Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CN1C(=O)CCC1>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:7]=2)[CH2:21][CH2:20]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)cc1Nc1ccccc1
Solvent: CN1CCCC1=O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(Nc3ccccc3)c2)CC1
Yield: 47.1 %

Procedure:
A solution of 5-bromo-2-nitro-N-phenylbenzenamine (1.0 g, 3.4 mmol) and 1-methylpiperazine (1.50 ml, 13.6 mmol) in 15 ml NMP was heated at 100° C. for 16 hours. The reaction was quenched with 100 ml water. The mixture was extracted with ethyl acetate (3×30 ml) and dried over anhydrous sodium sulfate. 5-(4-methylpiperazin-1-yl)-2-nitro-N-phenylbenzenamine (0.50 g, 49%) was obtained by flash column chromatograph (10% ethanol in dichloromethane). 5-(4-methylpiperazin-1-yl)-2-nitro-N-phenylbenzenamine hydrochloride was made by bubbling HCl gas in its ethyl ether solution and crystallized. 1H NMR (500 MHz, DMSO-d6) δ (ppm) 2.75 (s, 3H), 3.03 (dd, J=12.9, 12.0 Hz, 2H), 3.29 (dd, J=11.9, 12.9 Hz, 2H), 3.42 (d, J=12.0 Hz, 2H), 3.90 (d, J=12.9, Hz, 2H), 6.48 (d, J=1.5 Hz, 1H), 6.65 (dd, J=2.6, 9.7 Hz, 1H), 7.2 (m, 1H), 7.23-7.45 (m, 4H), 8.06 (d, J=9.7 Hz, 1H), 9.72 (s, 1H), 11.27 (s, 1H). 13C NMR (125 MHz, DMSO-d6): δ (ppm) 40.0, 43.4, 51.5, 96.7, 106.8, 123.5, 124.9, 128.3, 129.6, 138.9, 144.2, 154.5.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[N:14]([O-])=[O:15].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[N:14]=[O:15]
Reactant: Cc1cc(N)n(-c2ccccn2)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nn(-c2ccccn2)c(N)c1N=O
Yield: 53 %

Procedure:
By the method of Preparation 8(a), 5-amino-3-methyl-1-(2-pyridyl)pyrazole (2.21 g, 12.7 mmol) was treated with sodium nitrite in aqueous acetic acid. The precipitated solid was triturated with methanol (250 ml), and the mother liquors were concentrated under reduced pressure to give the title compound as a red-brown solid (1.37 g, 53%).
Reaction SMILES: [OH:1][C@:2]1([C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:25]=[CH:24][C:23]([CH:26]([OH:28])[CH3:27])=[CH:22][CH:21]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1.[CH3:37][C:38]([CH3:44])([CH3:43])[CH2:39][C:40](Cl)=[O:41]>>[OH:1][C@:2]1([C:30]([F:35])([F:36])[C:31]([F:32])([F:33])[F:34])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:21]=[CH:22][C:23]([CH:26]([O:28][C:40](=[O:41])[CH2:39][C:38]([CH3:44])([CH3:43])[CH3:37])[CH3:27])=[CH:24][CH:25]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1
Reactant: CC(O)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Reactant: CC(C)(C)CC(=O)Cl
Product: CC(OC(=O)CC(C)(C)C)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Yield: 63 %

Procedure:
In analogy to Example 1, 150 mg (0.29 mmol) of (8S,11R,13S,14S,17S)-17-hydroxy-11-[4-((RS)-1-hydroxyethyl)phenyl]-1 3-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one were converted using 3,3-dimethylbutyryl chloride and, after workup and purification, 113 mg (63%) of the title compounds were isolated as a colourless foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][C:7]=3[NH:8][C:9]=2[CH:10]=1.[H-].[Na+].[O:18]1[CH2:20][CH:19]1[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][C:7]=3[N:8]([CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[OH:18])[C:9]=2[CH:10]=1
Reactant: c1cc(C2CO2)ccn1
Reactant: CN1CCc2[nH]c3cc(Cl)ccc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(c3ccc(Cl)cc3n2CC(O)c2ccncc2)C1
Reaction time: 12 h

