Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([NH:10][CH2:11][C@@H:12]3[C@H:17]([CH3:18])[CH2:16][CH2:15][CH2:14][N:13]3[C:19]([O:21]CC=C)=O)=[N:7][C:6]=2[CH:25]=1.NC[C@@H]1[C@H](C)CCCN1C([C:37]1[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=1[N:44]1[CH:48]=[N:47][C:46]([C:49]([F:52])([F:51])[F:50])=[N:45]1)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([NH:10][CH2:11][C@@H:12]3[C@H:17]([CH3:18])[CH2:16][CH2:15][CH2:14][N:13]3[C:19]([C:37]3[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=3[N:44]3[CH:48]=[N:47][C:46]([C:49]([F:51])([F:52])[F:50])=[N:45]3)=[O:21])=[N:7][C:6]=2[CH:25]=1
Reactant: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: C=CCOC(=O)N1CCC[C@@H](C)[C@H]1CNc1nc2cc(Cl)ccc2o1
Product: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)c1

Procedure:
The title compound was synthesized following the same general protocol as described for (2S,3R)-allyl 2-(((5-chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidine-1-carboxylate in Example A27, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)phenyl)methanone. ESI-MS (m/z): 533 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:6]=1[NH2:12])[CH3:2].[C:14](Cl)(=O)[CH3:15].CCN(CC)CC.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[O:11][C:14]([CH3:15])=[N:12][C:6]=12)=[O:13])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1cccc(O)c1N
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cccc2oc(C)nc12
Temperature: 25 °C

Procedure:
A mixture of 2-amino-3-hydroxy-benzoic acid ethyl ester (5.52 mmol; J. Reisch, G. M. K. B. Gunaherath Monatshefte für Chemie, 1988, 119, 1169-1178), acetyl chloride (6.07 mmol), NEt3 (6.07 mmo) and pyridinium p-toluenesulfonate (1.47 mmol) in xylene (60 mL) is heated at reflux for 16 h, cooled to rt, diluted with EtOAc and washed with water. The organic layer is dried over MgSO4 and concentrated in vacuo to give a crude product which is purified by flash chromatography (gradient: heptane to heptane/EtOAc 6/4). LC-MS: tR=0.81 min; [M+H]+=206.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[C:15](Cl)[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18].[N:24]#[C:25][NH2:26].O1CCCC1.C(N(CC)CC)C>O>[NH2:26][C:25]1[N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][C:4]=2[Cl:12])[N:14]=[C:15]([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[N:24]=1
Reactant: FC(F)(F)c1cc(Cl)c(NN=C(Cl)C(F)(F)C(F)(F)F)c(Cl)c1
Reactant: N#CN
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1nc(C(F)(F)C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 60.2 %

Procedure:
20.5 g (0.05 mol) of pentafluoropropionyl chloride 2,6-dichloro-4-trifluoromethylphenylhydrazone and 2.5 g (0.06 mol) of cyanamide were added to 50 ml of tetrahydrofuran, and 6.1 g (0.06 mol) of triethylamine was dropwise added thereto under reflux and stirring. After completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hour to complete the reaction. After cooling, the reaction solution was poured into water, and the precipitate was extracted with ethyl acetate. The organic layer was washed with water and dried. Then, the solvent was distilled off under reduced pressure, and the residue was washed with n-hexane to obtain 12.5 g (yield: 60.1%) of the desired compound as white powder. Melting point: 181°-183° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[N:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=4)=[CH:13][C:12]3=[O:27])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][CH2:31][CH2:32][C:3]1=2.[ClH:40]>CO>[ClH:40].[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[N:18]=[N:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=4)=[CH:13][C:12]3=[O:27])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:28][NH:29][CH2:30][CH2:31][CH2:32][C:3]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nn5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CCC2
Agent: Cl
Solvent: CO
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nn5)cc4=O)cc31)CNCCC2
Yield: 80 %

