Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11](Cl)(=[O:13])=[O:12])[C:7](=[O:15])[CH:6]([CH3:16])[CH2:5]2.[NH3:17]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11](=[O:13])(=[O:12])[NH2:17])[C:7](=[O:15])[CH:6]([CH3:16])[CH2:5]2
Reactant: N
Reactant: CC1Cc2cc(Cl)c(S(=O)(=O)Cl)cc2C1=O
Product: CC1Cc2cc(Cl)c(S(N)(=O)=O)cc2C1=O

Procedure:
According to Example 1 (d), the reaction of 5-chloro-6-chlorosulfonyl-2-methyl-1-indanone with liquid ammonia yields the raw product having a melting point of from 180° to 184° C. After recrystallization from ethanol, the compound melts at 190° to 192° C.
Reaction SMILES: C1(C)C=CC(S(O[C@H:11]([CH2:13]/[CH:14]=[CH:15]/[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH3:12])(=O)=O)=CC=1.[CH3:23][NH2:24]>>[CH3:23][NH:24][C@@H:11]([CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[CH3:12]
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)O[C@@H](C)C/C=C/c2cccnc2)cc1
Product: CN[C@H](C)C/C=C/c1cccnc1
Temperature: 105 °C

Procedure:
A mixture of (2S)-(4E)-5-(3-pyridyl)-4-penten-2-ol p-toluenesulfonate (3.80 g, 11.97 mmol) and methylamine (20 mL, 2.0M solution in THF) was heated at 100-110° C. for 8 h in a sealed glass tube. The mixture was cooled to ambient temperature and concentrated under reduced pressure on a rotary evaporator. The resulting brown syrup was diluted with saturated NaHCO3 solution (25 mL) and extracted with chloroform (4×25 mL). The combined chloroform extracts were dried (K2CO3), filtered, and concentrated by rotary evaporation to afford a thick, brown syrup (2.00 g). The crude product was purified by column chromatography on silica gel, eluting with chloroform-methanol (95:5, v/v). Selected fractions were combined, concentrated by rotary evaporation affording a 800 mg (37.9%) of a pale-yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)=[CH:7][C:6]=1[CH3:27].C([O-])(O)=O.[Na+].O.[CH3:34][N:35]([CH:37]=O)C>>[N:35]1([CH2:2][CH2:3][O:4][C:5]2[C:10]([CH3:11])=[CH:9][C:8]([C:12]3[NH:21][C:20](=[O:22])[C:19]4[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=4[O:23][CH3:24])[N:13]=3)=[CH:7][C:6]=2[CH3:27])[CH2:37][CH2:7][CH2:6][CH2:5][CH2:10][CH2:34]1
Reactant: CN(C)C=O
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCBr)c(C)c3)nc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCN4CCCCCC4)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a suspension of 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.22 g, 0.50 mmol) in DMF (2 mL) was added hexamethyleneimine(azepane) (0.22 mL, 2.0 mmol) and the reaction mixture was stirred at room temperature for 17 hours. Saturated aqueous NaHCO3 solution (2 mL) was added and stirred for 2 hours. Water (10 mL) was added and stirred for another 0.5 hours. The solid was filtered, washed with water, and dried under vacuum to give the title compound as a white solid. Yield: 0.22 g (95%). MP 198-199° C. 1H NMR (400 MHz, CD3OD): δ 7.70 (s, 2H), 6.79 (s, 1H), 6.55 (s, 1H), 3.97 (t, J=6.0 Hz, 2H), 3.92 (s, 3H), 3.91 (s, 3H), 2.98 (t, J=6.0 Hz, 2H), 2.82 (t, J=5.2 Hz, 4H), 2.37 (s, 6H), 1.72 (m, 4H), 1.66 (m, 4H). MS (ES+) m/z: 452.27 (M+1). Analysis calculated for C26H33N3O4 (451.56), %: C, 69.16; H, 7.37; N, 9.31. Found, %: C, 68.94; H, 6.90; N, 9.30.
Reaction SMILES: [Si]([C:8]1[N:9](C(=O)C)[C:10]2[C:15]([C:16]=1[C:17](=[O:30])[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=1)=[CH:14][CH:13]=[C:12]([O:31][CH3:32])[CH:11]=2)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:32][O:31][C:12]1[CH:11]=[C:10]2[C:15]([C:16]([C:17]([C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=3)=[O:30])=[CH:8][NH:9]2)=[CH:14][CH:13]=1
Reactant: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c([Si](C)(C)C(C)(C)C)n(C(C)=O)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c[nH]c2c1
Yield: 108.8 %

