Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)=[C:2]=[O:3].[N:11]1([C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:10][C:7]1[CH:8]=[CH:9][C:4]([NH:1][C:2]([N:14]2[CH2:13][CH2:12][N:11]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=3)[CH2:16][CH2:15]2)=[O:3])=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc(N=C=O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N2CCN(C(=O)Nc3ccc(C)cc3)CC2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 2.7 %

Procedure:
A solution of 1-isocyanato-4-methyl-benzene (0.051 mol) in DCM p.a. (75 ml) was added dropwise to a solution of 4-(1-piperazinyl)-benzoic acid, ethyl ester (0.043 mol) and triethylamine (0.051 mol) in DCM p.a. (75 ml) while stirring at 0° C. (ice) for 20 minutes. The reaction mixture was stirred at room temperature for 1 hour and was then extracted with water. The organic layer was extracted with a saturated NaCl-solution and again with water, then separated, dried (MgSO4), filtered off and the filtrate was evaporated. The residue was stirred in DIPE and the formed precipitate was filtered off, washed with DIPE and dried. A part (0.5 g) of the residue (14.3 g, 90%) was crystallized from 2-propanol (10 ml) and the formed precipitate was filtered off and dried, yielding 0.42 g of 4-[4-[[(4-methylphenyl)amino]carbonyl]-1-piperazinyl]-benzoic acid, ethyl ester (interm. 1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:33][NH:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6](=[O:41])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][C:27]([NH2:30])=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:33][NH:34][C:35]([O:37][CH:38]([CH3:39])[CH3:40])=[O:36])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1oc(-c2ccc([N+](=O)[O-])cc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CNC(=O)OC(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccc(N)cc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CNC(=O)OC(C)C)c1
Reaction time: 18 h
Yield: 99.9 %

Procedure:
A mixture of 3-(2-(isopropoxycarbonylamino-methyl)-4-{2-[5-methyl-2-(4-nitro-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionic acid tert-butyl ester (207 mg, 0.365 mmol) and 10% Pd—C (27 mg) in EtOAc (20 mL) was stirred under H2 (1 atm) for 18 h. The reaction mixture was filtered through Celite and concentrated (75° C.) to give the title compound as a colorless oil (196 mg, 100%): MS (ESI) m/z 538 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[O:25]1[C:29]2[CH:30]=[CH:31][C:32](B(O)O)=[CH:33][C:28]=2[O:27][CH2:26]1.O1CCOCC1>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([C:2]3[N:7]4[N:8]=[CH:9][CH:10]=[C:6]4[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]4[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=4)[CH:3]=3)=[CH:33][C:28]=2[O:27][CH2:26]1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(-c3ccc4c(c3)OCO4)n3nccc3n2)cc1
Temperature: 100 °C
Yield: 47.3 %

Procedure:
A suspension of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 200 mg, 0.604 mmol), benzo[d][1,3]dioxol-5-ylboronic acid (200 mg, 1.21 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (35 mg, 48 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (2 mL of 1,4-dioxane and 1 mL of saturated aqueous NaHCO3) was prepared in a 2 mL microwave reaction vessel and the sealed reaction vessel warmed to 100° C. for 20 minutes. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC, 5-95% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a green solid (119 mg, 47%). 1H NMR (DMSO-d6) δ: 11.23 (s, 1H), 8.19 (d, J=2.3 Hz, 1H), 7.94-8.10 (m, 3H), 7.72 (d, J=1.5 Hz, 1H), 7.57-7.67 (m, 3H), 7.17 (d, J=8.3 Hz, 1H), 6.57 (d, J=2.3 Hz, 1H), 6.18 (s, 2H), 5.20 (s, 1H), 1.46 (s, 6H). ESI-MS: m/z 417.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]([CH3:27])([CH2:11][CH2:12][CH2:13][CH:14]([CH3:26])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:3][CH2:4][C:5](=O)[CH2:6][C:7](=O)[CH3:8].[CH3:28][O:29][C:30]([CH2:32][C:33]([CH2:35][C:36]([O:38][CH3:39])=[O:37])=[O:34])=[O:31].C[O-].[Na+]>CO>[OH:34][C:33]1[C:35]([C:36]([O:38][CH3:39])=[O:37])=[C:7]([CH3:8])[CH:6]=[C:5]([CH2:4][CH2:3][C:2]([OH:1])([CH3:27])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:26])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:23])[CH3:24])[C:32]=1[C:30]([O:29][CH3:28])=[O:31]
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: CC(=O)CC(=O)CCC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(C)cc(CCC(C)(O)CCCC(C)CCCC(C)CCCC(C)C)c(C(=O)OC)c1O
Temperature: 25 °C
Reaction time: 44 h
Yield: 103.5 %

