Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([N:17]2[CH2:38][CH2:37][C:20]3([NH:24]/[C:23](=[N:25]/[C:26]([C:28]4[C:33]([NH2:34])=[N:32][C:31]([NH2:35])=[C:30]([Cl:36])[N:29]=4)=[O:27])/[NH:22][CH2:21]3)[CH2:19][CH2:18]2)=[O:16])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].O[CH2:40][C:41]([N:43]1[CH2:47][CH2:46][CH2:45][CH:44]1[C:48](F)(F)F)=[O:42].OCCN1CCCCC1=O>>[O:42]=[C:41]1[CH2:40][CH2:45][CH2:46][CH2:47][N:43]1[CH2:44][CH2:48][O:7][C:6](=[O:8])[CH2:5][O:4][C:3]1[CH:9]=[CH:10][C:11]([CH2:13][CH2:14][C:15]([N:17]2[CH2:18][CH2:19][C:20]3([NH:24]/[C:23](=[N:25]/[C:26]([C:28]4[C:33]([NH2:34])=[N:32][C:31]([NH2:35])=[C:30]([Cl:36])[N:29]=4)=[O:27])/[NH:22][CH2:21]3)[CH2:37][CH2:38]2)=[O:16])=[CH:12][C:2]=1[Cl:1]
Reactant: O=C(CO)N1CCCC1C(F)(F)F
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)CCc4ccc(OCC(=O)O)c(Cl)c4)CC3)N2)nc1Cl
Agent: O=C1CCCCN1CCO
Product: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)CCc4ccc(OCC(=O)OCCN5CCCCC5=O)c(Cl)c4)CC3)N2)nc1Cl

Procedure:
The title compound was prepared by an analogous method to Example 4.0, replacing 3-(3-{2-[(E)-3,5-Diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]decane-8-carbonyl}-benzenesulfonylamino)-propionic acid with [2-Chloro-4-(3-{2-[(E)-3,5-diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]dec-8-yl}-3-oxo-propyl)-phenoxy]-acetic acid (Ex. 3, step 2), and 2-hydroxy-1-(2-(trifluoromethyl)pyrrolidin-1-yl)ethanone (Int. D) with 1-(2-hydroxy-ethyl)piperidin-2-one; 1H NMR (400 MHz, DMSO-D6) δ 11.1 (1H, s), 9.34 (1H, s), 9.06 (1H, s), 7.55-6.9 (4H, m), 4.84 (4H, s), 4.22 (2H, m), 3.95-3.41 (10H, m), 3.29 (2H, s), 2.77 (2H, m), 2.64 (2H, m), 2.59 (2H, m), 2.21 (2H, t), 1.88-1.59 (4H, m); LC-MS Rt 0.91 mins; 690.4 [M+H]+, Method 2minLC_v003.
Reaction SMILES: C([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([NH:18]C(=O)C)[C:8]([N+:15]([O-:17])=[O:16])=[CH:9][C:10]=2[Br:14])[CH2:5]1)(=O)C.[ClH:22]>>[ClH:22].[Br:14][C:10]1[CH:9]=[C:8]([N+:15]([O-:17])=[O:16])[C:7]([NH2:18])=[C:6]2[C:11]=1[CH2:12][CH2:13][NH:4][CH2:5]2
Reactant: CC(=O)Nc1c([N+](=O)[O-])cc(Br)c2c1CN(C(C)=O)CC2
Agent: Cl
Product: Nc1c([N+](=O)[O-])cc(Br)c2c1CNCC2
Temperature: 25 °C
Yield: 77 %

Procedure:
A solution of the product from Example 4 (11.7 g, 32.8 mmol) and 3N HCl (400 mL) was heated to reflux for 4 hours. Upon cooling to room temperature, the solids were filtered, washed with 3N HCl and diethyl ether, and air dried to give the title compound (7.8 g, 77% yield) as a yellow solid, mp-305-307° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13][C:14]=2[N:15]=1)#[N:2].[N:31]1([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH3:17][C:11]1([CH3:16])[C:12]2[NH:13][C:14]3[N:15]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[C:7]=2[C:8](=[O:30])[C:9]2[CH:21]=[CH:20][C:19]([N:40]3[CH2:41][CH2:42][CH:37]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH2:38][CH2:39]3)=[CH:18][C:10]1=2
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1nc(C#N)ccc21
Product: CC1(C)c2cc(N3CCC(N4CCOCC4)CC3)ccc2C(=O)c2c1[nH]c1nc(C#N)ccc21

