Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:13][CH3:14])(=[O:12])[CH2:8][C:9]([CH3:11])=[O:10].C(O)(C)(C)C.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>O1CCCC1>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][CH:8]([C:9](=[O:10])[CH3:11])[C:7]([O:13][CH3:14])=[O:12])=[CH:23][CH:22]=1
Reactant: COC(=O)CC(C)=O
Reactant: Fc1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: COC(=O)C(Cc1ccc(F)cc1)C(C)=O
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a suspension of potassium tert-butoxide (10.6 g, 95.0 mmol) in tetrahydrofuran (100 mL) were added methyl acetoacetate (10.0 g, 86.0 mmol) and tert-butanol (0.83 mL, 8.6 mmol) at room temperature. The resulting solution was stirred for 1 h, and then 4-fluorobenzylbromide (11.2 mL, 90 mmol) was added. The reaction mixture was stirred at room temperature for 18 h, and then partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (3×), the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Column chromatography of the residue on silica (5-20% ethyl acetate in hexanes) gave methyl 2-(4-fluorobenzyl)-3-oxobutanoate (14.5 g, 75% yield) as a colorless oil which was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:6]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[S:8][C:9]=1[C:10](OC)=[O:11])[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>O1CCCC1>[CH3:3][N:2]([CH2:4][C:5]1[N:6]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[S:8][C:9]=1[CH2:10][OH:11])[CH3:1]
Reactant: COC(=O)c1sc(-c2ccccn2)nc1CN(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CN(C)Cc1nc(-c2ccccn2)sc1CO
Reaction time: 18 h
Yield: 59.3 %

Procedure:
The compound prepared in Example 153 (180 mg) in tetrahydrofuran (2 mL) was stirred at 0° C. for 30 minutes. Lithium aluminum hydride (1.30 g) was added and the reaction was stirred for 18 hours. Rochelle's salt (sodium potassium tartrate; 10 g) was added and the solution was stirred for 30 minutes. The mixture was then partitioned between a saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated to obtain the title compound (0.096 g) having the following physical data.
Reaction SMILES: [F:1][CH:2]([F:12])[CH2:3][NH:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1I.[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[C:16]([O:23][CH3:24])[CH:15]=1>CCCCCCC.CCOC(C)=O>[F:1][CH:2]([F:12])[CH2:3][NH:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:17]1[CH:18]=[CH:19][C:14]([F:13])=[CH:15][C:16]=1[O:23][CH3:24]
Reactant: FC(F)CNc1cnccc1I
Reactant: COc1cc(F)ccc1B(O)O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1-c1ccncc1NCC(F)F

Procedure:
The title compound was prepared in analogy to example 72, from (2,2-difluoro-ethyl)-(4-iodo-pyridin-3-yl)-amine and 4-fluoro-2-methoxyphenylboronic acid (CAS RN 179899-07-1) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Light brown solid (78%). MS (ESI): m/z=283.18 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7](=[O:20])[CH:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Cl)=[CH:33][CH:32]=1.O>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:35][C:34]3[CH:37]=[CH:38][C:31]([O:30][CH3:29])=[CH:32][CH:33]=3)[C:7](=[O:20])[CH:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1NC(Cc2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2C(=O)C(Cc3ccccc3Cl)NC(=O)c3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