Procedure:
A mixture of the product of Step A (0.52 g, 1.05 mmol) and 1M TBAF in THF (1 ml) in THF (10 ml) was refluxed for 2 h. The solvent was evaporated and the residue was taken in EtOAc, washed with 1M HCl and organic layer was passed through silica gel bead. The solvent was evaporated and the residue was crystallized from MeOH to give the desired product (0.39 g; 100%), as creamy solid. 1H-NMR (CDCl3) 3.83 (s, 3H); 3.87 (s, 3H); 3.91 (s, 3H); 6.93-6.96 (m, 2H); 7.06 (s, 2H); 7.62 (s, 1H); 8.22 (d, 1H, J=9.36 Hz); 9.24 (broad s, 1H).
Reaction SMILES: [CH:1]1[C:6]([C:7]([NH2:9])=[S:8])=[CH:5][CH:4]=[N:3][CH:2]=1.Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14].N1C(C)=CC=CC=1C.O>C(O)C.C1COCC1>[N:3]1[CH:4]=[CH:5][C:6]([C:7]2[S:8][CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:9]=2)=[CH:1][CH:2]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)c1ccncc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1csc(-c2ccncc2)n1
Temperature: 70 °C
Reaction time: 48 h
Yield: 56 %

Procedure:
A suspension of iso-thionicotinamide (5 g, 36.2 mmol) was dissolved in ethanol (90 mL) and treated with ethyl bromopyruvate (5 mL, 1 equivalent) and 20 g of powdered 3 A molecular sieves. The reaction was stirred at 70° C. under a nitrogen atmosphere for 48 h. The mixture was filtered and evaporated to give 12.5 g of crude material. This material was dissolved in THF (200 mL) and treated with 2,6-lutidine (17 mL, 4 equivalents). The reaction was cooled to 0° C. followed by the addition of trifluoroactetic acid (10.2 mL, 2 equivalents). Stirring was continued for 2 hrs under a nitrogen atmosphere. Water (200 mL) was added and the reaction was extracted twice with ethyl acetate (600 mL, 150 mL). The combined organic layers were washed with brined, dried over magnesium sulfate, filtered and the solvent was removed by evaporation. The crude material was purified using chloroform:ethyl acetate (1:1) to give 4.70 g (56%) of the title compound.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][N:16]=1)[CH3:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:12]([O:14][C:15]1[N:16]=[CH:17][C:18]([C:21]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:22]=2)=[CH:19][CH:20]=1)[CH3:13]
Reactant: COC(=O)c1ccccc1S
Reactant: CCOc1ccc(C#N)cn1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOc1ccc(-c2nc(=O)c3ccccc3s2)cn1
Yield: 19.7 %

