Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-:18][CH2:19][CH3:20].[Na+].C(Cl)(=O)C.Cl>O1CCCC1>[C:19]([C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:18])[CH3:20]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: C1CCOC1
Product: CCOC(=O)C(C(C)=O)(C(=O)OCC)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of diethyl 2-phenylmalonate (100 mmol) in anhydrous tetrahydrofuran (300 mL) is added sodium ethoxide (110 mmol). The mixture is stirred at room temperature for 30 minutes, followed by the addition of a solution of acetyl chloride (110 mmol) in tetrahydrofuran (50 mL). After the addition is complete, the mixture is heated to reflux for 3 hours, cooled to room temperature, neutralized with 2 N HCl, then concentrated in vacuo. The residue is partitioned between H2O and CHCl3, the organic extracts washed with sodium bicarbonate, water, and brine, dried (MgSO4), filtered and concentrated.
Reaction SMILES: [O:1]([CH2:8][CH:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].Cl>O1CCCC1.O.C(OCC)(=O)C>[O:1]([CH2:8][CH:9]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=1)[CH3:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C(C)COc2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(COc1ccccc1)c1ccc(C(=O)O)cc1

Procedure:
A suspension solution of methyl 4-(1-phenoxypropan-2-yl)benzoate (0.1 g, 0.4 mmol) and lithium hydroxide (48 mg, 2 mmol) in tetrahydrofuran (20 mL) and water (10 mL) was stirred at room temperature for 2 hours. The mixture solution was diluting with ethyl acetate (50 mL), and acidified with hydrochloric acid to PH<4. The organic layer was separated, dried over sodium sulfate, and concentrated to dry. The residue 4-(1-phenoxypropan-2-yl)benzoic acid (60 mg, 65%) was used directly for the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:31]=[C:30]4[C:25]([C:26]([C:36]([O:38]C)=[O:37])=[CH:27][C:28]([C:32]([O:34]C)=[O:33])=[N:29]4)=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[C:12]([CH:40]([CH3:42])[CH3:41])[O:11][N:10]=1.CCO.O.[OH-].[Na+]>C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:31]=[C:30]4[C:25]([C:26]([C:36]([OH:38])=[O:37])=[CH:27][C:28]([C:32]([OH:34])=[O:33])=[N:29]4)=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[C:12]([CH:40]([CH3:42])[CH3:41])[O:11][N:10]=1
Reactant: COC(=O)c1cc(C(=O)OC)c2ccc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3c(C(=O)O)cc(C(=O)O)nc3c2)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 62.3 %

Procedure:
To a solution of 60 mg (0.10 mmol) of dimethyl 7-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2,4-quinolinedicarboxylate in a mixture of 1 mL THF, 3 mL EtOH, and 1 mL H2O was added 40 mg (0.99 mmol) of NaOH. The mixture was stirred at 60° C. for 16 hr. H2O (1.5 mL) was added to dissolve some solids then the solution was concentrated to ⅓ volume and added dropwise to 10 mL of 0.5 N HCl (aq). After sitting for 5 min, the resulting solids were collected by suction filtration, washed with H2O and dried to yield 36 mg (63%) of 7-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2,4-quinolinedicarboxylic acid as an orange solid. 1H NMR (400 MHz, DMSO-d6): δ 8.82 (d, J=9 Hz, 1H), 8.41 (s, 1H), 8.38 (s, 1H), 8.14 (dd, JA=2 Hz, JB=9 Hz, 1H), 7.79 (d, J=9 Hz, 2H), 7.61 (d, J=8 Hz, 2H), 7.55-7.51 (m, 1H), 6.94 (d, J=9 Hz, 2H), 4.88 (s, 2H), 3.45 (septet, J=7 Hz, 1H), 1.34 (d, J=7, 6H). ESI-LCMS m/z 578 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Br:22][C:23]1[CH:24]=[C:25]2[CH2:31][C:30](=[O:32])[NH:29][C:26]2=[N:27][CH:28]=1>>[Br:22][C:23]1[CH:24]=[C:25]2[C:31](=[CH:20][C:3]3[NH:4][C:5]4[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]5[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]5)[C:7](=[O:19])[C:6]=4[C:2]=3[CH3:1])[C:30](=[O:32])[NH:29][C:26]2=[N:27][CH:28]=1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Reactant: O=C1Cc2cc(Br)cnc2N1
Product: Cc1c(C=C2C(=O)Nc3ncc(Br)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Yield: 65.1 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-bromo-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one as starting materials to give 2-(5-bromo-2-oxo-1,2-dihydro-pyrrolo[2,3-b]pyridin-3-ylidenemethyl)-3-methyl-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (32 mg, 65.1%) as an orange solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([Cl:11])=[CH:4][CH:3]=1.Cl.[CH3:13]O>>[Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:13])=[O:9])[C:5]([Cl:11])=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)c1nc(Br)ccc1Cl
Agent: Cl
Product: COC(=O)c1nc(Br)ccc1Cl