Procedure:
To a stirred solution of 7-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.5 g, 2.265 mmol) in anhydrous DMF was added sodium hydride (271 mg, 3 eq.) portionwise followed by 4-(oxiran-2-yl)pyridine (548 mg, 4.5 mmol) at RT. The reaction mixture was stirred for 12 h. The reaction mixture was quenched with ice water and extracted with EtOAc, the organic layer washed with water, dried on anhydrous sodium sulfate, concentrated under vacuum to obtain crude product that was triturated with diethyl ether to obtain 2-(7-chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(pyridin-4-yl)ethanol as solid. 1H NMR (CDCl3, freebase) δ (ppm): 8.53 (d, 2H), 7.2 (m, 3H), 7.14 (d, 1H), 7.05 (d, 1H), 4.82 (t, 1H), 4.03 (d, 2H), 3.4 (q, 2H), 2.85 (m, 1H), 2.76 (m, 1H), 2.64 (m, 2H), 2.37 (s, 3H). Separation by chiral HPLC provided enantiomers 53a and 53b.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8].[CH3:9][S:10](Cl)(=[O:12])=[O:11]>C(Cl)Cl>[CH3:9][S:10]([O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: COCCOCCO
Solvent: ClCCl
Product: COCCOCCOS(C)(=O)=O
Reaction time: 0.08 h

Procedure:
To a solution of 2-(2-methoxyethoxy)ethanol (300 mg, 2.5 mmol) in DCM (5 mL) was added methanesulfonyl chloride (370 mg, 2.6 mmol) dropwise at 0° C. After stirred at this temperature for 5 min, TEA (505 mg, 5.0 mmol) was added. It was stirred at room temperature overnight. The mixture was partitioned between DCM and water. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give a crude oil product, which was used without purification. Product tlc [petroleum ether/ethyl acetate [1:1) developed with iodine, Rf 0.5]
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[C:37]1([S:43](Cl)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>>[OH:17][C@@H:16]1[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13][C@H:12]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][C:3]([CH2:2][NH:1][S:43]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:45])=[O:44])=[N:4][C:5]=2[NH:22][CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNS(=O)(=O)c4ccccc4)nc32)[C@H](O)[C@@H]1O
Yield: 79.3 %

Procedure:
The title compound was prepared by a similar method to example 3 from (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)-tetrahydro-3,4-furandiol (example 1) (110 mg, 0.22 mmol), benzenesulfonyl chloride (36 mg, 0.20 mmol) and triethylamine (0.1 ml, 0.72 mmol) to afford the title compound as a solid (100 mg). MS: 631 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:14]([CH3:17])([OH:16])[CH3:15])[C:11]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.F[C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:14]([CH3:15])([CH3:17])[O:16][C:31]3[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=3)[C:11]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(C)(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(Oc1ccc(C#N)cc1)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A solution of 1.0 g (2.39 mmol) (−)-1-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-1-cyclohexyl-2-methyl-propan-2-ol and 0.289 g (2.39 mmol) 4-fluorobenzonitrile (commercially available) in 10 ml anhydrous tetrahydrofuran was cooled down to 0° C. Then, 4.77 ml (2.39 mmol) potassium bis(trimethylsilyl)amide (0.5 M solution in toluene) were added dropwise to the reaction mixture. The cooling bath was removed and the reaction stirred at room temperature for 5 days. The yellow suspension was poured onto 10% aqueous ammonium chloride solution and the phases were separated. The aqueous layer was extracted three times with ethyl acetate, the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The compound was purified twice by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting first with n-heptane for 5 min, then with a gradient of dichloromethane:ethyl acetate (100:0 to 90:10). Colorless foam (40%). MS (Turbo Spray): m/z=520.2 [M+H].
Reaction SMILES: [CH2:1]([N:3]([CH3:6])[CH:4]=O)[CH3:2].[Cl:7][C:8]1[CH:22]=[CH:21][C:11]([O:12][C:13]2[N:18]=[CH:17][C:16]([NH2:19])=[C:15]([CH3:20])[CH:14]=2)=[CH:10][C:9]=1[C:23]([F:26])([F:25])[F:24].[OH-].[Na+]>ClCCl>[Cl:7][C:8]1[CH:22]=[CH:21][C:11]([O:12][C:13]2[N:18]=[CH:17][C:16]([N:19]=[CH:4][N:3]([CH2:1][CH3:2])[CH3:6])=[C:15]([CH3:20])[CH:14]=2)=[CH:10][C:9]=1[C:23]([F:26])([F:24])[F:25]
Reactant: Cc1cc(Oc2ccc(Cl)c(C(F)(F)F)c2)ncc1N
Reactant: CCN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCN(C)C=Nc1cnc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
In a 25 ml single-necked round-bottomed flask, ethylmethylformamide (349 mg) is solubilized in dry dichloromethane (4 ml) at ambient temperature (colourless solution). Under stirring phosphorous oxide chloride (0.37 ml) is added dropwise by syringe. Stirring at ambient temperature is continued for 1 hour, whereupon a pink-orange solution is obtained. To this solution, 6-(4-Chloro-3-trifluoromethyl-phenoxy)-4-methyl-pyridin-3-ylamine (605 mg) dissolved in 1.0 ml of dry dichloromethane is added dropwise by syringe, giving a yellow solution. Stirring is continued at an ambient temperature for 1 hour. The mixture is then poured into ice/water (pH=2, water phase). 2 M aqueous NaOH is then added to get a pH of about 11 and stirring is continued for 10 minutes. The mixture is then extracted with dichloromethane (2×50 ml). The combined organic phases are then dried over sodium sulfate, filtered and the solvent is removed in vacuo. Purification of this gum by flash chromatography over silica gel with hexane/ethyl acetate 1:1 (v:v) gives 0.67 g of the compound as a brownish oil.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[NH:8][N:7]=[C:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]=1.S(=O)(=O)(O)[O-].[K+]>CC(C)=O.O>[CH:3]([C:4]1[NH:8][N:7]=[C:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]=1)=[O:2]
Reactant: COC(OC)c1cc(C(=O)OC(C)(C)C)n[nH]1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1cc(C=O)[nH]n1
Reaction time: 0.17 h
Yield: 74.4 %

