Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[CH:8]=[C:9]([C:17]([OH:19])=O)[CH:10]=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.COC1C=CC=C2C=1OC1C=C(C(O)=O)C=CC=1C2=O.BrC1C=CC=C2C=1OC1C=C(C(O)=O)C=CC=1C2=O.CN(C(ON1N=N[C:69]2C=[CH:71][CH:72]=[N:73][C:68]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH2:72]([N:73]([CH2:68][CH3:69])[C:17]([C:9]1[CH:10]=[CH:11][C:12]2[C:13](=[O:16])[C:14]3[C:5]([O:6][C:7]=2[CH:8]=1)=[CH:4][CH:3]=[C:2]([F:1])[CH:15]=3)=[O:19])[CH3:71]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc2c(=O)c3cc(F)ccc3oc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: COc1cccc2c(=O)c3ccc(C(=O)O)cc3oc12
Agent: F[P-](F)(F)(F)(F)F
Product: CCN(CC)C(=O)c1ccc2c(=O)c3cc(F)ccc3oc2c1

Procedure:
Using an adaptation of the method described in Procedure 16, substituting 7-fluoro-9-oxo-9H-xanthene-3-carboxylic acid, 3e for 5-methoxy-9-oxo-9H-xanthene-3-carboxylic acid, 3d, and HATU for HBTU, the title compound 7-fluoro-9-oxo-9H-xanthene-3-carboxylic acid diethylamide, 4e was obtained. MS m/z (MH+) 314.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH:12]([N:15](C(C)C)CC)(C)C.Cl.CN>O1CCCC1>[CH3:12][NH:15][C:1](=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)c1ccccc1OC
Reaction time: 1 h

Procedure:
Combine o-anisoyl chloride (2-methoxybenzoyl chloride) (2.9 g, 17.0 mmol) and tetrahydrofuran (170 mL) and cool to 0° C. Add diisopropylethylamine (5.92 mL, 34 mmol). Add methylamine hydrochloride (1.26 g, 18.7 mmol). Allow to stir for 1 hour and concentrate in vacuo. Chromatograph on silica gel eluting sequentially with 50% ethyl acetate/hexane to give N-methyl-2-methoxybenzamide: TLC Rf =0.45 (silica gel, 50% ethyl acetate/hexane).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4]([OH:6])=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1.CO[C:23](OC)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>C1(C)C=CC=CC=1>[CH3:7][C:3]1([C:4]([OH:6])=[O:5])[CH2:8][O:9][C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:1][CH2:2]1
Reactant: COC(OC)(c1ccccc1)c1ccccc1
Reactant: CC(CO)(CO)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C(=O)O)COC(c2ccccc2)(c2ccccc2)OC1
Temperature: 27.5 °C
Reaction time: 3 h

Procedure:
In a round bottom flask, (12 g) 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoic acid and 35 ml toluene was taken. (99.4 mg) p-toluene sulfonic acid was added into the reaction mixture at 25-30° C. temperature. The reaction mixture was heated at reflux temperature, and 20.5 g (1 equiv.) dimethoxy diphenylmethane [IIa3] in 35 ml toluene was added and it was further refluxed under dean stark. Continuous removal and addition of toluene done upto 3 hrs. Then reaction mixture was cooled at 25-30° C. and dumped into water. The reaction mixture was stirred at 20-30° C. and filter it and wash the solid mass with water to obtain white solid product.
Reaction SMILES: [CH3:1][C@@H:2]([OH:5])[CH2:3][CH3:4].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.N1C=CC=CC=1.ClCCl>CN(C)C1C=CN=CC=1.O>[CH3:1][C@@H:2]([OH:5])[CH2:3][CH3:4].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O-:15])(=[O:5])=[O:14])=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: CC[C@@H](C)O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)([O-])c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67 %

Procedure:
A mixture of 8.2 g of (R)-(-)2-butanol, 31.5 g of 1-bromo-4-benzenesulfonyl chloride, 1.0 g of N,N-dimethyl-4-pyridinamine, 55.5 ml of pyridine and 293 ml of dichloromethane was stirred for 3 days at room temperature. After the addition of water, stirring was continued for 1 hour. The reaction mixture was washed twice with a diluted hydrochloric acid solution and once with water, dried, filtered and evaporated in vacuo. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated, yielding 11.5 g (35.6%) of (R)-2-butanol 4-bromobenzenesulfonate (ester) (interm. 3).
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:21](=[O:54])[N:22]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33](=[O:53])[CH2:34][NH:35][C:36]([O:38][CH2:39][CH:40]1[C:52]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[C:46]2[C:41]1=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37])[CH3:23])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)C)(C)(C)C>Cl.C(OCC)(=O)C>[CH:42]1[C:41]2[CH:40]([CH2:39][O:38][C:36](=[O:37])[NH:35][CH2:34][C:33](=[O:53])[NH:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[CH2:25][CH2:24][N:22]([CH3:23])[C:21](=[O:54])[C@H:9]([NH:7][CH3:6])[CH2:10][C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=3)[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:46]=2[CH:45]=[CH:44][CH:43]=1
Reactant: CN(CCc1ccccc1NC(=O)CNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)CCc1ccccc1NC(=O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 117.6 %