Procedure:
According to the method used for synthesizing Compound B2-1, trifluoromethanesulfonic acid 2-cyano-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluoren-8-yl ester was introduced with 4-morpholin-4-yl piperidine to obtain the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=2[O:34][CH3:35])[CH:26]=1.OS(O)(=O)=O.CCOC(C)=O>CN(C=O)C>[Cl:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:33]=[CH:32][C:30]([NH:31][C:2]3[N:3]=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[C:6]=4[N:7]=3)=[CH:29][C:28]=2[O:34][CH3:35])[CH:26]=1
Reactant: CC(C)Nc1nc(Cl)nc2c1CCC2c1ccccc1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc(NC(C)C)c3c(n2)C(c2ccccc2)CC3)ccc1-n1cnc(Cl)c1
Temperature: 94 °C
Reaction time: 20 h
Yield: 49.8 %

Procedure:
To a solution of 2-chloro-N-isopropyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (154 mg, 0.535 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (114 mg, 0.508 mmol) in DMF (2.5 mL) was added Conc. H2SO4 (0.040 mL, 0.749 mmol). The mixture was stirred at 94° C. for 20 hrs. After cooled down to room temperature, 100 mL of EtOAc was added, washed with saturated NaHCO3/H2O, dried over Na2SO4, and removed. The residue was purified via Biotage (12 g, hexanes-100% EtOAC) to give N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-isopropyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (120 mg, 0.253 mmol, 47.2% yield). LC-MS (M+H)+=475.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.92 (1H, d, J=2.1 Hz), 7.51 (1H, d, J=1.5 Hz), 7.31 (2H, d, J=7.3 Hz), 7.22-7.25 (2H, m), 7.22 (1H, s), 7.08 (1H, s), 7.04 (1H, d, J=8.5 Hz), 7.01 (1H, d, J=1.5 Hz), 6.74 (1H, dd, J=8.4, 2.3 Hz), 4.38-4.46 (1H, m), 4.33 (1H, d, J=7.9 Hz), 4.18-4.24 (1H, m), 3.49 (3H, s), 2.72-2.80 (1H, m), 2.61-2.71 (2H, m), 2.07-2.14 (1H, m), 1.33 (6H, t, J=6.6 Hz).
Reaction SMILES: [C:1]1([S:7][CH:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:20][C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]=4)[CH:15]=3)[O:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO.O1CCCC1>[C:1]1([S:7][C@H:8]2[C@H:17]([OH:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:20][C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]=4)[CH:15]=3)[O:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2cc(OCc3ccc4ccccc4n3)ccc2OCC1Sc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O[C@@H]1c2cc(OCc3ccc4ccccc4n3)ccc2OC[C@H]1Sc1ccccc1
Temperature: 25 °C
Yield: 59.8 %

Procedure:
To a suspension of the title product of Example 63 (1.85 g, 0.00447 mol) in 70 ml of methanol at 0-5° C. was added in portions 208 mg (0.00538 mol) of sodium borohydride. The reaction was warmed with stirring to room temperature, then diluted with 20 ml of tetrahydrofuran to obtain a homogeneous mixture, which, after stirring for 1.2 hours was concentrated in vacuo and the residue taken up in 400 ml ethyl acetate, washed with H2O and brine, dried over Na2SO4 and concentrated in vacuo to a yellow-white foam. Purification was carried out by silica gel column chromatography eluting with 20% ethyl acetate/CH2Cl2. The less polar cis-title product was isolated as a white solid (1.11 g, 60%). Recrystallization from isopropanol/hexanes gave 1.04 g of white crystals, m.p. 144-146° C. The more polar trans-title product was obtained as a mixture, contaminated with a small amount of the less polar product. It was re-chromatographed using the same eluant to yield 400 mg (22%) of trans-title product as a white foamy solid. Recrystallization from toluene-hexanes afforded 280 mg of white crystals, m.p. 100-102° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[C:4]#[N:5].[CH2:11]1[O:21][C:15]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[O:14][CH:12]1[CH3:13]>CN(C=O)C.CCOCC.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:11]1[O:21][C:15]2([CH2:20][CH2:19][N:18]([C:2]3[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=3[C:4]#[N:5])[CH2:17][CH2:16]2)[O:14][CH:12]1[CH3:13]
Reactant: CC1COC2(CCNCC2)O1
Reactant: Cc1ccc(F)c(C#N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCC3(CC2)OCC(C)O3)c(C#N)c1

