Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]2[CH:13]=[CH:14][CH:15]=[N:16][C:5]=2[N:4]([CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:3]1=[O:27].C(N(CC)CC)C.ON1C2=NC=CC=C2N=N1.[C:45]([O:49][C:50]([NH:52][C@@H:53]([CH3:57])[C:54](O)=[O:55])=[O:51])([CH3:48])([CH3:47])[CH3:46].Cl.CN(C)CCCN=C=NCC>ClCCl>[Si:20]([O:19][CH2:18][CH2:17][N:4]1[C:5]2[N:16]=[CH:15][CH:14]=[CH:13][C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:2]([NH:1][C:54](=[O:55])[C@@H:53]([NH:52][C:50](=[O:51])[O:49][C:45]([CH3:47])([CH3:46])[CH3:48])[CH3:57])[C:3]1=[O:27])([C:23]([CH3:24])([CH3:26])[CH3:25])([CH3:21])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OCCN1C(=O)C(N)c2ccccc2-c2cccnc21
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1C(=O)N(CCO[Si](C)(C)C(C)(C)C)c2ncccc2-c2ccccc21
Temperature: 25 °C
Yield: 86.5 %

Procedure:
Cool a mixture of 7-amino-5-[2-(tert-butyl(dimethyl)silyl)oxyethyl]-7H-pyrido[2,3-d][3]benzazepin-6-one (36.3 g, 89.9 mmol), dichloromethane (360 mL), triethylamine (16.3 mL, 116.9 mmol), 3-hydroxytriazolo[4,5-b]pyridine (15.9 g, 116.9 mmol), and (2S)-2-(tert-butoxycarbonylamino)propanoic acid (22.5 g, 116.9 mmol) to 0° C. Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22.4 g, 116.9 mmol) and after 5 minutes allow to warm to ambient temperature overnight. Wash with water (500 mL×2), saturated aqueous sodium bicarbonate solution (2×300 mL), brine (300 mL), and then dry over sodium sulfate and concentrate. Purify the residue by flash chromatography, eluting with isopropyl alcohol:hexane (5:95 to 10:90) to give the title compound as a white foam (43.14 g, 77.77 mmol, 86.50%). MS (m/z): 555 (M+1).
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([C:33]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([CH3:43])[CH:36]=2)=O)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH3:23]>C1COCC1>[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([C:33]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([CH3:43])[CH:36]=2)=[CH:9][C:10]#[N:11])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH3:23]
Reactant: CCOc1cc(C(=O)c2ccc(OC)c(C)c2)ccc1OC
Reactant: CCOP(=O)(CC#N)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1cc(C(=CC#N)c2ccc(OC)c(C)c2)ccc1OC
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 75 %

