Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[CH:10]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)[NH:9]1)=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:19][C:15]1[CH:14]=[C:13]([CH:12]2[C:11]([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)([C:20]#[N:21])[CH:10]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)C1NC(c2cccc(Cl)c2)C(C#N)(c2ccc(Cl)cc2)C1c1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1(c2ccc(Cl)cc2)C(c2cccc(Cl)c2)NC(C(=O)O)C1c1cccc(Cl)c1

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 42a (0.45 g, 0.85 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (0.49 g, 98%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:26]=[N:25][C:24]2[NH:23][CH2:22][CH2:21][O:20][C:19]=2[CH:18]=1.Br[C:28]1[CH:33]=[CH:32][CH:31]=C[C:29]=1[S:34]([NH:37][C@H:38]([CH3:41])[CH2:39][OH:40])(=[O:36])=[O:35]>>[O:20]1[CH2:21][CH2:22][NH:23][C:24]2[N:25]=[CH:26][C:17]([C:3]3[CH:4]=[CH:5][C:6]([C:8]4[C:29]([S:34]([NH:37][C@H:38]([CH3:41])[CH2:39][OH:40])(=[O:35])=[O:36])=[CH:28][CH:33]=[CH:32][CH:31]=4)=[CH:7][C:2]=3[F:1])=[CH:18][C:19]1=2
Reactant: CC1(C)OC(c2ccc(-c3cnc4c(c3)OCCN4)c(F)c2)OC1(C)C
Reactant: C[C@H](CO)NS(=O)(=O)c1ccccc1Br
Product: C[C@H](CO)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc3c(c2)OCCN3)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 444 using 7-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine and (R)-2-bromo-N-(1-hydroxypropan-2-yl)benzenesulfonamide. MS (ESI): mass calcd. for C22H22FN3O4S, 443.13; m/z found, 444.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.16-8.10 (m, 1H), 7.82-7.79 (m, 1H), 7.74-7.71 (m, 1H), 7.70-7.64 (m, 1H), 7.61-7.57 (m, 1H), 7.54-7.46 (m, 1H), 7.40-7.33 (m, 3H), 4.40-4.36 (m, 2H), 3.75-3.69 (m, 2H), 3.48-3.33 (m, 2H), 3.24-3.16 (m, 1H), 1.05-1.01 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=2)=[CH:4][CH:3]=1.CN(C)C=O.[I-:24].[K+].II>N.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=2)=[CH:6][C:7]=1[I:24]
Reactant: CCOC(=O)c1cccc(-c2ccc(O)cc2)c1
Reactant: [I-]
Agent: II
Agent: N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(-c2ccc(O)c(I)c2)c1
Reaction time: 1 h

Procedure:
The product from Example 143A (7.71 g, 31.8 mmol) was dissolved into N,N-dimethylformamide (30 mL), diluted with concentrated aqueous ammonia (320 mL), and treated with a solution of potassium iodide (27.72 g, 167 mmol) and iodine (8.48 g, 33.4 mmol) in water (100 mL) all at once. After the mixture was stirred for one hour, the ammonia was removed under reduced pressure on a rotary evaporator. The remaining solution was neutralized to pH 7 with aqueous hydrochloric acid, diluted with EtOAc (200 mL), worked up as usual, dried (Na2SO4), concentrated, and chromatographed on silica with a 33 to 100% gradient of CH2Cl2/hexanes to provide the title compound as a white microcrystalline solid (37% yield). 1HNMR (300 MHz, d6-DMSO) δ 1.35 (t, 3H), 4.35 (q, 2H), 7.00 (d, 1H), 7.53-7.60 (m, 2H), 7.84-7.91 (m, 2H), 7.97 (d, 1H), 8.08 (dd, 1H), 10.55 (bs, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH2:13][CH2:12][C:11](=O)[CH:10]=1.Cl.[NH2:16][OH:17].C(N(CC)CC)C>C(O)C>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH2:13][CH2:12][C:11](=[N:16][OH:17])[CH:10]=1
