Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[NH2:28][C:29]1[CH:30]=[C:31]([CH:35]([NH:37][C:38]2[C:47]3[C:42](=[C:43]([C:48]([NH2:50])=[O:49])[CH:44]=[CH:45][CH:46]=3)[N:41]=[CH:40][N:39]=2)[CH3:36])[CH:32]=[CH:33][CH:34]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH:28][C:29]1[CH:30]=[C:31]([CH:35]([NH:37][C:38]2[C:47]3[C:42](=[C:43]([C:48]([NH2:50])=[O:49])[CH:44]=[CH:45][CH:46]=3)[N:41]=[CH:40][N:39]=2)[CH3:36])[CH:32]=[CH:33][CH:34]=1)=[O:7]
Reactant: CC(Nc1ncnc2c(C(N)=O)cccc12)c1cccc(N)c1
Reactant: COc1ccc(C(=O)O)cc1F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2cccc(C(C)Nc3ncnc4c(C(N)=O)cccc34)c2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.5 %

Procedure:
To a solution of 3-fluoro-4-methoxybenzoic acid (26.00 mg; 0.15 mmol; 1.00 eq.) in DMF were added bis(2-oxo-1,3-oxazolidin-3-yl)phosphinic chloride (35.01 mg; 0.14 mmol; 0.90 eq.), 4-{[1-(3-aminophenyl)ethyl]amino}quinazoline-8-carboxamide (41.33 mg; 0.13 mmol; 0.88 eq.), and N-ethyl-N-isopropylpropan-2-amine (0.07 ml; 0.38 mmol; 2.50 eq.). The reaction mixture was stirred overnight at RT. Purified the crude by HPLC to obtain 20 mg of the title product in 28% yield. MS (M+1) 460
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4](=[O:27])[C:5](=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:6]([CH:8]=[CH:9][CH:10]([OH:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1.C(OCC)(=[O:30])C.C(=O)([O-])O.[Na+]>CO.O>[CH3:1][S:2]([C:3]1[C:4](=[O:27])[C:5](=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:6]([CH:8]=[CH:9][CH:10]([OH:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1)=[O:30]
Reactant: CCOC(C)=O
Reactant: CCCCCC(O)C=CC1C=C(SC)C(=O)C1=CCCCCCC(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCC(O)C=CC1C=C(S(C)=O)C(=O)C1=CCCCCCC(=O)OC
Reaction time: 0.5 h
Yield: 16 %

Procedure:
To a solution of 17.6 mg of 2-methylthio-5-(6-methoxycarbonylhexylidene)-4-(3-hydroxy-1-octenyl)-2-cyclopentenone obtained in Example 34 in methanol (0.5 ml) was added a solution of 2KHSO5 ·KHSO4 ·K2SO4 (27.4 mg) in water (0.2 ml) at 0° C., and the mixture was stirred for 30 minutes. To the reaction mixture were added ethyl acetate and saturated aqueous sodium hydrogencarbonate, and the product was extracted into the organic layer. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and filtered, followed by concentration. The concentrate was subjected to silica gel chromatography to obtain 3 mg (yield 16%) of 2-methylsulfinyl-5-(6-methoxycarbonylhexylidene)-4-(3-hydroxy-1-octenyl)-2-cyclopentenone.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[F:23][C:24]1[CH:25]=[C:26]([C:31]2([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:36][CH2:35][CH2:34][NH:33][C:32]2=O)[CH:27]=[CH:28][C:29]=1[F:30]>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:25]=[C:26]([C:31]2([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:36][CH2:35][CH2:34][NH:33][C:32]2=[S:10])[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C1(c2ccc(F)c(F)c2)CCCNC1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(c2ccc(F)c(F)c2)CCCNC1=S
Temperature: 110 °C
Reaction time: 4 h
Yield: 116.1 %

