Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[O:11])=[CH:5][CH:4]=1.[NH2:22][C@@H:23]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[OH:37][C:34]1[CH:33]=[CH:32][C:31]([C@H:23]([NH:22][C:17](=[O:19])[C:16]2[CH:15]=[CH:14][C:13]([NH:12][C:10](=[O:11])[CH2:9][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)[C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])=[CH:36][CH:35]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)O)cc2)cc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)c1ccc(O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N[C@H](C(=O)OC(C)(C)C)c3ccc(O)cc3)cc2)cc1
Reaction time: 2 h
Yield: 100 %

Procedure:
Prepared using General Procedure 6: To a stirred solution of 4-(2-(4-methoxyphenyl)acetamido)benzoic acid INT-12 (500 mg, 1.75 mmol) and (S)-tert-butyl 2-amino-2-(4-hydroxyphenyl)acetate (391 mg, 1.75 mmol) in DMF (10 mL) was added TEA (611 μL, 4.38 mmol) and HATU (700 mg, 1.84 mmol). After stirring for 2 h the reaction was diluted with EA (10 mL) and washed with brine (2×100 mL). The crude material was purified by chromatography (EA/hexanes) to give 860 mg (100%) of (S)-tert-butyl 2-(4-hydroxyphenyl)-2-(4-(2-(4-methoxyphenyl)acetamido)benzamido)acetate INT-13. LCMS-ESI (m/z) calculated for C28H30N2O6: 490; found 489, [M−H]−, tR=2.14 min (Method 4).
Reaction SMILES: C(O[K])(C)(C)C.F[C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][OH:30].Cl>C1COCC1.CCOC(C)=O>[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1cccnc1F
Reactant: COCCOCCOCCOCCO
Agent: CC(C)(C)O[K]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCOCCOCCOCCOc1ncccc1C(=O)O
Temperature: 100 °C
Yield: 89.9 %

Procedure:
A solution of tBuOK in THF (20% wt, 561.0 uL, 1.0 mmol) was added to a mixture of 2-fluoronicotinic acid (70.6 mg, 0.50 mmol) and tetraethyleneglycol monomethyl ether (105.5 μL, 0.50 mmol) in THF (2.0 mL) at ambient temperature under N2. The mixture was heated at 100° C. for 3 h. The reaction mixture was diluted with EtOAc. The organic phase was acidified with 1 N HCl solution, washed with saturated NaCl solution, then dried over Na2SO4. Filtration and concentration in vacuo provided compound D as light yellow liquid (148.1 mg, 90%) for next step without further purification. ESMS: 330.0 [M+H]+, 352.0 [M+Na]+, 368.0 [M+K]+.
Reaction SMILES: CS([O:5][C:6]1[C:11]([S:12](Cl)(=[O:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:16])(=O)=O.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([NH:21][S:12]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:16])[C:6]=1[OH:5])(=[O:14])=[O:13])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)N
Reactant: CS(=O)(=O)Oc1c(Cl)cccc1S(=O)(=O)Cl
Product: CC(C)(C)NS(=O)(=O)c1cccc(Cl)c1O

Procedure:
2-Chloro-6-chlorosulfonylphenyl methanesulfonate was treated with t-butylamine and then base to give N-t-butyl 3-chloro-2-hydroxybenzenesulfonamide. Without purification, this material was nitrated using nitric acid in acetic acid to give N-t-butyl 3-chloro-2-hydroxy-5-nitrobenzenesulfonamide. Using sodium dithionite, this compound was reduced to give the aminophenol. The hydrochloride salt of this has also been prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7](=[O:13])[CH:6]=[C:5]2[CH2:14]Cl.BrC1C=C2C(=CC=1O)[O:23][C:22](=[O:28])[CH:21]=C2CCl>>[C:22]([O:28][CH2:14][C:5]1[C:4]2[C:9](=[CH:10][C:11]([OH:12])=[C:2]([Cl:1])[CH:3]=2)[O:8][C:7](=[O:13])[CH:6]=1)(=[O:23])[CH3:21]
Reactant: O=c1cc(CCl)c2cc(Cl)c(O)cc2o1
Reactant: O=c1cc(CCl)c2cc(Br)c(O)cc2o1
Product: CC(=O)OCc1cc(=O)oc2cc(O)c(Cl)cc12
Yield: 28 %