Procedure:
A solution of tert-butyl 6-methyl-8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.11 g, 0.20 mmol) in 1.25 M HCl in MeOH (25 mL) was stirred at ambient temperature for 18 h. The mixture was concentrated to dryness and diluted with MeOH (5.0 mL) and Et2O (25 mL). The resulting solids were collected by filtration and dried to provide the title compound (77 mg, 80%) as a yellow solid: mp 248-252° C. decomp; 1H NMR (500 MHz, DMSO-d6) δ 9.03 (s, 2H), 8.71 (d, J=9.0 Hz, 1H), 8.46 (d, J=8.5 Hz, 1H), 7.91 (d, J=7.0 Hz, 1H), 7.71 (d, J=8.5 Hz, 1H), 7.63 (d, J=2.0 Hz, 1H), 7.38 (d, J=2.0 Hz, 1H), 7.17 (dd, J=7.0, 2.0 Hz, 1H), 7.13 (dd, J=8.5, 1.5 Hz, 1H), 4.46-4.45 (m, 2H), 3.75 (s, 3H), 3.46-3.44 (m, 2H), 3.12 (t, J=5.5 Hz, 2H), 2.08-2.07 (m, 2H); ESI MS m/z 440 [M+H]+; HPLC (Method A) 99.2% (AUC), tR=13.2 min.
Reaction SMILES: [Si]([C:8]1[O:9][C:10]2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:11]=2[C:12]=1[C:13](=[O:26])[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1)(C(C)(C)C)(C)C.[Br:33]Br>ClCCCl>[Br:33][C:8]1[O:9][C:10]2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:11]=2[C:12]=1[C:13](=[O:26])[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1
Reactant: BrBr
Reactant: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c([Si](C)(C)C(C)(C)C)oc2c1
Solvent: ClCCCl
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c(Br)oc2c1
Reaction time: 0.17 h
Yield: 37.2 %

Procedure:
To a stirred solution of 2-t-butyldimethylsilyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran (200 mg, 0.44 mmol) in 1,2-dichloroethane (2 mL) at 0° C. under nitrogen was added bromine (23 μl, 0.44 mmol) dropwise and the reaction mixture was stirred for 10 minutes. After this time the reaction was quenched with saturated sodium thiosulfate solution, extracted with ethyl acetate (20 mL), dried over magnesium sulfate and the solvent removed by distillation under vacuum. The crude product was re-crystallised from acetonitrile to afford the title compound as a colourless crystalline solid (69 mg, 37%); 1H NMR (300 MHz, CDCl3) δ 7.45 (d, 1H, J=8.78 Hz), 7.15 (s, 2H, benzoyl-Hs), 7.01 (d, 1H, J=2.18 Hz), 6.90 (dd, 1H, J=8.74, 2.27 Hz), 3.94 (s, 3H, OMe), 3.85 (s, 9H, 3×OMe); 13C NMR (75 MHz, CDCl3) δ 188.21 (CO), 158.29, 155.80, 152.72, 142.55, 131.99, 130.69, 120.98, 119.97, 119.67, 112.90, 107.00, 95.30, 60.67, 55.94, 55.43.
Reaction SMILES: Br[CH:2]=[C:3]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[CH:6]=1)[CH3:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.[CH3:29][N:30]1[CH2:43][CH2:42][C:33]2[NH:34][C:35]3[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][C:40]=3[C:32]=2[CH2:31]1>CN(C=O)C.[Cu]I>[Cl:12][C:7]1[CH:6]=[C:5](/[C:3](/[CH3:4])=[CH:2]/[N:34]2[C:35]3[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][C:40]=3[C:32]3[CH2:31][N:30]([CH3:29])[CH2:43][CH2:42][C:33]2=3)[CH:10]=[C:9]([Cl:11])[CH:8]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CC(=CBr)c1cc(Cl)cc(Cl)c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(C)CC2)c1cc(Cl)cc(Cl)c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
1-(2-Bromo-1-methyl-vinyl)-3,5-dichloro-benzene (315 mg, 1.2 mmol) was dissolved in DMF (2 mL) and potassium phosphate (414 mg, 2 mmol) was added followed by CuI (19 mg, 0.1 mmol), L-Proline (23 mg, 0.2 mmol) and 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g, 1 mmol). Nitrogen was purged in the reaction mixture for 5 min and the contents stirred at 85° C. overnight. The reaction mixture was poured into ice water (10 mL) to get the solid mass which was filtered off under vacuum. The residue obtained was purified through reverse phase HPLC to get desired product. 1H NMR (CD3OD, oxalate salt) δ (ppm): 7.80 (s, 1H), 7.50 (s, 2H), 7.38 (s, 1H), 7.20 (s, 1H), 7.0 (m, 2H), 4.42 (m, 2H), 3.60 (m, 2H), 3.05 (m, 2H), 3.0 (s, 3H), 2.38 (s, 3H), 1.82 (s, 3H).
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:10]=[C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[N:12]2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+].CNCCNC>C1(C)C=CC=CC=1.[Cu]I>[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:14]2[CH:15]=[CH:16][C:11]3=[N:10][C:9]([CH2:8][O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:18][N:12]3[C:13]2=[O:17])=[CH:22][CH:21]=1
Reactant: Fc1ccc(I)cc1
Reactant: O=c1[nH]ccc2nc(COc3ccccc3)cn12
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=c1n(-c2ccc(F)cc2)ccc2nc(COc3ccccc3)cn12
Temperature: 120 °C
Reaction time: 16 h
Yield: 63.9 %