Procedure:
Under an argon atmosphere, Lawesson's reagent (1.00 g) was added to a suspension of ethyl 3-(3,4-difluorophenyl)-2-oxopiperidine-3-carboxylate (1.00 g) in toluene (20 ml) at room temperature. The reaction mixture was stirred at 110° C. for 4 hr, and allowed to cool to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (859 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[F:35][C:36]1[CH:37]=[C:38]([CH:40]=[C:41]([F:43])[CH:42]=1)[NH2:39].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[F:35][C:36]1[CH:37]=[C:38]([NH:39][C:27]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:33])[CH:40]=[C:41]([F:43])[CH:42]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cc(F)cc(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cc(F)cc(F)c4)cc3)c2cc1OC
Yield: 64.3 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (50 mg) was dissolved in toluene (5 ml) with heat, after the addition of triethylamine (1 ml), triphosgene (55 mg) was added, and the admixture was refluxed with heat for 3 minutes. 3,5-Difluoroaniline (66 mg) was added to the reaction mixture, and the admixture was refluxed with heat for 20 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 49 mg of the title compound (yield: 64%).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:32]1([CH2:38][CH2:39][S:40][CH:41]([C:45](O)=[O:46])[C:42](O)=[O:43])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[OH:46][C:45]1[CH:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([S:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:9][CH:10]=2)[O:16][C:42](=[O:43])[C:41]=1[S:40][CH2:39][CH2:38][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(=O)c1ccc(Sc2ccccc2)cc1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(Sc3ccccc3)cc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-(phenylthio)acetophenone (1.15 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (56 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 120-121° C.; 1H NMR (400 MHz, DMSO-d6) δ2.76 (t, 2 H), 2.98 (t, 2 H), 6.72 (s, 1 H), 7.24 (m, 7 H), 7.45 (m, 5 H), 7.74 (d, 2 H).
Reaction SMILES: C([BH3-])#N.[Na+].[CH2:5]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH3:7]>C(O)(=O)C>[CH2:5]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9]1)[CH2:6][CH3:7]
Reactant: CCCc1cc2ccccc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCC1Cc2ccccc2N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.3 g (20 mmol) sodium cyanoborohydride were added to 0.75 g (4.7 mmol) 2-propyl-1H-indole in 10 mL conc. acetic acid and the mixture was stirred for 5 h at RT. The reaction mixture was evaporated down. The residue was mixed with 20 mL of a 4N HCl solution and stirred for 1 h at RT. Then 45 mL of a 4N sodium hydroxide solution was slowly added while cooling with ice and the mixture was extracted with ethyl acetate. The organic phase was dried on sodium sulphate and evaporated down.
Reaction SMILES: [CH3:1][N:2]([CH:12]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13]1)[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][CH:4]=1>C(O)C.[Pd]>[CH3:1][N:2]([CH:12]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13]1)[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1
Reactant: CN1CCC(N(C)c2ccc([N+](=O)[O-])cc2)C1
Agent: [Pd]
Solvent: CCO
Product: CN1CCC(N(C)c2ccc(N)cc2)C1
Yield: 93 %

Procedure:
A solution of methyl-(1-methyl-pyrrolidin-3-yl)-(4-nitro-phenyl)-amine (0.25 g, 1.1 mmol) in ethanol (20 mL) is hydrogenated overnight at atmospheric pressure over 10% Pd/C. The mixture is filtered through a pad of diatomaceous earth and concentrated under reduced pressure to give N-methyl-N-(1-methyl-pyrrolidin-3-yl)-benzene-1,4-diamine as a dark oil (0.21 g, 95%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[Cl:45][C:46]1[CH:50]=[C:49]([CH2:51][CH2:52][OH:53])[NH:48][C:47]=1[C:54](O)=[O:55].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:45][C:46]1[CH:50]=[C:49]([CH2:51][CH2:52][OH:53])[NH:48][C:47]=1[C:54]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:28]=1[F:44])=[O:55]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: O=C(O)c1[nH]c(CCO)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(CCO)cc3Cl)c2F)c1
Reaction time: 2 h
Yield: 2.2 %

