Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]1[C:19](=[O:38])[CH2:20][NH:21][C:22](=[O:37])[NH:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:25][C:26]([O:28]CC)=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>CO.O>[C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]1[C:19](=[O:38])[CH2:20][NH:21][C:22](=[O:37])[NH:23][CH:24]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:25][C:26]([OH:28])=[O:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(NC(=O)NCC(=O)N1C(C(=O)OC(C)(C)C)CCC1c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)C1CCC(c2ccccc2)N1C(=O)CNC(=O)NC(CC(=O)O)c1ccccc1
Yield: 56.9 %

Procedure:
By proceeding in a fashion similar to that described in Example 9, but starting from 3.9 g of ethyl (2RS,5SR)-3-{3-[2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}-3-phenylpropionate in solution in 60 cm3 of methanol and 0.45 g of potassium hydroxide dissolved in 20 cm3 of water and after treatment, 2.1 g of (2RS,5SR)-3-{3-[2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2oxoethyl]ureido}-3-phenylpropionic acid are obtained [proton NMR (250 MHz, DMSO D6, δ in ppm), 2 rotamers at room temperature, peak coalescence at 120° C.; 15. (bs, 9H, (CH3)3); 2.5 (t, 2H, CH2); 2.8 (t, 2H, CH2); 6.8 to 7.60 (m, 9H, aromatic). Infrared spectrum (KBr), characteristic bands in cm-1 : 3380, 3700 to 2250 with a maximum at 2625, 3160, 3060, 3030, 2980, 2930, 2880, 1735, 1635, 1610, 1595, 1560, 1495, 1450, 1440, 1395, 1370, 1310, 1225, 1155, 905, 890, 865, 840, 790, 760, 705].
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C@H:13]([C:17]([OH:19])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27]1([CH:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:34](Cl)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:34](=[O:35])[CH:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@H:13]([C:17]([OH:19])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: O=C(O)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1C(=O)C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 64 h

Procedure:
A solution of 1.00 g (3.78 mmole) of (S)-4-(benzyloxycarbonyl)piperazine-2-carboxylic acid (from Example 7, Step A) in 10 ml of DMF at 25° C. was treated with 0.755 g. (7.46 mmole) of triethylamine. The solution was cooled to 0° C. and 0.95 g (4.12 mmole) of diphenylacetyl chloride was added in Portions over 2 hours. The solution was stirred at 25° C. for 64 hours, concentrated in vacuo and partitioned between 60 ml. of 1N HCl and 60 ml of ethyl acetate. The ethyl acetate was dried over sodium sulfate, concentrated in vacuo and chromatographed in two portions over an 85×2.5 cm LH-20 column with 11 ml fractions of methanol. Fractions 38-41 from both columns were combined and concentrated in vacuo to 785 mg (44%) of oil which was homogeneous by TLC (80:20:2 chloroform-methanol-ammonia water, Rf =0.40).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:20][CH2:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([C:29]([C:31]3[CH:36]=[CH:35][N:34]=[C:33]([Cl:37])[CH:32]=3)=[O:30])[CH2:21]2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:37][C:33]1[CH:32]=[C:31]([C:29]([N:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]3([CH2:17][CH2:16][NH:15][CH2:20][CH2:19]3)[CH2:21]2)=[O:30])[CH:36]=[CH:35][N:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(C(=O)c1ccnc(Cl)c1)c1ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccnc(Cl)c1)N1CC2(CCNCC2)c2ccccc21
Reaction time: 0.25 h
Yield: 96 %