Procedure:
This compound was prepared by the same method as compound 5, starting with compound 12 rather than compound 11, to yield 75.4 mg (0.281 mmol, 28% yield) of compound 4 as an oil. 1H NMR (CDCl3+5% CD3OD) δ 7.43 (1H, s), 6.85 (1H, s), 6.25 (1H, s), 5.16 (2H, s), 3.30 (1H, s), 2.14 (3H, s); MS (ES, negative) 267.2 and 269.1; UV (KMOPS, pH 7.2) λmax (ε) 370 nm (16,000 M−1cm−1). ps 3,6,8-Tribromo-4-chloromethyl-7-hydroxycoumarin (13).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:23][OH:24]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][C:18](=[N:23][OH:24])[CH2:17][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(CCCCCCOCc2ccccc2)CC1
Reactant: NO
Agent: Cl
Product: ON=C1CCN(CCCCCCOCc2ccccc2)CC1

Procedure:
1-(6-Benzyloxyhexyl)-4-piperidone oxime is prepared from 1-(6-benzyloxyhexyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]2[N:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[N:17]=[C:16]([C:25]([OH:27])=O)[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C([N:49]3[CH2:54][CH2:53][NH:52][C:51](=[O:55])[CH2:50]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]2[N:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[N:17]=[C:16]([C:25]([N:49]3[CH2:54][CH2:53][NH:52][C:51](=[O:55])[CH2:50]3)=[O:27])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:13])([F:11])[F:12])[CH:8]=1
Reactant: COc1cc(OC(F)(F)F)cc(-c2cc(C(=O)O)nn2-c2cccnc2)c1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cccnc3)n2)CCN1
Agent: O=C1CNCCN1
Product: COc1cc(OC(F)(F)F)cc(-c2cc(C(=O)N3CCNC(=O)C3)nn2-c2cccnc2)c1

Procedure:
50 mg (0.13 mmol) of the compound of Example 56A is reacted analogously to the synthesis of the compound of Example 4 with 14 mg (0.14 mmol) of 2-oxopiperazine. 54 mg (89% of theory) of the title compound is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15](C(OC(C)(C)C)=O)[C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.[N:31]1([C:35]([C:37]2[CH:38]=[CH:39][C:40](Cl)=[N:41][CH:42]=2)=[O:36])[CH2:34][CH2:33][CH2:32]1.[H-].[Na+].Cl>CS(C)=O>[N:31]1([C:35]([C:37]2[CH:38]=[CH:39][C:40]([O:1][C:2]3[CH:3]=[C:4]([C:14]4[NH:15][C:16]([C:19]5[S:20][CH:21]=[CH:22][N:23]=5)=[CH:17][CH:18]=4)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=3)=[N:41][CH:42]=2)=[O:36])[CH2:34][CH2:33][CH2:32]1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Reactant: O=C(c1ccc(Cl)nc1)N1CCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cn2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
t-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (84 mg, 0.195 mmol) synthesized in Example (38d) and 5-(azetidin-1-ylcarbonyl)-2-chloropyridine (110 mg, 0.559 mmol) synthesized in Example (59a) were dissolved in dimethyl sulfoxide (3.0 mL), and sodium hydride (60%, 30 mg, 0.75 mmol) was added, followed by stirring at 100° C. for 2 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, 2N hydrochloric acid (30 mL) was added, and extraction was carried out with ethyl acetate (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=75%-90%) to afford the desired compound (56 mg, yield 59%) as a yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[NH:2]1[CH:3]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([N:32]5[CH2:33][CH2:34][N:29]([C:24]6[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=6)[CH2:30][CH2:31]5)=[O:20])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:5]=[N:1]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: c1ccc(N2CCNCC2)nc1
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCN(c2ccccn2)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 1-(pyridine-2-yl)piperazine (1.2 equiv) to give 168 (19.8 mg, M+1 459.1)
Reaction SMILES: OC[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH:17]=O.S(=O)(=O)(O)O.[Cl:28][C:29]1[CH:30]=[C:31]([CH:45]=[CH:46][C:47]=1[Cl:48])[CH:32]=[C:33]([C@@H:35]([C@H:37]([C@@H:39]([C@@H:41]([CH2:43][OH:44])[OH:42])[OH:40])[OH:38])[OH:36])[OH:34]>>[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH:17]=[C:43]([OH:44])[C@@H:41]([OH:42])[C@@H:39]([OH:40])[C@H:37]([OH:38])[C@@H:35]([OH:36])[C:33](=[CH:32][C:31]1[CH:45]=[CH:46][C:47]([Cl:48])=[C:29]([Cl:28])[CH:30]=1)[OH:34]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=Cc1ccc(Cl)c(Cl)c1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Agent: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Product: OC(=Cc1ccc(Cl)c(Cl)c1)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=Cc1ccc(Cl)c(Cl)c1
Temperature: 21 °C
Reaction time: 6 h
Yield: 0.5 %