7-Chloro-3-(2-chlorobenzyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (0.8 g, 2.39 mmol), powdered potassium carbonate (0.495 g, 3.58 mmol) and 4-methoxybenzyl chloride (0.39 mL, 2.86 mmol) were suspended in N,N-dimethylformamide (20 mL) and stirred at ambient temperature overnight. The solution was poured into water (100 mL) and ethyl acetate (150 mL). The layers were separated and the organic layer was washed with water (2×100 mL) then brine, and dried with sodium sulfate, decanted and concentrated in the presence of silica gel. The product was purified by column chromatography eluting with a gradient of 0-50% ethyl acetate in hexanes to yield 7-chloro-3-(2-chlorobenzyl)-1-(4-methoxybenzyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (0.65 g, 60%). 1H NMR (300 MHz, DMSO-d6) δ 3.06 (m, 1H), 3.30 (m, 2H), 3.66 (s, 3H), 4.13 (m, 1H), 4.82 (d, 1H), 5.34 (d, 1H), 6.76 (d, 2H, J=8.79 Hz), 6.96 (d, 2H, J=8.79 Hz), 7.21-29 (m, 2H), 7.36-45 (m, 2H), 7.54-7.61 (m, 3H), 8.97 (d, 1H, J=5.86 Hz); ESI m/z 455.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][C:12]1[N:13]=[CH:14][C:15]2[CH:21]=[C:20]([C:22]3[C:27]([Cl:28])=[C:26]([O:29][CH3:30])[CH:25]=[C:24]([O:31][CH3:32])[C:23]=3[Cl:33])[C:19](=[O:34])[N:18]([CH3:35])[C:16]=2[N:17]=1)([O-])=O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>CCOC(C)=O.O>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][C:12]1[N:13]=[CH:14][C:15]2[CH:21]=[C:20]([C:22]3[C:23]([Cl:33])=[C:24]([O:31][CH3:32])[CH:25]=[C:26]([O:29][CH3:30])[C:27]=3[Cl:28])[C:19](=[O:34])[N:18]([CH3:35])[C:16]=2[N:17]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3cnc(Nc4c(C)cccc4[N+](=O)[O-])nc3n(C)c2=O)c1Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(OC)c(Cl)c(-c2cc3cnc(Nc4c(C)cccc4N)nc3n(C)c2=O)c1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
A mixture of 2-(2-nitro-6-methylphenylamino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (10) (810 mg, 1.57 mmol) and tin(II) chloride hydrate (1.77 g, 7.86 mmol) in EtOAc (50 mL) was stirred at 60° C. for 2 hours. The reaction was monitored by LCMS. The reaction mixture was basified with saturated aqueous sodium bicarbonate to pH=8˜9, diluted with H2O (100 mL), and then extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate, filtered, and concentrated. The residue was recrystallized with dichloromethane/ethyl acetate/petroleum ether (DCM/EtOAc/PE)=1/1/2 to give 2-(2-amino-6-methylphenylamino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (11) (640 mg, 83% yield) as a grey solid. (MS (ES+) C23H21Cl2N5O3 requires: 485, 487. Found: 486, 488 [M+H]+; 1H-NMR (500 MHz, CDCl3) δ ppm 8.54 (s, 1H), 7.45 (s, 1H), 7.08 (t, J=7.5 Hz, 1H), 6.71 (dd, J=3.5, 7.5 Hz, 2H), 6.65 (br s, 1H), 6.62 (s, 1H), 3.94 (s, 6H), 3.88 (br s, 2H), 3.62 (br s, 3H), 2.24 (s, 3H).
Reaction SMILES: [OH:1][C:2]([C:8]1[CH:9]=[N:10][CH:11]=[N:12][CH:13]=1)([CH:5]([CH3:7])[CH3:6])[C:3]#[CH:4].I[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C.CCCCCC.C(OCC)(=O)C>C(#N)C>[OH:1][C:2]([C:8]1[CH:13]=[N:12][CH:11]=[N:10][CH:9]=1)([CH:5]([CH3:7])[CH3:6])[C:3]#[C:4][C:15]1[S:16][CH:17]=[CH:18][CH:19]=1
Reactant: C#CC(O)(c1cncnc1)C(C)C
Reactant: Ic1cccs1
Solvent: CC#N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)C(O)(C#Cc1cccs1)c1cncnc1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
3-Hydroxy-4-methyl-3-pyrimidin-5-ylpent-1-yne (1 g, 5.7 mmol), prepared as in Stage (2), 2-iodothiophene (1.2 g, 5.7 mmol), triethylamine (2 ml, 14.5 mmol), copper-I-iodide (mg), and bis(triphenylphosphine)palladium-II-chloride (200 mg) were brought together in dry acetonitrile (55 ml) and the mixture was heated at 65° C. under nitrogen. After 1 hour, the mixture was cooled, quenched in dilute aqueous HCl, neutralised with dilute aqueous ammonia and extracted with ether (3×15 ml). The combined organic extracts were washed with dilute aqueous ammonia, water, and brine before