Procedure:
To a stirred solution of cyanomethylphosphonic acid diethyl ester (1.3 mL, 8.3 mmol) in THF (20 mL) in an ice bath was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 8.3 mL, 8.3 mmol) dropwise. The mixture was stirred at room temperature for 40 min. A solution of (3-ethoxy-4-methoxy-phenyl)-(4-methoxy-3-methyl-phenyl)-methanone from above in THF (10 mL) was added to the mixture. The mixture was refluxed for 4 h. The solution was poured into ice water (30 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers was washed with water (50 mL), sodium hydrogen carbonate (50 mL, sat), brine (50 mL) and dried over magnesium sulfate. Removal of solvent and chromatography (Silica Gel) gave a mixture of (E/Z) 3-(3-ethoxy-4-methoxy-phenyl)-3-(4-methoxy-3-methyl-phenyl)-acrylonitrile as a white solid (0.97 g, 75% yield) (isomer ratio is 1:0.8 by HNMR): mp: 86-88° C.; 1H NMR (DMSO-d6) δ 1.30 (t, J=7 Hz, 3H, CH3), 2.13 (s, 3H, CH3), [2.17 (s)], 3.78 (s, 3H, CH3), 3.82 (s, 3H, CH3), [3.83 (s), 3.86 (s)], 3.93-4.04 (m, 2H, CH2), 6.01 (s, 1H, CH), [6.08 (s)], 6.72-7.26 (m, 6H, Ar); 13C NMR (DMSO-d6) 14.56, 14.59, 15.98, 63.77, 92.10, 92.42, 110.04, 110.18, 111.35, 111.51, 112.27, 113.83, 118.92, 122.27, 122.35, 125.61, 125.86, 128.05, 128.60, 128.92, 129.44, 130.14, 130.35, 130.82, 131.29, 147.36, 147.78, 150.15, 151.02, 158.44, 159.28, 161.47, 161.53; Anal. Calcd for C20H21NO3: C, 74.28; H, 6.55; N, 4.33. Found: C, 74.16; H, 6.48; N, 4.30.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH2:13][C:12](=[O:15])[NH:11][C:10]=2[CH:16]=1)=[O:4].[F:17][C:18]1[CH:30]=[CH:29][C:21]([CH2:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:20][CH:19]=1>C(OCC)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH:23]2[CH2:24][CH2:25][N:26]([CH2:2][C:3]([NH:5][C:6]3[CH:7]=[CH:8][C:9]4[O:14][CH2:13][C:12](=[O:15])[NH:11][C:10]=4[CH:16]=3)=[O:4])[CH2:27][CH2:28]2)=[CH:29][CH:30]=1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: O=C(CCl)Nc1ccc2c(c1)NC(=O)CO2
Solvent: CCOCC
Product: O=C(CN1CCC(Cc2ccc(F)cc2)CC1)Nc1ccc2c(c1)NC(=O)CO2

Procedure:
The title compound is prepared from 2-chloro-N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-acetamide (Example 155a) and 4-(4-fluoro-benzyl)-piperidine according to the method described in Example 142b. Melting Point: 185-187° C. (diethylether)
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[C:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:32])[CH3:31]>>[C:30]([N:33]1[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][O:4][C:5]2[C:13]3[C:8](=[N:9][CH:10]=[N:11][C:12]=3[NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=4)=[C:17]([Cl:29])[CH:16]=3)[NH:7][N:6]=2)[CH2:35][CH2:34]1)(=[O:32])[CH3:31]
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)cn1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(Oc5ccc(C)nc5)c(Cl)c4)c23)CC1
Yield: 32 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine and N-acetylpiperazine to give the title compound in 32% yield; NMR Spectrum: 1.96 (s, 3H), 2.45 (s, 3H), 2.46-2.53 (m, partially hidden by DMSO, 8H), 2.86 (t, 2H), 4.47 (t, 2H), 6.05 (br s, 1H), 7.20 (d, 1H), 7.26 (br s, 2H), 7.71 (d, 1H), 8.12 (s, 1H), 8.20 (s, 1H), 8.36 (s, 1H); Mass Spectrum: 523 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[CH:6]=1)[CH3:2].Br[C:25]1[CH:26]=[N:27][N:28]([CH2:30][CH3:31])[CH:29]=1>>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:25]3[CH:26]=[N:27][N:28]([CH2:30][CH3:31])[CH:29]=3)[C:13]=2[CH3:22])[CH:6]=1)[CH3:2]
Reactant: CCn1cc(Br)cn1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(CC)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 4-bromo-1-ethylpyrazole.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>C1COCC1>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:17][CH:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([OH:5])=[O:4])[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: COc1cccc(N)c1
Solvent: C1CCOC1
Product: COc1cccc(NC(C(=O)O)c2ccccc2)c1
Yield: 98.9 %

