Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@H:9]([OH:12])[CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>CN(C=O)C>[CH2:32]([O:31][C:29](=[O:30])[NH:11][CH2:10][C@@H:9]([OH:12])[C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:20])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 83.1 %

Procedure:
A solution of ((1S,2R)-3-amino-1-benzyl-2-hydroxy-propyl)-carbamic acid tert-butyl ester (D102) (25.6 g, 91.4 mmol, 1 equiv) in DMF (250 ml) at 0° C. was treated with NEt3 (15 ml, 108 mmol, 1.2 equiv) and then with benzyl chloroformate (14 ml, 98 mmol, 1.1 equiv) in DMF (50 ml) dropwise. The resulting solution was stirred at 0° C. for 1 h and at room temperature for 16 h and then concentrated in vacuo. The residue was partitioned between AcOEt and saturated aqueous NaHCO3 solution. The resulting precipitate was diluted with H2O and filtered to give ((2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-carbamic acid benzyl ester (D103) (31.5 g, 83%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:12]=[CH:13][S:14][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN1C(=O)CCC1>[C:16]1([NH:15][C:2]2[C:11]3[CH:12]=[CH:13][S:14][C:10]=3[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1
Reactant: Clc1nc2ccccc2c2sccc12
Solvent: CN1CCCC1=O
Product: c1ccc(Nc2nc3ccccc3c3sccc23)cc1
Temperature: 120 °C

Procedure:
4-chlorothieno[3,2-c]quinoline (23 mg) was mixed with aniline (0.1 ml) and NMP (0.1 ml) and the mixture was heated in a microwave oven at 120° C. for 10 min. NMP (0.8 ml) was added and the compound purified by preparative HPLC. Genevac evaporation afforded N-phenylthieno[3,2-c]quinolin-4-amine as a pinky solid (31 mg, quant.). LCMS (ES): 95% pure, m/z 277 [M+1-1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cc2c1O
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CCN2CCCCC2)c2ccc(C#CCO)cc2c1=O
Temperature: 90 °C
Reaction time: 48 h

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 5 (0.367 g) is dissolved in DMF (10 mL), and K2CO3 (0.55 g, 4.0 mmol) and 1-(2-chloroethyl)piperidine hydrochloride (0.375 g, 2.0 mmol) are added. The reaction mixture is heated to 90° C. for 3 h, and then allowed to stir at room temperature for 48 h. Water is added and a precipitate formed. The precipitate is filtered and allowed to dry at room temperature and then under reduced pressure to give 0.171 g of a solid. The solid is dissolved in CHCl3 and filtered. The filtrate is concentrated in vacuo and crystallized from ethyl acetate to give 0.066 g of the title compound as a solid.
Reaction SMILES: C([O:8][N:9]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH:17]([O:20][CH3:21])[O:18][CH3:19])[C:10]1=[O:22])C1C=CC=CC=1.C([O-])=O.[NH4+]>CCO.[Pd]>[CH3:21][O:20][CH:17]([O:18][CH3:19])[CH2:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][N:9]([OH:8])[C:10]1=[O:22]
Reactant: COC(CCCN1CCN(OCc2ccccc2)C1=O)OC
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC(CCCN1CCN(O)C1=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
To a solution of 1-Benzyloxy-3-(4,4-dimethoxy-butyl)-imidazolidin-2-one (1.61 g, 5.22 mmol) in EtOH (50 mL) was added ammonium formate (3.34 g, 52.9 mmol) and 10 wt % Pd/C (50% wet with water, 800 mg) and the mixture was stirred at room temperature for 2 hours. The mixture was vacuum filtered through celite and the cake was washed with EtOH. The solvent was removed from the filtrate under reduced pressure and the thus obtained solid was partitioned between water (10 mL) and CH2Cl2 (50 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (100% EtOAc) provided 0.75 g (66%) of 1-(4,4-Dimethoxy-butyl)-3-hydroxy-imidazolidin-2-one as a colorless oil. ES-MS m/z 241 (M+Na).
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].C(O[C:18]([NH:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([C:27](O)=[O:28])[CH2:23][CH2:22]1)=O)(C)(C)C>C1(C)C=CC=CC=1>[CH3:18][NH:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN[C@H]1CC[C@H](CO)CC1
Temperature: 105 °C