Procedure:
8.12 g (34.3 mmol) of 6-bromo-3-chloropyridine-2-carboxylic acid are admixed with 50 ml (1.25M; 62.5 mmol) of a solution of hydrogen chloride in methanol. The mixture is heated under reflux for 2 h, in the course of which 20 ml each time (1.25M; 25 mmol) of a solution of hydrogen chloride in methanol are added every 30 min. For workup, the reaction mixture is freed of the solvent on a rotary evaporator and the residue is admixed with diethyl ether and an aqueous sodium hydrogencarbonate solution. After the phase separation, the organic phase is dried; after the filtration, the filtrate is freed of the solvent on a rotary evaporator. The residue obtained is 7.78 g of the product with a purity of approx. 90% by weight.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:4][C:5]([C:11]2(OC)[C@H:16]([OH:17])[C@@H:15]([OH:18])[C@H:14]([OH:19])[C@@H:13]([CH2:20][OH:21])[O:12]2)=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl.CC#N>[Br:1][C:2]1[C:3]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[CH:4][C:5]([C@H:11]2[C@H:16]([OH:17])[C@@H:15]([OH:18])[C@H:14]([OH:19])[C@@H:13]([CH2:20][OH:21])[O:12]2)=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2
Reactant: COc1ccc(Cc2cc(C3(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3c(c2Br)CCC3)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CC#N
Solvent: CCOCC
Product: COc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3c(c2Br)CCC3)cc1
Temperature: -30 °C

Procedure:
To a solution of compound 15 (0.94 g, 1.85 mmol) in CH2Cl2/CH3CN (8.9 mL/8.9 mL) were added triethylsilane (0.59 mL, 3.7 mmol) and boron trifluoride diethyl etherate (0.46 mL, 3.7 mmol) at −60° C. under nitrogen atmosphere. The mixture was warmed up to −30° C. for 2 h. The reaction mixture was quenched with saturated NaHCO3 solution (15 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by prep HPLC (reverse phase) to provide the compound E001 (0.15 g, 0.306 mmol, 17%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([CH3:23])[NH:16][C:15]([CH2:24][O:25][CH2:26][CH2:27][NH:28][CH3:29])=[C:14]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([CH3:23])[NH:16][C:15]([CH2:24][O:25][CH2:26][CH2:27][N:28]([S:2]([CH3:1])(=[O:4])=[O:3])[CH3:29])=[C:14]1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)C1=C(COCCNC)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1=C(COCCN(C)S(C)(=O)=O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
Methanesulphonyl chloride (0.144 g) was added to a solution of 4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-[2-(methylamino)ethoxy methyl]-1,4-dihydropyridine (0.50 g) and triethylamine (0.126 g) in dichloromethane (15 ml). The mixture was stirred at room temperature for 1 hour, poured into ice-water and the layers separated. The organic layer was washed with water, dried (Na2SO4) and evaporated. Scratching the residual oil afforded a solid which was recrystallised from methanol to give the title compound (0.33 g), m.p. 93°-95° C. Found: C, 53.32; H, 5.97; N, 5.64. C22H29ClN2O7S requires C, 53.32; H, 5.92; N, 5.71%.
Reaction SMILES: [CH3:1][I:2].[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11](=[S:13])[NH2:12]>CC(C)=O>[IH:2].[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]([S:13][CH3:1])=[NH:12]
Reactant: CI
Reactant: NC(=S)c1cc(F)ccc1F
Solvent: CC(C)=O
Product: CSC(=N)c1cc(F)ccc1F
Product: I
Temperature: 25 °C
Reaction time: 24 h
Yield: 93 %