Procedure:
A 500 ml four-necked flask was charged with a 70 wt % aqueous solution of 52 g (0.20 mole) of D-sorbitol, 35.0 g (0.20 mole) of 3,4-dichlorobenzaldehyde and 6 g of 50 wt % sulfuric acid. The air inside the system was replaced with nitrogen gas. The contents of the flask were stirred at a temperature of 21° C. for 6 hours. The obtained reaction mixture was analyzed by GC. It was found that mono(3,4-dichlorobenzylidene)-D-sorbitol was produced in a yield of 70% and 0.5% or less of bis(3,4-dichlorobenzylidene)-D-sorbitol was also produced. After standing for 24 hours, the reaction mixture was neutralized for 2 hours using 8.6 g of potassium hydroxide, and filtered to obtain cake. The cake was dispersed in 150 ml of toluene and was filtered again. After drying at 100° C. under a pressure ranging from normal pressure to 5 mmHg for 7 hours, 19.7 g of 2,4-O-(3,4-dichlorobenzylidene)-D-sorbitol was obtained with a purity of 99.2% as measured by GC (yield 29.2%). The product had a melting point of 202 to 205° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:19][CH:18]=2)[C:12](=[O:30])[C:11]1=[O:31])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:32]([O:38][CH2:39]Cl)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>CN(C)C=O>[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH2:39][O:38][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[C:24]3[N:25]=[CH:26][CH:27]=[CH:28][N:29]=3)=[CH:19][CH:18]=2)[C:12](=[O:30])[C:11]1=[O:31])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C1C(=O)N(Cc2ccc(Nc3ncccn3)cc2)CCN1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCN(c1ccc(CN2CCN(Cc3ccccc3)C(=O)C2=O)cc1)c1ncccn1
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
To a mixture of 372 mg of sodium hydride (purity 50%) and 30 ml of N,N-dimethylformamide was added dropwise a solution of 3 g of 1-benzyl-4-[4-(2-pyrimidinylamino)benzyl]-2,3-dioxopiperazine in 20 ml of N,N-dimethylformamide with stirring over 30 min., after which the resulting mixture was subjected to reaction at 60° to 70° C. for one hour. After the completion of the reaction, 1.3 g of pivaloyloxymethyl chloride was dropped thereinto over 10 min. at the same temperature. After the completion of the dropwise addition, the resulting mixture was subjected to reaction at 70° to 80° C. for 30 min. After the completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was extracted with 100 ml of chloroform. The chloroform layer was washed with 30 ml of water and 40 ml of saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (Wakogel C-200, eluted with chloroform), and then recrystallized from ethyl acetate-diisopropyl ether, to obtain 2.5 g (64.3% yield) of 1-benzyl-4-{4-[N-pivaloyloxymethyl-N-(2-pyrimidinyl)amino]benzyl}-2,3-dioxopiperazine having a melting point of 144° to 146° C.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[CH2:5]([C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[CH2:6][CH3:7].[OH-].[K+]>C(O)C.O>[OH:4][CH2:3][CH2:2][O:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:11]2[CH2:10][CH2:9][C@H:8]([CH2:5][CH2:6][CH3:7])[CH2:13][CH2:12]2)=[CH:15][CH:16]=1
Reactant: CCC[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Reactant: OCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC[C@H]1CC[C@H](c2ccc(OCCO)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Bromo-1-ethanol (5.0 g, 0.04 mol) and 4-(trans-4-propylcyclohexyl)phenol (4.4 g, 0.02 mol) were dissolved in ethanol (300 ml) and agitated at room temperature. To this solution was gradually dropwise added a solution of KOH (10 g) in water (20 ml), over 30 minutes, followed by stirring for 40 hours, distilling off about 200 ml of ethanol under reduced pressure, adding water (500 ml) to deposit solids, separating the solids from liquid, dissolving them in toluene (100 ml), filtering off insoluble matter, washing the toluene solution twice with 2N-NaOH, then three times with water, drying over anhydrous sodium sulfate, distilling off toluene and recrystallizing the resulting crystals from n-heptane to obtain the objective 1-(2-hydroxyethoxy)-4-(trans-4-propylcyclohexyl)benzene. Yield: 1.8 g (34%). C-S: 71.5° C. S-I: 81.4° C.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([O:14]C2CCCCO2)[CH:11]=[CH:12][CH:13]=1.[Br:21]CCBr>Cl>[Br:21][C:9]1[C:8]([O:7][CH3:6])=[CH:13][CH:12]=[CH:11][C:10]=1[OH:14]
Reactant: BrCCBr
Reactant: COc1cccc(OC2CCCCO2)c1
Agent: Cl
Agent: [Li]CCCC
Product: COc1cccc(O)c1Br
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 30 %

