Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9][C:4]21CCCC2.CB(Br)C.[OH-:24].[Na+]>ClCCl>[CH2:13]([N:11]1[CH2:10][CH2:9][C:4](=[O:24])[CH:3]([CH2:2][OH:1])[CH2:12]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCC1CN(Cc2ccccc2)CCC12CCCC2
Reactant: [OH-]
Agent: CB(C)Br
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCN(Cc2ccccc2)CC1CO
Temperature: -78 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
A solution of 3.0 gm (11.4 mMol) 6-hydroxymethyl-8-benzyl-8-azaspiro[4,5]decane in 50 mL dichloromethane was cooled to −78° C. and then treated with 2.2 mL (22.8 mMol) dimethylboron bromide dropwise. After stirring at −78° C. for 4 hours, the reaction mixture was treated with 45 mL 1N sodium hydroxide and was allowed to warm to room temperature. The phases were separated and the aqueous phase was extracted well with dichloromethane. The organic phases were combined, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with dichloromethane containing from 0-5% methanol. Fractions containing product were combined and concentrated under reduced pressure to provide 1.1 gm (44%) 1-benzyl-3-hydroxymethyl-4-oxopiperidine.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16].CN(C)[CH:28]=[O:29].[Cl-].[NH4+].C([O-])(O)=O.[Na+]>O1CCCC1>[CH:28]([C:13]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16])=[O:29]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Br
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1ccc(C(F)(F)F)cc1C(=O)O
Temperature: -78 °C

Procedure:
To a 250 mL round-bottomed flask, was added 2.5 M n-butyllithium/hexane (8.92 mL, 22.30 mmol) in tetrahydrofuran (40 mL) and cooled to −78° C., followed by dropwise addition of 2-bromo-5-(trifluoromethyl)benzoic acid (3 g, 11.15 mmol) in tetrahydrofuran (20 mL). After 30 min N,N-dimethylformamide (0.978 g, 13.38 mmol) was added and the solution slowly allowed to warm to rt. To the reaction was added saturated ammonium chloride solution, followed by addition of saturated NaHCO3 solution until basic. The aqueous layer was separated, and 2 N HCl was added until acidic. The mixture was extracted with ethyl acetate (3×20 mL). The organic layers were combined, dried, filtered, and concentrated. The resulting solid was used without further purification. MS (DCI/NH3) m/z 512 (M+NH4)+.
Reaction SMILES: BrC1C(CC2(O)C3C(=CC=C(C)C=3)N(CCC(C)C)C2=O)=NC=CC=1.[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:31](=[O:44])[C:30]2=[O:45].[CH3:46][O:47][C:48]1[C:49]([CH3:54])=[N:50][CH:51]=[CH:52][CH:53]=1>>[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:31](=[O:44])[C:30]2([OH:45])[CH2:54][C:49]1[C:48]([O:47][CH3:46])=[CH:53][CH:52]=[CH:51][N:50]=1
Reactant: O=C1C(=O)N(CCc2ccccc2)c2ccc(Cl)cc21
Reactant: COc1cccnc1C
Agent: Cc1ccc2c(c1)C(O)(Cc1ncccc1Br)C(=O)N2CCC(C)C
Product: COc1cccnc1CC1(O)C(=O)N(CCc2ccccc2)c2ccc(Cl)cc21

Procedure:
This compound was prepared in an analogous manner to 3-((3-bromopyridin-2-yl)methyl)-3-hydroxy-1-isopentyl-5-methylindolin-2-one using 5-chloro-1-phenethylindoline-2,3-dione and 3-methoxy-2-methylpyridine. 1H-NMR δ 8.21 (dd, 1H), 7.33-7.17 (m, 8H), 6.95 (d, 1H), 6.62 (d, 1H), 5.5 (bs, OH), 3.98 (m, 1H), 3.86 (m, 1H), 3.78 (s, 3H), 3.37 (d, 1H), 3.09 (d, 1H), 2.96 (t, 2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([O:34]C)=[O:33])[CH2:29]2)[S:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])=[CH:15][CH:14]=2)[O:10][N:9]=1)[CH3:2].O.[OH-].[Li+].C(O)(=O)C.C(O)(=O)C(O)=O>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[CH2:29]2)[S:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])=[CH:15][CH:14]=2)[O:10][N:9]=1)[CH3:2]
Reactant: CCc1cc(CN2CC(C(=O)OC)C2)sc1-c1noc(-c2ccc(Oc3ccccc3F)cc2)n1
Agent: O=C(O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCc1cc(CN2CC(C(=O)O)C2)sc1-c1noc(-c2ccc(Oc3ccccc3F)cc2)n1
Yield: 42.3 %