Procedure:
A mixture of methyl thiosalicylate (1.85 g, 11.0 mmol), 2-ethoxy-5-cyanopyridine (1.48 g, 10.0 mmol), triethylamine (1.80 ml, 12.9 mmol) and toluene (10 ml) was refluxed under nitrogen atmosphere for 18 hrs. The reaction mixture was concentrated. The residue was combined with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated. The residue was subjected to a silica gel column chromatography, eluted with ethyl acetate-hexane (2:1, v/v) and recrystallized from chloroform-ethyl acetate to give the titled compound (0.56 g, 20%).
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.[NH2:7][C:8]1[N:16]=[C:15]2[C:11]([NH:12][C:13](=[O:20])[N:14]2[CH2:17][CH2:18][OH:19])=[C:10]([Cl:21])[N:9]=1.C([O-])([O-])=O.[Na+].[Na+].C1C=CN=C(C2C=CC=CN=2)C=1.[NH4+].[Cl-]>ClC(Cl)C.CN(C)C=O.CC([O-])=O.CC([O-])=O.[Cu+2].O>[NH2:7][C:8]1[N:16]=[C:15]2[C:11]([N:12]([CH:1]3[CH2:3][CH2:2]3)[C:13](=[O:20])[N:14]2[CH2:17][CH2:18][OH:19])=[C:10]([Cl:21])[N:9]=1
Reactant: OB(O)C1CC1
Reactant: Nc1nc(Cl)c2[nH]c(=O)n(CCO)c2n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: Nc1nc(Cl)c2c(n1)n(CCO)c(=O)n2C1CC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 27 %

Procedure:
A mixture of cyclopropylboronic acid (0.369 g, 44 mmol), 2-amino-6-chloro-9-(2-hydroxyethyl)-7H-purin-8-one (5 g, 22 mmol) and Na2CO3 (0.462 g, 44 mmol) were taken in dichloroethane (20 ml) and dimethylformamide (10 ml). A suspension of Cu(OAc)2 (0.399 g, 22 mmol) and bipyridine (0.343 g, 22 mmol) in hot dichloroethane (30 ml) was added to the above mixture. The mixture was stirred at 70° C. for 18 hours under air. The resulting mixture was cooled to room temperature, and a saturated aqueous NH4Cl solution was added, followed by water. The organic layer was separated and the aqueous layer was extracted three times with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to get crude 2-amino-6-chloro-7-cyclopropyl-9-(2-hydroxyethyl)purin-8-one (1.6 g, 27%) as an off white solid. 1HNMR (400 MHz, DMSO d6): δ 0.97-1.02 (m, 4H); 2.89-2.92 (m, 1H); 3.61-3.67 (m, 2H); 3.71-3.74 (m, 2H); 4.83 (t, J=12.8 Hz, 1H); 6.67 (bs, 2H)
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][SH:20].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O.CCOCC>[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][S:20][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CN(C)CCS
Reactant: O=C(c1ccccc1)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: CN(C)CCSc1ccc(C(=O)c2ccccc2)cc1
Yield: 55.8 %

Procedure:
12.85 g (0.064 mol) of 4-chlorobenzophenone, 13.6 g (0.13 mol) of 2-dimethylaminoethanethiol and 27.6 g (0.2 mol) of potassium carbonate in 100 ml of dimethylacetamide are kept at 100° C. for 12 hours, under N2 gas and with stirring. After cooling, the reaction mixture is poured into 200 ml of water. The oil which separates out is taken up in ether. The crude product is purified by means of hydrochloric acid extract and a bulb tube distillation (bath 200°-220° C./0.01 mm Hg). 10.2 g (59%) of product in the form of an oil are obtained.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:5]=[CH:6][C:7]2[N:20]=[C:19]3[C:11](=[CH:12][C:13]([CH:17]=[CH:18]3)=[N+](C)C)[S:10][C:8]=2[CH:9]=1)[CH3:3].CC[O:23]C(C)=O.CO>O.[NH4+].[OH-].[N+]([O-])([O-])=O.[Ag+]>[CH3:1][N:2]([CH3:3])[C:4]1[CH:9]=[C:8]2[C:7](=[CH:6][CH:5]=1)[N:20]=[C:19]1[C:11](=[CH:12][C:13](=[O:23])[CH:17]=[CH:18]1)[S:10]2
Reactant: CN(C)c1ccc2nc3ccc(=[N+](C)C)cc-3sc2c1
Reactant: CCOC(C)=O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CN(C)c1ccc2nc3ccc(=O)cc-3sc2c1