Procedure:
HATU (0.057 g, 0.15 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.047 g, 0.15 mmol), 3-chloro-5-(2-hydroxyethyl)-1H-pyrrole-2-carboxylic acid (0.028 g, 0.15 mmol) and DIPEA (0.026 mL, 0.150 mmol) in DMF (2 mL). The resulting solution was stirred for 2 hours then partitioned between water and EtOAc. The organic layer was separated, dried over MgSO4 and evaporated to a residue. The residue was purified by reverse-phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.0016 g, 2%) as a film. 1H NMR (400 MHz, Acetone-d6) δ ppm 7.60-7.68 (m, 1H), 7.48-7.53 (m, 1H), 7.41-7.45 (m, 2H), 7.37-7.40 (m, 2H), 6.03 (d, 1H), 4.69 (d, 2H), 3.78 (t, 2 H), 2.82 (t, 2H). LCMS: m/z=479.9 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[C:25]1([CH:31]2[CH2:40][CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([O:41][CH:42]4[CH2:47][CH2:46][CH:45](O)[CH2:44][CH2:43]4)[CH:37]=3)[O:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl.CN(C)C1C=CN=CC=1>[C:25]1([CH:31]2[CH2:40][CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([O:41][CH:42]4[CH2:47][CH2:46][CH:45]([O:5][C:4](=[O:6])[C:3]5[CH:7]=[CH:8][N:9]=[CH:10][C:2]=5[F:1])[CH2:44][CH2:43]4)[CH:37]=3)[O:32]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)c1ccncc1F
Reactant: OC1CCC(Oc2ccc3c(c2)CCC(c2ccccc2)O3)CC1
Agent: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OC1CCC(Oc2ccc3c(c2)CCC(c2ccccc2)O3)CC1)c1ccncc1F
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
To a solution of 158 mg of 3-fluoroisonicotinic acid (1.12 mmol) and 156 μl of triethylamine (1.12 mmol) in 16 ml of dichloromethane at 15° C. 138 μl of pivaloyl chloride (1.12 mmol) were added dropwise. The solution was stirred for 30 min. A solution of 110 mg of 4-(2-phenyl-chroman-6-yloxy)-cyclohexanol (0.34 mmol) in 4 ml of dichloromethane was added and 82 mg of 4-dimethylamino-pyridine (0.68 mmol) were added in one portion. Stirring at room temperature was continued for 16 h. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution, and the aqueous layer extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and filtered, and the solvent removed by evaporation. The resulting oil was purified by reversed phase HPLC. 104 mg of the title compound were isolated as solid (69%).
Reaction SMILES: [Li+].[OH-].C([O:5][C:6](=[O:25])[CH2:7][NH:8][C:9](=[O:24])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)C>C1COCC1.CO.O>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([NH:8][CH2:7][C:6]([OH:25])=[O:5])=[O:24])=[CH:11][CH:12]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)CNC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CNC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
LiOH (1.32 g, 31.5 mmol) was added to a stirred solution of (4-benzyloxy-benzoylamino)-acetic acid ethyl ester (2.47 g, 7.8 mmol) in THF:MeOH:H2O (2:2:1, 50 mL). The resulting mixture was stirred at room temperature overnight. The MeOH and THF were evaporated and the residue was diluted with water (20 mL) and acidified with 10% HCl solution. The resulting precipitate was washed with water followed by hexane and dried to afford 2.03 g (90.6 yield) of (4-benzyloxy-benzoylamino)-acetic acid. 1H NMR: (DMSO) δ 7.9 (d, 2H), 7.8 (s, 1H), 7.5 (m, 5H), 7.1 (d, 2H), 5.2 (s, 2H), 3.6 (d, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][N:10]2[CH:14]=[CH:13][CH:12]=[C:11]2[C:15]([O:17]C)=O)=[CH:4][CH:3]=1.[CH2:20]([NH2:23])[CH2:21][NH2:22]>O1CCOCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[NH:23][CH2:20][CH2:21][N:22]2[C:15](=[O:17])[C:11]2[N:10]([CH:14]=[CH:13][CH:12]=2)[CH2:9]3)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccn1CC(=O)c1ccc(O)cc1
Reactant: NCCN
Solvent: C1COCCO1
Product: O=C1c2cccn2CC2(c3ccc(O)cc3)NCCN12
Yield: 86.8 %

