Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.[CH3:13][C:14](N(C)C)=[O:15].C(N([CH2:24][CH3:25])CC)C>>[C:2]([C:12]1[CH:11]=[C:13]2[C:5](=[CH:24][CH:25]=1)[C:6](=[O:7])[O:8][C:14]2=[O:15])#[C:3][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][CH:12]=1)[C:6](=[O:7])[O:8][C:9]2=[O:10]
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Reactant: CC(=O)N(C)C
Reactant: CCN(CC)CC
Product: O=C1OC(=O)c2cc(C#Cc3ccc4c(c3)C(=O)OC4=O)ccc21
Temperature: 80 °C
Yield: 51 %

Procedure:
4-Bromophthalic anhydride (21.8 g), dimethylacetamide (66 ml) and triethyl amine (16 ml) were mixed and purged with nitrogen. Thereafter, triphenylphosphine (113 mg), bis(triphenylphosphine)palladium(II) dichloride (101 mg) and copper iodide (55 mg) were added. The resulting mixture was pressurized with acetylene (approximative 2 bar) and heated to 80° C. Once the 4-bromophthalic anhydride had been consumed, which was determined by HPLC subsequent to methanolysis, acetic acid (87 ml) was added and the resulting mixture was cooled to 40° C. Mixture was filtered, and resulting solid washed twice with 10 ml acetic acid. The resulting product was dried at <100 mbar at 110° C., providing 7.8 g 5,5′-(ethyne-1,2-diyl)bis(isobenzofuran-1,3-dione) in a yield of 51%. The bromide content of the final product was determined to be 150 ppm by ion chromatography.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:21]([CH3:33])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[OH:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[CH2:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:38]4[CH2:39][CH2:40][CH:35]([OH:34])[CH2:36][CH2:37]4)[C:17]=23)=[CH:20][C:21]=1[CH3:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: OC1CCNCC1
Reactant: Cc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1ccccc1
Product: Cc1cc(Nc2ncnc3[nH]nc(OCCN4CCC(O)CC4)c23)ccc1OCc1ccccc1
Yield: 60 %

Procedure:
The procedure described in Example 55 was repeated using 2-[(4-{[4-(benzyloxy)-3-methylphenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethyl methanesulfonate (prepared as described in Example 110) and 4-hydroxypiperidine to give the title compound in 60% yield; NMR Spectrum: 1.34-1.40 (m, 2H), 1.66-1.69 (m, 2H), 2.16 (t, 2H), 2.22 (s, 3H), 2.75-2.81 (m, 4H), 3.40-3.43 (m, 1H), 4.39 (t, 2H), 4.53 (d, 1H), 5.13 (s, 2H), 7.01 (d, 1H), 7.32-7.48 (m, 7H), 8.19 (s, 1H), 8.24 (s, 1H); Mass Spectrum: 475 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16]CCCC(C)(C#N)C)[C:12]([CH2:25][CH3:26])=[CH:11][C:10]=1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([C:36]([CH3:43])([CH3:42])[CH2:37][CH2:38][CH2:39][CH2:40]Br)#[N:35]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][CH2:40][CH2:39][CH2:38][CH2:37][C:36]([CH3:43])([C:34]#[N:35])[CH3:42])[C:12]([CH2:25][CH3:26])=[CH:11][C:10]=1[C:27]1[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C#N)CCCCBr
Reactant: CCc1cc(-c2ccc(F)cc2)c(OCc2ccccc2)cc1OCCCCC(C)(C)C#N
Product: CCc1cc(-c2ccc(F)cc2)c(OCc2ccccc2)cc1OCCCCCC(C)(C)C#N

Procedure:
1-(Benzyloxy)-4-ethyl-2-(4-fluorophenyl)-5-[(6-methyl-6-cyanoheptyl)oxy]-benzene was prepared as described in Example 1 for the synthesis of 1-(benzyloxy)-4-ethyl-2-(4-fluorophenyl)-5-[(5-methyl-5-cyanohexyl)oxy]-benzene substituting 6-cyano-6-methyl-1-bromoheptane for 5-cyano-5-methyl-1-bromohexane.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2].Br[CH2:26][CH2:27][O:28][C:29]([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:30][C:29]([CH3:32])([CH3:31])[O:28][CH2:27][CH2:26][N:14]1[CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6][N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:16][CH2:15]1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Reactant: CC(C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OCCN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Yield: 65 %