Procedure:
5.9 ml (94.2 mmol; 1.5 equivalents) of methyl iodide is added to 10.8 g (62 mmol) of 2,5-difluorobenzenecarbothioamide in solution in 70 ml of acetone. The reaction mixture is maintained under stirring at 25° C. for 24 hours, then the solvent is evaporated off under reduced pressure. Methyl 2,5-difluorobenzene carbimidothioate hydroiodide is obtained (18.4 g; yield=93%), after crystallization from ethyl ether, in the form of beige powder.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:27]=[CH:26][C:9]([CH2:10][NH:11][C:12]([C:14]2[CH:15]=[C:16]3[CH2:22][NH:21][C@@H:20]([CH:23]([CH3:25])[CH3:24])[C:17]3=[N:18][CH:19]=2)=[O:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][NH:11][C:12]([C:14]2[CH:15]=[C:16]3[CH2:22][N:21]([C:29]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:30])[C@@H:20]([CH:23]([CH3:24])[CH3:25])[C:17]3=[N:18][CH:19]=2)=[O:13])=[CH:26][CH:27]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN[C@H]3C(C)C)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN(C(=O)OCc2ccccc2)[C@H]3C(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (S)- N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide (11.3 mg, 29.2 μmol) in CH2Cl2 (1 mL) was added benzyl chloroformate (11.7 μL, 3.0 M in toluene), triethylamine (6.1 μL, 43.8 μmol) and 4-dimethylaminopyridine (50 μg, 4.09 μmol). The mixture was stirred at rt for 15 h, at which point it was quenched with saturated aqueous sodium bicarbonate (10 mL). The mixture was extracted with EtOAc (10 mL), then the organic phase was washed with brine (10 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 30% EtOAc in hexanes, gradient to 100%), then further purified by reverse-phase HPLC to yield 14.9 mg of benzyl (S)-3-((4-(ethylsulfonyl)benzyl)carbamoyl)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate as an HCl salt (16, 91%). LC-MS tR=0.91 min in 1 min chromatography, MS (ESI) m/z 522.5 [M+H]+. 1H NMR (CD3OD, 400 MHz): δ 9.00 (s, 1H), 8.34 (s, 1H), 7.87 (dd, J=1.6 Hz, 6.8 Hz, 2H), 7.63 (d, J=8.8 Hz, 2H), 7.42 (dd, J=1.6 Hz, 8.4 Hz, 2H), 7.33 (m, 3H), 5.20 (m, 3H), 4.96 (m, 1H), 4.71 (m, 3H), 3.20 (q, J=7.6 Hz, 2H), 2.57-2.36 (m, 1H), 1.19 (t, J=7.6 Hz, 3H), 1.00 (dd, J=6.8 Hz, 16.0 Hz, 3H), 0.78 (dd, J=6.8 Hz, 25.6 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[O:13]>>[OH:13][CH:12]([CH:2]([CH3:3])[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])[C:11]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCC(=O)c1ccccc1
Reactant: CCOC(=O)C=O
Product: CCOC(=O)C(O)C(C)C(=O)c1ccccc1
Temperature: 135 °C

Procedure:
A mixture of 13.4 g of propiophenone and 15.3 g of ethyl glyoxylate is heated at 135° C. for 5 hours.
Reaction SMILES: FC(F)(F)C(O)=O.ClC1C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)=C2N=C(C3C=CC(CN4CCOCC4)=CC=3)NC2=NC=1.[NH2:42][C:43]1[C:48]([NH2:49])=[C:47]([NH:50][C@H:51]2[C@H:56]3[CH2:57][C@H:53]([CH:54]=[CH:55]3)[C@H:52]2[C:58]([NH2:60])=[O:59])[C:46]([Cl:61])=[CH:45][N:44]=1.[CH3:62][O:63][C:64]1[CH:71]=[C:70]([N:72]2[CH2:77][CH2:76][N:75]([CH3:78])[CH2:74][CH2:73]2)[CH:69]=[CH:68][C:65]=1[CH:66]=O>>[Cl:61][C:46]1[C:47]([NH:50][C@H:51]2[C@H:56]3[CH2:57][C@H:53]([CH:54]=[CH:55]3)[C@H:52]2[C:58]([NH2:60])=[O:59])=[C:48]2[N:49]=[C:66]([C:65]3[CH:68]=[CH:69][C:70]([N:72]4[CH2:73][CH2:74][N:75]([CH3:78])[CH2:76][CH2:77]4)=[CH:71][C:64]=3[O:63][CH3:62])[NH:42][C:43]2=[N:44][CH:45]=1
Reactant: NC(=O)[C@H]1[C@@H](Nc2c(Cl)cnc(N)c2N)[C@@H]2C=C[C@H]1C2
Reactant: COc1cc(N2CCN(C)CC2)ccc1C=O
Agent: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CCN(C)CC2)ccc1-c1nc2c(N[C@@H]3[C@H](C(N)=O)[C@H]4C=C[C@@H]3C4)c(Cl)cnc2[nH]1
Yield: 5 %