Procedure:
To a solution of 1,1-dimethylethyl 5-[bis(methyloxy)methyl]-1H-pyrazole-3-carboxylate (18.6 g) in acetone (100 ml) was added 1M potassium bisulphate solution (200 ml) and the resultant suspension stirred at RT overnight. The mixture was diluted with water (200 ml), stirred for 10 min, filtered and the resultant solid washed sequentially with water, isopropanol and hexane and dried under high vacuum to give the title compound (11.2 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[OH:19].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].O>CN(C)C=O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: CCOC(=O)CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCOc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2
Reaction time: 0.5 h

Procedure:
6,7-Dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-one (12 g., 0.04 mole) is dissolved in dimethylformamide (50 ml.), treated with potassium carbonate (5.5 g., 0.04 mole) and heated and stirred on a steam bath for 30 minutes. Ethyl 6-bromohexanoate (8.9 g., 0.04 mole) is added dropwise with good stirring over 15 minutes, then the mixture is heated and stirred in a steam bath for two hours. The reaction mixture is poured into water (400 ml.) and extracted with ether (2×150 ml.) The either extract is dried over sodium sulfate, filtered and the ether removed at reduced pressure. The residue, which crystallizes upon standing, is recrystallized from a mixture of ether and petroleum ether to give ethyl 6-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]hexanoate, 16 g., m.p. 69°-72° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15]C(C)(C)C)=[CH:11][CH:10]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O)cc1
Reaction time: 0.08 h
Yield: 88.7 %

Procedure:
(1S,2S)-2-(4-tert-Butoxy-phenyl)-cyclopropanecarboxylic acid ethyl ester (10.5 g, 35.6 mmol) is dissolved in trifluoroacetic acid (15 mL, 196 mmol) and stirred for 5 minutes. The mixture is concentrated under vacuum, then re-evaporated five times from dichloromethane. The residue is dissolved in boiling cyclohexane (20 mL) and then allowed to cool. The cyclohexane layer is decanted off and the operation repeated. The residue is dried under vacuum to give the title compound (yield 6.51 g). GC (METHOD 1): tR=11.04 min; Mass spectrum (EI+): m/z=206 [M]+, e.e. 96% by chiral HPLC (Column: Daicel Chiralpak AS-H, 4.6×250 mm, 5 μm Mobile phase: hexane:ethanol 95:5, 1 mL/min, 25° C.) tR=14.17 (13.11) min.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][C:12]([NH2:15])=[N:13][CH:14]=2)O1.Cl[C:18]1[N:19]=[C:20]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[C:21]2[N:27]=[C:26]([CH2:28][N:29]3[CH2:34][CH2:33][CH:32]([C:35]([OH:38])([CH3:37])[CH3:36])[CH2:31][CH2:30]3)[CH:25]=[CH:24][C:22]=2[N:23]=1>>[NH2:15][C:12]1[N:13]=[CH:14][C:9]([C:18]2[N:19]=[C:20]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[C:21]3[N:27]=[C:26]([CH2:28][N:29]4[CH2:34][CH2:33][CH:32]([C:35]([OH:38])([CH3:37])[CH3:36])[CH2:31][CH2:30]4)[CH:25]=[CH:24][C:22]=3[N:23]=2)=[CH:10][N:11]=1
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: CC(C)(O)C1CCN(Cc2ccc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3n2)CC1

