Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1([O:12]/[N:13]=[C:14](/[C:45]2[N:46]=[C:47]([NH:50]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:48][CH:49]=2)\[C:15]([NH:17][CH:18]2[C:43](=[O:44])[N:20]3[C:21]([C:27]([O:29]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:28])=[C:22]([CH2:25]I)[CH2:23][S:24][C@H:19]23)=[O:16])[CH2:11][CH2:10][CH2:9]1)=[O:7])(C)(C)C.[S:70]1[C:78]2[CH:77]=[CH:76][N:75]=[CH:74][C:73]=2[N:72]=[CH:71]1>CS(C)=O.CCOCC>[NH2:50][C:47]1[S:48][CH:49]=[C:45](/[C:14](=[N:13]/[O:12][C:8]2([C:6]([OH:5])=[O:7])[CH2:11][CH2:10][CH2:9]2)/[C:15]([NH:17][CH:18]2[C:43](=[O:44])[N:20]3[C:21]([C:27]([O-:29])=[O:28])=[C:22]([CH2:25][N+:75]4[CH:76]=[CH:77][C:78]5[S:70][CH:71]=[N:72][C:73]=5[CH:74]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:46]=1
Reactant: CC(C)(C)OC(=O)C1(O/N=C(\C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CI)CS[C@H]23)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)CCC1
Reactant: c1cc2scnc2cn1
Solvent: CS(C)=O
Solvent: CCOCC
Product: Nc1nc(/C(=N/OC2(C(=O)O)CCC2)C(=O)NC2C(=O)N3C(C(=O)[O-])=C(C[n+]4ccc5scnc5c4)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 31 %

Procedure:
To a solution of diphenylmethyl 7-[(Z)-2-(1-t-butoxycarbonylcyclobut-1-oxyimino)-2-(2-tritylaminothiazol-4-yl)-acetamido]-3-iodomethyl-3-cephem-4-carboxylate [VIIe'] (482 mg, 0.45 mmole) in 2 mL of DMSO was added thiazolo[4,5-c]pyridine (68 mg, 0.5 mmole) in one portion. The mixture was stirred for 45 minutes at room temperature. The reaction mixture was then diluted with ether (50 mL) and the precipitated oil was triturated in ether (4×50 mL). The precipitate was mixed with anisole (0.5 mL), trifluoroacetic acid (5 mL) and water (0.5 mL), and the mixture was stirred with ice cooling for 30 minutes and at room temperature for 1 hour, and then was concentrated under reduced pressure (<30° C.). The residue was triturated with isopropyl ether (100 mL), and the resulting precipitate was collected by filtration to afford 395 mg of crude title compound, as a yellow powder. The crude product (387 mg) was purified on an HP-20 column (100 mL). The eluate containing desired product, which was eluted with 50% methanol, was concentrated and lyophilized to give 80 mg (31%) of the title product (Ie) as a pale yellow amorphous powder. Mp >170° C. (dec.).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=1)#[N:4].Cl[C:24]1[CH:25]=[C:26]2[N:33]([CH3:34])[CH2:32][CH2:31][N:27]2[C:28](=[O:30])[N:29]=1>C1COCC1>[C:3]([C:5]1[CH:20]=[C:19]([CH2:21][O:22][C:24]2[CH:25]=[C:26]3[N:33]([CH3:34])[CH2:32][CH2:31][N:27]3[C:28](=[O:30])[N:29]=2)[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=1)#[N:4]
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: N#Cc1ccc(Oc2ccc(CO)cc2C#N)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccc(C#N)c(F)c3)c(C#N)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using sodium hydride (9.37 mg, 0.234 mmol), 4-(2-cyano-4-(hydroxymethyl)phenoxy)-2-fluorobenzonitrile (41.9 mg, 0.156 mmol) in THF (8 mL) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimi-din-5(1H)-one (29 mg, 0.156 mmol).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[H][H].F[C:14]1[C:19]([C:20](=[O:29])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=[CH:16][N:15]=1>CCCCC.CN(C=O)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:14]2[C:19]([C:20](=[O:29])[CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:6][CH:5]=1
Reactant: O=C(CCc1ccccc1)c1cccnc1F
Reactant: [H][H]
Reactant: Oc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: O=C(CCc1ccccc1)c1cccnc1Oc1ccc(F)cc1
Temperature: 80 °C
Yield: 85.2 %