Procedure:
To a solution of methyl 1-[2-(4-hydroxyphenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylate (200 mg, 0.77 mmol) in 1,4-dioxane (40 mL) was added ethane-1,2-diamine (1 mL, 15 mmol), after 48 h extra ethane-1,2-diamine (1 mL, 15 mmol) was added and the mixture heated for 48 additional hours. After that time 90% of the starting material was converted into the above product. The resulting mixture was then concentrated in vacuo to give a residue that was purified by flash chromatography (Biotage SP4, 12 g cartridge, gradient 0-10% MeOH in CH2Cl2) to give 10a-(4-hydroxyphenyl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (180 mg, yield: 86%). ESI-MI m/z [M+H]+ 270.1.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6](Cl)=[O:7].[OH:29][CH:30]([CH2:35][CH3:36])[C:31]([O:33][CH3:34])=[O:32].C(N(CC)CC)C.CCOCC>C(Cl)Cl>[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]([O:29][CH:30]([C:31]([O:33][CH3:34])=[O:32])[CH2:35][CH3:36])=[O:7]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1F
Reactant: CCC(O)C(=O)OC
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC(CC)C(=O)OC)cc1F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 10.0 g 3-fluoro-4-(hexadecylamino)-benzoyl chloride hydrochloride in 200 ml methylene chloride is added dropwise a solution of 3 g. methyl α-hydroxybutyrate and 5 g triethylamine in 100 ml. ether. After 17 hours stirring at room temperature, the precipitate is collected and washed with several portions of ether. The ether solution is washed with water, dried and evaporated to yield 1-(methoxycarbonyl)propyl 3-fluoro-4-(hexadecylamino)benzoate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[C:16]([C:20]([O:22]C)=[O:21])[CH:17]=[CH:18][CH:19]=3)[C:11](=[O:24])[N:10]([CH2:25][C:26]3[NH:30][C:29]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]([F:41])([F:40])[F:39])=[N:28][N:27]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[C:16]([C:20]([OH:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[C:11](=[O:24])[N:10]([CH2:25][C:26]3[NH:30][C:29]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]([F:39])([F:40])[F:41])=[N:28][N:27]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(Cn2c(-c3ccc(Cl)cc3)nn(Cc3nnc(Cc4ccccc4C(F)(F)F)[nH]3)c2=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cccc(Cn2c(-c3ccc(Cl)cc3)nn(Cc3nnc(Cc4ccccc4C(F)(F)F)[nH]3)c2=O)c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
62 mg (0.11 mmol) of the compound from Example 28 were suspended in 1 ml of ethanol, and 213 μl (0.21 mmol) of 1 M aqueous sodium hydroxide solution were added. The mixture was stirred at 50° C. for 4 h. After cooling to RT, the reaction was neutralized with 215 μl of 1 M hydrochloric acid and concentrated under reduced pressure, and the residue was purified by chromatography [Method 19]. This gave 37 mg (61% of theory) of the target compound as a colorless foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]3[NH:22][C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[N:19]=3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.CN(C)C(=O)C.[H-].[Na+].Cl[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[F:43]>O>[F:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][N:22]1[C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[N:19]=[C:18]1[CH2:17][CH:14]1[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:12][CH2:13]1
Reactant: Fc1ccccc1CCl
Reactant: COc1ccc(CCN2CCC(Cc3nc4ccccc4[nH]3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc(CCN2CCC(Cc3nc4ccccc4n3Cc3ccccc3F)CC2)cc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 65.5 %

Procedure:
To a stirred mixture of 3.5 parts of 2-[[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]methyl]-1H-benzimidazole and 18 parts of N,N-dimethylacetamide were added portionwise 0.5 parts of a sodium hydride dispersion 59.4% at room temperature. After stirring for 35 minutes at room temperature and for 10 minutes at 60° C., a solution of 1.7 parts of 1-(chloromethyl)-2-fluorobenzene in 9 parts of N,N-dimethylacetamide was added dropwise at 60° C. After stirring for 10 minutes, the reaction mixture was cooled and poured into 150 parts of water. The product was extracted twice with 4-methyl-2-pentanone. The combined extracts were washed with water, dried, filtered and evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and 2-propanone. The product was filtered off and dried, yielding 3.0 parts (65.5%) of 1-[(2-fluorophenyl)methyl]-2-[[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]-methyl]-1H-benzimidazole; mp. 109.3° C. (515).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([Br:12])=[CH:4][N:3]=1.[C:13]1([CH:19]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Br:12][C:5]1[C:6]([N:24]2[CH2:25][CH2:26][N:21]([CH:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:20])[CH2:22][CH2:23]2)=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Reactant: CC(c1ccccc1)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(c1ccccc1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Temperature: 45 °C
Reaction time: 20 h

Procedure:
To a mixture of 2-amino-5-bromo-4-chloro-3-nitropyridine (0.252 g, 1.00 mmol) and isopropanol (18 ml) was added 1-(1-phenylethyl)piperazine (0.209 g, 1.10 mmol) followed by diisopropylethylamine (0.20 ml, 1.15 mmol). The reaction mixture was stirred at 45° C. for 20 h, then allowed to cool to room temperature and diluted with isopropanol (10 ml). The resulting precipitate was collected by filtration, washed with isopropanol (3×5 ml), diethyl ether (3×5 ml), and dried. The title compound was obtained as a yellow solid (0.300 g, 74%). 1H-NMR (500 MHz, DMSO-d6) 1.30 (d, J=6.7 Hz, 3H, CHCH3), 2.42 (m, 2H) and 2.54 (m, 2H) (piperazine N(CH2)2), 3.03 (br s, 4H, piperazine N(CH2)2), 3.45 (q, J=6.7 Hz, 1H, CHCH3), 6.95 (s, 2H, NH2), 7.23 (m, 1H) and 7.32 (m, 4H) (PhH), 8.13 (s, 1H, pyridine 6-H);
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)[C:10]2=[O:19])[CH2:5][CH2:4]1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[N:22]=1.C(N(CC)CC)C.CN1CCCC1=O>[Cu]I>[OH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][CH2:16][N:15]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[N:22]=4)[CH2:14]3)[C:10]2=[O:19])[CH2:5][CH2:4]1
Reactant: O=C1N([C@H]2CC[C@H](O)CC2)CCC12CCCNC2
Reactant: COc1cccc(Br)n1
Agent: [Cu]I
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COc1cccc(N2CCCC3(CCN([C@H]4CC[C@H](O)CC4)C3=O)C2)n1