Procedure:
Following General Procedure A, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine and 2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 were reacted to give 107. LCMS (MH+)=465.3. 1H-NMR (DMSO-d6): δ 8.29 (s, 1H), 8.09 (d, 1H), 7.80 (d, 1H), 7.09 (s, 2H), 4.50 (s, 4H), 4.01 (s, 1H), 3.81 (m, 4H), 3.68 (s, 2H), 2.91 (m, 2H), 1.97 (m, 2H), 1.65 (m, 2H), 1.29 (m, 2H), 1.17 (m, 1H), 1.03 (s, 6H)
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][C:11]1=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[I-].CS[C:21]1[S:25][CH:24]=[CH:23][S+:22]=1>O1CCCC1>[CH2:3]([N:10]1[CH2:15][CH2:14][C:13](=[O:16])[C:12](=[C:21]2[S:25][CH:24]=[CH:23][S:22]2)[C:11]1=[O:17])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CCN(Cc2ccccc2)C(=O)C1
Reactant: CSc1scc[s+]1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCN(Cc2ccccc2)C(=O)C1=C1SC=CS1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
Sodium hydride (60% dispersion in oil) (80 mg) is suspended in tetrahydrofuran (10 ml), and thereto are added 1-benzyl-2,4-dioxopiperidine (200 mg) and 2-methylthio-1,3-dithiolium iodide (273 mg). The mixture is stirred at room temperature for 30 minutes. The reaction mixture is poured onto water and extracted with chloroform. The extract is washed with a saturated sodium chloride solution, dried and then distilled to remove the solvent. The residue is purified by silica gel column chromatography (solvent; ethyl acetate:n-hexane=1:1) and recrystallized from isopropyl alcohol to give 1-benzyl-3-(1,3-dithiol-2-ylidene)-2,4-dioxopiperidine (262 mg, 87.8%) as pale yellow needles, m.p. 122°-124° C.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([NH:19][S:20]([CH2:23][CH2:24][NH2:25])(=[O:22])=[O:21])[CH2:15][CH2:14]1)([CH3:12])[CH3:11]>>[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([NH:19][S:20]([CH2:23][CH2:24][NH:25][C:7]([C:5]2[O:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:9])(=[O:21])=[O:22])[CH2:15][CH2:14]1)([CH3:12])[CH3:11]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CC(C)N1CCC(NS(=O)(=O)CCN)CC1
Product: CC(C)N1CCC(NS(=O)(=O)CCNC(=O)c2ccc(Br)o2)CC1

Procedure:
5-Bromo-furan-2-carboxylic acid [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-amide was prepared by an analogous procedure as described in example 9 starting from 126 mg (1.1 equiv.) 5-bromo-furan-2-carboxylic acid and 150 mg (0.60 mmol) 2-amino-ethanesulfonic acid (1-isopropyl-piperidin-4-yl)-amide. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 5-bromo-furan-2-carboxylic acid [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-amide. The title compound was obtained as its trifluoroacetate in form of a colorless amorphous material. Yield: 121 mg MS (ES+): m/e=422, bromo pattern.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(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>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)=[CH:18][CH:17]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CSc1ccc(C2=C(Br)CCC2)cc1
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
Product: CSc1ccc(C2=C(c3ccc(F)cc3)CCC2)cc1

Procedure:
Under nitrogen, 1.5 g (5.6 mmol) of 1-(2-bromocyclopenten-1-yl)-4-(methylthio)benzene (Step 2) was reacted with 1.5 g (11 mmol) of 4-fluorophenylboronic acid (Lancaster) in 30 mL of toluene, 20 mL of ethanol, and 25 mL of 2M Na2CO3 in the presence of 250 mg of Pd(PPh3)4. The reaction was vigorously stirred at reflux overnight and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, dried (MgSO4), and reconcentrated. Purification by silica gel chromatography with hexane gave 1-[2-(4-fluorophenyl)cyclopenten-1-yl]-4-(methylthio)benzene (41 in Synthetic Scheme X when R5 =SCH3, R10 =F, and R1, R2, R3, R4, R6, R7, R8, R9, R11, and R12 =H) as a colorless solid. mp 46-47° C.; NMR (CDCl3) d 2.04 (m, J=7 Hz, 2H), 2.45 (s, 3H), 2.86, (t, J=7 Hz, 4H), 6.86-6.94 (m, 2H), 7.08 (br s, 4H), 7.10-7.18 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=3)[C:9](/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1>C(O)(=O)C.O=[Pt]=O>[NH2:1][C:2]1[C:7]2=[C:8]([C:18]3[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=3)[C:9]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)/C=C/c1cn2ncnc(N)c2c1-c1ccc([N+](=O)[O-])cc1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CCOC(=O)CCc1cn2ncnc(N)c2c1-c1ccc(N)cc1
Reaction time: 24 h
Yield: 90.4 %