Procedure:
To the sodium hydride obtained by washing 351 mg (7.73 mmol) of 50% sodium hydride dispersion in mineral oil with pentane was added 10 mL of dimethylformamide followed by 867 mg (7.73 mmol) of p-fluorophenol. After the hydrogen evolution ceased, 886 mg (3.87 mmol) 1-(2-Fluoro-pyridin-3-yl)-3-phenyl-propan-1-one was added dissolved in a minimum amount of DMF. The mixture was heated to 80° C. for 3 h, and the solvent was evaporated under high vacuum. The residue was partitioned between 200 mL of ether and 50 mL of aqueous 1 N sodium hydroxide solution, and the separated organic layer was washed with aqueous 1 N sodium hydroxide solution (1×50 mL), brine (1×100 mL), dried (Na2SO4), and evaporated to 1.16 g of a white solid. Recrystallization from hexane gave 1.06 g (85% yield) of the title compound as a white solid, mp 82-83° C. Anal. Calcd for C20H16FNO2: C, 74.75; H, 5.02; N, 4.36. Found: C, 74.63; H, 4.97; N, 4.31.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][OH:5]
Reactant: COC(=O)c1cccc(Cl)c1N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1c(Cl)cccc1CO
Reaction time: 2 h
Yield: 74.8 %

Procedure:
A solution of methyl 2-amino-3-chlorobenzoate (1.7 g, 9.16 mmol) in THF (40 mL) was dropwise added to a suspension of the LAH (521 mg, 13.7 mmol) in THF (15 mL) at room temperature over 10 min under N2, and stirred for 2 hrs. The reaction was carefully quenched with saturated Na2SO4 (10 mL) at 0° C., extracted with Et2O (2×50 mL). The combined organic layers were washes with brine (30 mL), dried on MgSO4, and concentrated on rotary vacuum to afford the expected product as a yellow solid (1.08 g, 75%), which was pure enough to be used in the next step without further purification; 1H NMR (400 MHz, CDCl3) δ ppm 1.65 (s, 1 H), 4.59-4.70 (m, 4 H), 6.60-6.65 (m, 1 H), 6.96 (dd, J=7.55, 1.26 Hz, 1 H), 7.19-7.25 (m, 1 H); Mass spec. 158.02 (MH+), Calc. for C7H8ClNO2 157.03.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[N:10]=[CH:9][C:8]=2[N:7]=[C:6]1[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[C:2]#[C:3][CH3:4].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][Cl:29])=[CH:26][CH:25]=1.CN(C)C=O.CC(C)=O>C(OCC)C>[Cl-:29].[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[N:10]=[CH:9][C:8]=2[N:7]=[C:6]1[C:16]1[CH:21]=[CH:20][N+:19]([CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)=[CH:18][CH:17]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1c(-c2ccncc2)nc2cnn(C)c(=O)c21
Reactant: COc1ccc(CCl)cc1
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC#CCn1c(-c2cc[n+](Cc3ccc(OC)cc3)cc2)nc2cnn(C)c(=O)c21
Product: [Cl-]
Temperature: 65 °C
Reaction time: 4 h

Procedure:
0.045 g of 3-(2-butynyl)-5-methyl-2-(pyridin-4-yl)-3,5-dihydroimidazo[4,5-d]pyridazin-4-one and 0.060 μl of p-methoxybenzyl chloride were added to 0.100 ml of N,N-dimethylformamide, and the mixture was stirred at 65° C. under a nitrogen atmosphere for 4 hours. The reaction solution was cooled down, and 1 ml of acetone and 1 ml of diethyl ether were added thereto. The precipitate was collected by filtration to give 0.060 g of the title compound.
Reaction SMILES: [H-].[Na+].CS(C)=O.[F:7][C:8]([F:19])([F:18])[C:9]1[CH:10]=[C:11]([CH2:15][C:16]#[N:17])[CH:12]=[CH:13][CH:14]=1.Br[CH2:21][CH2:22][CH2:23]Br>CC(OC)(C)C>[F:7][C:8]([F:18])([F:19])[C:9]1[CH:10]=[C:11]([C:15]2([C:16]#[N:17])[CH2:23][CH2:22][CH2:21]2)[CH:12]=[CH:13][CH:14]=1
Reactant: N#CCc1cccc(C(F)(F)F)c1
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: COC(C)(C)C
Product: N#CC1(c2cccc(C(F)(F)F)c2)CCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.9 %

