Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([S:20][CH2:21][CH2:22][CH2:23][S:24][CH2:25][CH2:26][CH2:27][S:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][S:37][CH2:38][CH2:39][CH2:40][S:41][CH2:42][CH2:43][CH2:44][S:45]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>FC(F)(F)C(O)=O.C(Cl)Cl>[SH:45][CH2:44][CH2:43][CH2:42][S:41][CH2:40][CH2:39][CH2:38][S:37][CH2:36][CH2:35][O:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][S:28][CH2:27][CH2:26][CH2:25][S:24][CH2:23][CH2:22][CH2:21][SH:20]
Reactant: c1ccc(C(SCCCSCCCSCCOCCOCCSCCCSCCCSC(c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: SCCCSCCCSCCOCCOCCSCCCSCCCS
Temperature: 25 °C
Yield: 58 %

Procedure:
A 2.14 g amount of 1,26 ditrityl-1,5,9,18,22,26-hexathia-12,15-dioxahexacosane was dissolved in a mixture of 9.0 ml of triflouroacetic acid and 9.0 ml of methylene chloride. About 0.7 ml of triethylenesilane was added and stirred at room temperature for a half hour. About 100 ml of methylene chloride was added to the mixture and this was washed with 50 ml of water. The organic layer was then dried with magnesium sulfate and filtered. The solvent was evaporated from filtrate and the residue was purified on silica gel using a mixture of methylene chloride and acetone (5:1 v/v). About 620 mg (58%) of 1,5,9,18,22,26-hexathia-12,15-dioxahexacosane was obtained. The preparation scheme is shown below:
Reaction SMILES: [C:1](=[O:13])([O:11][CH3:12])[O:2][C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:4]=1[CH3:10].OS(O)(=O)=O.[N+:19]([O-])([O-:21])=[O:20].[K+]>>[C:1](=[O:13])([O:11][CH3:12])[O:2][C:3]1[CH:8]=[C:7]([N+:19]([O-:21])=[O:20])[C:6]([Br:9])=[CH:5][C:4]=1[CH3:10]
Reactant: COC(=O)Oc1ccc(Br)cc1C
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)Oc1cc([N+](=O)[O-])c(Br)cc1C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
4-Bromo-2-methylphenyl methyl carbonate (4.0 g, 16.32 mmol) was added portion-wise to H2SO4 (12.0 mL) to generate a homogeneous solution. This solution was then cooled to 0° C. internal temperature and KNO3 (2.0 g, 19.6 mmol) was added portion-wise maintaining the internal temperature below 5° C. The reaction was stirred for 2 h and then poured over ice. The aqueous layer was extracted with dichloromethane, washed with saturated NaHCO3 and water, dried over Na2SO4, and concentrated. Purification by silica gel chromatography (0-5% ethyl acetate/hexanes) provided 4-bromo-2-methyl-5-nitrophenyl methyl carbonate (3.4 g, 71% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.95 (s, 1H), 3.88 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[CH2:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>ClCCl>[CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:6][C:7]=1[N:1]1[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCc2ccccc2C1
Reactant: C1CNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: C1=C(N2CCC2)CCc2ccccc21
Temperature: 25 °C

Procedure:
A solution of azetidine (6.8 g, 0.12 mol), 3,4-dihydro-2(1 H)-naphthalenone (14.6 g, 0.10 mol), and p-toluenesulphonic acid (1.5 g) in dichloromethane (200 ml) was heated under reflux for 3 h in an apparatus fitted for the continuous removal of water, cooled to room temperature, washed with dilute aqueous sodium carbonate, dried (MgSO4), and evaporated in vacuo to give the product as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:5].Br[CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH2:31])=[O:30]>>[C:29]([CH2:28][CH2:27][CH2:26][CH2:25][O:1][C:2]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:5])(=[O:30])[NH2:31]
Reactant: O=C(NCc1ccccn1)c1cc(OCC(F)(F)F)ccc1O
Reactant: NC(=O)CCCCBr
Product: NC(=O)CCCCOc1ccc(OCC(F)(F)F)cc1C(=O)NCc1ccccn1
Yield: 66.9 %