Procedure:
Copper(I)iodide (11.8 mg, 0.062 mmol) was added to a stirred suspension of 2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (50 mg, 0.21 mmol), 4-fluoroiodobenzene (72.5 mg, 0.41 mmol), K2CO3 (57 mg, 0.41 mmol) and N,N′-dimethylethylenediamine (0.011 mL, 0.1 mmol) in toluene (1 mL) in a sealed tube. The mixture was stirred at 120° C. for 16 hours. The mixture was filtered through a pad of diatomaceous earth and then the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM with a gradient of 0/100 to 30/70). The desired fractions were collected and evaporated in vacuo to yield 6-(4-fluoro-phenyl)-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (45 mg, 65% yield) as a white solid. 1H NMR (500 MHz, CDCl3) 8 ppm 5.20 (s, 2H), 6.70 (d, J=7.8 Hz, 1H), 6.98 (t, J=7.2 Hz, 1H), 7.03 (d, J=8.1 Hz, 2H), 7.12 (d, J=7.8 Hz, 1H), 7.19-7.25 (m, 2H), 7.27-7.34 (m, 2H), 7.38-7.45 (m, 2H), 7.83 (s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH:17]2[CH2:19][CH2:18]2)=[N:7][C:8]([CH3:16])=[C:9]([OH:15])[C:10]=1[C:11](OC)=[O:12])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH:17]1([C:6]2[N:7]=[C:8]([CH3:16])[C:9]([OH:15])=[C:10]([CH2:11][OH:12])[C:5]=2[CH2:3][OH:2])[CH2:18][CH2:19]1
Reactant: COC(=O)c1c(C2CC2)nc(C)c(O)c1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(C2CC2)c(CO)c(CO)c1O
Temperature: 60 °C
Yield: 63.4 %