being dried over magnesium sulphate and concentrated under reduced pressure to give an oil. Flash chromatography on silica eluting with hexane-ethyl acetate (1:3) gave the title compound as a solid of melting point 113°-14.5° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[CH:14]=[C:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2ccc3ccccc3n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C(=C1CCNCC1)c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1-tert-Butoxycarbonyl-4-(2-quinolylmethylene)piperidine (17.6 g) was dissolved in dichloromethane (60 ml), and TFA (60 ml) was added to the solution under cooling on ice. The mixture was stirred for 2.5 hours at room temperature and concentrated under reduced pressure. A saturated solution of sodium hydrogencarbonate was added to the residue to neutralize, and the mixture was then extracted with chloroform. The organic phase was dried over sodium sulfate anhydrate and concentrated under reduced pressure. The title compound was recovered from an etherhexane solvent as white powder. This powder was also used for subsequent reaction without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([CH:13]1[CH:39]=[C:38]([CH3:40])[CH2:37][CH:36]([CH3:41])[CH2:35][CH:34]([O:42][CH3:43])[CH:33]2[O:44][C:29]([OH:48])([CH:30]([CH3:47])[CH2:31][CH:32]2[O:45][CH3:46])[C:28](=[O:49])[C:27](=[O:50])[N:26]2[CH:21]([CH2:22][CH2:23][CH2:24][CH2:25]2)[C:20](=[O:51])[O:19][CH:18]([C:52]([CH3:65])=[CH:53][CH:54]2[CH2:59][CH2:58][CH:57]([OH:60])[CH:56]([O:61][CH2:62][CH2:63][CH3:64])[CH2:55]2)[CH:17]([CH3:66])[CH:16]([O:67][Si:68]([CH:75]([CH3:77])[CH3:76])([CH:72]([CH3:74])[CH3:73])[CH:69]([CH3:71])[CH3:70])[CH2:15][C:14]1=[O:78])[CH3:12].C(N(CC)CC)C>C(Cl)Cl.O>[CH2:11]([CH:13]1[CH:39]=[C:38]([CH3:40])[CH2:37][CH:36]([CH3:41])[CH2:35][CH:34]([O:42][CH3:43])[CH:33]2[O:44][C:29]([OH:48])([CH:30]([CH3:47])[CH2:31][CH:32]2[O:45][CH3:46])[C:28](=[O:49])[C:27](=[O:50])[N:26]2[CH:21]([CH2:22][CH2:23][CH2:24][CH2:25]2)[C:20](=[O:51])[O:19][CH:18]([C:52]([CH3:65])=[CH:53][CH:54]2[CH2:59][CH2:58][C:57](=[O:60])[CH:56]([O:61][CH2:62][CH2:63][CH3:64])[CH2:55]2)[CH:17]([CH3:66])[CH:16]([O:67][Si:68]([CH:72]([CH3:73])[CH3:74])([CH:69]([CH3:71])[CH3:70])[CH:75]([CH3:77])[CH3:76])[CH2:15][C:14]1=[O:78])[CH3:12]
Reactant: CCCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O[Si](C(C)C)(C(C)C)C(C)C)C2C)C(OC)CC3C)CCC1O
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O[Si](C(C)C)(C(C)C)C(C)C)C2C)C(OC)CC3C)CCC1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution (-78° C.) of oxalyl chloride added dimethyl sulfoxide dropwise, followed by a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-propyloxycyclohexyl)-1'-methylvinyl]-14-triisopropylsiloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos18-ene-2,3,10,16-tetraone in dry methylene chloride. The reaction mixture is stirred for 30 min. at -78° C. and then triethylamine is added. The reaction temperature is raised to room temperature, reaction was poured into water, and extracted with ethyl acetate (three times). Combined organic layers were washed (water, sat'd NaHCO3), dried (anhydrous Na2SO4), and filtered. Removal of solvent followed by purification (silica gel column chromatography) gives the title compound.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[CH:14][C:10]=2[C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.C1C=[CH:30][C:31]2[N:36]([OH:37])N=[N:34][C:32]=2[CH:33]=1.CC1C(N)=CON=1>CN(C)C=O.O>[CH3:30][C:31]1[C:32]([NH:34][C:11](=[O:13])[C:10]2[CH:14]=[C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][C:9]=2[O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:33][O:37][N:36]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Agent: Cc1nocc1N