Procedure:
To a solution of 0.5 g (1.56 mmol) of Methylene blue in 50 mL of water was added 0.53 g (3.12 mmol) of AgNO3 dissolved in excess NH4OH. The reaction mixture was heated to reflux for an hour, filtered and extracted with EtOAc (20×5 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated under diminished pressure. The dark solid was purified on a silica gel column. Elution with 9:1 EtOAc/MeOH gave CPD-18 as a dark solid: yield-25 mg (6%); silica gel TLC Rf 0.27 (9:1 EtOAc/MeOH); 1H NMR (CDCl3) δ 3.16 (s, 1H), 6.60 (d, 1H, J 2.8 Hz), 6.69 (d, 1H, J 2.4 Hz), 6.83 (d, 1H, J 2 Hz), 6.86 (d, 1H, J 2.8 Hz), 7.67 (d, 1H, J 10 Hz), 7.71 (d, 1H, J 9.2 Hz); mass spectrum (MALDI-TOF), m/z 257.07 (M+H)+.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH2:2].[CH2:16]([Zn]CC)C.ICI.C([O-])(=O)C.[NH4+]>C(OCC)C>[CH:1]1([O:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:16][CH2:2]1
Reactant: C=COCCCCOCc1ccccc1
Reactant: CC[Zn]CC
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: ICI
Solvent: CCOCC
Product: c1ccc(COCCCCOC2CC2)cc1

Procedure:
To a solution of {[4-(vinyloxy)butoxy]methyl}benzene (3.16 g) in diethyl ether (63 mL) was added diethyl zinc (1.0M, hexane solution) (30.6 mL) under nitrogen atmosphere, and a solution of diiodomethane (8.49 g) in diethyl ether (13 mL) was added dropwise thereto. The reaction liquid was stirred under reflux for 1 hour, followed by stirring at room temperature for 12 hours. A saturated aqueous ammonium acetate solution (80 mL) was added to the reaction liquid, followed by extraction with diethyl ether (400 mL). The organic layer was washed sequentially with a saturated aqueous ammonium acetate solution and saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=95/5) to obtain {[4-(cyclopropyloxy)butoxy]methyl}benzene (2.41 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: C#C[Si](C)(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(C#C[Si](C)(C)C)cc1[N+](=O)[O-]
Yield: 107.6 %

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) (3.64 g, 10 mmol) and trimethylsilylacetylene (4.2 mL, 30 mmol) according to the general procedure F. Obtained as a green oil (3.6 g).
Reaction SMILES: Br[C:2]1[C:3]([CH3:15])=[C:4]([CH3:14])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[C:7](=[O:12])[C:6]=2[CH:13]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[O:29][CH2:28][CH2:27][NH:26][CH2:25]2)=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH:24]2[O:29][CH2:28][CH2:27][N:26]([C:2]3[C:3]([CH3:15])=[C:4]([CH3:14])[C:5]4[O:9][C:8]([CH3:11])([CH3:10])[C:7](=[O:12])[C:6]=4[CH:13]=3)[CH2:25]2)=[CH:22][CH:23]=1
Reactant: COc1ccc(C2CNCCO2)cc1
Reactant: Cc1c(Br)cc2c(c1C)OC(C)(C)C2=O
Product: COc1ccc(C2CN(c3cc4c(c(C)c3C)OC(C)(C)C4=O)CCO2)cc1
Yield: 34.1 %