Procedure:
A solution of 2-cyclopropyl-5-hydroxy-6-methyl-pyridine-3,4-dicarboxylic acid dimethyl ester (165) (30 g, 113 mmol) in anhydrous tetrahydrofuran (400 mL) was slowly cannulated into a suspension of LiAlH4 in anhydrous tetrahydrofuran (400 mL) at 0° C. The reaction mixture was heated at 60° C. for 3 hours, cooled in an ice bath and slowly quenched with water. The colorless gel formed was filtered off through a celite pad and washed with methyl alcohol. The filtrate was evaporated to dryness to give 6-cyclopropyl-4,5-bis-hydroxymethyl-2-methyl-pyridin-3-ol (166) (15.0 g, 63% yield) as a colorless solids.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][CH2:10][C:11]([CH2:16]O)([CH3:15])[C:12]([OH:14])=[O:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(=O)([O-])O.[Na+].C(OCC)C>[CH3:15][C:11]1([C:12]([OH:14])=[O:13])[CH2:10][O:9][CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:8][CH2:16]1
Reactant: CC(CO)(CO)C(=O)O
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC1(C(=O)O)COC(c2ccccc2)OC1
Temperature: 40 °C
Yield: 81.8 %

Procedure:
435 g of benzaldehyde and 550 g 2,2-bis(hydroxymethyl)propanoic acid were allowed to react in the presence of a small amount of p-toluenesulphonic acid. The reaction was under stirring carried out at room temperature followed by heating to 40° C. under a low pressure (15 mm Hg). Yielded product was then dissolved in a mixture of 8000 ml aqueous sodium hydrogencarbonate (0.54M) and 2500 ml of diethyl ether. The aqueous phase was now washed with diethyl ether and acidified with 800 g of tartaric acid. The precipitate was collected and washed with water. Obtained product was finally recrystallized from ethanol/ethyl acetate to yield 745 g of 5-methyl-2-phenyl-1,3-dioxane-5-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH3:12]>O1CCOCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH2:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: N
Solvent: C1COCCO1
Product: NS(=O)(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Chloro-pyridine-3-sulfonyl chloride (5.0 g, 0.024 mol) was dissolved in a 0.5M solution of ammonia in dioxane (125 mL) at −5° C. The mixture was allowed to warm to room temperature and the mixture stirred for 1 hour. The mixture was filtered through celite, washed twice with dioxane and concentrated in vacuo to afford 6-choro-pyridine-3-sulfonic acid amide as an off white solid 4.55 g (98% yield). LC@UV215 nm; Rt 1.05: 100%, m/z (ES+): 193/195 (400 MHz; d6-DMSO) 8.79 (1H, d), 8.21 (1H, dd), 7.75 (1H, d) 7.70 (2H, br S).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:10])[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:22][S:23]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1)(=[O:25])=[O:24]>>[F:1][C:2]1[CH:3]=[C:4]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:10])[CH:5]=[CH:6][C:7]=1[O:8][CH2:30][C:29]1[CH:28]=[CH:27][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:33][CH:32]=1
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Reactant: O=C(c1ccc(O)c(F)c1)N1CCC[C@H]1CN1CCCC1
Product: CS(=O)(=O)c1ccc(COc2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2F)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure C from (3-Fluoro-4-hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)methanone and 4-methylsulfonylbenzyl chloride. MS (ES+) 461.2
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]1>>[NH2:1][C:2]1[CH:9]=[C:8]([O:18][CH:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: CN1CCC(O)CC1
Product: CN1CCC(Oc2cc(N)ncc2C#N)CC1

Procedure:
From intermediate 21 and 1-methylpiperidin-4-ol, reacted in an analogous manner to the preparation of intermediate 45. (UPLC-MS 3) tR 0.30 min; ESI-MS 233.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:7][CH:6]([N:8]2[C:12](=[O:13])[C:11]3=[CH:14][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:17]=[C:10]3[C:9]2=[O:23])[CH2:5][C:4]([CH3:25])([CH3:24])[NH:3]1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>CN(C)C1C=CN=CC=1>[C:27]([N:3]1[C:4]([CH3:25])([CH3:24])[CH2:5][CH:6]([N:8]2[C:12](=[O:13])[C:11]3=[CH:14][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:17]=[C:10]3[C:9]2=[O:23])[CH2:7][C:2]1([CH3:1])[CH3:26])(=[O:29])[CH3:28]
Reactant: CCOC(=O)c1ccc2c(c1)C(=O)N(C1CC(C)(C)NC(C)(C)C1)C2=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Product: CCOC(=O)c1ccc2c(c1)C(=O)N(C1CC(C)(C)N(C(C)=O)C(C)(C)C1)C2=O
Temperature: 0 °C