Procedure:
The mixture of sodium hydride (1.312 g, 54.7 mmol) and DMSO was stirred for about 10 minutes at room temperature. Then a solution of 2-(3-(trifluoromethyl)phenyl)acetonitrile (5 g, 24.86 mmol) and 1,3-dibromopropane (5.02 g, 24.86 mmol) in MTBE (80 mL) was added dropwise via dropping funnel. After addition, the mixture was stirred for about 12 hours, and quenched with 60 mL of water. The aqueous phase was extracted with MTBE (3×30 mL). The combined organic layers were washed with water (3×30 mL) and brine (3×30 mL), dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel column (20:1 Hexanes/ethyl acetate) to obtain the title compound as a transparent liquid (3.8 g, 63.4%). LC-MS: m/z (M+H) 226.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH2:11]O.C1C=CC(P([N:27]=[N+:28]=[N-:29])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.CCOC(C)=O>[N:27]([CH2:11][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[C:7]([F:8])[C:2]=1[F:1])=[N+:28]=[N-:29]
Reactant: COc1cc(F)c(F)c(CO)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(F)c(F)c(CN=[N+]=[N-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2,3-difluoro-5-methoxy-phenyl)-methanol (715 mg, 4.11 mmol) in toluene (10 mL) was added DPPA (1.04 mL, 4.93 mmol) and DBU (0.805 mL, 5.34 mmol), followed by stirring at RT for 1 h. The reaction mixture was diluted with EtOAc, the organics were washed with diluted brine (20 mL), dried (Phase separator) and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 9:1) to afford the title compound as a colorless oil. TLC Rf (c-hexane/EtOAc 3:1)=0.55; MS (LC/MS): 208.0 [M+NH4]+; tR (HPLC conditions c): 5.46 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:3]=1.Br.[CH2:15](Br)[CH3:16].[CH3:18][NH:19][CH3:20].[OH-].[K+]>COCCOC>[C:10]([C:4]1[C:5]([O:9][CH2:16][CH2:15][N:19]([CH3:20])[CH3:18])=[CH:6][C:7]([CH3:8])=[C:2]([NH2:1])[CH:3]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CCBr
Reactant: CNC
Reactant: Cc1cc(O)c(C(C)(C)C)cc1N
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Product: Cc1cc(OCCN(C)C)c(C(C)(C)C)cc1N
Yield: 26 %

Procedure:
Heat a mixture of 4-amino-2-tert-butyl-5-methyl-phenol (600 mg, 3.2 mmol), N,N-dimethylamine ethyl bromide HBr salt (820 mg, 3.4 mmol), and potassium hydroxide (750 mg, 13.4 mmol) in 1,2-dimethoxyethane in a microwave vessel with irradiation of <10 Watts at a temperature of 150-170° C. for 5 minutes. After the reaction cools, filter via Celite® and wash with dichloromethane. Concentrate the filtrate and purify by silica gel column chromatography, with a gradient from 100% DCM to 5% MeOH in DCM to 5% (2N ammonia in MeOH) in DCM to yield the title compound as a red brown oil (26% yield). LCMS (ES), m/z 251 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:12](OCC)(OCC)OCC.[CH3:22][C:23]1([CH3:31])[O:28][C:27](=[O:29])[CH2:26][C:25](=[O:30])[O:24]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH:12]=[C:26]2[C:27](=[O:29])[O:28][C:23]([CH3:31])([CH3:22])[O:24][C:25]2=[O:30])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCOC(OCC)OCC
Reactant: COc1ccc(N)cc1OC
Product: COc1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
A mixture of 3,4-dimethoxybenzenamine (10 g, 65 mmol) and CH(OC2H5)3 (96.2 g, 650 mmol) in a 500 mL of round-bottom flask was stirred at room temperature for 30 minutes. 2,2-Dimethyl-1,3-dioxane-4,6-dione (9.4 g, 65 mmol) was then added and the reaction mixture was heated at 90° C. for 3.5 h. The reaction solution was cooled at −20° C. overnight. The solid was collected by filtration and washed with 2-methoxy-2-methyl propane (50 mL×3) to afford the title compound as a pale yellow powder (17.1 g, 85.5%).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1B(O)O.Br[C:12]1[CH:13]=[C:14]([C:18]([C:23]2[N:24]=[CH:25][N:26]([C:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:27]=2)([OH:22])[CH:19]([CH3:21])[CH3:20])[CH:15]=[CH:16][CH:17]=1>>[CH3:20][CH:19]([CH3:21])[C:18]([C:14]1[CH:13]=[C:12]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:10])[CH:17]=[CH:16][CH:15]=1)([C:23]1[N:24]=[CH:25][N:26]([C:28]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=1)[OH:22]
Reactant: CC(C)C(O)(c1cccc(Br)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Cc1ccccc1B(O)O
Product: Cc1ccccc1-c1cccc(C(O)(c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C(C)C)c1
Yield: 59.2 %