Procedure:
To a solution of 7-hydroxy-7,11,15,19-tetramethyleicosane-2,4-dione (72.5 g) and dimethyl acetonedicarboxylate (29.6 g) in methanol (190 ml) at 0° was added a solution of sodium methoxide in methanol (from 2.44 g of sodium and 90 ml of methanol). The solution was stirred at room temperature for 44 hr and was concentrated on a rotary evaporator to remove approx. 100 ml of methanol. The residual solution was poured onto ice (500 g) and 20% (v/v) aqueous hydrochloric acid (45 ml). The mixture was extracted with ether (3×300 ml) and the combined extracts were washed with brine and dried over anhydrous sodium sulfate and were concentrated on a rotary evaporator to give 91.65 g of crude dimethyl 2-hydroxy-4-methyl-6-(3-hydroxy-3,7,11,15-tetramethyl-hexadecanyl)-benzene-1,3-dicarboxylate as an orange oil. A 90.2 g portion of the oil was dissolved in ether (400 ml) and was washed with 20% by weight aqueous potassium carbonate (to remove the unreacted dimethyl acetonedicarboxylate), brine and was dried over anhydrous sodium sulfate. The solution was concentrated on a rotary evaporator to give 83.13 g of partially purified diester dimethyl 2-hydroxy-4-methyl-6-(3-hydroxy-3,7,11,15-tetramethyl-hexadecanyl)-benzene-1,3-dicarboxylate. The total material was chromatographed on 2.45 kg of silica gel eluting with 20-30% by volume ether in hexane to give 30.83 g of dimethyl 2-hydroxy-4-methyl-6-(3-hydroxy-3,7,11,15-tetramethyl-hexadecanyl)-benzene-1,3-dicarboxylate as a colorless oil. EXAMPLE 4
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:5]=[C:4](OS(C(F)(F)F)(=O)=O)[C:3]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[CH2:30][CH2:29]1)=[O:27].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:85][O:86][C:87]1[CH:94]=[CH:93][C:90]([CH2:91][NH2:92])=[CH:89][CH:88]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:85][O:86][C:87]1[CH:94]=[CH:93][C:90]([CH2:91][NH:92][C:4]2[C:3]([C:26]([N:28]3[CH2:29][CH2:30][CH:31]([N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)[CH2:32][CH2:33]3)=[O:27])=[C:2]([CH3:1])[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)[N:5]=2)=[CH:89][CH:88]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)nc(OS(=O)(=O)C(F)(F)F)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: COc1ccc(CN)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Product: COc1ccc(CNc2nc(-c3cccc(C(F)(F)F)c3)cc(C)c2C(=O)N2CCC(N3CCCC3)CC2)cc1

Procedure:
In analogy to the procedure described for the preparation of example 6, trifluoro-methanesulfonic acid 4-methyl-3-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-6-(3-trifluoromethyl-phenyl)-pyridin-2-yl ester (intermediate 10) was reacted with [rac]-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, palladium(II) acetate and 4-methoxy-benzylamine to give the title compound as yellow oil. MS: 553.4 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]([NH2:25])=[O:24])[C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[C:9]([C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16])[CH:8]=3.[CH2:26]([O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)[CH3:27].C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>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.CO>[CH2:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:3]=[C:4]([C:23]([NH2:25])=[O:24])[C:5]3[NH:6][C:7]4[C:12]([C:13]=3[CH:14]=2)=[CH:11][CH:10]=[C:9]([C:15]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[O:16])[CH:8]=4)=[CH:31][CH:30]=1)[CH3:27]
Reactant: CCOc1ccc(B(O)O)cc1
Reactant: NC(=O)c1cc(Br)cc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
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: CO
Solvent: Cc1ccccc1
Product: CCOc1ccc(-c2cc(C(N)=O)c3[nH]c4cc(C(=O)N5CCOCC5)ccc4c3c2)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 17.6 %