Reactant: O=C1C=C(c2ccc(O)cc2O)CC1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: ON=C1C=C(c2ccc(O)cc2O)CC1

Procedure:
3-[2,4-Bis(methoxymethoxy)phenyl]-2-cyclopenten-1-one (20 mg) was heated at 50° C. in MeOH (4 ml) containing acidic ion exchange resin (100 mg) for 3 hr. The reaction mixture was filtered and the resin washed with ethyl acetate (20 ml). The filtrate was concentrated in vacuo and the residue purified by flash column chromatography (SiO2, ethyl acetate/petrol, 7:3 v/v) to furnish 3-(2,4-dihydroxyphenyl)-2-cyclopenten-1-one (11 mg, 79%). 3-(2,4-Dihydroxyphenyl)-2-cyclopenten-1-one (6 mg), hydroxylamine hydrochloride (3.3 mg) and triethylamine (6.6 μl) were heated in ethanol (3 ml) under reflux for 3 hr. The reaction mixture was partitioned between ethyl acetate (20 ml) and water (20 ml). The aqueous phase was extracted with ethyl acetate (10 ml), and the combined organic phases were washed with brine (10 ml), dried over magnesium sulfate, and concentrated in vacuo. The crude residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 1:1 v/v) to furnish the title compound as a yellow solid and as one major isomer (4 mg, 62%). Data reported for the major isomer: δH (d4-MeOH) 2.74-2.77 (2H, m), 2.96-2.99 (2H, m), 6.34 (1H, dd), 6.38 (1H, d), 6.96 (1H, t), 7.22 (1H, d); m/z (ES−) 204 (M−H)−.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][OH:8])[CH2:2][CH2:3][CH3:4].[C:9]1([CH3:19])[C:10]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=1>N1C=CC=CC=1>[C:9]1([CH3:19])[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([O:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])(=[O:17])=[O:16]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CCCCOCCO
Solvent: c1ccncc1
Product: CCCCOCCOS(=O)(=O)c1ccccc1C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
To a cold (0° C.) solution of 118.18 (1 mol) of 2-butoxy-ethanol in anhydrous pyridine, was added 190.66 g (1 mol) of toluenesulfonylchloride. The resultant reaction mixture was allowed to react for approximately one hour at 0° C., then at room temperature for approximately two hours. When the reaction was substantially complete, as indicated by TLC, the reaction mixture was concentrated in vacuo to provide a residue. This residue was partitioned between diethyl ether and a 1N aqueous hydrochloric acid solution and the organic phase was washed sequentially with a 2N sodium hydroxide solution, a 1N hydrochloric acid solution, water, and brine, and then dried over sodium sulfate, filtered and concentrated in vacuo to provide 200.39 g of a light gold oil.