Procedure:
5 g (14.43 mmol) of 1,4,7-tris-(carboxymethyl)-1,4,7, 10-tetraazacyclododecane is stirred in 75 ml of dimethylformamide for 18 hours with 3.14 g (17.35 mmol) of (2-bromoethyl)-tert-butyl ether and 6.50 g of potassium carbonate at 95° C. It is concentrated by evaporation in a vacuum and the residue is dissolved in 100 ml of water, the pH is adjusted to 2 by adding 12 N hydrochloric acid and the solution is put on a column of 320 ml of cation exchanger IR-120 (H+ form). It is eluted with 2 l of water, which is discarded, then with 2 l of 0.5 N ammonia solution. This solution is concentrated by evaporation in a vacuum, the residue is dissolved in 100 ml of water. With stirring, enough cation exchanger IR-120 is added in portions up to pH 3.5. The solution is filtered and freeze-dried and 4.19 g of the title compound is obtained as white solid with a water content of 6.3%.
Reaction SMILES: CS(C)=O.ClCCl.C(Cl)(=O)C(Cl)=O.[OH:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(N(CC)CC)C>[CH3:26][C:19]([CH3:25])([CH2:18][CH2:17][CH2:16][CH:15]=[O:14])[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C(C)(C)CCCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)C(C)(C)CCCC=O
Reaction time: 0.17 h
Yield: 108.6 %

Procedure:
A 4.0 ml portion of DMSO was added at −78° C. to a 40 ml dichloromethane solution of 2.5 ml oxalyl chloride and stirred for 10 minutes, and then a dichloromethane solution of 2.7 g of ethyl 6-hydroxy-2,2-dimethylhexanoate synthesized by the technique described in “Tetrahedron”, 2000, vol. 56, p. 9195-9202, was added thereto and stirred at the same temperature for 15 minutes. A 12 ml portion of triethylamine was added to the reaction solution and stirred for 30 minutes, and the reaction was quenched by adding water. Successively, work-up was carried out in the standard method to obtain 2.9 g of ethyl 2,2-dimethyl-6-oxohexanoate as a crude product. EP: 187.
Reaction SMILES: C([Mg]Cl)(C)C.[CH2:6]([O:9][C:10]1[C:11](Br)=[N:12][CH:13]=[CH:14][CH:15]=1)[CH:7]=[CH2:8].[F:17][C:18]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:19]=1[CH:20]=[O:21].[Cl-].[NH4+]>O1CCCC1>[CH2:6]([O:9][C:10]1[C:11]([CH:20]([C:19]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:18]=2[F:17])[OH:21])=[N:12][CH:13]=[CH:14][CH:15]=1)[CH:7]=[CH2:8]
Reactant: O=Cc1cc(F)ccc1F
Reactant: C=CCOc1cccnc1Br
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCOc1cccnc1C(O)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.1 %

Procedure:
Under an argon atmosphere, a tetrahydrofuran solution (1.5 ml, 3 mmol) of isopropylmagnesium chloride was added dropwise to a tetrahydrofuran (2 ml) solution of the 3-allyloxy-2-bromopyridine (642 mg, 3 mmol) obtained in Referential Example 8 under ice cooling. The resulting mixture was stirred at room temperature for 60 minutes. To the resulting brown solution was added dropwise 2,5-difluorobenzaldehyde (328 μl, 3 mmol) under ice cooling. The temperature of the reaction mixture was gradually raised to room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, followed by extraction with ethyl acetate. The solvent was then dried and the residue obtained by concentration under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give the title compound (375 mg, 45%) as an oil.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)=[O:2].[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([O:11][CH3:14])=[O:10])=[CH:5][CH:4]=1)=[O:2]
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C=Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
A mixture of 4-formylcinnamic acid (7.04 g, 40 mmole), anhydrous potassium carbonate (16.5 g, 120 mmole) and methyl iodide (8.5 g, 60 mmole) in dry N,N-dimethylformamide (50 ml) was stirred overnight at room temperature and the solvent evaporated in vacuo. The product was partitioned between ether and water and the organic phase washed with brine and dried (MgSO4). Evaporation gave 7.32 g (97%) of the title ester of mp (aqueous methanol) 83°-85° C., νmax (mull) 1723, 1683, 1635 cm-1, δ(CDCl3) 3.83 (3H, s, CH3), 6.52 (1H, d, J15 Hz, C=CHCO2), 7.75 (1H, d, J 15 Hz, ArCH=C), 7.79 (4H, ABq, J 6 Hz, Δν16.5 Hz, arom), 10.08 (1H, s, CHO).
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:13][CH3:14])=O.[BH4-].[Na+].C(O)(=O)C>O1CCOCC1>[CH3:1][NH:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:13][CH3:14]
Reactant: COc1ccc([N+](=O)[O-])cc1NC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CNc1cc([N+](=O)[O-])ccc1OC
Temperature: 0 °C