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nocc1NC(=O)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-[(phenylmethyl)oxy]-5-(4-pyridinyl)benzoic acid (may be prepared as described in Description 79; 0.12 g, 0.36 mmol), EDC (0.14 g, 0.72 mmol) and HOBT (0.11 g, 0.72 mmol) in N,N-dimethylformamide (2 ml) was stirred in air at room temperature for 1 h, then 3-methyl-4-isoxazolamine (may be prepared as described in Description 91; 100 mg, 1.02 mmol) was added in one charge. The reaction mixture was stirred at 25° C. overnight. The reaction mixture was diluted with water (25 ml). The solid was filtered, washed with water (30 ml) and methanol (5 ml×2), and dried in vacuo to yield the title compound as a grey solid. 72 mg.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=1.CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C.[Cl-].[Na+].O>[C:4]([Si:1]([CH3:3])([CH3:2])[O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#Cc1ccc(OCCCO)nc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCCOc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.5 %

Procedure:
To a solution of t-butyldimethylsilyl chloride (0.93 g, 6.17 mmol) in CH2Cl2 (25 mL) was added 6-(3-hydroxypropoxy)nicotinonitrile (Example 66, 1 g, 5.61 mmol), Et3N (0.62 g, 6.17 mmol), and DMAP (0.014 g, 0.11 mmol). The mixture was stirred at rt for 18 h. The reaction mixture was diluted with brine and extracted with CH2Cl2 (3×25 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (2:1 hexanes/EtOAc) to give the title compound (1.14 g, 69%). 1H NMR (400 MHz, CDCl3) δ 8.40 (dd, 1H), 7.69 (dd, 1H), 6.72 (dd, 1H), 4.40 (t, 2H), 3.73 (t, 2H), 1.90-1.98 (m, 2H), 0.82 (s, 9H), 0.02 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:24][O:25][C:26]([NH:28][C:29](=NC(OC)=O)SC)=[O:27]>C(O)(=O)C.CO>[CH3:24][O:25][C:26]([NH:28][C:29]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([O:9][S:10]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][CH2:20][CH:21]4[CH2:22][CH2:23]4)=[CH:15][CH:14]=3)(=[O:12])=[O:11])=[CH:3][C:2]=2[N:1]=1)=[O:27]
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: Nc1ccc(OS(=O)(=O)c2ccc(NCC3CC3)cc2)cc1N
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2cc(OS(=O)(=O)c3ccc(NCC4CC4)cc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 14 h
Yield: 46.7 %

Procedure:
To a solution of 4-(cyclopropylmethyl-amino)-benzenesulfonic acid 3,4-diamino-phenyl ester (648 mg) in acetic acid (4.5 ml) and methanol (40 ml) at 80° C. was added 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (580 mg). The reaction mixture was refluxed for 4 hours then allowed to cool to ambient temperature and stirred at this temperature for 14 hours. The resultant precipitate was filtered, washed with diethyl ether and dried under vacuum to afford 4-(cyclopropylmethyl-amino)-benzene sulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl ester (378 mg) as a beige solid. Mass spectrum: 417 [M+H]+; retention time=13.16 minutes.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([C:26]5[CH2:31][CH2:30][N:29]([S:32]([CH2:35][CH2:36][CH2:37][C:38](O)=[O:39])(=[O:34])=[O:33])[CH2:28][CH:27]=5)[CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[NH2:55][CH2:56][C:57]([CH3:60])([OH:59])[CH3:58].CCN(CC)CC>C(Cl)Cl>[OH:59][C:57]([CH3:60])([CH3:58])[CH2:56][NH:55][C:38](=[O:39])[CH2:37][CH2:36][CH2:35][S:32]([N:29]1[CH2:30][CH2:31][C:26]([C:24]2[CH:23]=[CH:22][C:20]3[N:21]=[C:17]([O:16][CH:13]4[CH2:12][CH2:11][N:10]([C:7]5[N:6]=[CH:5][C:4]([CH2:1][CH2:2][CH3:3])=[CH:9][N:8]=5)[CH2:15][CH2:14]4)[S:18][C:19]=3[CH:25]=2)=[CH:27][CH2:28]1)(=[O:34])=[O:33]