Procedure:
A solution of 2-bromo-2-phenylacetic acid (0.5 g, 2.28 mmol) and 3-methoxyaniline (0.54 mL, 4.56 mmol) in THF (12 mL) is refluxed for 4 hours. Solvent is removed under vacuum, the residue is taken up with 1M HCl and extracted with EtOAc. The organic phase is dried (Na2SO4), filtered and evaporated. The crude is purified by flash chromatography (DCM/MeOH=98/2 to 9/1) to obtain intermeaditae I116 as a white solid (0.58 g, 99% yield).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(O[CH:17]=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])C.O>CN(C)C=O>[CH2:22]([O:21][C:19](=[O:20])[C:18](=[CH:17][NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:23]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCc1ccc2ncnc(N)c2c1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CNc1ncnc2ccc(CC)cc12)C(=O)OCC
Temperature: 110 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
A mixture of 4-amino-6-ethylquinazoline (6.35 g) and diethyl ethoxymethylenepropanedioate (9.52 g) in N,N-dimethylformamide (25 ml) was stirred for 3 hours at 110° C. and then cooled to ambient temperature. A small volume of water was added to the resultant mixture to precipitate crystals, which were separated by filtration and washed with water. The crystals were dissolved in chloroform, washed with an aqueous solution saturated with sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crystalline residue, which was recrystallized from a mixture of ethyl acetate and hexane to give crystalline diethyl[(6-ethyl-4-quinazolinylamino)methylene]propanedioate (8.40 g). Further, crystals (2.75 g) of the same compound were recovered from the motor liquor in the same manner as mentioned above.
Reaction SMILES: BrBr.[C:3]([C:5]([C:17]([O:19][CH3:20])=[O:18])=[N:6][C:7]([CH3:16])=[C:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:4].C(Cl)Cl.C[O-].[Na+]>CO>[CH3:20][O:19][C:17]([C:5]1[C:3]([NH2:4])=[N:15][C:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:7]([CH3:16])[N:6]=1)=[O:18]
Reactant: COC(=O)C(C#N)=NC(C)=C(N)c1ccccc1
Agent: BrBr
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1nc(C)c(-c2ccccc2)nc1N

Procedure:
A reactor provided with a stirring device, a bromine feed and a calcium chloride tube is filled with a solution of 4 parts of 1-cyano-1-methoxycarbonyl-3-methyl-4-amino-4-phenyl-2-aza-1,3-butadiene in 120 parts by volume of a mixture of dry methanol and dry methylene chloride (10 : 1 by volume.) 0.9 parts of sodium methylate dissolved in dry methanol are added rapidly at the ambient temperature with stirring. The reaction is finished at the end of 15 minutes, and the greater part of the solvents is evaporated under reduced pressure. The 2-methoxycarbonyl-3-amino-5-phenyl-6-methyl pyrazine which is precipitated is filtered off, then recrystallised from methanol and 3 parts of pyrazine are obtained. M.p. 162°C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:13]3[C:14]([CH3:28])=[C:15]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][CH2:10]2)=[CH:5][CH:4]=1)=O.[C:29]([O:32][CH2:33][CH3:34])(=[O:31])[CH3:30]>>[CH3:24][C:23]([CH3:26])([CH3:25])[CH2:22][C:21]([NH:20][C:15]1[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]2[O:11][CH2:10][CH:9]([C:6]3[CH:5]=[CH:4][C:3](/[CH:1]=[CH:30]/[C:29]([O:32][CH2:33][CH3:34])=[O:31])=[CH:8][CH:7]=3)[C:13]=2[C:14]=1[CH3:28])=[O:27]
Reactant: CCOC(C)=O
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C=O)cc1)CO2
Product: CCOC(=O)/C=C/c1ccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)cc1
Yield: 81 %

Procedure:
Using N-(3-(4-formylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 174, the title compound was synthesized in the same manner as in Example 177. Yield: 81%. Melting point: 176-177° C. (ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[S:16])[NH:11][CH2:12][C:13](N)=[O:14].[CH2:17](I)[CH3:18]>C(O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][N:11]=[C:10]1[S:16][CH2:17][CH3:18]
Reactant: CCI
Reactant: Cc1cccc(C)c1NC(=S)NCC(N)=O
Solvent: CCO
Product: CCSC1=NCC(=O)N1c1c(C)cccc1C
Yield: 28.7 %