Procedure:
To a 0.5M solution of 2-formamido-4-nitroanisole (745 mg, 3.8 mmol) in dioxane was added sodium borohydride (722 mg, 19 mmol) followed by dropwise addition of glacial acetic acid (1.09 mL, 19 mmol). The reaction mixture was refluxed for 40 minutes, then cooled to 0° C. and quenched slowly with MeOH. Excess MeOH was then added and the solution was concentrated under vacuum to yield 2-methylamino-4-nitroanisole. The crude product was dissolved in anhydrous MeOH (20 mL) and Pd/C (795 mg, 0.76 mmol) was added followed by bubbling hydrogen gas through the solution for 1 minute. The reaction mixture was then stirred for 1.5 h under 1 atmosphere of hydrogen. The reaction mixture was filtered through a pad of Celite and the filter pad was washed with MeOH (40 mL). To the combined filtrate and wash was added pentafluorophenylsulfonyl chloride (282 mL, 0.26 mmol). After stirring for 30 min the reaction mixture was concentrated under vacuum and purified by column chromatography (10-25% EtoAc in hexane) to yield 153 mg (21% for three steps) of the title compound as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ10.7 (s, 1H), 6.68 (d, J=8.4 Hz, 1H), 6.3 (dd, J=8.3, 2.5 Hz, 1H), 6.22 (d, J=2.2 Hz, 1H), 5.18 (bs, 1H), 3.7 (s, 3H), 2.6 (d, J=3Hz, 3H). MS(EI): m/z 785 (35, 2M+Na-2H), 382 (20, M+), 381 (100, M-H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([C@H:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[CH:30][CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:43]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH:44](=O)[CH2:45][CH3:46].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:44][CH2:45][CH3:46])[CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:29]=[CH:30][C:31]([C@H:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[CH:32][CH:33]=4)=[O:26])=[CH:20][C:19]=3[CH:43]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3)cc1
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3CCC)cc1
Reaction time: 20 h

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (120 mg) and propionaldehyde (0.15 ml) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (0.13 g) at room temperature, and the mixture was stirred for 20 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography (ethanol:ethyl acetate 1:2), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 83) (105.4 mg) as yellow crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:29]#[C:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:8][C:9]=1[N:10]1[C@H:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][O:13][C@@:12]([CH2:23][CH:24]([OH:27])[CH2:25][OH:26])([CH3:22])[C:11]1=[O:28])=[O:4].CO.O.O[Li].O>C1COCC1>[CH:16]1([C@H:15]2[N:10]([C:9]3[CH:8]=[C:7]([C:29]#[C:30][C:31]([CH3:34])([CH3:33])[CH3:32])[S:6][C:5]=3[C:3]([OH:4])=[O:2])[C:11](=[O:28])[C@:12]([CH2:23][CH:24]([OH:27])[CH2:25][OH:26])([CH3:22])[O:13][CH2:14]2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@](C)(CC(O)CO)OC[C@H]1C1CCCCC1
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C#Cc1cc(N2C(=O)[C@@](C)(CC(O)CO)OC[C@H]2C2CCCCC2)c(C(=O)O)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.7 %