Procedure:
The title compound (77 mg) was synthesized in a yield of 39% as a white crystalline solid by conducting the reaction similar to that mentioned in Example 1 (1g) using methyl 1-[(4-ethyl-5-{5-[4-(2-fluorophenoxy)phenyl]-1,2,4-oxadiazol-3-yl}-2-thienyl)methyl]azetidine-3-carboxylate (0.19 g, 0.38 mmol) that was obtained in Example 10 (10g), lithium hydroxide monohydrate (36 mg, 0.85 mmol), acetic acid (46 μL, 0.85 mmol), and oxalic acid (17 mg, 0.19 mmol).
Reaction SMILES: C(O)C.O1CCCC1.C([Li])CCC.[C:14]1([C:20]2[O:21][C@H:22]([C:31]([O:33]CC)=[O:32])[C@H:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[C:14]1([C:20]2[O:21][C@@H:22]([C:31]([OH:33])=[O:32])[C@H:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:24]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)[C@H]1OC(c2ccccc2)=N[C@H]1c1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)[C@@H]1OC(c2ccccc2)=N[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Ethanol (0.1 ml) was mixed with tetrahydrofuran (1.0 ml), and the mixture cooled to -78° C. n-Butyllithium (n-BuLi) (2.12M, 0.050 ml) was added dropwise, and the mixture warmed to 0° C. Solid (4S-cis)-4,5-dihydro-2,4-diphenyl-5-oxazolecarboxyiic acid, ethyl ester having the structure: ##STR34## (20 mg, 0.0678 mmol) was added and the reaction was stirred for 1 hour (a small amount of water was present). A mixture of cis oxazoline ethyl ester starting material and the corresponding trans oxazoline ethyl ester (5-position inversion) were observed by TLC (very little hydrolysis was noted at this point). The reaction mixture was stirred for another hour and then left with an ice bath overnight (0° C. to room temperature). After 18 hours TLC showed mostly the trans acid title product and a trace of the cis ester starting material (solvent systems hexane:EtOAc 2:1 (trace of cis ester) and EtOAc:acetone:H2O:MeOH 7:1:1:1 (title product)).
Reaction SMILES: Br[C:2]1[Se:3][CH:4]=[CH:5][CH:6]=1.[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[C:12]([F:19])[C:11]=1[F:20])[CH3:8].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[Se:3][CH:4]=[CH:5][CH:6]=2)=[C:12]([F:19])[C:11]=1[F:20])[CH3:8]
Reactant: CCOc1ccc(B(O)O)c(F)c1F
Reactant: Brc1ccc[se]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOc1ccc(-c2ccc[se]2)c(F)c1F

Procedure:
A mixture of 45.0 g (0.21 mol) of 2-bromoselenophene, 52.0 g (0.26 mol) of 4-ethoxy-2,3-difluorophenylboronic acid, 20.0 g (17.3 mmol) of tetrakis(triphenylphosphine)palladium(0) and 600 ml of 2 N sodium carbonate soln. in 1100 ml of toluene/ethanol (1:1) is heated under reflux for 20 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted with toluene. The combined organic phases are washed with sat. sodium hydrogencarbonate soln., 1 N hydrochloric acid and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:toluene=3:2). Further purification is carried out by recrystallisation from ethanol; 2-(4-ethoxy-2,3-difluorophenyl)selenophene is obtained as a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH:12]([C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])[C:13]([O:15]C)=[O:14])[N:4]=1.[OH-].[K+]>O1CCOCC1>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][CH:12]([C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH3:18])[C:13]([OH:15])=[O:14])[N:6]=1
Reactant: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(C)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(OC)nc(OC(C(=O)O)C(C)(c2ccccc2)c2ccccc2)n1
Temperature: 90 °C
Reaction time: 6 h
Yield: 64.5 %