Procedure:
Trifluoroacetic acid (30 ml) was added to a solution of solution of 1-(2-chloropyridin-4-yl)carbonylspiro[indoline-3,4′-piperidine]-1′-carboxylic acid tert-butyl ester (2.3 g) in anhydrous dichloromethane (50 ml), the solution darkening upon addition. The reaction was left as such for 15 min. The reaction mixture was evaporated in vacuo and the dark residue re-suspended in dry ether (100 ml). The residue was triturated until it became a free-flowing beige precipitate. The precipitate was collected by filtration and dried in a stream of nitrogen to give 2.28 g (96%) of the desired amine salt. M.p. 245° C. (decomposition). 1H NMR (400 MHz, d6-DMSO) 1.8 (m, 2H), 1.9 (m, 2H), 2.9 (m, 2H), 3.25 (m, 2H), 3.98 (s, 2H), 7.15-7.3 (m, 2H), 7.24 (d, J=8 Hz, 1H), 7.56 (d, J=7 Hz, 1H), 7.62 (s, 1H), 8.1 (br s, 1H), 8.56 (d, J=7 Hz, 1H), 8.8 (br s, 2H). MS (ES+) 328/330 (M+H+).
Reaction SMILES: [O:1]([CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][C:18]#[N:19]>>[O:1]([CH2:8][CH2:9][N:10]1[CH2:11][CH2:12][N:13]([CH2:17][C:18]#[N:19])[CH2:14][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(OCCN2CCNCC2)cc1
Reactant: N#CCBr
Product: N#CCN1CCN(CCOc2ccccc2)CC1

Procedure:
The title compound is synthesized by coupling of 1-(2-Phenoxy-ethyl)-piperazine (commercially available from CHESS GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+H=246.2: CtRet=4.31.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N+:3]=1[O-:9].[CH3:10][CH:11]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:12][OH:13].[OH-].[Na+]>CS(C)=O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:13][CH2:12][CH:11]([CH3:10])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[N+:3]=1[O-:9]
Reactant: [O-][n+]1c(Cl)cccc1Cl
Reactant: CC(CO)CC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(COc1cccc(Cl)[n+]1[O-])CC(C)(C)C

Procedure:
The 0.82 g (0.0050 moles) of 2,6-dichloropyridine N-oxide and 0.664 g (98%) (0.0050 moles) of 2,4,4-trimethyl-1-pentanol was reacted with 0.211 g (0.0050 moles) of ground sodium hydroxide in 8.2 ml of DMSO at 100° C. overnight to give 2-chloro-6-(2,4,4-trimethypentyloxy)pyridine N-oxide. It was reacted with 0.600 g (0.015 moles) of ground sodium hydroxide at 100° C. for 4.5 hours to give 1-hydroxy-6-(2,4,4-trimethylpentyloxy)pyridine-2(1H)-one. After cooling, it was added 74 ml of water and was adjusted with 6N HCl to pH 3. It was extracted with ethyl acetate (3×25 ml). The combined ethyl acetate extract was washed with a saturated sodium chloride solution (2×10 ml) and dried over sodium sulfate. The ethyl acetate extract was filtered and stripped in vacuo to give 1.08 g (90%). It was recrystallized from ethyl acetate and hexanes: mp 133.5°-134° C.
Reaction SMILES: [CH2:1]([S:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4].Cl.[CH3:27]O>>[CH2:1]([S:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:24])(=[O:25])[NH2:23])[C:14]=1[O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:9]([O:11][CH3:27])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CO
Reactant: CCCCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: Cl
Product: CCCCSc1cc(C(=O)OC)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 5 h

Procedure:
A mixture of 3-n-butylthio-4-phenoxy-5-sulfamylbenzoic acid (2.5 g) and methanol (75 ml) is saturated with gaseous hydrogen chloride. The reaction mixture is allowed to warm during saturation. After cooling and standing for 5 hours, the reaction mixture is evaporated in vacuo. The residue is triturated with water and sufficient sodium hydrogen carbonate to neutralize traces of hydrochloric acid. The precipitated methyl 3-n-butylthio-4-phenoxy-5-sulfamylbenzoate is collected and recrystallized from methanol/water to yield the ester with a melting point of 122°-123°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ccc(-c3ccccn3)cc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2cc(-c3ccccn3)ccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-pyridin-2-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14].[B:15](OC)([O:18]C)[O:16]C.Cl>O1CCCC1>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[B:15]([OH:18])[OH:16]
Reactant: COB(OC)OC
Reactant: COc1ccccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccccc1B(O)O
Temperature: 25 °C
Yield: 100.4 %

