC(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCN1C2=C3CC1C(C)C1(C)C=NCC(Cl)=CC3=C1CC2

Procedure:
10-Chloro-3-cyano-6,12-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-9H-pyrrolo[3,2-h][3]benzazocine (6.41 g) was dissolved in 300 ml of tetrahydrofuran, and with stirring, 4.06 g of lithium aluminum hydride was added, under nitrogen. The suspension was heated at reflux for 2 hr and ethyl acetate was added dropwise. To the mixture was added water, 15% aqueous sodium hydroxide solution, and water. The suspension was filtered, and the filtrate was concentrated. The residue was triturated with ether. The mother liquor was concentrated and 2-g portions of the residue were alkylated with phenethyl bromide and 4-bromo-2-methylbut-2-ene according to the procedures described in Examples 23 and 26 to give 0.35 g (20%) and 0.41 g (24%), respectively, of product. Column chromatography (alumina, ether) followed by recrystallization from dichloromethane-ether-pentane afforded the analytical sample, mp 208°-210° C. (dec.).
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[CH:17]=[CH:16][O:15][CH:14]=1)[CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.S([Cl:35])(C1C=CC(C)=CC=1)(=O)=O>CN(C)C1C=CN=CC=1.ClCCl>[Cl:35][CH2:10][CH2:9][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:12][C:13]1[CH:17]=[CH:16][O:15][CH:14]=1
Reactant: OCCN(Cc1ccccc1)Cc1ccoc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: ClCCN(Cc1ccccc1)Cc1ccoc1
Yield: 77.2 %

Procedure:
2-(Benzyl-(3-furylmethyl)amino)ethanol (6.5 g, 28 mmol), triethylamine (5.9 ml, 42 mmol), 4-dimethylaminopyridine (250 mg, 2.1 mmol) and tosyl chloride (6.4 g, 34 mmol) were stirred at room temperature for 17 hours in dichloromethane (260 ml). The reaction solution was mixed with dichloromethane, washed with water and saturated brine and then dried with anhydrous magnesium sulfate. The solvent was removed by evaporation from the organic layer under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 5.4 g of crude 1-chloro-2-(benzyl-(3-furylmethyl)amino)ethane. The crude 1-chloro-2-(benzyl-(3-furylmethyl)amino)ethane (1.8 g) was dissolved in anhydrous tetrahydrofuran (35 ml) and cooled to 0° C. In an atmosphere of argon, n-butyl lithium hexane solution (14 mmol) was added thereto to carry out 2 hours of the reaction at room temperature. The reaction solution was mixed with 1 N sodium hydroxide aqueous solution, the reaction product was extracted with dichloromethane, and then the organic layer was washed with saturated brine and dried with anhydrous magnesium sulfate. The solvent was removed by evaporation from the organic layer under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 1.1 g (5.1 mmol, 73% in yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:6].CC(C)=O.[CH3:21][N:22]=[C:23]=[O:24]>C(N(CC)CC)C>[CH3:21][NH:22][C:23](=[O:24])[NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:6]
Reactant: CN=C=O
Reactant: Nc1cccc(C(=O)Nc2ccccn2)c1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CNC(=O)Nc1cccc(C(=O)Nc2ccccn2)c1
Yield: 85 %

Procedure:
A mixture of the 3-amino-N-2-pyridylbenzamide (6.4 g), acetone (60 ml), methyl isocyanate (1.8 ml) and a catalytic amount of triethylamine were stirred at room temperature for 24 hours. The resulting crystal was collected by filtration and recrystallized from acetone to provide 6.9 g of 3-(3-methylureido)-N-2-pyridylbenzamide as a colorless acicular crystal (compound 37) (yield: 85%, m.p. 163°-164° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH2:13][CH2:14][NH2:15])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([CH2:13][CH2:14][NH:15][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=3)=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: NCCc1cnc(-c2ccc(F)cc2)o1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCCc1cnc(-c2ccc(F)cc2)o1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 20 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-5-yl)ethanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (28 mg, yield 20%). 1H NMR (400 MHz, MeOD) δ 8.56-8.55 (m, 1H), 8.30-8.28 (dq, J=7.8 Hz, 0.9 Hz, 1H), 8.06-8.04 (m, 1H), 8.00-7.96 (dd, J=9.0 Hz, 5.3 Hz, 2H), 7.71-7.69 (t, J=7.8 Hz, 1H), 7.21-7.17 (t, J=8.8 Hz, 2H), 7.03 (s, 1H), 3.78-3.75 (t, J=6.7 Hz, 2H), 3.15-3.12 (m, 2H). MS (ESI) m/z: Calculated for C21H14F4N4O3: 446.10. found: 447.0 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:6]([NH:12][C:13](=[O:19])[O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[N:7][CH:8]=[C:9]([CH3:11])[N:10]=1.[Cl:20][C:21]1[C:26]([S:27](Cl)(=[O:29])=[O:28])=[CH:25][CH:24]=[CH:23][N:22]=1.Cl>O.CN(C=O)C>[Cl:20][C:21]1[C:26]([S:27]([N:12]([C:13]([O:14][CH2:15][CH:16]([CH3:17])[CH3:18])=[O:19])[C:6]2[C:5]([O:4][CH3:3])=[N:10][C:9]([CH3:11])=[CH:8][N:7]=2)(=[O:29])=[O:28])=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Reactant: COc1nc(C)cnc1NC(=O)OCC(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1Cl
Temperature: 25 °C
Yield: 43.5 %