Procedure:
3-[(2R,5R)-5-Cyclohexyl-2-(2,3-dihydroxy-propyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester from the previous step was dissolved in 4.0 ml of THF and 0.3 mL of solution was taken out for the reaction. To the stirred solution was added THF (0.3 mL), MeOH (0.3 mL), water (0.3 mL), and LiOH.H2O (25.6 mg, 0.61 mmol, 10.0 equiv) and the resulting solution was stirred at room temperature for 30 minutes. The reaction was quenched by addition of 3.0 N HCl aqueous solution until pH=5. To the solution was then added EtOAc and the phases were separated. The aqueous layer was extracted by EtOAc. The organic layers were combined, dried (over Na2SO4) and concentrated. The residue was purified by HPLC (0.1% NH4OH, MeCN/H2O, 10%-90%) to give product (11 mg, 37.7% yield) as white solid. MS: 478 [M−H+].
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:21])[C:8]3[N:9]2[C:12]([CH:15]2[CH2:20][CH2:19][CH2:18][O:17][CH2:16]2)=[N:13][CH:14]=3)=[CH:4][C:3]=1[C:22](O)=[O:23].[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[CH2:35][CH2:34][NH:33][C:30]2=[CH:31][N:32]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>O.CN(C)C=O>[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[CH2:35][CH2:34][N:33]([C:22]([C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][C:2]=3[CH3:1])[N:9]3[C:12]([CH:15]5[CH2:20][CH2:19][CH2:18][O:17][CH2:16]5)=[N:13][CH:14]=[C:8]3[C:7](=[O:21])[NH:6]4)=[O:23])[C:30]2=[CH:31][N:32]=1
Reactant: COc1cc2c(cn1)NCC2
Reactant: Cc1cc2c(cc1C(=O)O)[nH]c(=O)c1cnc(C3CCCOC3)n12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2c(cn1)N(C(=O)c1cc3[nH]c(=O)c4cnc(C5CCCOC5)n4c3cc1C)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
To a mixture of 200 mg of 8-methyl-4-oxo-1-(tetrahydro-2H-pyran-3-yl)-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxylic acid, 100 mg of 5-methoxy-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine, 0.42 mL of N,N-diisopropylethylamine, and 5 mL of N,N-dimethyl formamide was added 235 mg of TBTU, followed by stirring at room temperature overnight. To the reaction mixture were added water and a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/0-95/5). The obtained solid was washed with methanol to obtain 148 mg of 7-[(5-methoxy-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)carbonyl]-8-methyl-1-(tetrahydro-2H-pyran-3-yl)imidazo[1,5-a]quinoxalin-4(5H)-one.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>CC#N.CN(C1C=CN=CC=1)C.O>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])=[CH:12][CH:11]=1
Reactant: COc1ccc(CO)cc1
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(COC(=O)CCC(=O)O)cc1
Temperature: 30 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
To a solution of succinic anhydride (10 g, 0.1 mol) in CH3CN (200 mL) were added (4-methoxyphenyl)methanol (69.0 g, 0.5 mol) and DMAP (12.2 g, 0.1 mol). The reaction mixture was stirred for 3 h at about 30° C. and then diluted with water (700 mL) The resulting mixture was adjusted to pH=10 with saturated Na2CO3 solution and washed with ethyl acetate (300 mL×4) to remove an excess of (4-methoxyphenyl)methanol. The aqueous phase was adjusted to pH=2 with saturated citric acid solution and then extracted with ethyl acetate (200 mL×2). The combined extracts were dried over anhydrous Na2SO4 and concentrated to give product (21.0 g, 88% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:5]=2[N:6]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1>CN(C1C=CN=CC=1)C.C(O)C>[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:2]2[S:3][C:4]3[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:5]=3[N:6]=2)=[CH:15][CH:14]=1
Reactant: Nc1ccc(S)cc1
Reactant: Clc1ccc2sc(Cl)nc2c1
Agent: CN(C)c1ccncc1
Solvent: CCO
Product: Nc1ccc(Sc2nc3cc(Cl)ccc3s2)cc1
Yield: 22.3 %

Procedure:
2,5-Dichlorobenzothiazole (0.049 moles, 10.0 g), 4-aminothiophenol (0.049 moles, 6.1 g) and DMAP (0.049 moles, 6.0 g) were stirred for 3 days at room temperature in 250 ml ethanol, filtered, and concentrated. Ethyl acetate was added and the solution washed with water, dried over sodium sulfate and concentrated. The product was purified by HPLC over silica gel eluted with 25% ethyl acetate in hexane to yield 2-(4-aminophenylthio)-5-chlorobenzothiazole 3.2 g, 22%. Mass spec (FD) 292. Calculated for C13H9ClN2S2 : C, 53.33; H, 3.10; N, 9.57. Found: C, 53.03; H, 3.30; N, 9.70.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:9][CH2:10]Br)=[CH:4][CH:3]=1.[OH:19][C:20]1([CH3:34])[C:24]2([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[O:23][C:22](=[O:30])[N:21]1[CH2:31][CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:9][CH2:10][N:27]2[CH2:28][CH2:29][C:24]3([O:23][C:22](=[O:30])[N:21]([CH2:31][CH2:32][CH3:33])[C:20]3([OH:19])[CH3:34])[CH2:25][CH2:26]2)=[CH:4][CH:3]=1
Reactant: CCCN1C(=O)OC2(CCNCC2)C1(C)O
Reactant: Fc1ccc(C(=CCBr)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCN1C(=O)OC2(CCN(CC=C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)C1(C)O
Yield: 86 %