Procedure:
Using the general method of Example I Part A, 4.7 g (0.014 mole) of 2-hydroxy-N-(2-pyridylmethyl)-5-(2,2,2-trifluoroethoxy)benzamide was reacted with 2.3 g (0.013 mole) of 5-bromovaleramide to give 3.7 g of white powdery 2-(4-carbamoylbutoxy)-N-(2-pyridylmethyl)-5-(2,2,2-trifluoroethoxy)benzamide, m.p. 178°-180° C. Analysis: Calculated for C20H22F3N3O4 : %C, 56.5; %H, 5.2; %N, 9.9; Found: %C, 56.7; %H, 5.2; %N, 9.9.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([O-])=[O:25])=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[Li+].[CH3:28][N:29]1[CH:33]=[C:32]([CH2:34][NH2:35])[N:31]=[CH:30]1>>[CH3:28][N:29]1[CH:33]=[C:32]([CH2:34][NH:35][C:24]([C:21]2[O:22][C:23]3[C:15]([N:12]4[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[CH2:14][CH2:13]4)=[CH:16][CH:17]=[CH:18][C:19]=3[CH:20]=2)=[O:25])[N:31]=[CH:30]1
Reactant: O=C([O-])c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Reactant: Cn1cnc(CN)c1
Agent: [Li+]
Product: Cn1cnc(CNC(=O)c2cc3cccc(N4CCN(CCc5ccccn5)CC4)c3o2)c1

Procedure:
The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (70 mg, 0.18 mmol) and (1-methyl-1H-imidazol-4-yl)methylamine (24 mg, 0.22 mmol). Yield: 42 mg (48%).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH2:17][CH3:18])([CH3:16])[C:13](=[O:19])[C:12]=2I)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH2:17][CH3:18])([CH3:16])[C:13](=[O:19])[C:12]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: OB(O)c1ccccc1
Reactant: CCC1(C)OC(c2ccc(S(N)(=O)=O)cc2)=C(I)C1=O
Product: CCC1(C)OC(c2ccc(S(N)(=O)=O)cc2)=C(c2ccccc2)C1=O
Yield: 34.2 %

Procedure:
100 mg of 5-{4-(aminosulfonyl)phenyl}-2-ethyl-4-iodo-2-methyl-3(2H)-furanone was reacted with 90 mg of benzeneboronic acid by following a procedure similar to Step 2 of Example 35 to give 30 mg of 5-{4-(aminosulfonyl)phenyl}-2-ethyl-2-methyl-4-phenyl-3(2H)-furanone as a solid. mp: 153-154° C. NMR: δ0.95 (t, J=7.5 Hz, 3H), 1.54 (s, 3H), 1.97 (m, 2H), 4.89 (br s, 2H), 7.26 (m, 2H), 7.36 (m, 3H), 7.79 (d, J=8.7 Hz, 2H), 7.90 (d, J=8.7 Hz, 2H). IR (cm−1): 3340, 3256, 1684, 1616, 1392, 1342, 1161.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]O.O=S(Cl)[Cl:23].CO>C(Cl)(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][Cl:23]
Reactant: OCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: O=S(Cl)Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-(2-quinolylmethoxy)benzyl alcohol 3.58 g, 13.5 mmol) in CHCl3 (100 ml) was added SOCl2 (2 ml). The mixture was stirred at room temperature for 24 hours. A small amount of methanol was added to the reaction mixture, and the solvent thereof was removed under reduced pressure, to thereby obtain the title compound as white powder.
Reaction SMILES: [NH2:1][C:2](=[S:14])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1.Br[CH2:16][C:17](=O)[C:18]([OH:20])=[O:19]>>[CH2:12]([O:11][C:9]([C:7]1[CH:6]=[N:5][N:4]([CH2:3][C:2]2[S:14][CH:16]=[C:17]([C:18]([OH:20])=[O:19])[N:1]=2)[CH:8]=1)=[O:10])[CH3:13]
Reactant: CCOC(=O)c1cnn(CC(N)=S)c1
Reactant: O=C(O)C(=O)CBr
Product: CCOC(=O)c1cnn(Cc2nc(C(=O)O)cs2)c1
Yield: 57.9 %