Reactant: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCN(S(=O)(=O)CCCC(=O)O)CC5)cc4s3)CC2)nc1
Reactant: CC(C)(O)CN
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCN(S(=O)(=O)CCCC(=O)NCC(C)(C)O)CC5)cc4s3)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
To a solution of 4-(4-(2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridin-1(2H)-ylsulfonyl)butanoic acid (30 mg, 0.051 mmol), HOBT (10.2 mg, 0.067 mmol), and EDC (12.8 mg, 0.067 mmol) in CH2Cl2 (1 mL) was added 1-amino-2-methylpropan-2-ol (6.9 mg, 0.077 mmol) followed by slow addition of Et3N (0.03 mL, 0.205 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with CH2Cl2 (2 mL), washed with water (2 mL), then brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was recrystallized from 10% water in CH3CN to afford N-(2-hydroxy-2-methylpropyl)-4-(4-(2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridin-1(2H)-ylsulfonyl)butanamide (24 mg, 0.035 mmol, 68% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.17 (s, 2H), 7.63 (d, J=2.2 Hz, 1H), 7.62 (d, J=4.1 Hz, 1H), 7.38 (dd, J=8.5, 1.7 Hz, 1H), 6.06 (dt, J=3.2, 1.8 Hz, 1H), 6.04-5.99 (m, 1H), 5.45 (tt, J=7.9, 3.8 Hz, 1H), 4.22 (ddd, J=13.3, 6.9, 4.0 Hz, 2H), 4.02 (q, J=2.6 Hz, 2H), 3.73-3.62 (m, 2H), 3.57 (t, J=5.6 Hz, 2H), 3.28 (d, J=6.1 Hz, 2H), 3.10 (t, J=7.0 Hz, 2H), 2.70-2.64 (m, 2H), 2.49 (t, J=6.7 Hz, 2H), 2.41 (t, J=7.4 Hz, 2H), 2.26-2.14 (m, 5H), 1.94 (dtd, J=12.8, 8.3, 3.9 Hz, 2H), 1.62-1.55 (m, 2H), 1.23 (s, 6H), 0.94 (t, J=7.3 Hz, 3H). LCMS (m/z)=657 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:17]([C:19]2[CH:24]=[CH:23][NH:22][C:21](=[O:25])[CH:20]=2)=[O:18])=[N:13][C:12]=1[CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O[C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:43]=1N=CC=C2.IC1C=CC=CC=1>CS(C)=O.[Cu]I>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:17]([C:19]2[CH:24]=[CH:23][N:22]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:43]=3)[C:21](=[O:25])[CH:20]=2)=[O:18])=[N:13][C:12]=1[CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(NC(=O)c2cc[nH]c(=O)c2)sc1C(=O)NCc1ccccc1
Reactant: Oc1cccc2cccnc12
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Ic1ccccc1
Solvent: CS(C)=O
Product: Cc1nc(NC(=O)c2ccn(-c3ccccc3)c(=O)c2)sc1C(=O)NCc1ccccc1
Temperature: 130 °C
Yield: 20 %

Procedure:
To a degassed solution of N-benzyl-4-methyl-2-(2-oxo-1,2-dihydropyridine-4-carboxamido)thiazole-5-carboxamide (0.060 g, 0.16 mmol), potassium carbonate (0.033 g, 0.24 mmol) and 8-hydroxyquinoline (0.0034 g, 0.024 mmol) in dimethyl sulfoxide (5 mL) were added iodobenzene (0.039 g, 0.19 mmol) and finally copper(I) iodide (0.0046 g, 0.025 mmol). The reaction mixture was heated at 130° C. for 16 hours, then cooled to ambient temperature and filtered. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (40 mL) and washed with saturated aqueous sodium bicarbonate solution (2×20 mL), and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrate in vacuo. The residue was recrystallized from ethyl acetate and methanol to yield a colorless solid in 20% yield (0.012 g); m.p. 260-262° C.; 1H NMR (DMSO-d6, 300 MHz) δ 13.11 (s, br., 1H), 8.63 (t, J=5.8 Hz, 1H), 7.78 (d, J=7.1 Hz, 1H), 7.58-7.37 (m, 5H), 7.35-7.26 (m, 4H), 7.23-7.18 (m, 1H), 7.14 (d, J=1.5 Hz, 1H), 6.75 (dd, J=1.5, 7.1 Hz, 1H), 4.38 (d, J=5.8 Hz, 2H), 2.51 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) δ 165.5, 162.0, 162.0, 161.3, 140.7, 140.2, 140.0, 139.9, 137.9, 129.6, 128.9, 128.7, 127.7, 127.2, 127.0, 120.9, 103.7, 43.1, 16.9; MS (ES+) m/z 445.0 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[K].[CH:16](=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19]>O>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[O:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[CH:16]=[O:24])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: O=Cc1ccccc1O