Procedure:
In the same fashion as for Compound III, (1R,2R,3S,4S)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 2-Methoxy-4-(4-methyl-piperazin-1-yl)-benzaldehyde were reacted to produce the title compound (5%). 1H NMR (d-6 DMSO): 12.19 (br s, 1H), 9.67 (br s, 1H), 8.05 (d, J=8 Hz, 1H), 7.94 (s, 1H), 7.77 (s, 1H), 7.18 (m, 1H), 6.79 (d, J=8 Hz, 1H), 6.71 (s, 1H), 6.35 (s, 2H), 5.20 (m, 1H), 4.07 (d, J=8 Hz, 2H), 3.98 (s, 3H), 3.28-2.18 (m, 11H), 1.45 (m, 2H), 1.39 (m, 1H). MS: 508.1 (M+H). HPLC retention time: 1.82 minutes (G Method).
Reaction SMILES: Cl.[N:2]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][N:4]=[CH:3]1.[Br:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28])[CH:21]=[CH:20]2>C(O)C.CCCCCC>[Br:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:31][CH2:32][N:33]([C:11](=[O:13])[C:10]3[CH:9]=[CH:8][C:7]([N:2]4[CH:6]=[CH:5][N:4]=[CH:3]4)=[CH:15][CH:14]=3)[CH2:34][CH2:35]1)(=[O:28])=[O:29])[CH:21]=[CH:20]2
Reactant: O=C(O)c1ccc(-n2ccnc2)cc1
Reactant: O=S(=O)(c1ccc2cc(Br)ccc2c1)N1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: CCCCCC
Product: O=C(c1ccc(-n2ccnc2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Br)ccc3c2)CC1
Yield: 85 %

Procedure:
By an exactly analogous method to that described in Example 1, starting from 4-(1-imidazolyl)benzoic acid hydrochloride and 1-(6-bromonaphth-2-ylsulphonyl)piperazine was prepared 1-(6-bromonaphth-2-ylsulphonyl)-4-[4-(1-imidazolyl)benzoyl]piperazine (444 mg, 85% yield), m.p. 207-209° C. (from ethanol/hexane), 1H NMR (d6DMSO) 3.0-3.2 ppm (broad s,4H), 3.5-3.8 ppm (broad s,4H), 7.1 ppm (s,1H), 7.4 ppm (d,2H), 7.6 ppm (d,2H), 7.75 ppm (s,1H), 7.8 ppm (t,2H), 8.2 ppm (t,2H), 8.3 ppm (s,1H), 8.4 ppm (s,1H), 8.45 ppm (s,1H), the spectrum also contained signals due to ethanol (<0.2 mol eq.); microanalysis, found: C, 55.0; H, 4.3; N, 10.4; S, 6.2%; C24H21N4O3BrS requires: C, 54.9; H, 4.0; N, 10.7; S, 6.1%; MS (M+H)+ 525/527.
Reaction SMILES: [CH3:1][C:2]1[NH:3][NH:4][C:5](=[O:7])[CH:6]=1.Br[CH2:9][CH3:10].C(=O)(O)[O-].[Na+]>>[CH2:9]([N:4]1[C:5](=[O:7])[CH2:6][C:2]([CH3:1])=[N:3]1)[CH3:10]
Reactant: Cc1cc(=O)[nH][nH]1
Reactant: CCBr
Agent: O=C([O-])O
Agent: [Na+]
Product: CCN1N=C(C)CC1=O
Temperature: 130 °C