Procedure:
N-{(1R)-1-[N-(2-{2-[2-((Fluoren-9-ylmethoxycarbonyl)amino)acetylamino]phenyl}ethyl)-N-methylcarbamoyl]-2-(2-naphthyl)ethyl}-N-methylcarbamic acid tert-butyl ester (1.18 g, 1.59 mmol) was dissolved in 3.0 M hydrogen chloride in ethyl acetate (8 ml). The reaction mixture was stirred for 2.25 h at room temperature. The solvent was removed in vacuo. The residue was washed with diethyl ether (3×20 ml) and dried in vacuo to give 1.198 g of crude [(2-{2-[N-methyl-N-((2R)-2-methylamino-3-(2-naphthyl)propionyl)amino]ethyl}phenylcarbamoyl)methyl]carbamic acid (fluoren-9-yl)methyl ester as hydrochloride, which was used for the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([N+:16]([O-:18])=[O:17])=[N:11][CH:12]=[C:13](Br)[N:14]=1.[NH2:19][CH2:20][CH2:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:19][CH2:20][CH2:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=2)[CH:12]=[N:11][C:10]=1[N+:16]([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ncc(Br)nc1-c1ccc(Cl)cc1Cl
Reactant: NCCNc1ccc([N+](=O)[O-])cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(NCCNc2cnc([N+](=O)[O-])c(-c3ccc(Cl)cc3Cl)n2)nc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of 3-(2,4-dichlorophenyl)-5-bromo-2-nitropyrazine (20 mg, 0.057 mmol) in DMF (1 ml), (2-aminoethyl)(5-nitro(2-pyridyl))amine (11.3 mg, 0.06 mmol) and diisopropylethyl amine (40 μl, 0.228 mmol) were added. The reaction mixture was stirred for 12 hours at 80° C. The crude mixture was concentrated in vacuo and subjected to column chromatography (5% methanol in methylene chloride) to afford the title compound as bright yellow solid.
Reaction SMILES: [OH-].[Na+].[C:3]1([CH3:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[NH:11]1[CH:15]=[C:14]([C:16]2([CH2:25][OH:26])[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17]2)[N:13]=[CH:12]1.C(Cl)C1C=CC=CC=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:9]([N:11]1[CH:15]=[C:14]([C:16]2([CH2:25][OH:26])[CH2:17][C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:24]2)[N:13]=[CH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccccc1
Reactant: OCC1(c2c[nH]cn2)Cc2ccccc2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: ClCc1ccccc1
Solvent: O
Product: OCC1(c2cn(Cc3ccccc3)cn2)Cc2ccccc2C1
Reaction time: 2 h

Procedure:
0,0237 g of tetrabutylammonium bromide, 1 ml of 48% NaOH, 5 ml of toluene, 0,58 g of [2,3-dihydro-2-(1H-imidazol-4-yl)-1H-inden-2-yl]methanol hydrochloride prepared according to example 9a and 0,30 g of benzyl chloride were combined. The mixture was stirred for 2 h at 60°-70° C. Then the mixture was cooled and water was added, toluene was evaporated and the aqueous solution was made acidic while cooling simultaneously. The acid solutation was washed with ether and the product separated as an oily layer. The product was extracted in methylene chloride as hydrochloride.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]([CH3:8])([SH:7])[CH3:6].Br[CH2:10][C:11]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]>CO>[CH3:4][C:5]([CH3:8])([S:7][CH2:10][C:11]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14])[CH3:6]
Reactant: CC(C)(C)S
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1CSC(C)(C)C
Yield: 92 %