Procedure:
By using 5-bromo-2,2,6,7-tetramethyl-1-benzofuran-3(2H)-one (488 mg, 1.72 mmol) synthesized in Reference Example 18 and 2-(4-methoxyphenyl)morpholine (500 mg, 2.59 mmol), the reaction was carried out in the same manner as Reference Example 59 to synthesize 224 mg of the title compound (yield 34%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12]S[CH:10]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=O.[S:32]([O-:36])([O-])(=[O:34])=S.[Na+].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][S:32](=[O:36])(=[O:34])[CH:10]([C:14]2[CH:15]=[CH:16][C:17]([Br:20])=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCSC(c2ccc(Br)cc2)C1
Reactant: O=S([O-])([O-])=S
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCS(=O)(=O)C(c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-bromo-phenyl)-thiomorpholine-4-carboxylic acid tert-butyl ester (3.60 g; 10.05 mmol) in CH2Cl2 (100 mL) was added 3-chloroperoxybenzoic acid (5.20 g; 30.14 mmol), at 0° C. The resulting mixture was stirred overnight at RT, and subsequently, a saturated aqueous sodium thiosulfate solution was added and the mixture stirred for another 30 min. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined EtOAc layers were washed twice with an aqueous Na2CO3 solution. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to afford 2-(4-Bromo-phenyl)-1,1-dioxo-1λ6-thiomorpholine-4-carboxylic acid tert-butyl ester (4.06 g) which was used as such in the next step.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[S:21][C:20]([S:22](Cl)(=[O:24])=[O:23])=[N:19][C:18]=2[CH:26]=1>>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][S:22]([C:20]1[S:21][C:17]2[CH:16]=[CH:15][C:14]([Cl:13])=[CH:26][C:18]=2[N:19]=1)(=[O:24])=[O:23])[CH3:4]
Reactant: CCOC(=O)CNCCN
Reactant: O=S(=O)(Cl)c1nc2cc(Cl)ccc2s1
Agent: Cl
Product: CCOC(=O)CNCCNS(=O)(=O)c1nc2cc(Cl)ccc2s1
Yield: 86.9 %

Procedure:
The title compound (657 mg, 87%) was synthesized by the reaction of N-(2-aminoethyl)-glycine ethyl ester 2HCl (398 mg, 2.0 mmol) with 5-chloro-benzothiazole-2-sulfonyl chloride (536 mg, 2.0 mmol) as per the procedure of example 1. 1H NMR (500 MHz; DMSO-d6) δ 8.32 (d, 1H), 8.31 (s, 1H), 7.71 (d, 1H), 4.02 (q, 2H), 3.25 (s, 2H), 3.14 (t, 2H), 2.62 (t, 2H), 1.15 (t, 3H).
Reaction SMILES: C(O[Li])(C)=O.[C:6]1([S:12]([O:15][C:16]2[C:25]([Br:26])=[C:24]3[C:19]([CH:20]=[CH:21][C:22]([CH:27]=[O:28])=[N:23]3)=[CH:18][CH:17]=2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Si]([CH2:33][C:34]#[N:35])(C)(C)C>CN(C=O)C>[C:6]1([S:12]([O:15][C:16]2[C:25]([Br:26])=[C:24]3[C:19]([CH:20]=[CH:21][C:22]([CH:27]([OH:28])[CH2:33][C:34]#[N:35])=[N:23]3)=[CH:18][CH:17]=2)(=[O:14])=[O:13])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C[Si](C)(C)CC#N
Reactant: O=Cc1ccc2ccc(OS(=O)(=O)c3ccccc3)c(Br)c2n1
Agent: [Li]OC(C)=O
Solvent: CN(C)C=O
Product: N#CCC(O)c1ccc2ccc(OS(=O)(=O)c3ccccc3)c(Br)c2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 50.2 %