Procedure:
A suspension of PtO2 (16 mg, 0.070 mmol) in acetic acid (0.5 ml) was added to a suspension of ethyl (2E)-3-[4-amino-5-(4-nitrophenyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]acrylate (144 mg, 0.408 mmol) in acetic acid (2 ml) under N2 atmosphere. The flask was evacuated and refilled with hydrogen gas (3×) and the reaction proceeded under a hydrogen atmosphere (1 atm) for 1 d. Additional PtO2 (50 mg, 0.22 mmol) in acetic acid (0.5 ml) was added and the reaction proceeded under H2 atmosphere for an additional 1 d. The reaction was filtered through a Celite pad and washed with MeOH. It was evaporated to dryness, diluted with EtOAc and washed with aqueous Na2CO3. The aqueous layer was back extracted with EtOAc (2×). Organic was dried (Na2SO4), filtered, and evaporated to dryness to afford the above compound as a yellow solid (120 mg, yield 90%). 1H-NMR (CD3OD) δ 7.70 (s, 1H), 7.47 (s, 1H), 7.12 (d, J=8.3 Hz, 2H), 6.84 (d, J=8.3 Hz, 2H), 4.06 (q, J=7.8 Hz, 2H), 2.82 (t, J=7.8 Hz, 2H), 2.48 (t, J=7.7 Hz, 2H), 1.18(t, J=7.8 Hz, 3H); MS [M+H]+=326; LCMS RT=1.20 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[S:12][C:13]2[CH2:14][N:15]([C:20](SC)=[N:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:16][CH2:17][C:18]=2[N:19]=1)=[O:10].[N:30]#[C:31][NH2:32]>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[S:12][C:13]2[CH2:14][N:15]([C:20]([NH:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:32][C:31]#[N:30])[CH2:16][CH2:17][C:18]=2[N:19]=1)=[O:10]
Reactant: CSC(=Nc1ccccc1)N1CCc2nc(C(=O)Nc3ccccc3N)sc2C1
Reactant: N#CN
Solvent: C1CCOC1
Product: N#CN=C(Nc1ccccc1)N1CCc2nc(C(=O)Nc3ccccc3N)sc2C1

Procedure:
A solution of methyl 2-[(2-aminophenyl)carbamoyl]-N-phenyl-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carbimidothioate obtained in step IV (1 eq), cyanamide (10 eq) in very small quantity of THF was heated at reflux temperature for 15 h. Solvent was evaporated and the residue was purified by either column chromatography or preparative HPLC to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1([OH:8])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[Cl:13][CH2:12][CH2:11][CH2:10][N:5]1[CH2:6][CH2:7][C:2]([CH3:1])([OH:8])[CH2:3][CH2:4]1
Reactant: CC1(O)CCNCC1
Reactant: ClCCCBr
Product: CC1(O)CCN(CCCCl)CC1

Procedure:
4-methylpiperidin-4-ol (made via literature methods) and 1-bromo-3-chloropropane are reacted using the procedure for Example OO to afford 1-(3-chloropropyl)-4-methylpiperidin-4-ol.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:24][NH2:25]>>[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:24][NH:25][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: NCc1cc(F)cc(F)c1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: Fc1cc(F)cc(CNc2nccc(-n3cnc4ccccc43)n2)c1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 3,5-difluorobenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 338.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.58 (s, 1H); 8.45 (d, J=5.5 Hz, 1H); 7.98 (br s, 1H); 7.85 (d, J=8.5 Hz, 1H); 7.36 (m, 2H); 6.95 (d, J=6.4 Hz, 2H); 6.89 (d, J=5.4 Hz, 1H); 6.74 (m, 1H); 5.87 (br s, 1H); 4.75 (d, J=6.4 Hz, 2H).