Procedure:
A mixture of 49 g 3-methyl-3-pyrazolin-5-one and 60.0 g bromoethane was sealed in a glass pressure tube and heated in an oil bath at 130° C. for 40 hours. After cooling, the tube was opened and the contents were poured into 200 g ice-water. Sodium bicarbonate (42.00 g) was added in small portions with stirring. The resulting mixture was stirred and heated to 100° C. for 1 hour, cooled to room temperature, and extracted with 10×50 ml portions of chloroform. The combined extracts were dried over anhydrous calcium chloride, evaporated under reduced pressure and the residue recrystallized from ethanol to give 20.1 g as colorless prisms, m.p. 112°-113° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:22][CH2:21][N:11]2[C:12]3[N:20]=[CH:19][CH:18]=[CH:17][C:13]=3[NH:14][CH2:15][CH2:16][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](Cl)=[O:32])=[CH:26][CH:25]=1.CO>C(Cl)Cl>[CH2:1]([N:8]1[CH2:22][CH2:21][N:11]2[C:12]3[N:20]=[CH:19][CH:18]=[CH:17][C:13]=3[N:14]([C:31](=[O:32])[CH2:30][C:27]3[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=3)[CH2:15][CH2:16][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CN2CCN3c4ncccc4NCCC3C2)cc1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Solvent: CO
Solvent: ClCCl
Product: O=C(Cc1ccc(Cl)cc1)N1CCC2CN(Cc3ccccc3)CCN2c2ncccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of the product of Example 52 (135 mg, 0.367 mmol) in CH2Cl2 (3 mL) was added to 4-chlorophenylacetyl chloride (Aldrich, 0.058 mL, 0.38 mmol), and the resulting solution was stirred at room temperature for 45 minutes. Methanol (0.5 mL) was added and the mixture was stirred for 10 minutes and then concentrated under vacuum. The residue was crystallized from ethanol (4 mL) and water (0.2 mL) to provide the title compound as the HCl salt: 1H NMR (400 MHz, pyridine-d5) δ ppm 2.57-2.86 (m, 3H), 2.92-3.31 (m, 2H), 3.32-3.59 (m, 7H), 4.29-4.66 (m, 2H), 6.69-6.88 (m, 1H), 6.91-7.04 (m, 2H), 7.21 (d, J=8.2 Hz, 2H), 7.25 (d, J=7.3 Hz, 1H), 7.27-7.36 (m, J=7.3, 7.3 Hz, 3H), 7.37-7.44 (m, 2H), 8.23-8.33 (m, 1H), one proton obscured by solvent; MS (ESI) m/z 447/449 (M+H)+. Elemental analysis is calculated for C26H27N4OCl.HCl.0.4H2O: C, 63.65; H, 5.92; N, 11.42. Found: C, 63.72; H, 5.75; N, 11.26.
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[I-].[Na+].C(O)(C)C.O.O.[C:20]([OH:25])(=[O:24])[C:21]([OH:23])=[O:22].[CH3:26][NH2:27]>C(O)C>[C:20]([OH:25])(=[O:24])[C:21]([OH:23])=[O:22].[CH3:26][NH:27][CH2:2][CH2:3][C@@H:4]([OH:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:26][NH:27][CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]
Reactant: CN
Reactant: O[C@H](CCCl)c1ccccc1
Agent: O=C(O)C(=O)O
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(C)O
Product: CNCC[C@@H](O)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of (R)-3-chloro-1-phenylpropanol (1.0 g, 5.85 mmol) and a catalytic amount of sodium iodide in ethanol (7 mL) and 40% methylamine aqueous solution (15 mL) was stirred at 60° C. for 7 hours. The reaction mixture was evaporated to 3 mL, and the pH of the solution was adjusted to pH>12 via the addition of aqueous NaOH solution. The mixture was then extracted with toluene twice and the combined extracts were washed with brine. The toluene layer was evaporated to dryness and the residue dissolved in toluene (5 mL) and isopropanol (5.mL) and oxalic acid dihydrate (0.4 g, 3.2 mmol) was added. It was stirred at room temperature for 2Hours and the suspension was filtered and rinsed with toluene/isopropanol to provide 0.9 g of (R)—N-methyl-3-hydroxy-3-phenylpropylamine hemioxalate salt as an off-white solid. 1H NMR (D2O) δ 7.5-7.2 (m, 5H), 4.8 (at, J=6.6 Hz, 1H), 5.15-2.9 (m, 2H), 2.64 (s, 3H), 2.2-2.0 (m, 2H). Elemental Analysis for C11H16NO3; Calculated: H 7.67%; C 62.84%; N 6.66%.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[C:17]4[CH2:22][NH:21][CH2:20][C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.CN1CCOCC1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:51][C:52](=[O:58])[CH2:53][CH2:54][C:55](O)=[O:56]>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[C:17]4[CH2:22][N:21]([C:55](=[O:56])[CH2:54][CH2:53][C:52]([NH2:51])=[O:58])[CH2:20][C:18]=4[N:19]=3)=[CH:12][CH:13]=2)[CH2:2][CH2:3]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CNC2
Reactant: NC(=O)CCC(=O)O
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CN(C(=O)CCC(N)=O)C2
Temperature: 25 °C
Yield: 20.8 %