Procedure:
To a solution of 34.7 g of sodium methoxide in 600 ml methanol was added 57.9 g of 1,1-dimethylethanethiol below 25°. The resulting solution was stirred one hour before the portionwise addition of 172.7 g of methyl 2-bromomethyl-3-nitrobenzoate. The resulting suspension was refluxed two hours. The mixture was cooled, and the solvent evaporated in vacuo. The residual oil was partitioned between ether and water. The organic solution was washed twice with 2.5% sodium hydroxide solution, twice with water, followed by brine, then dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo to give 164.2 g of crude methyl 2-[(1,1-dimethylethylthio)methyl]-3-nitrobenzoate as an oil.
Reaction SMILES: C1S[C:4]([C:6]23[C:14](=O)[CH:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9][N:8]([CH3:16])[CH:7]3CC)([O-:5])SC1.[CH2:20]([OH:22])[CH3:21]>[Ni]>[CH2:20]([O:22][C:4]([C:6]12[CH2:14][CH:10]([CH2:11][CH2:12][CH2:13]1)[CH2:9][N:8]([CH3:16])[CH2:7]2)=[O:5])[CH3:21]
Reactant: CCC1N(C)CC2CCCC1(C1([O-])SCCS1)C2=O
Reactant: CCO
Agent: [Ni]
Product: CCOC(=O)C12CCCC(CN(C)C1)C2

Procedure:
2.42 g of ethyl(3-methyl-9-oxo-3-azabicyclo[3.3.1]non-1-yl)carboxylate ethylenedithioketal was dissolved in ethanol (200 ml). After adding 40 g of Raney nickel, the resulting mixture was heated under reflux for 2 hours. Then the reaction mixture was filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluted with toluene/ethyl acetate) to thereby give 0.95 g of the title compound as a slightly yellow oily substance.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH:7]1[CH2:12][CH2:11][N:10](C(OCC2C=CC=CC=2)=O)[CH2:9][CH2:8]1)=[CH2:6])C.Cl>O1CCOCC1>[NH:10]1[CH2:11][CH2:12][CH:7]([C:5](=[CH2:6])[C:4]([OH:23])=[O:3])[CH2:8][CH2:9]1
Reactant: C=C(C(=O)OCC)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C=C(C(=O)O)C1CCNCC1
Temperature: 100 °C
Yield: 115.1 %

Procedure:
To a solution of 2-(1-benzyloxycarbonylpiperidin-4-yl)prop-2-enoic acid ethyl ester (0.40 g, 1.4 mmol) in 1 mL of dioxane was added 5 mL of 6 N HCl. The solution was heated to 100° C. for 18 hours. The reaction mixture was evaporated in vacuo to afford 2-(piperidin-4-yl)prop-2-enoic acid (0.25 g, 100%) as a hydrogen chloride salt.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:17]O>OS(O)(=O)=O>[CH3:17][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=[C:2]([OH:1])[CH:3]=1
Reactant: O=C(O)c1cc(O)cc(N2CCCC2=O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(O)cc(N2CCCC2=O)c1
Temperature: 25 °C
Yield: 74 %

Procedure:
3-Hydroxy-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid (D36) (400 mg, 1.72 mmol, 1 equiv) was heated at reflux in a mixture of MeOH (20 ml) and concentrated H2SO4 (4 drops) for 7 h. The solution was then cooled to room temperature and concentrated in vacuo to give of 3-hydroxy-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (D37) (300 mg, 74%) as a light brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24]#[N:25])[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(=O)(O)[O-:27].[Na+]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24]([NH2:25])=[O:27])[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=C([O-])O
Reactant: COc1ccc2c(OCc3nnc4ccc(C#N)cn34)ccnc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COc1ccc2c(OCc3nnc4ccc(C(N)=O)cn34)ccnc2c1
Temperature: 50 °C
Yield: 95 %

Procedure:
3-((7-Methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile (0.050 g, 0.15 mmol) was dissolved in concentrated sulfuric acid (0.5 mL). The reaction mixture was heated at 50° C. for 30 minutes. The reaction mixture was slowly poured in to cold saturated aqueous sodium bicarbonate. A precipitate formed which was collected on a glass frit, washing with water. The solid was transferred with dichlororethane/methanol to a flask and dried under high vacuum to afford 3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide (0.050 g, 95% yield) as a tan solid.
Reaction SMILES: [CH2:1]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH2:5][CH2:4][N:3]2[CH2:13][CH2:14][CH2:15][CH2:16][CH:2]12.[ClH:17].CN(C)CCCN=C=NCC.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:35]=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[NH2:34].C(N(C(C)C)CC)(C)C>ClCCl.Cl>[ClH:17].[ClH:17].[CH2:1]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([NH:34][C:33]2[CH:35]=[C:36]([O:40][CH3:41])[C:37]([O:38][CH3:39])=[C:31]([O:30][CH3:29])[CH:32]=2)=[O:12])[CH2:5][CH2:4][N:3]2[CH2:13][CH2:14][CH2:15][CH2:16][CH:2]12
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=C(O)CCCN1CCN2CCCCC2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NC(=O)CCCN2CCN3CCCCC3C2)cc(OC)c1OC