Reaction SMILES: C(OC([N:8]1[C@H:12]([C:13](=[O:25])[NH:14][C@H:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)[CH2:11][Si:10]([CH3:27])([CH3:26])[CH2:9]1)=O)(C)(C)C.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>C(Cl)Cl>[OH:34][C:28]([C:30]([F:33])([F:32])[F:31])=[O:29].[CH3:26][Si:10]1([CH3:27])[CH2:11][C@@H:12]([C:13]([NH:14][C@H:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)=[O:25])[NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1C[Si](C)(C)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[Si]1(C)CN[C@H](C(=O)N[C@@H]2CCCc3ccccc32)C1
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of (R)-tert-butyl-3,3-dimethyl-5-((R)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)-1,3-azasilolidine-1-carboxylate (4.9 g, 12 mmol) in CH2Cl2 (50 mL) was added TFA (7 mL) at rt. After 4 h, the reaction mixture was concentrated in vacuo to obtain (R)-3,3-dimethyl-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,3-azasilolidine-5-carboxamide TFA salt (5.0 g, 12 mmol, 100% yield) as a white solid, which was used directly in the next step. 1H NMR (400 MHz, CD3OD) δ 7.14-7.25 (m, 4H), 5.12 (t, J=5.5 Hz, 1H), 4.0 (dd, J=11.9, 6.6 Hz, 1H), 2.79 (m, 2H), 2.76 (d, J=4.5 Hz, 1H), 2.45 (dd, J=15, 4.5 Hz, 1H), 1.85-2.06 (m, 4H), 1.53 (dd, J=15, 6.8 Hz, 1H), 1.08 (dd, J=15, 4.5 Hz, 1H), 0.41 (3H), 0.38 (s, 3H); MS(ESI+) m/z 289 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH2:22][C:23](O)=[O:24])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[CH2:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=1)[CH3:27]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:20])([CH3:21])[CH3:19])=[CH:14][CH:13]=2)(=[O:10])=[O:11])[CH2:22][C:23]([N:28]([CH2:26][CH3:27])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=2)=[O:24])=[CH:4][CH:3]=1
Reactant: CCNCc1cccc(C)n1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc(N)nc2)cc1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1ccc(N)nc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(6-amino-pyridin-3-yl)-(4-tert-butyl-benzenesulfonyl)-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9](Br)[CH:8]=[N:7][C:6]=1[NH:12][CH3:13])[CH3:2].[CH2:15]([Zn]CC)[CH3:16]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([CH2:15][CH3:16])[CH:8]=[N:7][C:6]=1[NH:12][CH3:13])[CH3:2]
Reactant: CCOC(=O)c1cc(Br)cnc1NC
Reactant: CC[Zn]CC
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(CC)cnc1NC
Yield: 15 %

Procedure:
A solution of 5-bromo-2-methylamino-nicotinic acid ethyl ester (400 mg, 1.54 mmol), diethylzinc solution (1 M in hexane, 3.1 mL, 3.1 mmol), and dichloro[1,1′-bis(diphenylphosphine)ferrocene]palladium(II) (34 mg, 46 μmol) in 1,4-dioxane was heated at reflux for 2 h, then partitioned between ethyl acetate and sat. aq. ammonium chloride solution. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded the title compound (48 mg, 15%). Colourless liquid, MS (ISP): 209.3 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=1)=[O:4].[CH2:23]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:24]1([CH2:23][N:30]([CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:6]=2)=[O:4])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(CBr)c1cccc(OCCCOCc2ccccc2)c1
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(CN(Cc1ccccc1)Cc1ccccc1)c1cccc(OCCCOCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-bromo-1-[3-({3-[(phenylmethyl)oxy]propyl}oxy)phenyl]ethanone (13.17 g), dibenzylamine (6.4 g) and dichloromethane (25 mL) was added a solution of sodium carbonate (7.6 g) in water (50 mL). The reaction mixture was stirred at ambient temperature overnight. The organic layer was separated and concentrated to a minimum and tert-butyl methyl ether was added. The organic layer was washed with dilute acetic acid (4 times) and 0.1N sodium hydroxide once and brine once. The organic solution was concentrated to dryness. The oil was washed with methanol and purified by chromatography to give the title compound.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([OH:10])=[O:9].[CH3:11][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[ClH:1].[CH3:11][O:9][C:8]([C@@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[NH2:2])=[O:10]