Procedure:
To a stirred solution of AcOLi (27 mg, 0.41 mmol) in DMF (1 mL) were added successively a solution of 8-bromo-2-formylquinolin-7-yl benzenesulfonate (1.60 g, 4.08 mmol) in anhydrous DMF (10 mL) and TMSCH2CN (465 mg, 4.11 mmol) at 0° C. And the reaction mixture was slowly warmed to room temperature. The mixture was stirred for 12 h at the same temperature and quenched with 15% citric acid (5.0 mL) and MeOH (5.0 mL). After the removal of MeOH in vacuo, the mixture was extracted with AcOEt and organic layer was washed with brine and dried over anhydrous Na2SO4, and evaporated. Purification by silica gel chromatography (Hexanes/EtOAc=2/1) gave S0187 as a yellow gum (0.89 g, 2.05 mmol, 50% yield). 13CNMR (ppm, 500 MHz, CDCl3, 298 K) δ: 159.989, 148.716, 144.388, 138.493, 135.675, 135.042, 129.556, 128.819, 128.189, 127.380, 123.481, 119.173, 118.419, 117.117, 68.926, 26.812. 1HNMR (ppm, 500 MHz, CDCl3, 298 K) δ: 8.262 (d, 1H, J=8.5 Hz), 7.968 (d, 2H, J=8.0 Hz), 7.836 (d, 1H, J=9.0 Hz), 7.716 (t, 1H, J=7.0 Hz), 7.633 (d, 1H, J=9.0 Hz), 7.588-7.545 (m, 3H), 5.224−5.188 (m, 1H), 5.126 (d, 1H, J=6.0 Hz), 3.031−2.929 (m, 2H). MS-ESI (m/z): [M+H]+ calculated for C18H14BrN2O4S, 433.0 (79Br) and 435.0 (81Br); found 432.9 (79Br) and 434.9 (81Br).
Reaction SMILES: C1C2CCC3C=CC=CC=3N(CCCCO)C=2C=CC=1.CS(Cl)(=O)=O.C(C(C(C(O)=O)O)O)(O)=O.[CH2:36]([O:38][C:39]([C@@H:41]1[CH2:46][CH2:45][CH2:44][NH:43][CH2:42]1)=[O:40])[CH3:37].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CC(C)=O.O.C(N(CC)CC)C>[CH2:36]([O:38][C:39]([CH:41]1[CH2:46][CH2:45][CH2:44][NH:43][CH2:42]1)=[O:40])[CH3:37]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: CS(=O)(=O)Cl
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The above alcohol (5.4 g, 0.02 mol) was dissolved in toluene (160 ml) and triethylamine (7 ml) was added. Methanesulfonyl chloride (2.5 ml, 0.032 mol) was added dropwise and when addition was complete the reaction mixture was stirred for 2 h. Water was added and the phases were separated. The organic phase was dried (MgSO4) and the solvent evaporated in vacuo affording a residue which was dissolved in acetone (85 ml). To this solution (R)-3-piperidinecarboxylic acid ethyl ester tartrate (9.0 g, 0.03 mol) and potassium carbonate (7.0 g, 0.051 mol) were added and the mixture was heated at reflux temperature for 16 h. After cooling to room temperature and filtration on filter aid (celite) the solvent was removed by evaporation. The residue was dissolved in diethyl ether (100 ml) and extracted with a 5% tartaric acid solution (3×125 ml). The combined aqueous extracts were washed with diethyl ether and pH was adjusted to 7-8 with a potassium carbonate solution. The neutralised aqueous mixture was extracted with ethyl acetate (4×200 ml). The combined ethyl acetate extracts were washed with water, brine and dried (MgSO4). The solvent was evaporated in vacuo affording 2.6 g (32%) of 1-(4-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-butyl!-3-piperidinecarboxylic acid ethyl ester, obtained as an oil. The residue was purified further by column chromatography on silica gel (65 g) using a mixture of dichloromethane and methanol (99.2:0.8) as eluent. Rf : 0.20 (SiO2 ; n-heptane/ethyl acetate=1:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[NH:20][N:19]=[C:18]([CH3:21])[CH:17]=3)[CH:12]=[C:11]([N:22]3[CH2:25][CH2:24][CH2:23]3)[N:10]=2)=[CH:4][CH:3]=1.[C:26]1([CH3:35])[CH:31]=[CH:30][CH:29]=[C:28]([C:32](Cl)=[O:33])[CH:27]=1>N1C=CC=CC=1>[CH3:21][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[CH:12]=[C:11]([N:22]3[CH2:23][CH2:24][CH2:25]3)[N:10]=[C:9]([S:8][C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:32](=[O:33])[C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([CH3:35])[CH:27]=4)=[CH:3][CH:4]=3)[N:14]=2)[NH:20][N:19]=1
Reactant: Cc1cc(Nc2cc(N3CCC3)nc(Sc3ccc(N)cc3)n2)[nH]n1
Reactant: Cc1cccc(C(=O)Cl)c1
Solvent: c1ccncc1
Product: Cc1cccc(C(=O)Nc2ccc(Sc3nc(Nc4cc(C)n[nH]4)cc(N4CCC4)n3)cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.1 %