Procedure:
1.2 g of the compound obtained in Step B, 1.05 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.92 g of 3,4,5-trimethoxyaniline in solution in 50 ml of dichloromethane and 1.75 ml of diisopropylethylamine are stirred, under argon, for 24 hours at room temperature. The reaction mixture is washed with 50 ml of water, decanted, dried over Na2SO4 and concentrated under a partial vacuum. The hydrochloride is then prepared in 20 ml of ethanol and 2 ml of an ethereal hydrogen chloride solution, enabling the expected product to be obtained.
Reaction SMILES: [O-][N+:2]1[CH:31]=[CH:30][C:5]2[N:6]=[C:7]3[CH2:12][C@H:11]([C:13]4[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=4[F:21])[C@@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:9][N:8]3[C:4]=2[CH:3]=1.O(Cl)[Cl:33].[P+3]>C(Cl)(Cl)Cl>[Cl:33][C:3]1[C:4]2[N:8]3[CH2:9][C@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C@@H:11]([C:13]4[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=4[F:21])[CH2:12][C:7]3=[N:6][C:5]=2[CH:30]=[CH:31][N:2]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1Cn2c(nc3cc[n+]([O-])cc32)C[C@@H]1c1cc(F)c(F)cc1F
Reactant: ClOCl
Agent: [P+3]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@H]1Cn2c(nc3ccnc(Cl)c32)C[C@@H]1c1cc(F)c(F)cc1F
Temperature: 25 °C

Procedure:
To the product of Step A in 1.5 mL of chloroform was added 0.008 mL (0.09 mmol) of phosphorus(III) oxychloride and the resultant mixture was refluxed for 1.5 h. The reaction mixture was cooled to ambient temperature, diluted with chloroform (10 mL), and sequentially washed with saturated aqueous sodium bicarbonate solution (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude oil was purified by preparative thin layer chromatography using an Analtech® 1000 micron plate (4% methanol/ethyl acetate) to give the title compound as a viscous oil. LC/MS 453.0 (M+1), 454.8 (M+2).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][CH:16]=[C:17]([CH2:19][OH:20])[N:18]=2)=[CH:10][CH:9]=1.[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][OH:39])=[CH:32][CH:31]=2)[C:25]([C:40]#[N:41])=[C:24](SC2C=CC=CC=2)[N:23]=1.O>C(COC)OC.C(O)(=O)C>[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26]([C:30]2[CH:31]=[CH:32][C:33]([O:36][CH2:37][CH2:38][OH:39])=[CH:34][CH:35]=2)[C:25]([C:40]#[N:41])=[C:24]([O:20][CH2:19][C:17]2[N:18]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][CH:12]=3)[O:15][CH:16]=2)[N:23]=1
Reactant: OCc1coc(-c2ccc(Cl)cc2)n1
Reactant: N#Cc1c(N)nc(Sc2ccccc2)c(C#N)c1-c1ccc(OCCO)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: COCCOC
Solvent: O
Product: N#Cc1c(N)nc(OCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
72 mg (0.64 mmol) of potassium tert-butoxide were suspended in 1 ml of dry dimethoxyethane. 270 mg (1.29 mmol) of [2-(4-chlorophenyl)-1,3-oxazol-4-yl]methanol and 50 mg (0.13 mmol) of the compound from Example 48A were then added in succession. The reaction mixture was stirred at 60° C. for 2 h and then cooled to RT and stirred at this temperature for 8 h. 5 ml of water and 1 ml of 2N acetic acid were added to the reaction mixture. A precipitate is formed, which was filtered off with suction. The residue was purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). Removal of the solvent on a rotary evaporator gave the product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([CH2:19][C:20]([O:22]CC)=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][C:12]=3[N:11]=[C:10]2[CH:25]([CH3:27])[CH3:26])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([CH2:19][C:20]([OH:22])=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][C:12]=3[N:11]=[C:10]2[CH:25]([CH3:27])[CH3:26])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC1CCCCc2nc(C(C)C)n(Cc3ccc(Cl)cc3)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(CC(=O)O)CCCC2
Reaction time: 1 h
Yield: 60.8 %