Procedure:
n-Butyl lithium (13.0 ml of a 1.6M solution in hexanes, 19.8 mmol) was added dropwise to a solution of 2-bromoanisole (3.74 g, 19.0 mmol) in anhydrous tetrahydrofuran (15 ml) cooled to below -70° C., maintaining the temperature during the addition below -60° C. The solution was stirred for 20 minutes before the addition of trimethyl borate (5.9 ml, 57.0 mmol), and then stirred at below -70° C. for a further hour before warming to room temperature overnight. The reaction mixture was cooled to 0° C. acidified to pH 5.0 with 5% aqueous hydrochloric acid solution (25 ml), the resulting layers separated and the aqueous phase extracted with ethyl acetate (2×25 ml). The combined orgnic layers were washed with brine (25 ml), dried (MgSO4) and concentrated in vacuo to yield the title compound as a white solid (2.9 g, 97%) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH3:28].[NH2:29][CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1>CN(C=O)C>[OH:16][C@H:15]([CH2:17][NH:29][CH2:30][CH2:31][CH2:32][N:33]1[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]1)[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[C:22]4[CH3:28])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H]1CO1
Reactant: CN1CCN(CCCN)CC1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H](O)CNCCCN1CCN(C)CC1
Temperature: 70 °C
Yield: 29.4 %

Procedure:
A mixture of (2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (100 mg, 0.28 mmol), (prepared as described in Example 278), and 1-(3-aminopropyl)-4-methylpiperazine (132 mg, 0.84 mmol) in DMF (5 ml) was heated to 70° C. for 3 hours. The solvents were removed in vacuo and the residue taken up in dichloromethane. This was washed with water, dried (MgSO4), filtered and evaporated. The residue was purified by silica column chromatography using gradient elution (dichloromethane, 5% methanol/95% dichloromethane, 20% methanolic ammonia (7M)/80% dichloromethane) to give (2R)-7-(2-hydroxy-3-(3-(4-methylpiperazin-1-yl)propylamino)propoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (44 mg, 31%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][C:12]3[NH:13][C:14](=[O:16])[NH:15][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.C(O)(C(F)(F)F)=O>CC(O)C>[NH:13]1[C:12]2[CH:17]=[CH:18][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:33][C:30]4[CH:29]=[CH:28][C:27]([N:24]5[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]5)=[N:32][CH:31]=4)[N:7]=3)=[CH:10][C:11]=2[NH:15][C:14]1=[O:16]
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Reactant: O=c1[nH]c2ccc(Nc3nc(Cl)ncc3F)cc2[nH]1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2ccc(Nc3ncc(F)c(Nc4ccc5[nH]c(=O)[nH]c5c4)n3)cn2)CC1
Temperature: 85 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
To a vial with 5-(2-chloro-5-fluoropyrimidin-4-ylamino)-1H-benzo[d]imidazol-2(3H)-one (28.0 mg, 0.1 mmol) and 6-(4-methylpiperazin-1-yl)pyridin-3-amine (38.4 mg, 0.2 mmol), i-PrOH (2 mL) was added, followed by TFA (10 μL, 0.13 mmol). The vial was tightly closed, and the solution was stirred at 85° C. for 2 days. The solvent was removed in vacuo, and the crude product was purified by RP-HPLC. Purified compound (as a trifluoroacetate salt) was dissolved in MeOH—H2O (1:4, 2 mL) and was passed through a PL-HCO3-MP-SPE column, washing with same solvents (1 mL). The filtrate was collected and the solvent was removed by lyophilization. N4-(Benzimidazolin-2-on-5-yl)-N2-[2-(4-methylpiperazin-1-yl)pyridin-5-yl]-5-fluoropyrimidine-2,4-diamine was obtained as a purple solid: 26.2 mg (60% yield); 1H NMR (300 MHz, DMSO) δ 10.56 (s, 1H), 10.52 (s, 1H), 9.16 (s, 1H), 8.85 (s, 1H), 8.27 (br d, J=2.3, 1H), 8.00 (br d, J=3.8, 1H), 7.84 (dd, J=2.3, 9.1, 1H), 7.30 (dd, J=1.7, 8.2, 1H), 7.17 (d, J=1.7, 1H), 6.86 (d, J=8.2, 1H), 6.73 (d, J=9.1, 1H), 3.40-3.37 (m, 4H, overlapped with H2O), 2.44-2.41 (m, 4H), 2.25 (s, 3H); LCMS (M+) m/z 436.50.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]([C:18]([N:20]4[CH:25]5[CH2:26][CH2:27][CH:21]4[CH2:22][C:23]([C:29]([F:32])([F:31])[F:30])([OH:28])[CH2:24]5)=[O:19])[CH2:13][C:12]=3[CH:33]=2)=[CH:4][C:3]=1[N+:34]([O-])=O.[H][H]>[Pd].C(O)(=O)C>[NH2:34][C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]([C:18]([N:20]4[CH:21]5[CH2:27][CH2:26][CH:25]4[CH2:24][C:23]([C:29]([F:32])([F:31])[F:30])([OH:28])[CH2:22]5)=[O:19])[CH2:13][C:12]=3[CH:33]=2)[CH:6]=[N:7][C:2]=1[NH2:1]
Reactant: [H][H]
Reactant: Nc1ncc(-c2ccc3c(c2)CN(C(=O)N2C4CCC2CC(O)(C(F)(F)F)C4)CCO3)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1cc(-c2ccc3c(c2)CN(C(=O)N2C4CCC2CC(O)(C(F)(F)F)C4)CCO3)cnc1N
Yield: 92 %