Procedure:
Sodium hydride (60% dispersion in oil; 0.083 g) was added to a stirred solution of isobutyl N-(3-methoxy-5-methylpyrazin-2-yl)-carbamate (0.451 g) in dry N,N-dimethylfonmamide (DMF; 8 ml) at 4° C. The mixture was stirred whilst warming to ambient temperature over I hour, was recooled to 4° C. and 2-chloropyridine-3-sulphonyl chloride (0.40 g) was added in portions over 2 minutes. The mixture was allowed to warm to ambient temperature and stirred a further 30 minutes. Water (40 ml) was added, followed by 1M hydrochloric acid to acidify. This mixture was extracted with ethyl acetate (4×15 ml) and the organic extracts were washed with water (10 ml) and saturated sodium chloride solution (10 ml) and then dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by gradient elution with 0-35% ethyl acetate/hexane through a silica gel Mega Bond Elut column and triturated with ether to give 2-chloro-N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)-pyridine-3-sulphonamide (0.34 g) as a solid, m.p. 99°-101° C.; 1H NMR (CDCl3): 0.7 (d, 6 H), 1.7 (m, 1 H), 2.5 (s, 3 H), 3.8 (d, 2 H), 4.0 (s, 3 H), 7.45 (dd, 1 H), 7.9 (s, 1 H), 8.6 (dd, 1 H), 8.7 (dd, 1 H); mass spectrum (+ve ESP): 415 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[CH:17][C:3]=1[C:4]([NH:6][CH2:7][CH:8]([O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH3:9])=[O:5].[NH:27]([CH2:31][CH2:32][OH:33])[CH2:28][CH2:29][OH:30]>>[OH:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][OH:33])[C:2]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[CH:17][C:3]=1[C:4]([NH:6][CH2:7][CH:8]([O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH3:9])=[O:5]
Reactant: CC(CNC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl)OC1CCCCO1
Reactant: OCCNCCO
Product: CC(CNC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1N(CCO)CCO)OC1CCCCO1
Yield: 94.6 %

Procedure:
Reaction of 12e (1.45 g, 3.75 mmol) with diethanolamine (1.67 g) as above gave 2-[bis(2-hydroxyethyl)amino]-3,5-dinitro-N-[2-(tetrahydro-2H-pyran-2-yloxy)propyl]benzamide (1.62 g, 95%) as a yellow foam that was used directly;
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=O)[CH3:10].[C:13]([O-])(=O)[CH3:14].[Pb+4].C(=O)([O-])[O-].[Ca+2].C(O[C@H:27]1[CH2:46][C@@]2(C)[C@@H:38]([CH2:39][CH2:40][C@@H:41]2[CH:42]([OH:44])[CH3:43])[C@H:37]2[C@H:28]1[C@:29]1([CH3:52])[C:34](=[CH:35][CH2:36]2)[CH2:33]C2(OCCO2)C[CH2:30]1)(=O)C.II.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>C1CCCCC1.CC(C)=O>[C:1]([O:4][C@H:27]1[CH2:46][C@@:10]2([CH2:9][OH:12])[C@@H:38]([CH2:39][CH2:40][C@@H:41]2[C:42](=[O:44])[CH3:43])[C@H:37]2[C@H:28]1[C@:29]1([CH3:52])[C:34](=[CH:35][CH2:36]2)[CH2:33][C:5]2([O:8][CH2:14][CH2:13][O:7]2)[CH2:6][CH2:30]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1C[C@]2(C)[C@@H](C(C)O)CC[C@H]2[C@@H]2CC=C3CC4(CC[C@]3(C)[C@H]21)OCCO4
Reactant: CC(=O)[O-]
Agent: O=[Cr](=O)=O
Agent: II
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Solvent: C1CCCCC1
Product: CC(=O)O[C@H]1C[C@]2(CO)[C@@H](C(C)=O)CC[C@H]2[C@@H]2CC=C3CC4(CC[C@]3(C)[C@H]21)OCCO4