Procedure:
A solution of 2-fluoro-5-methylbenzonitrile (2.76 g, 20.4 mmol) and 4-piperidone propylene ketal (3.39 g, 21.5 mmol) in DMF (50 mL) was heated in an oil bath (90° C., 20 h). The mixture was diluted with ether and sodium carbonate solution. The aqueous layer was extracted with two additional portions of ether and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (SiO2, 6 mm, 50-0% hexane/CHCl3) afforded the title compound (29).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:16][C:17]1[CH:29]=[C:28]([CH2:30][N:31](C2C(C)=C(C3C=CC(C(F)(F)F)=CC=3)N=CN=2)[CH2:32][CH2:33][CH3:34])[CH:27]=[CH:26][C:18]=1[O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([N:31]([CH2:30][C:28]3[CH:27]=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:17]([CH3:16])[CH:29]=3)[CH2:32][CH2:33][CH3:34])[C:7]=2[CH3:8])=[CH:10][CH:11]=1
Reactant: CCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1ncnc(-c2ccc(C(F)(F)F)cc2)c1C
Reactant: Cc1c(Cl)ncnc1-c1ccc(Cl)cc1
Product: CCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1ncnc(-c2ccc(Cl)cc2)c1C

Procedure:
Using 4-chloro-6-(4-chlorophenyl)-5-methylpyrimidine (167 mg, 0.7 mmol) and the synthetic procedure described for Intermediate 80. Purification by Biotage™ chromatography (Si, 40 g) eluting 9:1 cyclohexane:EtOAc afforded the title compound as a pale yellow oil (116 mg).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][N:15]=1)[CH3:13]>C(Cl)(Cl)Cl>[CH2:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][N+:15]=1[O-:6])[CH3:13]
Reactant: CCc1ccc(OC)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCc1ccc(OC)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Chloroperoxybenzoic acid (5.66 g, 32.8 mmol) was added to a stirred solution of 2-ethyl-5-methoxy-pyridine (3 g, 22 mmol) dissolved in CHCl3 (100 mL). The reaction was stirred at room temperature for 3 hours and then quenched with satd Na2SO3. The reaction mixture was partitioned between H2O and CH2Cl2. The organic layer was washed with 1N NaOH, dried over Na2SO4 and concentrated to an oil (3.3 g, 99%). 1H NMR (400 MHz, CDCl3): δ 1.29 (t, J=7.5 Hz, 3H), 2.89 (q, J=7.5 Hz, 2H), 3.82 (s, 3H), 6.86 (d, J=8.4 Hz, 1H), 7.11 (d, J=8.3 Hz, 1H), 8.04 (s, 1H).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Br:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[NH:50][CH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1>CN(C=O)C.O>[Br:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[NH:50][CH:51]1[CH2:56][CH2:55][N:54]([C:11](=[O:13])[CH2:10][NH:9][C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:53][CH2:52]1
Reactant: Brc1ccccc1NC1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Br)CC1)c1ccc(-c2ccccc2)cc1
Reaction time: 8 h
Yield: 46.9 %

Procedure:
To a stirred solution of [(biphenyl-4-carbonyl)-amino]-acetic acid (0.075 g, 0.00029 mol) in DMF (2 mL), was added DIPEA (0.1139 g, 0.00088 mol) HOBt (0.0398 g, 0.00029 mol) and EDCI.HCl (0.06758 g, 0.00035 mol) at ambient temperature. After 2 minutes (2-bromo-phenyl)-piperidin-4-yl-amine dihydrochloride (0.09639 g, 0.00029 mol) was added and the resulting mixture was stirred at the same temperature for overnight. The reaction mixture was diluted with cold water and the resulting precipitate was isolated by filtration, washed with hexane followed by ether and dried to afford 0.067 g (46%) of biphenyl-4-carboxylic acid {2-[4-(2-bromo-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 492.0 (M+1)+, 90.08%, 1H NMR (DMSO-d6): δ 8.62 (t, 1H), 7.94 (d, 2H), 7.79 (m, 4H), 7.5 (t, 2H), 7.4 (t, 2H), 7.2 (t, 1H), 6.84 (d, 1H), 6.57 (d, 1H), 4.6 (d, 1H), 4.3 (d, 1H), 4.2 (d, 2H), 3.9 (d, 1H), 3.6 (d, 1H), 2.7 (t, 1H), 1.9 (bs, 2H), 1.5-1.2 (m, 3H).
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[N:4][CH:3]=1.[CH:7]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)([CH3:9])[CH3:8]>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.[OH-].[K+].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C1(C)C=CC=CC=1>[CH:7]([N:10]1[CH2:15][CH2:14][N:13]([C:2]2[S:6][CH:5]=[N:4][CH:3]=2)[CH2:12][CH2:11]1)([CH3:9])[CH3:8]
Reactant: CC(C)N1CCNCC1
Reactant: Brc1cncs1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CC(C)N1CCN(c2cncs2)CC1
Temperature: 110 °C