Procedure:
Vitride solution (65%, 767 ml, 2.465 mol) was added dropwise over 1 h to a solution of trans-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid (commercially available, 100 g, 0.4109 mol) in toluene (1 l). After the addition was complete the reaction mixture was heated to reflux for 100-110° C. The reaction mixture was quenched with aq. Sodium sulphate solution (800 ml) at temperatures below 10° C. The reaction mixture was filtered through celite and the filter cake washed with DCM (500 ml) followed by water (100 ml). The organics layer was separated and the aqueous layer extracted twice with DCM (600 ml then 400 ml). The combined organics layers were dried over sodium sulphate and concentrated in vacuo to give the title compound (62 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:8]2)[CH:2]=1.[Br:21]N1C(=O)CCC1=O.O>C(#N)C>[Br:21][C:6]1[N:1]=[CH:2][C:3]([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:8]2)=[CH:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccnc2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(Br)nc2)CC1
Temperature: 0 °C

Procedure:
1-(3-Pyridyl)-4-tert-butoxycarbonyl homopiperazine (25.0 g, 90.1 mmol) was solved in acetonitrile (400 ml) and cooled to 0° C. N-Bromosuccinimide (19.3 g, 108.2 mmol) was added during 10 min. Water (400 ml) was added and the mixture was extracted twice with diethyl ether (200 ml). Chromatography on silica gel with a mixture of petroleum: ethyl acetate (1:1) gave the title compound as free base. Yield 18.7 g, 58%.
Reaction SMILES: [CH:1]([SiH:4]([CH:14]([CH3:16])[CH3:15])[C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].OS(O)(=O)=O.[CH3:22]O>C(Cl)(Cl)Cl>[CH3:22][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:5]([SiH:4]([CH:1]([CH3:3])[CH3:2])[CH:14]([CH3:16])[CH3:15])=[CH:6][CH:7]=1
Reactant: CO
Reactant: CC(C)[SiH](c1ccc(C(=O)O)cc1)C(C)C
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc([SiH](C(C)C)C(C)C)cc1
Yield: 93 %

Procedure:
4-diisopropylsilanylbenzoic acid (9 g, 38 mmol)was dissolved in methanol (300 mL), and conc. H2SO4 (15 mL) was added dropwise to the solution cooled on ice. After being heated to reflux for 2 hours, the reaction solution was dissolved in chloroform (500 mL). The solution was then extracted two times with water (300 mL) and three times with 5 wt % aqueous solution (300 ml) of sodium hydrogen carbonate. An organic layer was collected and dehydrated with anhydrous sodium sulfate and filtered so that the resulting solvent was distilled out under a reduced pressure. The resulting crude product was then purified by silica gel column chromatography. After eluted with hexane having 0-5% ethyl acetate gradient, the solvent was distilled out to give a desired product (8.8 g, 93%). Its NMR data are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[N:23])[CH:20]=3)[N:15]=[CH:14][C:13]=2[C:24]([OH:26])=[O:25])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[F:27][C:28]1[C:33](O)=[C:32]([F:35])[C:31]([F:36])=[C:30]([F:37])[C:29]=1[F:38].C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C.C(OCC)(=O)C>[F:27][C:28]1[C:33]([O:25][C:24]([C:13]2[CH:14]=[N:15][C:16]3[C:21]([C:12]=2[NH:11][CH2:10][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=2)=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=3)=[O:26])=[C:32]([F:35])[C:31]([F:36])=[C:30]([F:37])[C:29]=1[F:38]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: COc1ccc(CNc2c(C(=O)O)cnc3ccc(C#N)cc23)cc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CNc2c(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)cnc3ccc(C#N)cc23)cc1Cl
Reaction time: 18 h
Yield: 41 %

Procedure:
To 275 mg (0.748 mmol) of 4-[[(3-chloro-4-methoxyphenyl)-methyl]amino]-6-cyano-3-quinolinecarboxylic acid was added 276 mg (1.50 mmol, 2.0 eq) pentafluorophenol, and the mixture was dispersed in 5 mL anhydrous DMF under nitrogen. To this dispersion was added a solution of 231 mg (1.12 mmol, 1.5 eq) of dicyclohexylcarbodiimide (Aldrich) in 2 mL anhydrous ethyl acetate at RT. The resulting mixture was stirred for 18 hours. The reaction was then diluted with 10 mL EtAc, and the white precipitate was filtered and discarded. The filtrate was concentrated in vacuo, and the residue was triturated with 5% MeOH/95% CH2Cl2 to give 164 mg (0.307 mmol, 41% yield) of the title compound as a white solid: LC/MS: M/Z 534 (M+H) observed, 100% purity; mp: decomposed 215-217° C. LC: 4.15.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:10]C)=[O:8])=[C:4]([NH2:12])[CH:3]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>CCO>[Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([N:12]=[CH:15][N:16]([CH3:18])[CH3:17])[CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)c1sc(Br)cc1N
Solvent: CCO
Product: COC(=O)c1sc(Br)cc1N=CN(C)C