Agent: [K]
Solvent: O
Product: O=Cc1ccccc1Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 150 °C

Procedure:
200 Parts of 4-chloro-3-nitrobenzo-trifluoride is heated to 160° C. and stirred and 160 parts of the potassium salt of salicylaldehyde is added over a period of 30 minutes. After the addition is complete, an exothermic reaction takes place and the temperature rises to about 195° C. Heating is then discontinued until the reaction subsides and the mixture is then heated for 1 hour at 150° C. The mixture is cooled, ice and water are added, and it is then extracted with ether. The ether layer is filtered to remove insoluble material and the resultant solution is dried over sodium sulfate. The ether solvent is then evaporated and the residual oil is recrystallized from a mixture of hexane and benzene to give 2-(2-nitro-4-trifluoromethylphenoxy)benzaldehyde melting at about 79°-81° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=[CH:11][C:4]=1[CH2:5][CH2:6][NH:7][C:8](=O)[CH3:9].O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH3:9][C:8]1[C:11]2[C:4](=[C:3]([O:2][CH3:1])[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=2)[CH2:5][CH2:6][N:7]=1
Reactant: COc1ccc(CCNC(C)=O)c(OC)c1OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc2c(c(OC)c1OC)CCN=C2C
Yield: 88.9 %

Procedure:
A solution of the acetamide 43 (280 mg, 1.1 mmol) in toluene (5 mL) containing POCl3 (0.8 mL, 8.5 mmol) was heated at reflux under Ar for 2 h. The excess POCl3 and the solvent were evaporated under vacuum. The black residue was washed with petroleum ether (10 mL). The residue was dissolved in distilled water (10 mL) and made basic by 5% NH4OH aq (10 mL). The aqueous solution was extracted with CHCl3 (20, 10, and 5 mL). The combined CHCl3 layer was washed successively with water (10 mL) and saturated NaCl solution (10 mL) and dried over anhydrous Na2SO4. Evaporation of the filtrate and chromatography (ether:ethanol, 98:2 by volume, silica gel 230-400 mesh) gave compound 44 as a pale brown oil (230 mg, 89.2%): 1H NMR (CDCl3, 200 MHz) δ6.84 (s, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 3.85 (s, 3H), 3.61 (t, 2H, J=8 Hz), 2.64 (t, 2H, J=8 Hz), 2.36 (s, 3H). EIMS m/e 235 (M+, 84).
Reaction SMILES: [C:1]([Si:5]([CH3:12])([CH3:11])[O:6][CH2:7][C:8]([CH3:10])=O)([CH3:4])([CH3:3])[CH3:2].[CH3:13][C:14]([S@@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15].[Cl-].[Na+]>C1COCC1.CCO.CCO.CCO.CCO.[Ti]>[Si:5]([O:6][CH2:7]/[C:8](=[N:19]/[S@:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])/[CH3:10])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: CC(=O)CO[Si](C)(C)C(C)(C)C
Agent: [Ti]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: C/C(CO[Si](C)(C)C(C)(C)C)=N\[S@@](=O)C(C)(C)C
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 761 mg of 1-{[tert-butyl (dimethyl)silyl]oxy}acetone in 20 ml of THF were added 2.1 ml of tetraethyl orthotitanate and 490 mg of (S)-2-methylpropane-2-sulfinamide, followed by stirring at 70° C. for 8 hours. The reaction mixture was left to be cooled to room temperature and a saturated aqueous sodium chloride solution was then added thereto, followed by stirring and filtering over Celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain (S)—N-[(2E)-1-{[tert-butyl(dimethyl)silyl]oxy}propan-2-ylidene]-2-methylpropane-2-sulfinamide.