Procedure:
To a stirred solution of (S)-1-cyclopropyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (Example 3) (100 mg, 0.25 mmol) and N-methylmorpholine (56 μL, 0.5 mmol) in DMF (5 ml, anhydrous) was added EDC (53 mg, 0.28 mmol), HOBT (38 mg, 0.28 mmol), and 4-amino-4-oxobutanoic acid (29.7 mg, 0.25 mmol). The reaction mixture was stirred at room temperature until analysis by LCMS deemed reaction complete. Solvent was then removed in vacuo. Purified by prep. HPLC (high pH) to afford a white solid (25.7 mg, 0.052 mmol, 21%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][O:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)[CH:5]=[C:4]([CH2:14][O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[N:30]1[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]1)[NH2:26].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH:11]1([CH2:10][O:9][CH2:8][C:6]2[CH:5]=[C:4]([CH2:14][O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[N:3]=[C:2]([NH:26][C:25]3[CH:27]=[CH:28][C:29]([N:30]4[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]4)=[C:23]([O:22][CH3:21])[CH:24]=3)[N:7]=2)[CH2:13][CH2:12]1
Reactant: FC(F)(F)COCc1cc(COCC2CC2)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(COCC3CC3)cc(COCC(F)(F)F)n2)ccc1-n1cnc(C)c1
Temperature: 120 °C

Procedure:
2-Chloro-4-((cyclopropylmethoxy)methyl)-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (approximately 50% pure, 33 mg, 0.11 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (26 mg, 0.13 mmol), palladium (II) acetate (4 mg, 0.02 mmol), 2-(dicyclohexylphosphino)-biphenyl (6 mg, 0.02 mmol) cesium carbonate (69 mg, 0.21 mmol) and dioxane (2 mL) were mixed in a vial. The vial was capped, evacuated and flushed with nitrogen. The mixture was heated by microwave irradiation at 120° C. for 1.5 h. The mixture was filtered through a pad of silica, the pad was washed with 10% methanol in ethyl acetate. The solvents were evaporated and the residue was purified by preparative HPLC to give the title compound as a dry film, 15 mg (28%).
Reaction SMILES: C(NC(C)C)(C)C.[C:8]([O:13][CH2:14][CH3:15])(=[O:12])[CH:9]([CH3:11])[CH3:10].[Br:16][CH2:17][CH2:18][CH2:19]Br.[Cl-].[NH4+]>O1CCCC1>[Br:16][CH2:17][CH2:18][CH2:19][C:9]([CH3:11])([CH3:10])[C:8]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: BrCCCBr
Reactant: CCOC(=O)C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)(C)CCCBr
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 28.7 ml of diisopropylamine in 150 ml of tetrahydrofuran was added 126 ml of 1.6M n-butyllithium-hexane with stirring at -5° to 0° C. and the mixture was further stirred for 30 minutes. This reaction mixture was cooled to -78° C. and 26.7 ml of ethyl isobutyrate was added dropwise. The mixture was stirred for 1 hour, after which 41.8 g of 1,3-dibromopropane was added dropwise. The reaction mixture was stirred at -78° C. for 1 hour and then at room temperature for 2 hours. The mixture was then poured in aqueous solution of ammonium chloride and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was then distilled off and the residue was subjected to vacuum distillation to provide 40.3 g of the title compound as colorless oil. b.p. 76°-78° C./0.27 mmHg