Procedure:
Into a 125 ml reaction flask equipped with a magnetic stirrer, thermometer, condenser and nitrogen atmosphere were placed the HALS of Example 4 (0.9 g, 0.0025 mol), 4-dimethylaminopyridine (0.03 g) and 25 ml of acetic anhydride. The reaction was refluxed for 2 hours, then poured into a beaker containing 200 ml ice water. A brown oil separated immediately and the mixture was stirred until the oil solidified into a tan solid. This solid was isolated by filtration and washed on the filter funnel with several portions of water. The wet solid was dissolved in 50 ml methylene chloride and dried with anhydrous magnesium sulfate. The solvent was stripped to give 0.9 g of light tan crystals melting at 119°-121° C. The infrared spectrum (in chloroform) showed a broad carbonyl absorption at 1710 cm-1 (imide and ester) and an amide carbonyl at 1615 cm-1.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([OH:24])=[O:23])=O)(C)(C)C.Cl.O1CCOCC1>CO>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([OH:24])=[O:23]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (530 mg, 1.49 mmol) in MeOH (10 mL) was added HCl in dioxane (4 M, 5 mL, 20.0 mmol). The reaction mixture was stirred at room temperature for 48 hr and the solvents removed under reduced pressure to give 5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid as the hydrochloride salt. 1H NMR (400 MHz, d6-DMSO) δ 7.57-7.45 (m, 1H), 7.29-7.18 (m, 2H), 5.30 (br s, 3H).
Reaction SMILES: Br[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:9][CH:8]=2)[C:5]([C:32]#[N:33])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:39][S:40]SC>>[Si:15]([O:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:2]([S:40][CH3:39])=[CH:3][CH:4]=[C:5]2[C:32]#[N:33])=[CH:12][CH:11]=1)([C:28]([CH3:29])([CH3:30])[CH3:31])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](OCc1ccc(-n2c(Br)ccc2C#N)cc1)(c1ccccc1)c1ccccc1
Reactant: CSSC
Agent: [Li]CCCC
Product: CSc1ccc(C#N)n1-c1ccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of N,N,N'-N'-tetramethylethylenediamine (1.55 ml) and 5-bromo-1-(4-tert-butyldiphenylsilyloxymethylphenyl)pyrrole-2-carbonitrile (3.80 g) was added dropwise n-butyllithium solution (1.6M solution in n-hexane, 5.2 ml) during a period of 20 minutes at -60° C. under nitrogen atmosphere. The mixture was stirred for one hour at the same temperature and then dimethyldisulfide (1 ml) was added therein in one portion. The reaction mixture was allowed to warm to ambient temperature, stirred overnight at the same temperature and then poured into ice water. The separated oil was extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated in vacuo to give the residue, which was purified by column chromatography on silica gel to yield 1-(4-tert-butyldiphenylsilyloxymethylphenyl)-5-methylthiopyrrole-2-carbonitrile (1.94 g) as a solid.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=1)[C:8]([NH:10][C:11]1[S:12][C:13]2[CH2:40][CH2:39][CH2:38][CH2:37][C:14]=2[C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)=[O:17])=[O:9])(=[O:4])=[O:3].[CH3:44][NH:45][CH2:46][CH:47]([OH:50])[CH2:48][OH:49]>ClCCl>[OH:50][CH:47]([CH2:48][OH:49])[CH2:46][N:45]([CH3:44])[S:2]([C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=1)[C:8]([NH:10][C:11]1[S:12][C:13]2[CH2:40][CH2:39][CH2:38][CH2:37][C:14]=2[C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)=[O:17])=[O:9])(=[O:4])=[O:3]
Reactant: CNCC(O)CO
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)Cl)c4)sc4c3CCCC4)cc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)N(C)CC(O)CO)c4)sc4c3CCCC4)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A mixture of 250 mg of methyl 4-[2-(4-{[(2-{[3-(chlorosulfonyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 83 mg of 3-(methylamino)propane-1,2-diol, and 2.5 mL of dichloromethane was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane-chloroform) to obtain 241 mg of methyl 4-{2-[4-({[2-({3-[(2,3-dihydroxypropyl)(methyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate as a pale yellow foamed solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=O.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=1.O>CN(C)C=O>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=3)[N:19]=2)[CH:18]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: Nc1ccc(Cl)cn1
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(-c2cn3cc(Cl)ccc3n2)cc1
Yield: 8.8 %