Procedure:
The title compound was prepared by the procedure described in Example 12 using 8.0 g of 2-[3-(2,6-dimethylphenyl)-thioureido]-acetamide, 25.0 g of ethyl iodide, and (200 mL) ethanol. Crystallization from hexane/diethyl ether mixture afforded the title compound as a light yellow solid (2.4 g), m.p. 86°-88° C. Anal. Calcd. for. C12H16N2O S: C, 62.87; H, 6.49; N, 11.28. Found: C, 62.98; H, 6.57; N, 11.30. Mass spectrum (El, M.+) m/z 248 1H-NMR (DMSO-d6 ; 400 MHz) δ7.27-7.30 (m, 1H), 7.21 (m, 1H), 7.19 (m, 1H), 7.33 (d, 1H), 4.42 (s, 2H), 3.06 (q, 2H), 2.07 (s, 6H), and 1.26 ppm (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14](Br)[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[C:21]1C=C(NS(C2C=CC(NC(=O)C)=CC=2)(=O)=O)C=C(C)[N:22]=1>CN.C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:22][CH3:21])[N:15]=[C:16]([CH3:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2cc(C)nc(Br)c2)cc1
Reactant: Cc1cc(NS(=O)(=O)c2ccc(N)cc2)cc(Br)n1
Agent: CN
Solvent: CCO
Product: CNc1cc(NS(=O)(=O)c2ccc(N)cc2)cc(C)n1
Yield: 48 %

Procedure:
0.94 g (0.00275 mol) of 4-amino-N-(2-bromo-6-methyl-pyridin-4-yl)-benzenesulfonamide was stirred in 50 ml of 8M methylamine in ethanol in an autoclave at 135° C. for 40 hours. The methylamine was allowed to evaporate, the residue was dissolved in ethanol, treated with 2 g of silica gel, concentrated and the residue was chromatographed on silica gel, firstly with ethyl acetate/hexane 1:1, then 9:1. There was obtained 0.39 g (48%) of 4-amino-N-(2-methyl-6-methylamino-pyridin-4-yl)-benzenesulfonamide as colourless crystals; m.p.: 173-175° C. 0.081 g (0.00028 mol) thereof was recrystallized from methanol, diethyl ether and hexane, dried in a high vacuum, dissolved in 3 ml of methanol and treated with 2.8 ml of 0.1N NaOH. The methanol was distilled off and the residue was freeze-dried twice. There was obtained 0.084 g (97%) of 4-amino-N-(2-methyl-6-methylamino-pyridin-4-yl)-benzenesulfonamide sodium salt (1:1) as white crystals; MS (ISP): me/e=293 (C13H17N4O2S+). 0.31 g (0.0011 mol) of 4-amino-N-(2-methyl-6-methylamino-pyridin-4-yl)-benzenesulfonamide was dissolved in 2 ml of methanol, treated with 1 ml of 2.4N HCl in diethyl ether and freed from solvent. The residue was dissolved in 1 ml of methanol and slowly added dropwise to diethyl ether while stirring-vigorously. A colourless precipitate thereby separated and this was isolated and dried in a high vacuum. There was obtained 0.33 g (87%) of 4-amino-N-(2-methyl-6-methylamino-pyridin-4-yl)-benzenesulfonamide hydrochloride (1:1.86) as white crystals; m.p.: >170° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.[Br:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17](Br)[CH:18]=1.C(=O)(O)[O-].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:12][C:13]1[CH:18]=[C:17]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH:16]=[CH:15][CH:14]=1
Reactant: Brc1cccc(Br)c1
Reactant: COc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccccc1-c1cccc(Br)c1
Reaction time: 8 h
Yield: 190.7 %