Procedure:
1.8 g (4.4 mmol) of methyl 2-(4,6-dimethoxy-2-pyrimidinyloxy)-3,3-diphenylbutyrate were dissolved in 25 ml of dioxane, and 26.5 ml (26.5 mmol) of a 1M KOH solution were added, and the mixture was stirred at 90° C. for 6 hours. The mixture was then concentrated, taken up in water and extracted three times with ethyl acetate. The combined organic phases were dried over MgSO4 and evaporated. The residue was recrystallized from ethanol. 1.12 g (65%) of 2-(4,6-dimethoxy-2-pyrimidinyloxy)-3,3-diphenylbutyric acid of melting point 229-234° C. were obtained.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:7]=1[C:8]#[N:9]>OS(O)(=O)=O>[Cl:5][C:6]1[CH:13]=[C:12]([F:14])[C:11]([N+:1]([O-:4])=[O:2])=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: O=[N+]([O-])O
Reactant: N#Cc1ccc(F)cc1Cl
Agent: O=S(=O)(O)O
Product: N#Cc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Fuming HNO3 (2.9 mL, 64 mmol) was added dropwise to a solution of 2-chloro-4-fluorobenzonitrile (5.0 g, 32 mmol) in conc. H2SO4 (5 mL) at 0° C. The mixture was stirred at 0° C. for 15 min and at rt for 30 min whereafter it was poured into ice. The precipitate was filtered off, washed with water and dried under vacuum.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([O:12][CH2:13]/[C:14](/[C:25]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1)=[C:15](/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)\[C:16]([OH:18])=[O:17])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]Br.C([O-])([O-])=O.[K+].[K+].[Cl-].[NH4+]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([O:12][CH2:13]/[C:14](/[C:25]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1)=[C:15](/[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)\[C:16]([O:18][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][Br:35])=[O:17])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCCCCCCBr
Reactant: CC(C)(C)OC(=O)NCC(=O)OC/C(=C(\C(=O)O)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)OC/C(=C(\C(=O)OCCCCCCBr)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Yield: 83.8 %

Procedure:
A solution of 1.88 g of (2Z)-4-{[N-(tert-butoxycarbonyl)glycyl]oxy}-3-[4-(methylsulfonyl)phenyl]-2-phenylbut-2-enoic acid and 9.6 g of 1,6-dibromohexane in 20 mL of DMF was stirred at rt with 550 mg of K2CO3 for 2 h. Then saturated ammonium chloride solution was added and extracted with EtOAc. The organic layer was combined and washed with brine and dried over Na2SO4. The solvent was evaporated and the residue was purified by flash chromatography over silica gel (5–50% EtOAc/hexane) to afford 2.1 g of the titled compound as a colorless oil. 1H NMR (500 MHz, acetone-d6): δ 7.76 (d, 2H), 7.43 (d, 2H), 7.17 (m, 3H), 7.08 (d, 2H), 6.24 (br s, NH), 5.27 (s, 2H), 4.24 (t, 2H), 3.68 (d, 2H), 3.45 (t, 2H), 3.05 (s, 3H), 1.81 (m, 2H), 1.68 (m, 2H), 1.44–1.32 (m, 4H), 1.39 (s, 9H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[O:12]=[C:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[N:23][C:18]=2[CH2:17][CH2:16][CH2:15][N:14]1[CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:26][CH2:25]1.S(OS([O-])=O)([O-])=O.[Na+].[Na+]>ClCCl>[O-:9][N+:23]1[C:18]2[CH2:17][CH2:16][CH2:15][N:14]([CH:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][CH2:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)=[O:31])[CH2:28][CH2:29]3)[C:13](=[O:12])[C:19]=2[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(OCc1ccccc1)N1CCC(N2CCCc3ncccc3C2=O)CC1
Agent: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(N2CCCc3c(ccc[n+]3[O-])C2=O)CC1
Reaction time: 0.33 h
Yield: 53.3 %

Procedure:
m-Chloroperbenzoic acid (2.45 g) was added to a mixture of benzyl 4-(5-oxo-5,7,8,9-tetrahydro-6H-pyrido[3,2-c]azepin-6-yl)piperidine-1-carboxylate (1.8 g) and dichloromethane (50 mL), and the resultant mixture was stirred at room temperature for 3 hours. A 10% aqueous sodium disulfite solution was added to the reaction mixture, and the mixture was stirred for 20 minutes, followed by extraction with dichloromethane. The organic layer was washed with water and saturated saline and dried over sodium sulfate, and then, the solvent was distilled off under reduced pressure to obtain the title compound (1.0 g).
Reaction SMILES: [N:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])=O.[NH4+].C(=O)([O-])[O-].[K+].[K+].Cl[C:22]1[N:27]=[CH:26][C:25](CC)=[CH:24][N:23]=1>CO.CN(C)C=O>[N:23]1[CH:24]=[CH:25][CH:26]=[N:27][C:22]=1[NH:10][S:7]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:9])=[O:8]
Reactant: CCc1cnc(Cl)nc1
Reactant: NS(=O)(=O)N1CCCCC1
Agent: O=C([O-])[O-]
Agent: O=C[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1ncccn1)N1CCCCC1
Reaction time: 4 h
Yield: 60 %