Procedure:
A solution of ethyl 5-bromo-3-amino-2-thiophenecarboxylate (1.0 g, 4.2 mmol) and dimethylformamide dimethylacetal (1.1 mL, 8.5 mmol) in EtOH (30 mL). was heated to reflux for 50 min. After cooling, the solvent was removed in vacuo. The residue was coevaporated with toluene (2×20 mL) to yield methyl 5-bromo-3-(((dimethylamino)methylene)amino)-2-thiophenecarboxylate. The residue and 1-((4-amino-2-methoxy)phenoxy)-2-methyl-2-propanol (0.90 mg, 4.2 mmol) (described in Part B of Example 82) were mixed with phenol (4 g) prior to heating at 130° C. for 40 min. After cooling, the mixture was chromatographed (120 g silica, CH2Cl2 to 50% EtOAc-CH2Cl2) to provide 1-(4-(6-bromo-4-oxo-thieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)-2-methyl-2-propanol as a tan solid (1.2 g, 67%).
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N+:14]=[N-:15].CI.[Cl-].[NH4+]>CCCCCC.C1COCC1>[N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([CH3:1])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N+:14]=[N-:15]
Reactant: CCOC(=O)CCCCCN=[N+]=[N-]
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CI
Product: CCOC(=O)C(C)CCCCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.91 ml (2.28 mmol) of a 2.5 M solution of n-butyllithium in n-hexane was added dropwise to a solution, cooled to −78° C., of 0.32 ml (2.28 mmol) diisopropylamine in 2 ml abs. THF. During the addition, the reaction temperature was kept below −60° C. After 30 min of stirring at −60° C. to −70° C., this solution was added dropwise to a solution, cooled to −78° C., of 352 mg (1.9 mmol) of ethyl 6-azidohexanoate in 2 ml of abs. THF. After the end of the addition, the mixture was warmed to −20 C and stirred for another 20 min, and 0.18 ml (2.85 mmol) of methyl iodide were then added dropwise. After the end of the addition, the mixture was slowly warmed to RT and stirred for a further 2 h. The reaction mixture was then added to saturated aqueous ammonium chloride solution. The mixture was extracted three times with dichloromethane, and the combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The product was purified by chromatography on silica gel (mobile phase cyclohexane/dichloromethane 60:1). This gave 96.4 mg (25.5% of theory) of the target compound.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][C:9](=[O:14])[CH2:8]2)=[CH:3][CH:2]=1.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20].ClC1C=CC(C2CC(=O)C(=CN(C)C)C(=O)C2)=CC=1>>[CH3:18][N:19]([CH:21]=[C:10]1[C:9](=[O:14])[CH2:8][CH:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:15])=[CH:6][CH:5]=2)[CH2:12][C:11]1=[O:13])[CH3:20]
Reactant: Cc1ccc(C2CC(=O)CC(=O)C2)cc1
Reactant: COC(OC)N(C)C
Agent: CN(C)C=C1C(=O)CC(c2ccc(Cl)cc2)CC1=O
Product: Cc1ccc(C2CC(=O)C(=CN(C)C)C(=O)C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The title compound was prepared from 5-p-tolyl-cyclohexane-1,3-dione (1.0 g, 4.85 mmol), example 1/c, and N,N-dimethylformamide dimethylacetal (5 ml), following the procedure described for 5-(4-chloro-phenyl)-2-dimethylaminomethylene-cyclohexane-1,3-dione (example 2/a stage 1) except that the reaction was stirred at ambient temperature for 16 h.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7]([OH:17])=[C:6]([C:18]([O:20]CC)=O)[C:5]2=[O:23].[H-].[Na+].[CH2:26]([Mg]Br)[CH2:27][CH:28]=[CH2:29]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)[C:7]([OH:17])=[C:6]([C:18](=[O:20])[CH2:29][CH2:28][CH:27]=[CH2:26])[C:5]2=[O:23]
Reactant: C=CCC[Mg]Br
Reactant: CCOC(=O)C1=C(O)C2(CCOCC2)c2ccc(Cl)cc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCC(=O)C1=C(O)C2(CCOCC2)c2ccc(Cl)cc2C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78.2 %