Procedure:
3-Bromo-7-(morpholine-4-carbonyl)-9H-carbazole-1-carboxamide (57 mg, 0.142 mmol), 4-ethoxyphenylboronic acid (35.3 mg, 0.213 mmol), Pd(Ph3P)4 (16.37 mg, 0.014 mmol) and aqueous Na2CO3 (2M) (0.177 mL, 0.354 mmol) were mixed with toluene (2 mL) and MeOH (1 mL) in a sealed microwave tube. The mixture was degassed and filled with N2. then stirred at 100° C. for 12 hrs. The reaction mixture was concentrated and purified using preparative HPLC to give 11.1 mg of titled product. MS (ESI) m/z 444.21 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.53 (s, 1H), 8.64 (s, 1H), 8.37 (bs, 1H), 8.29 (m, 2H), 7.81 (m, 3H), 7.56 (bs, 1H), 7.22 (d, 1H, J=8), 7.07(m, 2H), 4.10 (q, 2H, J=6.9), 3.64 (bm, 8H), 1.37 (t, 3H, J=6.9).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20]Br>C(O)C>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1
Reactant: O=C1CCNCC1
Reactant: Clc1ccc(CBr)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a suspension of 4-piperidone hydrochloride (3.52 g, 22.9 mmol) in ethanol (40 ml) was added triethylamine (10.8 ml, 91.6 mmol), followed by the addition of 3,4-dichlorobenzyl bromide (5.0 g, 20.8 mmol) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and the residue was partitioned between water and ethyl acetate. The ethyl acetate layer was separated, washed with brine, dried over magnesium sulfate and concentrated in vacuo. Column chromatography with 25% ethyl acetate and 25% dichloromethane in hexanes gave 1-(3,4-dichlorobenzyl)-4-piperidone (4.4 g) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:14])=[O:11])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc(Br)cc1
Solvent: ClCCl
Product: O=C(Cl)Cc1ccc(Br)cc1
Yield: 73.1 %

Procedure:
To a stirred solution of 4-bromo-phenyl acetic acid (25 g, 116 mmol) in dichloromethane (250 ml) was added thionyl chloride (13 ml, 170 mmol). The mixture was heated under reflux for 24 hours and then the solvent and the excess reagent were removed. The residue was distilled under reduced pressure (110° C./2 mmHg) to yield 19.8 g (73%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[NH2:11])=[O:5])[CH3:2].[CH3:12][C:13]1[C:21]2[N:20]=[C:19]([CH:22]=O)[NH:18][C:17]=2[CH:16]=[CH:15][C:14]=1[CH3:24].CC(O)=O.[BH3-]C#N.[Na+].[OH-].[Na+]>CO>[CH3:12][C:13]1[C:21]2[N:20]=[C:19]([CH2:22][NH:11][C:10]3[CH:9]=[CH:8][NH:7][C:6]=3[C:4]([O:3][CH2:1][CH3:2])=[O:5])[NH:18][C:17]=2[CH:16]=[CH:15][C:14]=1[CH3:24]
Reactant: CCOC(=O)c1[nH]ccc1N
Reactant: Cc1ccc2[nH]c(C=O)nc2c1C
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)c1[nH]ccc1NCc1nc2c(C)c(C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.5 %

Procedure:
3-Amino-1H-pyrrole-2-carboxylic acid ethyl ester (0.077 g, 0.5 mmol), 4,5-dimethyl-1H-benzimidazole-2-carbaldehyde (0.130 g, 0.75 mmol) and HOAc (0.045 g, 0.75 mmol) were stirred in methanol (4 mL) followed by addition of NaCNBH3. The resulting mixture was stirred at r.t. for 16 h. The reaction mixture was neutralized with 2M NaOH and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and extracted with water. The organic layer was dried (Na2SO4) and concentrated. The crude product was purified by flash column chromatography (heptane/ethyl acetate gradient; 0 to 100% ethyl acetate), obtaining a white solid, 0.043 g (27%) of the title compound, as a tautomeric mixture (1:1).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][CH2:5][CH2:6][NH:7]C(=O)CC.Cl>C(O)C.O>[ClH:1].[NH2:7][CH2:6][CH2:5][O:4][C:3]1[C:2]([Cl:1])=[CH:15][C:14]([F:16])=[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[N:19]([CH3:28])[C:18]2=[O:29])[CH:12]=1
Reactant: CCC(=O)NCCOc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OCCN)c(Cl)cc2F)c1=O