Procedure:
2-(4-Aminophenylthio)-6-(azetidin-1-yl)-N-(3-methyl-1H-pyrazol-5-yl)pyrimidin-4-amine (200 mg, 0.57 mmol) was taken up in pyridine (2 mL) and m-toluoyl chloride (0.187 mL, 1.42 mmol) was added dropwise at room temperature. After 15 minutes the reaction mixture was concentrated in vacuo and the residue taken up in methanol (3 mL). Sodium methoxide (25% w/w solution in MeOH, 1 mL) was added and the resulting cloudy solution stirred at room temperature for 15 minutes. The reaction mixture was purified directly by chromatography (silica, 5-100% EtOAc-petrol gradient elution) to give the title compound (89 mg, 33%) as a white solid. 1H NMR: (400 MHz, DMSO) 1.99 (3H, brs), 2.31 (2H, qn), 2.42 (3H, s), 3.88 (4H, t), 5.39 (1H, brs), 5.67 (1H, vbrs), 7.43-7.46 (2H, m), 7.54 (2H, d), 7.73-7.76 (2H, m), 7.91 (2H, d), 9.23 (1H, brs), 10.42 (1H, s), 11.67 (1H, brs). ES+472.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([O:18]C)(=[O:17])[CH2:11][CH2:12][C:13]([O:15]C)=O.CC(C)([O-])C.[K+].O>O1CCCC1.C(OCC)C>[OH:15][C:13]1[C:9]2[C:2](=[CH:3][CH:4]=[C:5]([CH3:6])[CH:8]=2)[CH:1]=[C:11]([C:10]([OH:18])=[O:17])[CH:12]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: COC(=O)CCC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc2cc(C(=O)O)cc(O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
To a solution of 4-methylbenzaldehyde (0.70 g) and dimethyl succinate (0.95 g) in tetrahydrofuran (15 mL) was added potassium tert-butoxide (0.73 g) at room temperature, and the reaction mixture was stirred overnight. To the reaction mixture were added water and diethyl ether, and the two layers were separated. The aqueous layer was acidified with 1 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. This organic layer was washed with a saturated sodium carbonate aqueous solution. The aqueous layer was acidified with 1 mol/L hydrochloric acid, and the mixture was extracted with diethyl ether. The organic layer was dried over magnesium sulfate, and concentrated. To the residue were added acetic acid (5 mL), acetic anhydride (5 mL) and sodium acetate (3.0 g), and the mixture was heated under reflux for 6 hours. After cooling to room temperature, the reaction mixture was poured into water. The resulting mixture was extracted with diethyl ether. The organic layer was washed with water and a saturated sodium hydrogen carbonate aqueous solution, and concentrated. To the obtained residue were added methanol (20 mL) and 1 mol/L sodium hydroxide aqueous solution (20 mL), and the mixture was heated under reflux for 5 hours. After the reaction mixture was cooled to room temperature, methanol was removed under reduced pressure. The obtained solution was acidified with 2 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated to give the title compound (0.20 g).