Procedure:
33 mL (52.8 mmol) n-butyllithium (1.6 M in hexane) were added dropwise to a solution 10 gm (48.1 mMol) tetrahydropyran-2-yl 3-methoxyphenyl ether in 100 mL tetrahydrofura over 15 minutes. After stirring for 2.5 hours at room temperature, the reaction mixture was cooled to 0° C. and then 4.6 mL (53.2 mMol) 1,2-dibromoethane were added dropwise. The reaction mixture was then allowed to stir at room temperature for about 14 hours. The reaction mixture was then diluted with 50 mL 1 N hydrochloric acid and was stirred for 1 hour. The aqueous phase was extracted with three 100 mL portions of diethyl ether. The organic phases were combined and extracted well with 5 N sodium hydroxide. These basic aqueous extracts were combined and cooled in an ice/water bath. The pH of this aqueous solution was adjusted to about 1 with 5 N hydrochloric acid and then extracted with three 100 mL portions of diethyl ether. These ether extracts were combined and washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography, eluting with a gradient of hexane containing from 0 to 10% ethyl acetate. Fractions containing the desired compound were combined and concentrated under reduced pressure to provide 2.91 gm (30%) of a residue which crystallized upon standing.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Br:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17](=[N:19]O)[NH2:18]>>[Br:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]1[N:19]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[O:7][N:18]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NC(=NO)c1sccc1Br
Product: Clc1ccc(-c2nc(-c3sccc3Br)no2)cc1

Procedure:
The title compound was prepared from 4-chloro-benzoyl chloride (60 μL, 0.47 mmol) and 3-bromo-thiophene-2-amidoxime (102 mg, 0.461 mmol) similar to Example 36c, and yielded 80 mg (51%) of white solid. 1H NMR (CDCl3): 8.15 (dd, J=9.09, 2.06 Hz, 2H), 7.54 (dd, J=8.51, 2.20 Hz, 2H), 7.50 (d, J=5.22 Hz, 1H), 7.18 (d, J=5.22 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([O:18]C)=[O:17])[N:15]=1.[OH-].[Li+]>CO.O>[F:10][C:4]1[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=[C:2]([F:1])[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1
Reactant: COC(=O)c1csc(-c2c(F)cc(OC)cc2F)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a solution of methyl 2-(2,6-difluoro-4-methoxy-phenyl)thiazole-4-carboxylate (2.403 mmol, 685.5 mg) in methanol (15 mL) and water (5 mL) was added lithium hydroxide (1.9 equiv., 4.54 mmol, 111 mg). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with 1N HCl (aq.), then partitioned between EtOAc and brine. The organic layer was concentrated. The residue was dried on highvac to afford 2-(2,6-difluoro-4-methoxy-phenyl)thiazole-4-carboxylic acid (650 mg, quant.) as a brown solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[Br:18][C:19]1[CH:20]=[N:21][C:22](I)=[N:23][CH:24]=1>CS(C)=O.O>[Br:18][C:19]1[CH:20]=[N:21][C:22]([O:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)=[N:23][CH:24]=1
Reactant: Brc1cnc(I)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COc2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.2 %

Procedure:
A solution of N-Boc-4-piperidinemethanol (1.0 g, 4.50 mmol) in DMSO (2 mL) was added dropwise to a suspension of NaH (60% in mineral oil, 0.27 g, 6.76 mmol) in DMSO (4 mL). The mixture was stirred at ambient temperature for 1 h, then 30 minutes at 50° C. Cooled to ambient temperature, a solution of 5-bromo-2-iodopyrimidine (1.38 g, 4.73 mmol) in DMSO (4 mL) was added dropwise, and the reaction mixture was stirred at ambient temperature overnight, then heated at 100° C. for 5 h. Cooled to ambient temperature, the mixture was poured in water, extracted with EtOAc. The organic extract was washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a dark brown oil. The crude product was purified by chromatography on ISCO silica gel column eluted with a EtOAc:hexane gradient (hexane to 15% EtOAc) to give 0.455 g (28%) of 1,1-dimethylethyl 4-{[(5-bromo-2-pyrimidinyl)oxy]methyl}-1-piperidinecarboxylate as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.51 (s, 2H), 4.20-4.10 (m, 4H), 2.80-2.65 (m, 2H), 2.05-1.95 (m, 1H), 1.90-1.75 (m, 2H), 1.45 (s, 9H), 1.35-1.20 (m, 2H); LRMS (ESI), m/z 372/374 (M+H).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)=[CH:17][CH:16]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1>C(=O)([O-])[O-].[Na+].[Na+].C(#N)C.C(OCC)(=O)C>[CH3:28][N:29]1[CH:33]=[C:32]([C:2]2[N:10]=[CH:9][C:8]3[NH:7][C:6]4[N:11]=[CH:12][C:13]([C:15]5[CH:20]=[CH:19][C:18]([CH2:21][N:22]6[CH2:23][CH2:24][O:25][CH2:26][CH2:27]6)=[CH:17][CH:16]=5)=[CH:14][C:5]=4[C:4]=3[CH:3]=2)[CH:31]=[N:30]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCOCC4)cc3)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cc3c(cn2)[nH]c2ncc(-c4ccc(CN5CCOCC5)cc4)cc23)cn1
Temperature: 130 °C
Yield: 24.8 %