Procedure:
A solution of 17.0 g of N-[2-{2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4 -trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorophenoxy}-ethyl]propionamide in 100 ml of ethanol is heated at reflux temperature for 5 hours with a solution of 75 ml of concentrated hydrochloric acid in 75 ml of water. The ethanol is subsequently distilled off at 50° C. and the clear aqueous solution is neutralized with sodium bicarbonate. The oily precipitate is dissolved in ethyl acetate and the solution is washed with water, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The resinous residue is dissolved in 200 ml of 2N hydrochloric acid at 50° C., the mixture is extracted with a small amount of ethyl acetate and the aqueous phase is evaporated under reduced pressure until crystallization occurs. 50 ml of diethyl ether are subsequently added and the mixture is stirred. The crystals are filtered off under suction, washed with diethyl ether and dried at 50° C. in a vacuum. There is obtained 3-[5-(2-aminoethoxy)-4-chloro-2-fluorophenyl]-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 217°-227° C. (decomposition).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([C:41]1[S:45][N:44]=[N:43][C:42]=1[CH3:46])=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:39]([C:41]2[S:45][N:44]=[N:43][C:42]=2[CH3:46])=[O:40])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CON(C)C(=O)c1snnc1C
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Product: Cc1nnsc1C(=O)c1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N2C[C@@H](C)O[C@@H](C)C2)c(F)c1F

Procedure:
Starting materials: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,3-difluorophenyl]-2,6-dimethylmorpholine (Intermediate 3) and N-methoxy-N,4-dimethyl-1,2,3-thiadiazole-5-carboxamide
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:26]3[O:25][CH2:24][CH2:23][C:22]=3[CH:21]=[CH:20][CH:19]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[O:25]1[C:26]2[C:18]([C:16]([NH:15][C:6]3([C:4]([OH:5])=[O:3])[CH2:14][C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[CH2:7]3)=[O:17])=[CH:19][CH:20]=[CH:21][C:22]=2[CH2:23][CH2:24]1
Reactant: CCOC(=O)C1(NC(=O)c2cccc3c2OCC3)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1cccc2c1OCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
The mixture of 2-[(2,3-Dihydro-benzofuran-7-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (39) (250 mg, 0.71 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (5 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT overnight. After concentration in vacuo, the residue is dissolved in water (30 mL) and acidified with conc. HCl until no more white precipitate came out of the water. The precipitate is filtered to give a pure product (40) as white solid (200 mg, 87%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:31][C:20]3[C:21](=[O:30])[N:22]([CH3:29])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[C:19]=3[N:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[N:31]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:20]3[C:21](=[O:30])[N:22]([CH3:29])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[C:19]=3[N:18]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Cn1c(=O)c2[nH]c(C3CCN(C(=O)OCc4ccccc4)CC3)nc2c2ccccc21
Agent: [H-]
Agent: [Na+]
Product: Cn1c(=O)c2c(nc(C3CCN(C(=O)OCc4ccccc4)CC3)n2Cc2ccccc2)c2ccccc21
Yield: 83.2 %

Procedure:
As described in example 3 step E, 4-(5-methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]quinolin-2-yl)-piperidine-1-carboxylic acid benzyl ester (50 mg, 0.102 mmol), was alkylated by treating with NaH (5 mg, 0.12 mmol, 60% in mineral oil), and benzyl bromide (26 mg, 0.15 mmol) to give after work-up and chromatography, 4-(3-benzyl-5-methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]quinolin-2-yl)-piperidine-1-carboxylic acid benzyl ester (43 mg, 83% yield). 1H-NMR (CDCl3): δ 8.34 (dd, 1H, J=8.0, 1.6 Hz), 7.53 (m, 1H), 7.42 (m, 1H), 7.26–7.37 (m, 9H), 7.10 (m, 2H), 5.91 (m, 2H), 5.13 (s, 2H), 4.28 (m, 2H), 3.79 (s, 3H), 2.89 (m, 3H), 1.98 (m, 2H), 1.68 (m, 2H). MS: calculated for C24H24N4O3+H 507.2; found: 507.6.
Reaction SMILES: [CH2:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH2:15])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][CH2:2]1.N1CCOCC1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[F:22][C:23]([F:32])([F:33])[C:24]1[CH:25]=[CH:26][C:27]([CH:28]=[N:15][C:13]2[C:12]3[C:7]([N:6]=[C:5]4[C:14]=2[CH2:1][CH2:2][CH2:3][CH2:4]4)=[CH:8][CH:9]=[CH:10][CH:11]=3)=[CH:30][CH:31]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: Nc1c2c(nc3ccccc13)CCCC2
Solvent: Cc1ccccc1
Solvent: C1COCCN1
Product: FC(F)(F)c1ccc(C=Nc2c3c(nc4ccccc24)CCCC3)cc1