Procedure:
By the reaction in the same manner as in Example 1-(i) using o-tolylboronic acid (0.69 g) and 1-(3-bromophenyl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.01 g), the amorphous title compound (0.61 g) was obtained.
Reaction SMILES: O[C:2]([C:15]1[C:16](=[O:52])[NH:17][C:18](=[O:51])[N:19]([CH:50]=1)[C@@H:20]1[O:49][C@H:39]([CH2:40][O:41][Si](C(C)(C)C)(C)C)[C@@H:30]([O:31][Si](C(C)(C)C)(C)C)[C@H:21]1[O:22][Si](C(C)(C)C)(C)C)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>ClCCl.C([SiH](CC)CC)C>[C:9]1([CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:15]2[C:16](=[O:52])[NH:17][C:18](=[O:51])[N:19]([CH:50]=2)[C@@H:20]2[O:49][C@H:39]([CH2:40][OH:41])[C@@H:30]([OH:31])[C@H:21]2[OH:22])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C(O)(c3ccccc3)c3ccccc3)c(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1C(c1ccccc1)c1ccccc1
Reaction time: 0.33 h
Yield: 84.2 %

Procedure:
The product of step (i) (8.9 g) was dissolved in dichloromethane (100 ml) and triethylsilane (2 ml). Trifluoroacetic acid (8.9 ml) was added dropwise over 5 minutes and the mixture was stirred for a further 20 minutes. The volatiles were removed under reduced pressure and any residual traces were removed by addition of toluene (50 ml) and evaporation under reduced pressure (three times). The residual gum was treated with tetra-n-butylammonium fluoride (35 ml of a 1M solution in tetrahydrofuran) for 1 hour at room temperature. The volatiles were removed under reduced pressure and the gummy residue purified by silica-gel chromatography eluting with chloroform-methanol mixtures to give 5-diphenylmethyluridine as a white solid (4 g).
Reaction SMILES: CN(C(O[N:9]1N=N[C:11]2[CH:12]=CC=C[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[Si:35]([O:42][CH2:43][C:44]1[C:45]([N+:53]([O-:55])=[O:54])=[C:46]([CH:50]=[CH:51][CH:52]=1)[C:47]([OH:49])=O)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].C(N(CC)C(C)C)(C)C.C(N)C#C>CN(C=O)C.CCOC(C)=O>[Si:35]([O:42][CH2:43][C:44]1[C:45]([N+:53]([O-:55])=[O:54])=[C:46]([CH:50]=[CH:51][CH:52]=1)[C:47]([NH:9][CH2:10][C:11]#[CH:12])=[O:49])([C:38]([CH3:39])([CH3:40])[CH3:41])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(C(=O)O)c1[N+](=O)[O-]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: C#CCN
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CCNC(=O)c1cccc(CO[Si](C)(C)C(C)(C)C)c1[N+](=O)[O-]
Yield: 55 %