Procedure:
A slurry of 8-{[7-(6-amino-5-nitropyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octan-3-ol (1.1 g, 2.2 mmol), Pd/C (5% wt./wt., 0.20 g) and acetic acid (40 mL) was subjected to an atmosphere of hydrogen (45 PSI) using a Parr apparatus. After 2 hours the reaction mixture was filtered through Celite and concentrated to give 8-{[7-(5,6-diaminopyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octan-3-ol (0.95, 92% yield) as an orange oil. MS (ES) for C23H26F3N5O3: 478 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([NH2:13])[S:11][CH:12]=1.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[S:23](Cl)(=[O:25])=[O:24]>>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[S:23]([NH:13][C:10]1[S:11][CH:12]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:9]=1)(=[O:25])=[O:24]
Reactant: Nc1nc(-c2ccccc2Cl)cs1
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1nc(-c2ccccc2Cl)cs1

Procedure:
The title compound was prepared from 4-(2-chlorophenyl)-1,3-thiazol-2-amine and 2,4 -dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (40.3 mg) with purity >90%. MS (pos) m/z 435.0, 437.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[CH:4][C:3]=1[NH2:20].N1C=CC=CC=1.[C:27](Cl)(Cl)=[O:28]>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[C:3]([N:20]=[C:27]=[O:28])=[CH:4][C:5]([O:9][CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:17])([CH3:19])[CH3:18])([CH3:14])[CH3:15])=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCCOc1cc(N)c(Br)cc1Cl
Reactant: O=C(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OCCOc1cc(N=C=O)c(Br)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-phenylamine (0.15 g, 0.393 mmol) in toluene (3 ml) was added pyridine (0.038 ml, 0.472 mmol), DMAP (0.048 g, 0.393 mmol) and 20% phosgene in toluene (0.224 ml, 0.433 mmol). The mixture was stirred at room temperature for two hours. The mixture was filtered and the filtrate was concentrated to dryness under reduced pressure to give [2-(4-bromo-2-chloro-5-isocyanato-phenoxy)-ethoxy]-tert-butyl-dimethyl-silane (0.155 g) as a white solid, which was used directly in the next step.
Reaction SMILES: CO[C:3](=[O:26])[C@H:4]([CH2:24][OH:25])[NH:5][C:6](=[O:23])[C@H:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].O.[NH2:28][NH2:29]>CO>[C:12]([O:11][C:9]([NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([NH:28][NH2:29])=[O:26])[CH2:24][OH:25])=[O:23])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:10])([CH3:13])([CH3:15])[CH3:14]
Reactant: NN
Reactant: COC(=O)[C@H](CO)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CO)C(=O)NN
Temperature: 25 °C
Reaction time: 15 h