Procedure:
To a slurry of the piperidine sulfonamide from part F (6.3 g, 12.0 mmol) in methanol (25 mL) was added ammonium formate (2.2 g, 34.5 mmol). The system was purged with nitrogen for 10 minutes. The nitrogen stream was removed and palladium on carbon (1.2 g of 10 weight % on activated carbon, 50% water) was added. The reaction was refluxed for forty five minutes, cooled, filtered through Celite under nitrogen, and concentrated in vacuo. The residue (4.5 g, 10 mmol) was dissolved in dry dimethylformamide (20 mL) and potassium carbonate (3.45 g, 325 mmol) and 2-chloro-5-ethylpyrimidine (1.82 mL, 15 mmol) were added. The reaction was stirred at eighty degrees Celsius for four hour and then concentrated in vacuo. The residue was taken up in ethyl acetate and filtered through Celite. The filtrate washed with water two times, saturated sodium chloride solution, dried over Na2SO4, filtered, and concentrated in vacuo. The product was recrystallized (methanol) to give the N-pyrimidinyl piperidine sulfonamide as a white solid (3.33 g, 60%).
Reaction SMILES: [NH2:1][C:2]1[C:21]([C:22]2[CH:27]=[C:26]([C:28](=[O:39])[NH:29][C:30]3([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:32][CH2:31]3)[CH:25]=[CH:24][C:23]=2[F:40])=[CH:20][C:5]2[C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.[CH3:41][S:42](Cl)(=[O:44])=[O:43].CS(NS(C)(=O)=O)(=O)=O>>[F:40][C:23]1[CH:24]=[CH:25][C:26]([C:28](=[O:39])[NH:29][C:30]2([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:31][CH2:32]2)=[CH:27][C:22]=1[C:21]1[C:2]([NH:1][S:42]([CH3:41])(=[O:44])=[O:43])=[CH:3][C:4]2[O:8][C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)=[C:6]([C:16]([NH:18][CH3:19])=[O:17])[C:5]=2[CH:20]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(-c3cc(C(=O)NC4(c5ccccc5)CC4)ccc3F)cc12
Reactant: CS(=O)(=O)Cl
Agent: CS(=O)(=O)NS(C)(=O)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(-c3cc(C(=O)NC4(c5ccccc5)CC4)ccc3F)cc12

Procedure:
Prepared from the coupling between 6-amino-5-(2-fluoro-5-(1-phenylcyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide and methanesulfonyl chloride (N,N-diisopropylethylamine, ClCH2CH2Cl, r.t.), followed by hydrolysis of the intermediate N-(methylsulfonyl)methanesulfonamide (Cs2CO3, 1:5 H2O/1,4-dioxane, 90° C.). Purification by Shimadzu-VP preparative reverse phase HPLC using the separation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire 19×100 mm S5, Fraction Collection: 6.70-7.25 min. (UV detection at 220 nm). 1H NMR (500 MHz, CD3OD) δ 8.00-7.95 (overlapping m, 4H), 7.83 (s, 1H), 7.66 (s, 1H), 7.35 (t, J=9.00, 1H), 7.30-7.27 (overlapping m, 6H), 7.18 (m, 1H), 2.94 (s, 3H), 2.88 (s, 3H), 1.37-1.35 (appeared as d, 4H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters MICROMASS®. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: XTERRA® MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)+=616.48, HPLC Rt=1.563 min. Analytical HPLC were performed by using Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H2O-0.1% TFA, Solvent B=95% MeCN-5% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150 mm, Rt=6.57 min; Column: XBridge phenyl 3.5 um, 4.6×150 mm, Rt=5.80 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[O:14]1[C:22]2[CH2:21][CH2:20][NH:19][CH2:18][C:17]=2[CH:16]=[CH:15]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:20][CH2:21][C:22]4[O:14][CH:15]=[CH:16][C:17]=4[CH2:18]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: c1cc2c(o1)CCNC2
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2occc2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4,5,6,7-tetrahydro-furo[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[NH:12][C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)=[C:10](C(OCC)=O)[C:9]2=[O:29])([O-:3])=[O:2].Cl>O1CCOCC1>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[NH:12][C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=1)=[CH:10][C:9]2=[O:29])([O-:3])=[O:2]
Reactant: CCOC(=O)c1c(-c2cccc(C(F)(F)F)c2)[nH]c2c([N+](=O)[O-])cccc2c1=O
Agent: Cl
Solvent: C1COCCO1
Product: O=c1cc(-c2cccc(C(F)(F)F)c2)[nH]c2c([N+](=O)[O-])cccc12
Temperature: 190 °C
Yield: 86 %