Procedure:
HBTU (183 mg, 0.482 mmol) and HOBt (65.1 mg, 0.482 mmol) were added to a stirring solution of Compound 10 (150 mg, 0.482 mmol) in anhydrous DMF (4.82 mL) followed by N,N-diisopropylethylamine (187 mg, 1.45 mmol) and propargyl amine (79.6 mg, 1.45 mmol). The resulting solution was stirred for 30 h at room temperature after which time 25 mL of EtOAc were added and the solution was washed with water (3×10 mL), aqueous saturated NH4Cl (1×10 mL), and brine (1×10 mL). The organic layer was dried over MgSO4, filtered, and concentrated on a rotary evaporator. The resulting oil was purified by silica gel chromatography (50% EtOAc:hexanes) to yield Compound 11 as a white solid (92.3 mg, 55%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][OH:16].CCN(CC)CC.[O:24](S(C1C=CC(C)=CC=1)(=O)=O)[S:25]([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=O)=[O:26]>C(Cl)Cl.[NH4+].[Cl-]>[CH3:32][C:31]1[CH:33]=[CH:34][C:28]([S:25]([O:16][CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)(=[O:26])=[O:24])=[CH:29][CH:30]=1
Reactant: OCc1ccccc1COC1CCCCO1
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCc2ccccc2COC2CCCCO2)cc1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 78.7 %

Procedure:
A solution of {2-[(tetrahydro-2H-pyran-2-yloxy)methyl]phenyl}methanol (5.52 g, 24.84 mmol) in CH2Cl2 (100 ml) was cooled to 0° C. and treated with Et3N (6.92 ml, 49.68 mmol) followed by the addition of Ts2O (8.9 g, 27.33 mmol). The reaction stirred at 0° C. for 3.5 hours. The mixture was diluted with sat. NH4Cl and extracted with CH2Cl12 (2×). The combined organic solutions were washed with water, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by normal phase chromatography (10% EtOAc/hexanes—20%) to give a light brown oil (7.36 g).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH2:59]([NH2:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>C(Cl)Cl.O>[CH2:59]([NH:66][C:24]([CH:21]1[CH2:22][CH2:23][N:18]([C:16]([C:8]2[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:28][CH:27]=3)[C:15]3[C:10]([CH:9]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)=[O:17])[CH2:19][CH2:20]1)=[O:25])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1ccccc1)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Reaction time: 8 h

Procedure:
1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (200 mg, 0.500 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (115 mg, 0.600 mmol), and 1-Hydroxybenzotriazole (81 mg, 0.600 mmol) were dissolved in 10.0 mL of DCM. The reaction was allowed to stir for 10 minutes before N,N-Diisopropylethylamine (131 μL, 0.750 mmol) and benzylamine (82 μL, 0.750 mmol) were added. The reaction was allowed to stir overnight. The reaction was diluted with water and dichloromethane. The layers were separated and the organic layer was washed with water, saturated ammonium chloride, and saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude material was purified using 10 gram silica Biotage column, with the gradient 30% ethyl acetate: hexanes to 100% ethyl acetate. After purification, pure white solid was obtained. Yield: 105 mg (White solid)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:13][CH2:14][CH:15](O)[CH2:16][F:17].[F:19][C:20]1[N:25]=[C:24]2[S:26][C:27]([NH2:29])=[N:28][C:23]2=[CH:22][CH:21]=1>>[F:13][CH2:14][CH:15]([CH2:16][F:17])[O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:29][C:27]1[S:26][C:24]2[C:23]([N:28]=1)=[CH:22][CH:21]=[C:20]([F:19])[N:25]=2
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: Nc1nc2ccc(F)nc2s1
Reactant: OC(CF)CF
Product: FCC(CF)Oc1ccc2ncnc(Nc3nc4ccc(F)nc4s3)c2c1