Procedure:
By a reaction in the same manner as in Example 1c and using the compound (1.07 g, 5.0 mmol) obtained in Example 1b and bromopyruvic acid (920 mg, 5.5 mmol), the title compound (814 mg, 57%) was obtained as bister crystals.
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=2[C:6]([OH:8])=O)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.Cl.[N:52]1([CH:57]2[CH2:62][CH2:61][O:60][CH2:59][CH:58]2[NH2:63])[CH2:56][CH2:55][CH2:54][CH2:53]1>CN(C)C=O>[CH:1]1([C:4]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=2[C:6]([NH:63][CH:58]2[CH:57]([N:52]3[CH2:53][CH2:54][CH2:55][CH2:56]3)[CH2:62][CH2:61][O:60][CH2:59]2)=[O:8])[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C1CC1
Reactant: NC1COCCC1N1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1COCCC1N1CCCC1)c1ccc(C(F)(F)F)cc1C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
2-Cyclopropyl-4-trifluoromethyl-benzoic acid (intermediate J, 118 mg, 0.513 mmol) was dissolved in 2.5 mL dimethylformamide. N,N-Diisopropyl ethyl amine (338 mg, 2.62 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (195 mg, 0.513 mmol) were added. After 10 minutes of stirring at room temperature trans-(4-pyrrolidin-1-yl-tetrahydro-pyran-3-ylamine dihydrochloride (intermediate 1,187 mg, 0.769 mmol) was added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated off. The residue was taken up in 2N sodium carbonate solution and ethyl acetate and was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (heptane/ethyl acetate/triethylamine 1:0:0→10:10:1) yielded the title compound as a white solid (121 mg, 62%), MS: m/e=383.3 [(M+H)+].
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=2)=[CH:5][CH:4]=1)=O.[CH:23]1([CH2:28][CH2:29][NH2:30])[CH2:27][CH2:26][CH2:25][CH2:24]1.[BH4-].[Na+].O>CO>[CH:23]1([CH2:28][CH2:29][NH:30][CH2:1][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:5][CH:4]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)c3ccccc23)nc1
Reactant: NCCC1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NC(=O)c1ccc(Oc2ccc(CNCCC3CCCC3)c3ccccc23)nc1
Reaction time: 16 h

Procedure:
To a solution of 6-(4-formylnaphthalen-1-yloxy)nicotinamide (Preparation 2) (200 mg, 0.7 mmol) in MeOH (10 mL) was added 2-cyclopentyl ethylamine (116 mg, 1.0 mmol) and 4 Å molecular sieves (200 mg). The mixture was stirred for 16 h before adding NaBH4 (130 mg, 3.4 mmol). After 1.5 h water (1 mL) was added and the mixture filtered. Solvent was removed in vacuo and the residue purified by column chromatography (0.5% NH3: 2% MeOH:DCM) to give the title compound: RT=2.68 min; m/z (ES+)=390.2 [M+H]+.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:13][CH2:14][OH:15])[C:7]2=[O:12].N([O-])=O.[Na+].CS(C)=O.[IH:24].C([O-])(O)=O.[Na+]>>[OH:15][CH2:14][CH2:13][N:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[I:24])[C:7]1=[O:12]
Reactant: Nc1cccc2c(=O)n(CCO)ccc12
Reactant: I
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=c1c2cccc(I)c2ccn1CCO
Reaction time: 1 h

Procedure:
5-Amino-2-(2-hydroxyethyl)isoquinolin-1(2H)-one (1.62 g, 0.00793 mol) was added to a solution of sodium nitrite (2 g, 0.03 mol) in dimethyl sulfoxide (40 mL, 0.5 mol) at 35° C. Aqueous hydrogen iodide (4 mL, 0.03 mol) in dimethyl sulfoxide (40 mL, 0.5 mol) was added, and the reaction mixture was stirred for 1 hour. The cooled reaction mixture was neutralized with sat. aq. NaHCO3 and extracted with methylene chloride (3×50 mL). The combined methylene chloride extracts were washed with brine, dried over sodium sulfate and reduced in vacuo. The mixture was purified by column chromatography using an ethyl acetate:hexanes (0-100) gradient. The combined pure fractions were reduced in vacuo to yield the title compound as an off white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]([N:6]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:7]1[C:12]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:11][CH:10]=[C:9]([C:17]([F:20])([F:19])[F:18])[N:8]=1)=O.CO.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][O:2][C:3]([C:4]1[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:7]2[C:12]([C:13](=[O:16])[C:14]=1[CH3:15])=[CH:11][CH:10]=[C:9]([C:17]([F:20])([F:19])[F:18])[N:8]=2)=[O:27]
Reactant: CCC(=O)c1ccc(C(F)(F)F)nc1N(C(=O)C(=O)OC)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)c1c(C)c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1
Yield: 53.6 %