Procedure:
A microwave vial was charged with of 8-nitro-4-oxo-2-(3-(trifluoromethyl)phenyl)-1,4-dihydroquinoline-3-carboxylate 36 (1.0 g, 2.46 mmol), dioxane (8 mL) and 1N HCl (4 mL). The reaction mixture was heated at 190° C. in the microwave for 50 min. The volatiles were evaporated and the residue dried under vacuum to give 37 (707 mg, 86% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:28]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56 %

Procedure:
To the solution of 1-tert-butoxycarbonylpiperazine (1.86 g, 10.0 mmol) and triethylamine (1.67 mL, 12.0 mmol) in dichloromethane (30 mL) was added 4-fluorobenzenesulfonyl chloride (2.34 g, 12.0 mmol), and the mixture was stirred at room temperature for 24 hours. To the mixture was added water(30 mL), and the mixture was concentrated under reduced pressure. To the concentrate was added ethyl acetate (70 mL). The organic layer was washed with water (30 mL), 1N-hydrochloric acid (10 mL×3), a saturated aqueous solution of sodium hydrogencarbonate (10 mL×3), saturated sodium chloride solution (10 mL), successively, dried over magnesium sulfate and concentrated under reduced pressure. To the concentrate was added diisopropyl ether, and the resulting precipitates were collected by filtration. The precipitates were washed with diisopropyl ether, and dried under reduced pressure to give the titled compound (1.94 g, 5.6 mmol, Yield 56%) as white crystals.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([NH:8][C:9]([N:11]2[C:15]3[N:16]=[C:17]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)[N:18]=[C:19]([C:20]4[CH:21]=[N:22][C:23]([N:26]([CH2:36][C:37]5[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=5)[CH2:27][C:28]5[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=5)=[N:24][CH:25]=4)[C:14]=3[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:51]([N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)[CH3:52].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH2:51]([N:53]1[CH2:58][CH2:57][N:56]([C:2]2[CH:3]=[C:4]([NH:8][C:9]([N:11]3[C:15]4[N:16]=[C:17]([N:45]5[CH2:50][CH2:49][O:48][CH2:47][CH2:46]5)[N:18]=[C:19]([C:20]5[CH:21]=[N:22][C:23]([N:26]([CH2:36][C:37]6[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=6)[CH2:27][C:28]6[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=6)=[N:24][CH:25]=5)[C:14]=4[CH2:13][CH2:12]3)=[O:10])[CH:5]=[CH:6][CH:7]=2)[CH2:55][CH2:54]1)[CH3:52]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)Nc3cccc(I)c3)cn2)cc1
Reactant: CCN1CCNCC1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCN(c2cccc(NC(=O)N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)c2)CC1

Procedure:
4-{2-[Bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid (3-iodo-phenyl)-amide (48 mg) obtained in Step A, 1-ethyl-piperazine (77.5 μl), tris(dibenzylideneacetone)dipalladium (5.5 mg), S-Phos (5.0 mg) and potassium phosphate (26.0 mg) were stirred in DMF (5 ml) at 100° C. for 3 hours. To this, water was added, to filter the solid, which was dissolved in dichloromethane, followed by drying over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off under reduced pressure, followed by purification by silica gel column chromatography (dichloromethane/methanol=100/1 to 20/1), to obtain 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid [3-(4-ethyl-piperazin-1-yl)-phenyl]-amide as a crude product. To this compound (23.1 mg), N-Acetylcysteine (10 mg) was added, followed by refluxing in TFA (1 ml) for 6 hours. TFA was distilled off, followed by purification by silica gel column chromatography (dichloromethane/2M-ammonia methanol=1/0 to 20/1), and further the resulting solid was washed with saturated sodium hydrogencarbonate aqueous solution (3 ml), water (3 ml) and acetonitrile (3 ml), to obtain the desired compound (D-81) as a yellow solid (12.5 mg, 79%).