Reactant: N[C@H]1CCC[C@H]1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)[C@@H]1CCC[C@@H]1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(1R,2S)-2-Amino-cyclopentanecarboxylic acid hydrochloride (96 mg, 0.58 mmol) was dissolved in a 1:1 mixture of benzene and methanol (6 mL). The mixture was cooled to 0° C. A 2.0 M solution of (trimethylsilyl)diazomethane in hexanes (0.44 mL, 0.87 mmol) was added and the reaction was stirred at 25° C. for 30 min. The mixture was concentrated and dried in vacuo. The crude product was directly used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[NH2:17][C:18]1[C:22]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=2)=[CH:21][NH:20][N:19]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:19]3[N:20]=[CH:21][C:22]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=4)=[C:18]3[N:17]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2c[nH]nc2N)ccn1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)cc1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)cc4)nc23)ccn1
Yield: 43.2 %

Procedure:
Reaction of 1-(4-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (125 mg, 0.5 mmol), prepared from commercially available 4-chloro-acetophenone according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [see part synthesis of amino-pyrazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (84 mg, 43%). MS (ISP) 389.1 [(M+H)+]; mp 220° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:6]2[CH2:7][NH:8][CH2:9][CH2:10][N:5]2[C:4](=[O:11])[O:3]1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>O1CCCC1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([N:8]2[CH2:9][CH2:10][N:5]3[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[CH:6]3[CH2:7]2)=[O:22])=[CH:16][CH:15]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC1(C)OC(=O)N2CCNCC21
Solvent: C1CCOC1
Product: CC1(C)OC(=O)N2CCN(C(=O)Nc3ccc(F)cc3)CC21
Temperature: 50 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
Hexahydro-1,1-dimethyl-3H-oxazolo[3,4-a]pyrazin-3-one (0.10 g, 0.59 mmol) was dissolved in tetrahydrofuran (10 mL). 4-Fluorophenyl isocyanate (0.12 g, 0.88 mmol) was added thereto, and the mixture was stirred at 50° C. for 4 hours. The reaction solution was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1 to 1:9). After purification, the crystals, which were precipitated while concentrating under reduced pressure, were collected by filtration to obtain the title compound (136 mg, yield 75%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][C:14]3([CH3:20])[CH3:19])[N:8]2[CH3:11])=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:3]=1.[O:27]1[CH2:30][C:29](=O)[CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH:29]4[CH2:30][O:27][CH2:28]4)[CH2:15][C:14]3([CH3:20])[CH3:19])[N:8]2[CH3:11])=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:3]=1
Reactant: Cn1c(CN2CCNCC2(C)C)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1c(CN2CCN(C3COC3)CC2(C)C)nc2c(N3CCOCC3)nc(Cl)nc21
Reaction time: 16 h

Procedure:
A mixture of 2-chloro-8-(2,2-dimethylpiperazin-1-ylmethyl)-9-methyl-6-morpholin-4-yl-9H-purine (198 mg, 0.52 mmol), oxetan-3-one (42 mg, 0.58 mmol) and 4 Å powdered molecular sieves in DCE (10 mL) was allowed to stir at r.t for 4 h before the addition of sodium triacetoxyborohydride (144 mg, 0.68 mmol). The resulting mixture was allowed to stir for 16 h then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording the title compound (192 mg, 85%).—1H NMR (CDCl3, 400 MHz): δ 4.63 (2 H, t, J=6.48 Hz), 4.55 (2 H, t, J=6.08 Hz), 4.27 (4 H, brd s), 3.84-3.80 (7 H, m), 3.49 (2 H, s), 3.38-3.37 (1 H, m), 2.50-2.40 (2 H, m), 2.23-2.04 (4 H, m), 1.20 (6 H, s)