Procedure:
In a 250 mL pear-shaped flask, N-phenyl-N-(3-propionyl-6-trifluoromethyl-pyridin-2-yl)-oxalamic acid methyl ester (1.74 g, 4.58 mmol) was combined with methanol (25 mL) to give a yellow solution. Potassium carbonate (3.8 g, 27.5 mmol) was added and the reaction mixture was refluxed for 2 hr. The reaction mixture was cooled, diluted with H2O (75 mL) and extracted with ethyl acetate (3×75 mL). The organic layers were combined, washed with brine (1×50 mL), dried over MgSO4, and concentrated in vacuo to give 1.7 g crude product as a yellow solid. The crude material was purified by flash chromatography (silica gel, 120 g, 20% to 50% ethyl acetate in hexanes) to give 3-methyl-4-oxo-1-phenyl-7-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester (0.89 g, 3.7%) as an off-white solid. 1H NMR (DMSO-d6) δ ppm 8.84 (d, J=8.2 Hz, 1H) 7.91 (d, J=8.2 Hz, 1H) 7.32-7.70 (m, 5H) 3.51 (s, 3H) 2.01 (s, 3H). MS calcd. for C18H13F3N2O3 [(M+H)+] 363.0, obsd. 363.0.
Reaction SMILES: S([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[N:19]=[C:14]2[CH:13]=[CH:12]1)(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+]>O1CCOCC1.O>[N:19]1[C:18]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:17][N:16]=[C:15]2[NH:11][CH:12]=[CH:13][C:14]=12
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=O)OC(C)(C)C)cnc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1cnc2[nH]ccc2n1
Temperature: 85 °C
Yield: 78.3 %

Procedure:
tert-Butyl (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamate (5.08 g, 12.6 mmol) in a mixture of 1,4-dioxane (40 mL) and water (10 mL) was treated with NaOH (2.02 g, 50.5 mmol) then heated to about 85° C. for about 75 min. The mixture was cooled to rt then most of the solvent was removed under reduced pressure. The mixture was diluted with water (25 mL) then DCM (25 mL) and EtOAc (50 mL) were added. The layers were separated then the aqueous layer was extracted with EtOAc (2×25 mL). The combined organics were washed with brine (15 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give tert-butyl (5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamate (2.45 g, 78%): LC/MS (Table 2, Method b) Rt=1.75 min; MS m/z 249 (M+H)+.
Reaction SMILES: [OH-].[Li+].C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:16][C:10]=2[CH2:9]1)=O)C>O.O1CCOCC1>[O:18]([CH2:17][C:15]1[O:16][C:10]2[CH2:9][NH:8][CH2:13][CH2:12][C:11]=2[N:14]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)N1CCc2nc(COc3ccccc3)oc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: c1ccc(OCc2nc3c(o2)CNCC3)cc1
Temperature: 170 °C
Reaction time: 0.67 h
Yield: 45.4 %

Procedure:
Lithium hydroxide (0.66 g, 27.7 mmol) was added to a stirred solution of 6,7-dihydro-2-(phenoxymethyl)-oxazolo[5,4-c]pyridine-5(4H)-carboxylic acid ethyl ester (1.77 g, 5.55 mmol) in a mixture of H2O (5 mL) and 1,4-dioxane (15 mL) under N2. The mixture was stirred at 170° C. for 40 minutes under microwave irradiation, diluted with H2O and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo to yield 4,5,6,7-tetrahydro-2-(phenoxymethyl)-oxazolo[5,4-c]pyridine (0.58 g, 45% yield) as a purple oil that was used in the next step without further purification. C13H14N2O2 LCMS: Rt 1.07, m/z 231 [M+H]+ (using method, LC-MS Method 6).
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=O)[CH:20]=1>>[CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[CH:25][C:21]1[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=1
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1cccnc1
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(=Cc1cccnc1)C(=O)N2
Yield: 75 %