Procedure:
A mixture of 2-methoxyphenylboronic acid (4.3 g, 28.3 mmol), 3,5-dibromobenzene (20 g, 85.5 mmol, 3 equiv.) and bis(triphenylphosphine)palladium(II) dichloride (100 mg) in ethyleneglycol dimethylether (25 mL) and a solution of sodium bicarbonate (8.2 g, 0.098 mol) in water (140 mL) were kept at reflux under nitrogen with good stirring overnight. After cooling, the reaction mixture was partitioned between ethyl acetate (600 mL) and water (300 mL). The organic phase was washed with water (2×300 mL), dried over sodium sulfate and filtered. The solvent was removed in vacuo and the crude product was purified by chromatography on silica (150 g) with heptane (6 L) to afford pure 21 (14.2 g, 58%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>C(#N)C>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=3)[O:26][CH2:28][C:29]([O:31][CH3:32])=[O:30])[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CBr
Reactant: Oc1cccc(CCc2nc(-c3ccccc3)c(-c3ccccc3)s2)c1
Solvent: CC#N
Product: COC(=O)COc1cccc(CCc2nc(-c3ccccc3)c(-c3ccccc3)s2)c1
Yield: 84.5 %

Procedure:
A mixture of 3-[2-(4,5-diphenyl-2-thiazolyl)-ethyl]phenol (3.65 g, 10 mmol), methyl bromoacetate (1.72 g, 1.06 mL, 11 mmol) potassium carbonate (1.69 g, 12 mmol) and acetonitrile (60 mL) was stirred at reflux for 90 minutes. The mixture was filtered and concentrated to leave an oil which was subjected to chromatography on a column of silica gel. Elution with a mixture of hexanes and diethyl ether (2:1) afforded methyl [3-[2-(4,5-diphenyl-2-thiazolyl)-ethyl]phenoxy]acetate (3.63 g, 82%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5]Br.[C:11]([O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18]2)(=[O:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:11]([O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:5][C:4]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=1)[C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18]2)(=[O:13])[CH3:12]
Reactant: CCOC(=O)c1cc2cc(OC(C)=O)ccc2[nH]1
Reactant: Clc1ccc(CBr)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc2cc(OC(C)=O)ccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Yield: 62.5 %

Procedure:
3,4-Dichlorobenzyl bromide (5.96 g) was added to a stirred solution of ethyl 5-acetoxyindole-2-carboxylate (5.4 g) and potassium carbonate (6.94 g) in acetonitrile (500 ml) under an atmosphere of argon. The reaction was heated at 80° C. for 16 hours, then concentrated in vacuo and the residue partitioned between ethyl acetate and water. Combined organic extracts were washed with water, saturated aqueous sodium chloride and dried. The solvent was removed in vacuo and the residue was triturated with iso-hexane to yield the product as a cream solid (5.55 g, 63%). NMR: δ 1.27 (t, 3H), 2.27 (s, 3H), 4.28 (q, 2H), 5.82 (s, 2H), 6.90 (d, 1H), 7.09 (dd, 1H), 7.33-7.40 (m, 2H), 7.46 (d, 1H) 7.52 (d, 1H), 7.60 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:26])=[CH:4][N:3]=1.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C>[Cl:26][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccccc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(CN1CCN(c2c(Cl)cnc3[nH]c(-c4ccccc4)nc23)CC1)Nc1nccs1
Temperature: 70 °C