Procedure:
1,2,3,4-Tetrahydro-9-acridinamine (4.00 g) was refluxed for twenty-four (24) hours in 400 ml of toluene that contained morpholine (3.50 g) and 4-trifluoromethylbenzaldehyde (4.35 g). At this time, an additional 2.0 g of aldehyde was added and reflux was continued for another sixteen (16) hours. At the end of this time the reaction mixture was concentrated and the residue was purified by flash chromatography (CH2Cl2, then 20% EtOAc/CH2Cl2). Fractions containing the product were concentrated and recrystallized from benzene/pentane to give 3.46 g of analytically pure product, m.p. 203°-205° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N+:3]=1[O-:9].C(Cl)(Cl)Cl.O.[N+:15]([O-])([OH:17])=[O:16]>OS(O)(=O)=O>[CH3:1][C:2]1[CH:7]=[C:6]([N+:15]([O-:17])=[O:16])[CH:5]=[C:4]([CH3:8])[N+:3]=1[O-:9]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(C)[n+]1[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc([N+](=O)[O-])cc(C)[n+]1[O-]
Yield: 76 %

Procedure:
A solution of 2.23 g (18.1 mmol) of 2,6-dimethylpyridine 1-oxide (Alfa Aesar) in 7 mL of H2SO4 and 2.7 mL of HNO3 was stirred at 130° C. for 23.5 h. The solution was added to ice with CHCl3 and H2O, and the aqueous layer was extracted with CHCl3 (2×). The combined extracts were washed with 75 mL of saturated NaHCO3 solution, and the aqueous layer was extracted with CHCl3. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to give 2.3 g of 2,6-dimethyl-4-nitropyridine 1-oxide in 76% yield which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=[O:4].ClCCl.[NH2:11][C:12]1[CH:37]=[CH:36][C:15]([O:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][N:23]([C:26]3[N:31]([CH3:32])[C:30](=[O:33])[N:29]([CH3:34])[C:28](=[O:35])[CH:27]=3)[CH2:22][CH2:21]2)=[CH:14][CH:13]=1>C(Cl)(Cl)Cl.[OH-].[Na+]>[CH3:32][N:31]1[C:26]([N:23]2[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][CH2:17][O:16][C:15]3[CH:36]=[CH:37][C:12]([NH:11][C:3](=[O:4])[C:2]([F:7])([F:6])[F:1])=[CH:13][CH:14]=3)[CH2:21][CH2:22]2)=[CH:27][C:28](=[O:35])[N:29]([CH3:34])[C:30]1=[O:33]
Reactant: Cn1c(N2CCN(CCCOc3ccc(N)cc3)CC2)cc(=O)n(C)c1=O
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cn1c(N2CCN(CCCOc3ccc(NC(=O)C(F)(F)F)cc3)CC2)cc(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
0.5 ml of anhydrous trifluoroacetic acid was added dropwise at 0° C. to 20 ml of a dichloromethane solution containing 1.1 g of 6-[4-(3-[4-aminophenoxy]propyl)piperazin-1-yl]-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione obtained in Example 6, and the solution was then stirred at the same temperature for 10 minutes and further at room temperature for 1 hour. Next, the reaction mixture was diluted with 100 ml of chloroform and 50 ml of a 0.5N aqueous sodium hydroxide solution so as to dissolve insolubles therein, and the resultant organic layer was then separated. The aqueous layer was neutralized and then extracted with 50 ml of chloroform, and the extract layer was mixed with the organic layer previously separated and the mixture was dried and then concentrated to obtain 0.52 g (yield: 38% ) of 1,3-dimethyl-6-[4-(3-[4-trifluoroacetylaminophenoxy]propyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.