Procedure:
Starting from 5-(3,6-dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazin-5-yl)-1,3-dihydro-2H-indol-2-one and pyridine 3-carboxaldehyde and following the method described in Example 10, the desired compound was obtained.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH2:8][CH2:9][CH3:10].Cl[CH2:18][CH2:19][CH2:20][N:21]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[S:24][CH2:23][C:22]1=[O:31].CO>C(#N)C>[CH2:7]([CH:11]1[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH2:20][N:21]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[S:24][CH2:23][C:22]2=[O:31])[CH2:13][CH2:12]1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCC1CCNCC1
Reactant: O=C1CSc2ccccc2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: CCCCC1CCN(CCCN2C(=O)CSc3ccccc32)CC1
Reaction time: 13 h

Procedure:
NAI (1.24 g, 8.27 mmol), K2CO3 (1.14 g, 8.27 mmol), and 4-butylpiperidine (0.62 g, 4.34 mmol) in acetonitrile (10 mL) were stirred at rt. 4-(3-chloropropyl)-4H-benzo[1,4]thiazin-3-one (1.0 g, 4.14 mmol) in acetonitrile (15 mL) was added via a syringe. The reaction was stirred at 60 C. for 13 hours and then 80 C. for another 25 hours under nitrogen atmosphere and concentrated in vacuo. Water (150 mL) was added and the reaction mixture was extracted with ethyl acetate (3×150 mL). The combined organic phases were dried (Na2SO4) and concentrated in vacuo to give 1.63 g of crude. The crude product was subjected to CC[eluent:EtOAC:MeOH(100:1-5%)] to give the pure title compound. Yield 1.06 g 74.2% HPLC-MS [M+H]+347 (UV/MS(%)=100/99. 1H NMR (CDCl3): δ 0.88 (t, 3H), 1.23 (m, 9H), 1.64 (d, 2H), 1.85 (m, 4H), 2.34 (t, 2H), 2.83 (d, 2H), 3.36 (s, 1H), 4.03 (t, 2H), 6.99 (m, 1H), 7.22 (d, 2H), 7.34 (d, 1H), 13C NMR (CDCl3): δ 14.21, 23.03, 25.23, 29.15, 31.80, 32.63, 35.90, 36.44, 43.28, 54.26, 55.91, 118.18, 123.45, 124.17, 127.27, 128.56, 139.63, 165.19.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:5]([Cl:24])=[C:6]([C:20]([Cl:23])=[CH:21][CH:22]=1)[CH2:7][O:8][C:9]1[C:10]2[N:11]([C:15]([Br:19])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1.N1C=CC=CC=1.[CH2:31]([N:33]=[C:34]=[O:35])[CH3:32]>CN1CCCC1=O>[Br:19][C:15]1[N:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][C:6]3[C:20]([Cl:23])=[CH:21][CH:22]=[C:4]([NH:3][C:34]([NH:33][CH2:31][CH3:32])=[O:35])[C:5]=3[Cl:24])[C:10]2=[N:17][C:16]=1[CH3:18]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N)c3Cl)cccn2c1Br
Reactant: CCN=C=O
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: CCNC(=O)Nc1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a mixture of 8-(3-amino-2,6-dichlorobenzyloxy)-3-bromo-2-methylimidazo[1,2-a]pyridine dihydrochloride (100 mg), pyridine (0.5 ml) and N-methylpyrrolidone (1.5 ml) was added ethyl isocyanate (0.10 ml). The mixture was stirred at 60° C. for 6 hours. The insoluble material was filtered off and washed with water. The filtrate and washings were combined and separated precipitate was collected by filtration. The precipitate was purified by preparative thin-layer chromatography (20% solution of methanol in dichloromethane) followed by recrystallization from n-hexane to give 3-bromo-8-[2,6-dichloro-3-(N'-ethylureido)benzyloxy]-2-methylimidazo[1,2-a]pyridine (13 mg) as crystals.
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[N:8]2[CH:14]=[N:13][CH:12]=[C:9]2[S:10][CH:11]=1)=O)C.Cl.[NH2:16][OH:17].[O-]CC.[Na+].Cl>C(O)C>[OH:17][NH:16][C:4]([CH2:6][C:7]1[N:8]2[CH:14]=[N:13][CH:12]=[C:9]2[S:10][CH:11]=1)=[O:3]
Reactant: NO
Reactant: CCOC(=O)Cc1csc2cncn12
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(Cc1csc2cncn12)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
To 2 ml of an ethanol solution containing 204.3 mg of 3-ethoxycarbonylmethylimidazo[5,1-b]thiazole, 108.2 mg of hydroxylamine hydrochloride and 210.2 mg of a sodium ethoxide powder were added, and the mixture was then stirred at room temperature for 2 hours. Under ice-cooling, 0.4 ml of 1N hydrochloric acid was added to the reaction solution to neutralize the solution. The solvent was evaporated under reduced pressure, and the resulting residue was purified by Diaion HP-20 Resin to obtain 140 mg of the title compound.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:32]=[CH:31][C:10]([O:11][C@@H:12]([CH3:30])[C@H:13]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:9][CH:8]=1.C([O:36][B:37](OC(C)C)[O:38]C(C)C)(C)C.C(OCC)(=O)C>O1CCCC1>[Si:23]([O:22][C@H:13]([CH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[C@H:12]([CH3:30])[O:11][C:10]1[CH:31]=[CH:32][C:7]([B:37]([OH:38])[OH:36])=[CH:8][CH:9]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: C[C@H](Oc1ccc(Br)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C