Procedure:
A mixture of ethyl 6-chloro-2-hydroxy-4-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (2.53 g, 8 mmol, Example 1 A-C) in 20 mL THF was stirred at room temperature and treated with sodium hydride (0.6 g, 15 mmol, 60% in oil). The resulting mixture was stirred for 10 minutes. The mixture was then treated with 3-butenylmagnesium bromide (15 mL, 8 mmol). After 5 minutes, the mixture was warmed to 60° C., and the reaction was stirred for another 0.5 hours. The mixture was cooled to 0° C., quenched with 20 mL saturated NH4Cl, and 100 mL EtOAc was added. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-20% EtOAc/hexane to give 2.17 g white solid. MS m/e: 347 (M+H)+.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])[O:19][C:18](=[O:20])[C:17]2[N:21]=[C:14]([S:15][CH:16]=2)[S:13][CH2:12][CH2:11][N:10]2[C@H:6]([CH2:7][O:8][C:9]2=[O:22])[CH:5]=[CH:4][CH2:3]1.[OH:30][C@@H](C(C)(C)CCCC)/C=C/[C@H]1COC(=O)N1CCSC1SC=C(C(OCC)=O)N=1.O1CCCC1>CO>[O:22]=[C:9]1[N:10]([CH2:11][CH2:12][S:13][C:14]2[S:15][CH:16]=[C:17]([C:18]([OH:19])=[O:20])[N:21]=2)[C@@H:6](/[CH:5]=[CH:4]/[CH2:3][C@:2]([OH:30])([CH3:1])[CH2:23][CH2:24][CH2:25][C:26]([F:27])([F:29])[F:28])[CH2:7][O:8]1
Reactant: CCCCC(C)(C)[C@H](O)/C=C/[C@H]1COC(=O)N1CCSc1nc(C(=O)OCC)cs1
Reactant: C[C@]1(CCCC(F)(F)F)CC=C[C@H]2COC(=O)N2CCSc2nc(cs2)C(=O)O1
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@](O)(C/C=C/[C@H]1COC(=O)N1CCSc1nc(C(=O)O)cs1)CCCC(F)(F)F

Procedure:
By the same procedure as the reaction of Example 8 using the compound 64-2 (More polar) instead of the compound 7 and using a mixture of tetrahydrofuran and methanol instead of methanol, the title compound having the following physical data was obtained.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([CH3:15])[C:13]2[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[C:17]([F:20])[CH:18]=[CH:19][C:12]=2[N:11]=1)[CH3:9])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:20][C:17]1[CH:18]=[CH:19][C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:14]([CH3:15])[C:13]=2[C:16]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)c(-c3ccccn3)c2n1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)c1nc2ccc(F)c(-c3ccccn3)c2n1C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
[(S)-1-(6-Fluoro-1-methyl-7-pyridin-2-yl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (0.3 g, 0.81 mmol) was dissolved in 20% TFA in DCM (10 mL). The resulting solution was stirred for 1 h then the mixture was passed through an SCX column. The column was washed with DCM, MeOH and the product was eluted with 2M NH3 in MeOH. The product fractions were concentrated to give a yellow solid (0.2 g, 92%). LCMS (Method J): RT 1.39 min [M+H]+ 271
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][CH:36]=[CH:35][C:3]=1[O:4][C:5]1[N:6]=[C:7]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:8]2[N:13]=[C:12]([C:14]3[CH:28]=[C:27]([CH3:29])[C:17]([O:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[C:16]([CH3:30])[CH:15]=3)[O:11][C:9]=2[N:10]=1.FC(F)(F)C(O)=O>>[F:1][C:2]1[CH:38]=[CH:37][CH:36]=[CH:35][C:3]=1[O:4][C:5]1[N:6]=[C:7]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:8]2[N:13]=[C:12]([C:14]3[CH:28]=[C:27]([CH3:29])[C:17]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[C:16]([CH3:30])[CH:15]=3)[O:11][C:9]=2[N:10]=1
Reactant: Cc1cc(-c2nc3c(CC(C)C)nc(Oc4ccccc4F)nc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2nc3c(CC(C)C)nc(Oc4ccccc4F)nc3o2)cc(C)c1OCC(=O)O
Yield: 57.8 %