Procedure:
18.3 g of tert-butyloxycarbonyl-L-phenylalanyl-L-serine methyl ester were dissolved in 50 ml of methyl alcohol, and to this solution 7.5 ml of 80% hydrazine mono hydrate were added. The mixture was stirred for 15 hours at room temperature and then the reaction mixture was concentrated under reduced pressure to give a solid substance. The solid substance was allowed to re-crystallization with ethyl alcohol and thereby tert-butyloxycarbonyl-L-phenylalanyl-L-serine hydrazide was obtained.
Reaction SMILES: C(N(CC)CC)C.Cl[CH:9]([C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])=[O:11].[C:27]1([OH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C>[CH3:23][C:22]([CH3:25])([CH3:24])[C:21](=[O:26])[CH:9]([O:33][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])=[O:11]
Reactant: Oc1ccccc1
Reactant: CC(C)(C)C(=O)C(Cl)C(=O)Nc1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)C(=O)C(Oc1ccccc1)C(=O)Nc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
Triethylamine (57.35 g, 566 mmol) was added to a stirred solution of N-[2-chloro-4,4,-dimethyl-3-oxopentanoyl]-2,4-dichloroaniline prepared as above (155.9 g, 483 mmol) and phenol (49.9 g, 530 mmol) in dry acetonitrile (1.3 L) under argon. After the addition had been completed, the mixture was heated at reflux for 7 hours. The reaction mixture was then cooled and the solvent was removed under reduced pressure. The residue was dissolved in methanol (300 mL) and allowed to stir at room temperature until crystallization began. After 2 hours, the mixture was cooled in an ice bath for a further 1 hour. The product was removed by filtration, washed with cold methanol, and dried to afford N-[4,4-dimethyl-3-oxo-2-phenoxypentanoyl]-2,4-dichloroaniline (99 g, 54% yield) as a white crystalline solid which melted at 112°-113.5° C. The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:14]1)=[O:11].Br[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.O>[CH2:44]([O:43][C:41](=[O:42])[CH2:40][CH2:39][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:14]1)=[O:11])[CH3:45]
Reactant: CCOC(=O)CCBr
Reactant: CC(C)CN(C(=O)c1nc2ccccc2[nH]1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)CCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 70 °C
Reaction time: 15 h
Yield: 73.3 %

Procedure:
To a solution of tert-butyl (3S,5R)-3-[(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (257 mg) and ethyl 3-bromopropanoate (181 mg) in N,N-dimethylacetamide (5 ml) was added cesium carbonate (489 mg), and the mixture was stirred at 70° C. for 15 hr. Ethyl 3-bromopropanoate (181 mg) was added to the reaction mixture, and the mixture was further stirred at 70° C. for 5 hr. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (6:4) was concentrated under reduced pressure to give the object product (225 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:23]([O:25]C)=[O:24])[CH:14]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1.[OH-].[Na+].O>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:23]([OH:25])=[O:24])[CH:14]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc2nc(-c3cncc(Br)c3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a solution of methyl 2-(5-bromopyridin-3-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (150.0 mg, 0.36 mmol) in methanol (30 mL) was added sodium hydroxide (43 mg, 1.08 mmol) and water (1 mL) The reaction mixture was stirred overnight at room temperature and concentrated under vacuum. The residue was dissolved in water (30 mL) and adjusted to PH 5 with HCl (3 N). The product were collected by filtration to afford 2-(5-bromopyridin-3-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a light yellow solid (120.0 mg, 80%).
Reaction SMILES: C(OC1C=CN([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=2[CH3:26])=[O:17])C(=O)C=1)C1C=CC=CC=1.[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[N:41][NH:40][C:39](=[O:43])[CH:38]=2)=[N:33][CH:34]=1>>[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[N:41][N:40]([CH2:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=3[CH3:26])=[O:17])[C:39](=[O:43])[CH:38]=2)=[N:33][CH:34]=1
Reactant: O=c1cc(OCc2ccc(F)cn2)cn[nH]1
Reactant: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Product: Cc1cc(CO)ccc1C(=O)Cn1ncc(OCc2ccc(F)cn2)cc1=O
Yield: 91 %

Procedure:
5-(5-Fluoro-pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one is prepared following preparation 1c employing 5-(5-fluoro-pyridin-2-ylmethoxy)-2H-pyridazin-3-one (described in WO 09/103,478) instead of 4-benzyloxy-1H-pyridin-2-one.