Procedure:
A degassed mixture of 6-bromo-3-(4-morpholin-4-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (245 mg, 0.58 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (241 mg, 1.16 mmol), 1,1′-[bis(diphenylphosphino)ferrocene] dichloropalladium(II) (47 mg, 0.06 mmol) in 2N aqueous sodium carbonate solution (7 mL) and acetonitrile (7 mL) was heated under microwave irradiation at 130° C. for 20 minutes. The cooled reaction mixture was diluted with ethyl acetate (75 mL) and washed with water (50 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 10 g column, Biotage, 0-10% methanol in DCM) to afford the title compound as a white solid (61 mg, 25%). 1H NMR (CDCl3, 300 MHz): 8.86 (d, J=1.1 Hz, 1H), 8.81 (d, J=2.2 Hz, 1H), 8.77 (d, J=2.2 Hz, 1H), 8.31 (d, J=1.1 Hz, 1H), 8.07 (s, 1H), 8.05 (d, J=0.8 Hz, 1H), 7.73-7.67 (m, 2H), 7.54-7.48 (m, 2H), 4.01 (s, 3H), 3.80-3.73 (m, 4H), 3.63 (s, 2H), 2.60-2.52 (m, 4H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:8][C:7]=1[C:23]1[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>ClCCl>[C:36]([NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:8][C:7]=1[C:23]1[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=1)(=[O:38])[CH3:37]
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C(=O)Nc2ccc(OCCNC(C)=O)c(-c3ccnn3C)c2)c1
Reaction time: 0.25 h
Yield: 54.3 %

Procedure:
The N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide hydrochloride (30.0 mg, 74.5 μmol) and triethylamine (31.1 μL, 3.0 eq) were taken up in 2 mL of dichloromethane and stirred for 15 mins. To this was added acetyl chloride (6.35 μL, 1.2 eq) and the reaction was stirred at room temperature for 18 hrs. The solvents were evaporated under a stream of nitrogen and it was purified by HPLC. The proper fractions were collected and lyophilized to afford the title compound as a white solid in 54.3% yield. LCMS m/z (%)=409 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ ppm 1.97 (s, 3H), 3.49-3.56 (m, 2 H), 3.85 (s, 3 H), 3.88 (s, 3 H), 4.09 (t, J=5.05 Hz, 2 H), 6.36 (t, J=6.32 Hz, 1 H), 6.39 (d, J=2.02 Hz, 1 H), 7.02 (d, J=8.59 Hz, 1 H), 7.09-7.13 (m, 1 H), 7.36-7.45 (m, 2 H), 7.61 (dd, J=9.09, 2.53 Hz, 1H), 7.69 (d, J=1.52 Hz, 1 H), 7.75 (d, J=2.02 Hz, 2 H), 7.85 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:17])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[C:11]([OH:16])[CH:10]=[CH:9][CH:8]=3.[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH2:20]([O:16][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[O:13][C:14]1[CH:15]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[C:6]2=[O:17])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: O=c1c2ccc(Cl)cc2oc2c(O)cccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2ccc(Cl)cc2oc2c(OCc3ccccc3)cccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The 3-chloro-5-hydroxyxanthone (11 g.) in dimethylformamide (50 ml.) is added to a suspension of sodium hydride (1.5 g.) in dimethylformamide (100 ml.). The mixture is stirred at room temperature for 15 minutes and benzyl bromide (6 ml.) is added dropwise. The mixture is poured into water/ice (600 ml.), extracted with chloroform and the chloroform extract dired with MgS04. Evaporation of the solvent gives a light-brown solid which is recrystallised from ethanol to give 5-benzyloxy-3-chloroxanthone, m.p. 154° C.