Reaction SMILES: Cl.[CH2:2]([C:4]1[O:8][C:7]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:25])[N:12]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:11]2=[O:32])=[N:6][N:5]=1)[CH3:3].[CH2:33]([O:35][C:36]1[C:45]([O:46][CH3:47])=[CH:44][C:43]2[C:42]([C:48]3[CH:56]=[CH:55][C:51]([C:52](O)=[O:53])=[CH:50][CH:49]=3)=[N:41][C@@H:40]3[CH2:57][CH2:58][S:59][CH2:60][C@@H:39]3[C:38]=2[CH:37]=1)[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:33]([O:35][C:36]1[C:45]([O:46][CH3:47])=[CH:44][C:43]2[C:42]([C:48]3[CH:49]=[CH:50][C:51]([C:52]([N:29]4[CH2:30][CH2:31][CH:26]([N:12]5[C:13](=[O:25])[C:14]6[S:18][C:17]([C:19]7[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=7)=[CH:16][C:15]=6[N:10]([CH2:9][C:7]6[O:8][C:4]([CH2:2][CH3:3])=[N:5][N:6]=6)[C:11]5=[O:32])[CH2:27][CH2:28]4)=[O:53])=[CH:55][CH:56]=3)=[N:41][C@@H:40]3[CH2:57][CH2:58][S:59][CH2:60][C@@H:39]3[C:38]=2[CH:37]=1)[CH3:34]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: CCc1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nnc(CC)o5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(5-ethyl-1,3,4-oxadiazol-2-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (200 mg; compound B29) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (168 mg; compound C10) and HBTU (191 mg) in DCM (10 ml) in the presence of DIPEA (0.29 ml) according to the procedure described in example 2 to afford the title compound after purification by twofold flash column chromatography [silica gel, eluation gradient: cyclohexane/EtOAc, 3/2 to 0/1 and DCM/MeOH, 1/0 to 1/1 (v/v)] as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]#[CH:10].[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][SH:17])=[CH:14][CH:13]=1.[Na]>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]\[CH:16]([S:17][CH:16](/[CH:10]=[CH:9]\[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1])[C:15]1[CH:18]=[CH:19][C:12]([Br:11])=[CH:13][CH:14]=1)[C:15]1[CH:18]=[CH:19][C:12]([Br:11])=[CH:13][CH:14]=1
Reactant: C#Cc1cccc(Cl)c1Cl
Reactant: SCc1ccc(Br)cc1
Agent: [Na]
Product: Clc1cccc(/C=C\C(SC(/C=C\c2cccc(Cl)c2Cl)c2ccc(Br)cc2)c2ccc(Br)cc2)c1Cl

Procedure:
A solution of 2,3-dichlorophenylacetylene (0.02 mol), 4-bromobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-2,3-dichlorostyryl-4-bromobenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3]/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:38])C(=O)C1>CN(C=O)C>[Br:38][CH2:1][CH2:2][CH2:3]/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCC/C=C/CCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCCC/C=C/CCCBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of trans-dec-4-en-1-ol (1.52 g, 9.74 mmol) in DMF (25 mL) was added triphenylphosphine (2.81 g, 10.7 mmol). The solution was cooled to 0° C. and NBS (1.85 g, 10.4 mmol) was added in portions. After stirring for 30 min at room temperature, the reaction was quenched with methanol (1 mL). The solution was diluted with ether (100 mL), washed with water, saturated aqueous NaHCO3 and brine successively. The organic layer was dried and concentrated. The residue was purified by flash chromatography on silica gel, eluting with hexane to afford trans-1-bromo-dec-4-ene (1.60 g, 75%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 5.49 (1H, m), 5.35 (1H, m), 3.42 (2H, t, J=6.6 Hz), 2.15 (2H, m), 1.96 (4H, m), 1.29 (6H, m), 0.90 (3H, t, J=7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 132.36, 127.89, 33.61, 32.80, 32.73, 31.65, 31.14, 29.45, 22.82, 14.36.
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:9]2[CH:14]=[CH:13][C:12](OC)=[CH:11][CH:10]=2)=O)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:17]([NH:24][OH:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[N:1]1([CH2:6][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N+:24]([O-:25])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: ONCc1ccccc1
Reactant: COc1ccc(C(=O)Cn2ccnc2)cc1
Product: [O-][N+](Cc1ccccc1)=C(Cn1ccnc1)c1ccccc1

Procedure:
2-(1H-Imidazol-1-yl)-1-phenyl-N-(phenylmethyl)ethanimine N-oxide (2, R1 =R2 =C6H5, X=CH) Compound 2 (R1 =R2 =C6H5, X=CH) was prepared by the procedure described in Example 1, Method B, by reacting 2-(1H-imidazol-1-yl)acetophenone (1, R1 =C6H5, X=CH) with N-benzylhydroxylamine. Compound 2 (R1 =R2 =C6H5, X=CH) was obtained as a light yellow oil.