Procedure:
A mixture of 21.7 g of lead tetraacetate and 9.8 g of calcium carbonate in 1000 ml of cyclohexane is heated at reflux under argon for 1 hour and then cooled. To the resulting suspension is added 8.2 g of 11β-acetoxy-3,3-ethylenedioxypregn-5-en-20-ol and 2.5 g of iodine and the resulting purple suspension is heated to reflux and irradiated with a 275 W sunlamp until the color of the iodine has faded (1-1.5 hours). The mixture is then cooled and filtered through Celite and the filtrate is washed with aqueous sodium bisulfite, water, aqueous sodium bicarbonate and brine. The organic solution is then dried and concentrated and the residue obtained is dissolved in acetone and treated with 10 ml of standard Jones reagent at 0° C. for 1 hour. Excess Jones reagent is destroyed by the addition of 2-propanol and the resulting mixture is filtered to remove the precipitated inorganic salts. The filtrate is then concentrated to a small volume and the residue is partitioned between ether and water. The aqueous solution is extracted with ether and the ether solutions are combined, washed with aqueous sodium bicarbonate, dried and concentrated. The residue is dissolved in water:dioxane (1:9, 700 ml) and 7.2 g of silver acetate is added. The mixture is stirred and heated rapidly to 60°-65° C. and then maintained at that temperature for 4 hours. The mixture is then cooled, filtered and concentrated. The residue is dissolved in ether, filtered again and concentrated. The resulting material is chromatographed on silica gel to give 11β-acetoxy-3,3-ethylenedioxy-18-hydroxypregn-5-en-20-one.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][C:10](O)=[S:11])[CH:6]=[CH:5][CH:4]=1)#[N:2].ClC(OCC(C)C)=O.C([N:23](CC)CC)C.[NH4+]>C(OCC)(=O)C.C1COCC1>[C:1]([C:3]1[N:8]=[C:7]([CH2:9][C:10]([NH2:23])=[S:11])[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1cccc(CC(O)=S)n1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1cccc(CC(N)=S)n1
Reaction time: 2 h
Yield: 56.5 %

Procedure:
A mixture of (6-cyano-2-pyridyl)thioacetic acid (0.95 g, 4.89 mmol), isobutyl chloroformate (1.05 ml, 7.33 mmol), triethylamine (1.03 ml, 7.33 mmol) and THF (150 ml) was stirred under ice cooling condition for 2 hrs. 28% ammonium solution (100 ml) was added to the mixture, and the mixture was stirred under ice cooling condition for 2 hrs. The reaction mixture was combined with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated to give the titled compound (0.49 g, 52%) as pale yellow crystals
Reaction SMILES: NC1C=CC(S(NC2C=CC=CC=2C)(=O)=O)=CC=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-])=O)=[CH:33][CH:32]=2)(=[O:30])=[O:29])=[CH:23][CH:22]=1>>[NH2:37][C:34]1[CH:35]=[CH:36][C:31]([S:28]([NH:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)(=[O:29])=[O:30])=[CH:32][CH:33]=1
Reactant: COc1ccc(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Agent: Cc1ccccc1NS(=O)(=O)c1ccc(N)cc1
Product: COc1ccc(NS(=O)(=O)c2ccc(N)cc2)cc1
Yield: 79 %

Procedure:
(RK1-1-27E II) I This compound was prepared according to the procedure described for compound 12a except using 11g to obtain the required product as a light yellow solid, (197 mg, 79%). Mp: not determined; 1H NMR. (400 MHz, CDCl3) δ 7.45 (d, J=9.0 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 6.76 (d, J=9.0 Hz, 2H), 6.58 (d, J=8.8 Hz, 2H), 6.09 (br s, 1H), 4.07 (br s, 2H), 3.76 (s, 3H).