Procedure:
Analogously to example 1 (j), the reaction of 64 mg of tert-butyl {4-[5-(2-fluorophenoxy)-7-isobutyloxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethylphenoxy}acetate with trifluoroacetic acid gave 33 mg (56%) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:34][CH:35]([F:37])[F:36])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:32])[NH:27][CH:28]3[CH2:31][CH2:30][CH2:29]3)=[CH:22][C:21]=1[Cl:33])[C:10]([CH2:17][CH3:18])=[N:11]2.[OH-].[Li+]>O1CCCC1>[Cl:33][C:21]1[CH:22]=[C:23]([C:26](=[O:32])[NH:27][CH:28]2[CH2:31][CH2:30][CH2:29]2)[CH:24]=[CH:25][C:20]=1[CH2:19][C:9]1[C:10]([CH2:17][CH3:18])=[N:11][C:12]2[C:7]([C:8]=1[O:34][CH:35]([F:37])[F:36])=[C:6]([O:5][CH2:4][C:3]([OH:38])=[O:2])[CH:15]=[CH:14][C:13]=2[F:16]
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(C(=O)NC2CCC2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(C(=O)NC2CCC2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of [3-(2-chloro-4-cyclobutylcarbamoylbenzyl)-4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy]acetic acid methyl ester (0.23 g), tetrahydrofuran (5.0 mL) and 1.0 M aqueous lithium hydroxide solution (1.2 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, acidified by the addition of sodium dihydrogenphosphate and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure. Purification of the residue by column chromatography on C-18 column, eluting with a mixture of water and methanol gave title compound as an off-white solid, 0.13 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]2[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:3]1>CO.[Pd]>[CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]2[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:3]1
Reactant: CC1(C)CN(c2ncccc2[N+](=O)[O-])c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CC1(C)CN(c2ncccc2N)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
To a solution of 4a (30 mg, 0.111 mmol) in MeOH was added 10% Pd/C (10 mg). The reaction mixture was stirred at rt under H2 for 2 h. The catalyst was filtered through a cake of Celite® and the filtrate was evaporated under reduced pressure to afford 4b (20 mg, 76%) as a yellowish powder. MS (ES) m/z 240 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCC)(=O)C>C1COCC1>[C:13]1([S:19]([N:8]2[C:9]3=[N:10][C:2]([Cl:1])=[CH:3][CH:4]=[C:5]3[CH:6]=[CH:7]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1ccc2cc[nH]c2n1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2ccc(Cl)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
6-Chloro-7-azaindole (9.3 g, 61.1 mmol), prepared as described (Synthesis, 1992), was dissolved in 100 ml anhydrous THF under N2. At 0° C., a 60% dispersion of NaH 3.5 g (65.9 mmol) in mineral oil was added. After stirring for 1 hour at room temperature, the mixture was cooled (0° C.) and 8.7 ml (67.2 mmol) benzenesulfonyl chloride dissolved in 20 ml anhydrous THF was added. The reaction mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the mixture and the organic layer was washed three times with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether/PE gradient (1:4 to pure diethyl ether) to give 1-benzenesulfonyl-6-chloro-1H-pyrrolo[2,3-b]pyridine (amorphous, 14.4 g, 80.7%) (TLC diethyl ether/PE (1/1) Rf 0.37). LCMS; Rt: 1.98 min, ([M+H]+=293).
Reaction SMILES: C[N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)=O.Cl.NC1[N:21]=[CH:22][NH:23][C:24]=1[C:25]([NH2:27])=[O:26].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH3:16][O:15][C:9]1[CH:8]=[C:7]([C:5]2[N:21]3[CH:22]=[N:23][C:24]([C:25]([NH2:27])=[O:26])=[C:17]3[N:2]=[CH:3][CH:4]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: NC(=O)c1[nH]cnc1N
Reactant: COc1ccc(C(=O)C=CN(C)C)cc1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(-c2ccnc3c(C(N)=O)ncn23)cc1OC
Yield: 53.8 %

Procedure:
A stirred mixture of 15.0 g of 3-dimethylamino-3',4'-dimethoxyacrylophenone (prepared as described in Example 6) and 8.0 g of 4-amino-5-imidazolecarboxamide hydrochloride in 150 ml of glacial acetic acid was heated at reflux for 24 hours. The solvent was evaporated in vacuo to give an oil. The oil solidified on standing at room temperature, and this was treated with 200 ml of saturated sodium bicarbonate solution and then it was filtered to collect the crystals. The material was treated by boiling with 700 ml of ethanol and then was filtered. The solid was recrystallized from methanol-chloroform to give 7.9 g of the desired product, mp 262°-265° C.