Procedure:
The compound of Example 29 was manufactured by the same method as in Example 22, by a similar method thereto or by a combination of such a method with a conventional method using 4-chloro-6-hydroxy-quinazoline, 1,3-difluoro-2-propanol and 5-fluoro-thiazolo[5,4-b]pyridin-2-yl-amine.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[C:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:17]=2)=[N:13][CH:14]=1.[CH3:29][C:30]1[C:34]([CH3:35])=[C:33]([NH:36][C:37](=O)[O:38]C2C=CC=CC=2)[O:32][N:31]=1.CC1C(C)=C(N)ON=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=2)[CH:22]=[C:23]2[CH2:24][CH2:25][N:26]([C:37]([NH:36][C:33]3[O:32][N:31]=[C:30]([CH3:29])[C:34]=3[CH3:35])=[O:38])[CH2:27][CH2:28]2)=[N:13][CH:14]=1
Reactant: Brc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: Cc1noc(NC(=O)Oc2ccccc2)c1C
Agent: Cc1noc(N)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1noc(NC(=O)N2CCC(=Cc3cccc(Oc4ccc(Br)cn4)c3)CC2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
5-Bromo-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine trifluoroacetate (0.584 mmol, from Step 5), in acetonitrile (1.75 mL) was treated with phenyl 3,4-dimethylisoxazol-5-ylcarbamate (100 mg, 0.467 mmol, prepared according to the procedure described in Synthesis, 1997, 1189-1194 from 3,4-dimethylisoxazol-5-amine) and diisopropylethylamine (0.305 mL, 1.75 mmol) and stirred at room temperature. After 2 h, the reaction was concentrated and the residue was purified by flash chromatography on silica gel (0-6% ethanol (containing 11% aq NH4OH):dichloromethane) to afford a clear oil which was evaporated from isopropyl ether/dichloromethane and evaporated again from diethyl ether/dichloromethane to give the title compound (0.200 g, 96% yield) as a white foam. MS (APCI) M+1=483.1; 1H NMR (400 MHz, CDCl3) δ ppm 1.89 (s, 3H) 2.20 (s, 3H) 2.43-2.49 (m, 2H) 2.56-2.62 (m, 2H) 3.45-3.52 (m, 2H) 3.56-3.62 (m, 2H) 6.41 (br. s, 1H) 6.61 (br. s, 1H) 6.86 (dd, J=8.68, 0.49 Hz, 1H) 6.95-7.02 (m, 2H) 7.04-7.09 (m, 1H) 7.37 (t, J=7.90 Hz, 1H) 7.79 (dd, J=8.58, 2.53 Hz, 1H) 8.22-8.24 (m, 1H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([O:18][CH:19]([O:24][CH2:25][CH3:26])[CH2:20][CH2:21][CH2:22][NH2:23])[CH3:17].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:25]([O:24][CH:19]([O:18][CH2:16][CH3:17])[CH2:20][CH2:21][CH2:22][NH:23][C:13]([N:10]1[CH2:11][CH2:12][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1)=[O:14])[CH3:26]
Reactant: O=C(Cl)N1CCC(c2ccccc2)CC1
Reactant: CCOC(CCCN)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(CCCNC(=O)N1CCC(c2ccccc2)CC1)OCC
Reaction time: 8 h

Procedure:
A solution of 895 mg (4 mmol) of 4-phenylpiperidine-1-carbonylchloride in 4 mL dichloromethane is added to 0.69 mL (4 mmol) 4,4-diethoxybutylamine and 1.68 mL (12 mmol) of triethylamine dissolved in 20 mL of dichloromethane. The mixture is stirred overnight. 20 mL of saturated sodium carbonate solution is added. The organic phase is separated, dried with sodium sulfate and the solvent evaporated.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([NH:14][C:15](OC3C=CC=CC=3)=[S:16])[C:11]([N:24]3[CH2:29][CH2:28][CH:27]([CH3:30])[CH2:26][CH2:25]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>O1CCOCC1>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([NH:14][C:15]([N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)=[S:16])[C:11]([N:24]3[CH2:29][CH2:28][CH:27]([CH3:30])[CH2:26][CH2:25]3)=[CH:10][C:8]=2[N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN1CCNCC1
Reactant: CC1CCN(c2cc3nc(C(C)(C)C)sc3cc2NC(=S)Oc2ccccc2)CC1
Solvent: C1COCCO1
Product: CC1CCN(c2cc3nc(C(C)(C)C)sc3cc2NC(=S)N2CCN(C)CC2)CC1

Procedure:
A solution of 0.5 g of 2-tert-butyl-5-(4-methyl-piperidin-1-yl)-6-phenoxythiocarbonylaminobenzothiazole and 0.11 g of 4-methylpiperazine in 20 ml of dioxane is refluxed for 16 hours. Evaporation of the solvent and chromatography of the residue over silica gel and elution with methylene dichloride-methanol (98:2) gives 2-tert-butyl-6-[(4-methylpiperazin-1-yl)thiocarbonylamino]-5-(4-methylpiperidin-1-yl)benzothiazole, identical with the compound described in Example 1.