Procedure:
To a mixture of 2-[4-(2-amino-5-chloro-3-nitro-pyridin-4-yl)-piperazin-1-yl]-N-thiazol-2-yl-acetamide (0.040 g, 0.10 mmol), ethanol (3 ml), and benzaldehyde (0.015 g, 0.14 mmol) was added a freshly prepared aqueous solution of sodium dithionite (Na2S2O4) (1M; 0.4 ml, 0.4 mmol). The reaction mixture was heated at 70° C. for 6 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 70% dichloromethane in ethyl acetate and then 2% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as an off white solid after trituration with diethyl ether (0.011 g, 24%); 1H-NMR (500 MHz, DMSO-d6) 2.73 (br s, 4H, piperazine N(CH2)2), 3.40 (s, 2H, CH2CO), 3.75 (br s, 4H, piperazine N(CH2)2), 7.23 (d, J=3.46 Hz, 1H) and 7.49 (d, J=3.46 Hz, 1H) (thiazole 4-H, 5-H), 8.12 (s, 1H, imidazo[4,5-b]pyridine 5-H), 7.60 (m, 3H) and 8.19 (d, J=7.00 Hz, 2H) (ArH), 11.92 (s, 1H, CONH), 13.49 (s, 1H, imidazo[4,5-b]pyridine N—H); LC-MS (ESI, m/z) Rt=6.16 min—454, 456 [(M+H)+, Cl isotopic pattern]. ESI-HRMS: Found: 454.1230, calculated for C21H21N7OSCl (M+H)+: 454.1217.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.[NH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 95.9 %

Procedure:
4-amino-5-chloro-2-methoxybenzoic acid (compound of formula 9) (16.6 g, 82.28 mmol) was dissolved in dimethylformamide (166 mL) and the solution was cooled to 0° C. Then, tertiary butyl 4-(aminomethyl)piperidine-1-carboxylate (21.16 g, 98.74 mmol), triethylamine (11.56 mL, 246.84 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC, 20.51 g, 106.96 mmol), and 1-hydroxybenzotriazole (HOBT, 16.68 g, 123.42 mmol) were added thereto. The reaction mixture was warmed to room temperature, stirred for 4 hours, and extracted with ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford the title compound (31.4 g, 96%).
Reaction SMILES: [Br:1]Br.ClC(Cl)C.[CH3:7][O:8][CH:9]([O:20][CH3:21])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[CH3:19].[OH-].[Na+]>CO>[Br:1][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH:9]([O:20][CH3:21])[O:8][CH3:7])=[C:13]([CH3:19])[C:14]=1[CH3:18]
Reactant: COC(COc1cccc(C)c1C)OC
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(Cl)Cl
Product: COC(COc1ccc(Br)c(C)c1C)OC
Reaction time: 1 h
Yield: 92.1 %

Procedure:
Bromine (140 g) was added dropwise to a 760 ml of dichloroethane solution containing 180 g of 1-(2,2-dimethoxyethoxy)-2,3-dimethylbenzene while stirring and cooling (ice bath) and maintaining the temperature of the reaction mixture not exceeding 10° C. After stirring for 30 minutes after completion of the addition, the reaction mixture was condensed under reduced pressure (a temperature of 40° C. or lower). The condensate was added dropwise in a solution comprising 37 g of sodium hydroxide dissolved in 185 g of methanol while stirring. Stirring was continued for one hour after completion of the addition, methanol was removed under reduced pressure, and 30 ml of dichloroethane and 570 ml of water were added to the residue and then the mixture was separated with each other. The organic layer was condensed under reduced pressure, a resulting brownish oil was distilled under reduced pressure to give 228 g of 1-bromo-4-(2,2-dimethoxyethoxy)-2,3-dimethylbenzene. Boiling point: 128° to 131° C./0.5 mmHg; Melting point: 40° to 41° C.; and Yield: 92%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]2[CH:11]=[CH:10][C:9]3=[N:12][S:13][CH:14]=[CH:15][C:8]3=[C:6]2[N:7]=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([O:1][CH2:2][C:3]2[N:4]=[C:5]3[CH:11]=[CH:10][C:9]4=[N:12][S:13][CH:14]=[CH:15][C:8]4=[C:6]3[N:7]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: OCc1nc2ccc3nsccc3c2n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCc2nc3ccc4nsccc4c3n2)cc1

Procedure:
2-Hydroxymethyl-thiazinobenzimidazole derivative (Ia) is reacted with p-toluenesulfonyl chloride to produce 2-p-toluenesulfonyloxymethyl-thiazinobenzimidazole derivative (Ib).