Procedure:
9.3 g of 3,3-bis(4-fluorophenyl)-2-propenyl bromide dissolved in 50 ml of acetone are portionwise added to a mixture containing 6.85 g of 4-hydroxy-4-methyl-2-oxo-3-n-propyl-1-oxa-3,8-diazaspiro[4,5]decane and 4.2 g of anhydrous potassium carbonate in 68 ml of anhydrous acetone at room temperature during 1 hour while stirring, then the reaction mixture is stirred at room temperature for an additional 1 hour. After filtering off the inorganic salts and evaporating the solvent under reduced pressure, the residue is taken up in benzene, washed with water, dried over anhydrous sodium sulfate and then the solution is evaporated to its tenth volume under reduced pressure. The product is precipitated by adding n-hexane to the evaporation residue. The crystals are filtered off and dried to give the title compound in 86% yield, m.p.: 128°-129° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C@:4]2([C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([NH2:20])=[CH:10][CH:11]=3)[N:3]=[C:2]1[NH2:21].[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO.CCOC(C)=O>[NH2:21][C:2]1[O:1][CH2:6][CH2:5][C@:4]2([C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([NH:20][C:29](=[O:30])[C:26]2[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][N:27]=2)=[CH:10][CH:11]=3)[N:3]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1ncccc12
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Solvent: CCOC(C)=O
Product: NC1=N[C@@]2(CCO1)c1cc(NC(=O)c3ccc(Cl)cn3)ccc1Oc1ncccc12
Reaction time: 2 h
Yield: 29.6 %

Procedure:
The (S)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.008 g, 0.028 mmol) was dissolved in MeOH (1 mL). The 5-chloropicolinic acid (4.91 mg, 0.031 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (8.63 mg, 0.031 mmol) were added. After 2 h, additional MeOH (0.5 mL) was added, followed by additional 5-chloropicolinic acid (2.5 mg, 0.015 mmol) and additional 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (4.3 mg, 0.015 mmol). After 14 h, the reaction was taken up in EtOAc (75 mL). The organic phase was washed with half-saturated NaHCO3 (2×10 mL), then with saturated brine (10 mL), dried over MgSO4 and concentrated. The residue was purified by preparative TLC, using 12.5% MeOH-dcm to afford (S)—N-(2′-amino-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-7-yl)-5-chloropicolinamide (3.5 mg, 0.0083 mmol). MS (m/z) 422 (M+H)+. 1H NMR (400 MHz, CDCl3) δ: 9.88 (s, 1H), 8.57 (s, 1H), 8.27 (m, 2H), 7.89 (d, 1H, J=8.4 Hz), 7.82 (d, 1H, J=7.4 Hz), 7.76 (m, 2H), 7.32 (d, 1H, J=8.4 Hz), 7.20 (m, 1H), 4.23 (m, 1H), 4.11 (m, 1H), 1.98 (m, 1H), 1.93 (m, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7](Cl)[C:6]([Cl:10])=[C:5]([Cl:11])[N:4]=1.[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+]>O.C(C(C)=O)C>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][N:22]([C:7]2[C:6]([Cl:10])=[C:5]([Cl:11])[N:4]=[C:3]([NH:2][CH3:1])[N:8]=2)[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CNc1nc(Cl)c(Cl)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CNc1nc(Cl)c(Cl)c(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Yield: 58.8 %

Procedure:
Methyl-(4,5,6-trichloro-pyrimidin-2-yl)-amine (2.8 g, 12.2 mmol), 1-Boc-piperazine (2.27 g, 12.2 mmol), potassium carbonate (0.84 g 6.1 mmol) in water (2.5 ml) and methyl ethyl ketone (50 ml) were refluxed for 12 hours. After cooling to room temperature the precipitate was filtered, and washed with water to give the title compound (2.6 g, 59%), melting point: 205-206° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11](O)=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:20][N:21]([CH3:25])[C:22](Cl)=[S:23].[OH2:26]>CN(C=O)C>[CH3:20][N:21]([CH3:25])[C:22](=[O:26])[S:23][C:11]1[CH:12]=[CH:13][C:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][C:10]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1cc(Cc2ccccc2)ccc1O
Reactant: CN(C)C(=S)Cl
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)Sc1ccc(Cc2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a yellow solution of 4-benzyl-2-nitrophenol (2.0 g, 8.7 mmol) in 20 mL DMF at 0° C. was added sodium hydride (0.38 g, 9.6 mmol). The reaction became deep orange, and after 30 min dimethylthiocarbamoyl chloride (1.2 g, 9.6 mmol) was added. The reaction was stirred over the weekend at room temperature. Water was added, and the mixture was extracted with DCM 3 times. The combined extracts were washed with 0.5M NaHCO3, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a brown oil. The oil was heated to 160° C. for a total of 2 h. The reaction was cooled, and the resulting oil was loaded directly onto a 120 g ISCO column and eluted with 0-30-50% EtOAc/hexanes, to give S-4-benzyl-2-nitrophenyl dimethylcarbamothioate. MS (ESI) m/z: Calculated: 316.1; Observed: 317.1 (M++1).