Procedure:
Prepared according to the method described in Example 5b) from tert-butyllithium (3.95 ml, 1.7M in hexanes), (3R,4S)-3-[4-(4-bromophenoxy)-3-(tert-butyldimethyl-silanyloxy)pentyl]pyridine (2.52 g, Example 11b)) and tri-isopropylborate (1.68 ml) in tetrahydrofuran (20 ml) to afford the sub-title compound as a foam (1.22 g) after chromatography on silica eluting with ethyl acetate and then ethyl acetate:methanol (4:1).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][N:4]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[CH3:14][N:15]([CH3:17])/[CH:16]=[CH:10]/[C:9]([C:7]1[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=1)=[O:11]
Reactant: COC(OC)N(C)C
Reactant: CSc1nccc(C(C)=O)n1
Product: CSc1nccc(C(=O)/C=C/N(C)C)n1

Procedure:
A solution of 1-[2-(methylthio)pyrimidin-4-yl]ethanone (1-3, 300 mg) in N,N-dimethylformamide dimethyl acetal (10 mL) was heated at 85° C. for16 hours. The mixture was concentrated to give (2E)-3-(dimethylamino)-1-[2-(methylthio)pyrimidin-4-yl]prop-2-en-1-one (1-4) as a yellow oil which crystallized upon standing. LRMS m/z: Calc'd for C10H14N3OS (M+H) 224.1. found 224.0.
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][N:6]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]2([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:7]1=[O:20])=[O:3].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][C:2]([O:4][CH2:5][N:6]1[C:19]2[C:14](=[CH:15][C:16]([CH2:26][C:25]3[CH:28]=[CH:29][C:22]([Cl:21])=[CH:23][CH:24]=3)=[CH:17][CH:18]=2)[C:8]2([CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[C:7]1=[O:20])=[O:3]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)OCN1C(=O)C2(CCNCC2)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(=O)OCN1C(=O)C2(CCNCC2)c2cc(Cc3ccc(Cl)cc3)ccc21

Procedure:
1-(Methylcarbonyloxy-methyl)-spiro[indoline-3,4′-piperidin]-2-one (0.026 g, 0.095 mmol) and 4-chloro-benzaldehyde (0.02 g, 0.14 mmol) were dissolved in dry 1,2-dichloroethane (1.5 mL). To the reaction mixture was then added glacial acetic acid (0.006 g, 0.095 mmol) under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 30 minutes. To the reaction mixture was then added, at room temperature, sodium triacetoxyborohydride (0.034 g, 0.16 mmol) under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then partitioned with aqueous NaHCO3 and dichloromethane. The organic layer was washed with brine, dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (2.5% methanol/dichloromethane) to yield the title compound as a solid.