Procedure:
A mixture of 2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one hydrochloride (35 mg, 0.00012 mol), 2-bromo-6-methoxypyridine (34 mg, 0.00018 mol), triethylamine (200 μL, 0.001 mol), and copper(I) iodide (28 mg, 0.00014 mol) in N-methylpyrrolidinone (1.0 mL, 0.010 mol) was microwave irradiated at 180° C. for 20 min. After allowing the reaction mixture to cool to rt the crude mixture was purified by prep.-HPLC to afford 8.3 mg of the desired product. LC-MS: 360.3 (M+H)+.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:25](=[O:26])[C:14]3[CH:15]=[N:16][C:17]4[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[N:12]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:11]2=[O:33])[CH:7]=[CH:8][CH:9]=1.[CH:34]([N:37]=[C:38]=[O:39])([CH3:36])[CH3:35]>>[CH:34]([NH:37][C:38]([N:30]1[CH2:31][CH2:32][CH:27]([N:12]2[C:13]3[C:22]4[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH3:24])[C:17]=4[N:16]=[CH:15][C:14]=3[C:25](=[O:26])[N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=3)[C:11]2=[O:33])[CH2:28][CH2:29]1)=[O:39])([CH3:36])[CH3:35]
Reactant: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCNCC3)c12
Reactant: CC(C)N=C=O
Agent: Cl
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCN(C(=O)NC(C)C)CC3)c12

Procedure:
4-[3-(3-Chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido[5,4-c]quinolin-1-yl]-piperidine-1-carboxylic acid isopropylamide (39 mg) was prepared according to general procedure H from 3-(3-chloro-phenyl)-7-methoxy-1-piperidin-4-yl-1H-pyrimido[5,4-c]quinoline-2,4-dione.dihydrochloride (50 mg, 0.10 mmol) and isopropyl isocyanate. LCMS: m/z 508 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:14][O:13][CH:12]1[C:20]([F:23])([F:22])[F:21].[SiH](CC)(CC)CC>C(Cl)(Cl)Cl.O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:12][C:20]([F:23])([F:22])[F:21])[C@H:15]([CH2:16][CH:17]([CH3:18])[CH3:19])[CH2:14][OH:13]
Reactant: CC(C)C[C@@H]1COC(C(F)(F)F)N1c1ccc([N+](=O)[O-])cc1F
Agent: CC[SiH](CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)C[C@H](CO)N(CC(F)(F)F)c1ccc([N+](=O)[O-])cc1F
Yield: 43.4 %

Procedure:
To a solution of (4R)-3-(2-fluoro-4-nitrophenyl)-4-isobutyl-2-trifluoromethyloxazolidine (4.8 g, 14.3 mmol) and Et3SiH (21.6 g, 186 mmol) in 60 mL chloroform was added BF3OEt2 (14.2, 60 mmol, added in portions) The reaction was heated at reflux for 1 d After cooling, the reaction was poured in water (200 mL) and extracted with chloroform (3 ×150 mL). The organic layers were combined, washed sequentially with water (200 mL) and brine (200 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to a brown oil. Flash chromatography (gradient elution, hexanes:ethyl acetate 95:5 to 3:1) afforded 2.1 g (44%) of (2R)-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-4-methyl-1-pentanol, an orange oil. Data for (2R)-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-4-methyl-1-pentanol: Rf0.8 (3:1 hexanes:EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.98 (dd, 1H, J=9.3, 2.4), 7.94 (dd, 1H, J=12.9, 2.5), 7.40 (dd, 1H, J=8.7, 8.7), 4.21–4.10 (m, 1H), 3.89–3.78 (m, 1H), 3.79–3.65 (m, 3H), 1.96–1.89 (m, 1H), 1.67–1.54 (m, 1H), 1.55–1.44 (m, 1H), 1.32–1.22 (m, 1H), 0.91 (d, 3H, J=6.6), 0.77 (d, 3H, J=6.6).