Procedure:
Intermediate 5 (94 mg) was dissolved in methanol (2 ml) and treated with sodium hydroxide, 2 M aq. (2 ml). The RM was left in solution for 1 hour. The RM was concentrated under vacuum. The residue was purified by MDAP (Method A). The desired fractions were combined and concentrated under nitrogen blowdown to give the title compound (53 mg). LC/MS MH+ 361, Rt 1.63 min (5 minute run).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:22]=[CH:21][C:8]2[N:9]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[S:11][C:7]=2[CH:6]=1)=[NH:4].[C:23](Cl)(=O)[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>C(O)(=O)C>[CH:18]([N:15]1[CH2:14][CH2:13][N:12]([C:10]2[S:11][C:7]3[CH:6]=[C:5]([C:3]4[N:4]=[C:23]([C:24]5[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=5)[O:1][N:2]=4)[CH:22]=[CH:21][C:8]=3[N:9]=2)[CH2:17][CH2:16]1)([CH3:19])[CH3:20]
Reactant: O=C(Cl)c1ccncc1
Reactant: CC(C)N1CCN(c2nc3ccc(C(=N)NO)cc3s2)CC1
Solvent: CC(=O)O
Product: CC(C)N1CCN(c2nc3ccc(-c4noc(-c5ccncc5)n4)cc3s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.6 %

Procedure:
To a solution of N-hydroxy-2-(4-isopropylpiperazin-1-yl)benzothiazole-6-carboxamidine (1.30 g, 4.07 mmol) in acetic acid (50 mL) was added isonicotinoyl chloride (1.42 g, 10.0 mmol). The reaction mixture was stirred overnight at room temperature and then heated at refluxed for 8 h. The reaction mixture was concentrated in vacuo and the residue was dissolved into 0.5 N hydrochloric acid (40 mL). The aqueous solution was extracted with diethyl ether (3×15 mL). The organic extracts were discarded and the aqueous phase was basified to pH 13 with 4 N sodium hydroxide and then extracted with ethyl acetate (4×10 mL). The combined organic extracts were evaporated and the residue was recrystallized from a mixture of CH2Cl2 and MeOH to give 175 mg (11%) of 2-(4-isopropylpiperazin-1-yl)-6-(5-pyridin-4-yl-[1,2,4]oxadiazol-3-yl)benzothiazole.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](OS(C(F)(F)F)(=O)=O)=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2ccc(Cl)cc2c1Cc1ccccc1Cl
Product: CCOC(=O)c1c(N2CCCCC2)nc2ccc(Cl)cc2c1Cc1ccccc1Cl

Procedure:
This compound was prepared in analogy to example 29 step D from 6-chloro-4-(2-chloro-benzyl)-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid ethyl ester (prepared as described in example 29 step C, 100 mg, 0.2 mmol) and piperidine (0.039 ml, 0.39 mmol). Pale yellow solid (52 mg, 60%). LC-MS (ESI): 443 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][CH2:29][C:30](OC)=[O:31])[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[CH3:34][NH:35][CH2:36][CH2:37][OH:38]>>[OH:38][CH2:37][CH2:36][N:35]([CH3:34])[C:30](=[O:31])[CH2:29][O:28][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[C:18]([NH:17][C:13]1[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[N:9]=[CH:10]3)=[N:19][CH:20]=[N:21]2
Reactant: CNCCO
Reactant: COC(=O)COc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Product: CN(CCO)C(=O)COc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Yield: 59.7 %

Procedure:
Using the same procedure as in Example 5, methyl [(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]acetate (200 mg, 0.45 mmol) was reacted with 2-(methylamino)ethanol (0.219 ml, 2.73 mmol) to give the title compound as a white solid (130 mg, 59%), except that the reaction was run at 45° C. for 18 hours. NMR Spectrum (2 rotamers, ratio 2/1) 2.97 and 3.08 (s, 3H), 3.62-3.43 (m, 4H), 4.73 and 4.99 (t, 1H), 5.16 and 5.23 (s, 2H), 5.77 (s, 2H), 6.96 (d, 1H), 7.37-7.18 (m, 3H), 7.75-7.69 (m, 3H), 7.90 (m, 1H), 8.15 (s, 1H), 8.53 (m, 2H), 8.57 (s, 1H), 11.20 and 11.21 (br s, 1H); Mass spectrum MH+ 484.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:5]=[N:4]1)[CH3:2].BrC1C=NN([C:23]2[CH:28]=CC=[CH:25][CH:24]=2)C=1>>[C:1]1([N:3]2[CH:7]=[C:6]([B:8]3[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:15])([CH3:16])[O:9]3)[CH:5]=[N:4]2)[CH:25]=[CH:24][CH:23]=[CH:28][CH:2]=1
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1cnn(-c2ccccc2)c1
Product: CC1(C)OB(c2cnn(-c3ccccc3)c2)OC1(C)C

Procedure:
The title compound was prepared in the same manner as 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole starting with 4-bromo-1-phenyl-1H-pyrazole.