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH2:26]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1COCC1.[CH3:43][NH2:44]>>[CH3:43][NH:44][CH2:26][CH2:25][CH2:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[C:14]2[S:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:13])=[O:12]
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCCCOc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)cc1
Solvent: C1CCOC1
Product: CNCCCOc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
A solution of toluene-4-sulfonic acid 3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl ester (0.422 g, 0.786 mmol) in 2.0 M methylamine in THF (8.0 mL, 16 mmol). was stirred for 15 hours at 70° C. in a sealed tube. After cooling to ambient temperature, the reaction mixture was concentrated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with brine. The aqueous phases were extracted with chloroform, and both organic phases were combined and dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 0.75% ammonium hydroxide/7.5% methanol in chloroform. Methyl-{3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl}-amine was obtained as a light yellow foam (0.209 g, 67.2%). Methanol and ethereal hydrochloride were added to the compound. The resulting solution was concentrated and dried for 14 hours at 84° C. in vacuo. The hydrochloride was obtained as a light yellow foam (0.217 g). Mass Spectrum (−EI, [M−H]−) m/z 394. 1HNMR (500 MHz, DMSO-d6): δ14.16 (s, 1H), 8.74-8.76 (m, 1H), 8.67 (s, br, 2H), 8.52 (dd, 1H, J=7.44 Hz and 1.22 Hz), 8.27 (d, 1H, J=8.30 Hz), 8.02-8.05 (m, 1H), 7.70-7.75 (m, 1H), 7.54-7.65 (m, 3H), 7.29 (d, 1H, J=2.19 Hz), 7.08-7.11 (m, 1H), 4.09 (t, 2H, J=5.98 Hz), 3.05 (s, br, 2H), 2.55 (s, 3H), 2.05-2.11 ppm (m, 2H). Elemental Analysis for C21H21N3O3S.1.00 mol HCl.0.45 mol H2O: Calcd: C, 57.32; H, 5.25; N, 9.55; Found: C, 57.64; H, 5.33; N, 9.39.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH:26]C(=O)OC(C)(C)C)([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=3)[CH:9]=2)[CH2:4][O:3]1.[CH2:35]([O:42][C:43]1[CH:44]=[C:45]([SH:49])[CH:46]=[CH:47][CH:48]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[NH2:26][C:5]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([S:49][C:45]3[CH:46]=[CH:47][CH:48]=[C:43]([O:42][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:44]=3)[CH:14]=2)[CH:9]=1)([CH2:4][OH:3])[CH2:6][OH:7]
Reactant: Sc1cccc(OCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc3cc(OS(=O)(=O)C(F)(F)F)ccc3c2)COC(C)(C)OC1
Product: NC(CO)(CO)c1ccc2cc(Sc3cccc(OCc4ccccc4)c3)ccc2c1

Procedure:
The compound was prepared from tert-butyl 2,2-dimethyl-5-(6-(trifluoromethylsulfonyloxy)naphthalen2-yl)-1,3-dioxan-5-ylcarbamate and 3-benzyloxy-benzenethiol in reactions analogous to those described in Examples 154 and 191. 1H NMR (MeOD) δ: 7.82 (s, 1H), 7.76 (d, J=8.6 Hz, 2H), 7.71 (s, 1H), 7.48 (dd, J=8.6, 2.0 Hz, 1H), 7.31 (dd, J=8.6, 1.5 Hz, 1H), 7.11-7.26 (m, 6H), 6.80-6.89 (m, 3H), 4.93 (s, 2H), 3.95-4.03 (m, 2H), 3.86-3.94 (m, 2H). MS (M+1): 432.0.