Procedure:
2-Bromo-1-(4-chlorophenyl)ethanone (9.08 g, 39 mmol) was added to a solution of 5-chloro-2-pyridinamine (5.0 g, 39 mmol) in dimethylformamide (100 mL) and the mixture was heated under reflux for 20 h. The mixture was cooled and poured into water (400 mL) and the solid was collected. The solid was dissolved in dichloromethane (300 mL), washed with water (50 mL) and brine (50 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was recrystallised from ethanol/water and the solid was collected and dried in vacuo to give the title compound (0.9 g, 9%). 1H NMR (360 MHz, CDCl3) δ 8.17 (1H, d, J 2.0 Hz), 7.87 (2H, d, J 8.9 Hz), 7.81 (1H, s), 7.56 (1H, d, J 9.5 Hz), 7.41 (2H, d, J 8.9 Hz), and 7.16 (1H, dd, J 9.5, 2.0 Hz). n/z (ES+) 263, 265 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1.CCN(CC)CC.[CH3:20][C@H:21]1[CH2:26][O:25][CH2:24][CH2:23][NH:22]1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][C@@H:21]2[CH3:20])[C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: C[C@H]1COCCN1
Reactant: Clc1nc(Cl)c2c(n1)CCCS2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1SCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
To a solution of 2,4-dichloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine (500 mg, 2.26 mmol) and Et3N (457 mg, 4.52 mmol) in DMF (5.0 mL) at 0° C. was added 3-(S)-methylmorpholine (252 mg, 2.49 mmol) dropwise. The reaction was stirred overnight at rt, then the solvent removed under vacuum to give a residue which was partitioned between water and ethyl acetate. The organic layer was separated, dried and concentrated to give the crude product which was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10/1) to give 2-chloro-7,8-dihydro-4-((S)-3-methylmorpholino)-6H-thiopyrano[3,2-d]pyrimidine (380 mg, 87%) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][CH:3]1[O:8][CH2:7][C:6](=[O:9])[CH:5]=[CH:4]1.[Br:10]Br.C(N(CC)CC)C>C(Cl)Cl.C1(C)C=CC=CC=1>[Br:10][C:5]1[C:6](=[O:9])[CH2:7][O:8][CH:3]([O:2][CH3:1])[CH:4]=1
Reactant: COC1C=CC(=O)CO1
Reactant: BrBr
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC1C=C(Br)C(=O)CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
To a solution of 6-methoxy-2H-pyran-3(6H)-one 12.8 (0.1 mole) in 40 ml CH2Cl2 at 0° C. was added 16.0 g (0.1 mole) of bromine in 10 ml of CH2Cl2. Then 14 ml of triethylamine was added dropwise at 0° C. and the reaction was allowed to warm to room temperature and stir for two hours. The reaction was then diluted with 200 ml of toluene. After filtration, the organic solution was then washed with 5% NaHCO3 and brine, dried with Na2SO4, filtered and concentrated to yield the crude product as light brown solid. Recrystallisation from ethyl acetate afforded the title compound (17 g, 82%) as a white crystalline solid. m.p. 74-75° C.