Procedure:
To a 5 mL microwave reaction tube containing 5-bromothiazole (359 mg, 2.19 mmol), isopropylpiperazine (330 mg, 1.1 eq.), Bis(tri-t-butylphosphine)palladium (0) (22 mg, 15 mol %), cetyltrimethylammonium bromide (15 mg, 30 mol %), toluene (3 mL) was added one drop of 50% KOH aqueous solution. The reaction was heated to 110° C. for 4 hours. The reaction was cooled down and extracted using ethyl acetate/brine. The organic layers were concentrated and purified via Combiflash (0-20% MeOH/Ethyl acetate) to give desired product. LCMS-ESI+: calc'd for C10H18N3S: 212.1 (M+H+); Found: 212.1 (M+H+).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:13]2[CH:12]=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=2[C:7](=[O:15])[C:6]2[N:16]([CH3:19])[N:17]=[CH:18][C:5]1=2.S(Cl)([Cl:22])=O>O1CCCC1.CN(C)C=O>[Cl:22][CH2:2][CH2:3][N:4]1[C:13]2[CH:12]=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=2[C:7](=[O:15])[C:6]2[N:16]([CH3:19])[N:17]=[CH:18][C:5]1=2
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc2c(c1)c(=O)c1c(cnn1C)n2CCO
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c(=O)c1c(cnn1C)n2CCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.1 %

Procedure:
To a solution of 4-(2-hydroxyethyl)-1,7-dimethyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one (EXAMPLE 62, step 2, 468 mg, 1.82 mmol) in tetrahydrofuran (10 ml) and N,N-dimethylformamide (5 ml) was added dropwise thionyl chloride (0.20 ml, 2.7 mmol). After stirring at room temperature for 2 h, the mixture was concentrated in vacuo, poured into water (100 ml) and extracted with ethyl acetate (100 ml×3). The combined organic layer was dried over magnesium sulfate and evaporated. The residue was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (1:1.5 to ethyl acetate only) to give 151 mg (30%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:27])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:25][CH3:26])=[C:16]([CH2:19][NH:20][CH2:21][CH2:22][O:23][CH3:24])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.CC[O:30][C:31]([C@@H:33](OS(C(F)(F)F)(=O)=O)[CH3:34])=[O:32]>>[Cl:1][C:2]1[C:3]([F:27])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:25][CH3:26])=[C:16]([CH2:19][N:20]([CH2:21][CH2:22][O:23][CH3:24])[C@@H:33]([C:31]([OH:32])=[O:30])[CH3:34])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COCCNCc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC
Reactant: CCOC(=O)[C@H](C)OS(=O)(=O)C(F)(F)F
Product: COCCN(Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC)[C@H](C)C(=O)O

Procedure:
N-(3-Chloro-2-fluorophenyl)-7-methoxy-6-{[(2-methoxyethyl)amino]methyl}quinazolin-4-amine (prepared as described in Example 50) was coupled with ethyl O-trifluoromethanesulfonyl-L-lactate and hydrolysed using analogous methods to those described for the equivalent steps in Example 46 to give N-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N-(2-methoxyethyl)-D-alanine; 1H NMR Spectrum: (DMSO-d6) 1.28 (d, 3H); 2.85 (t, 2H); 3.13 (s, 3H); 3.34 (m, 2H); 3.56 (q, 1H); 3.93 (m, 5H); 7.18 (s, 1H); 7.28 (t, 1H); 7.48 (t, 1H); 7.57 (m, 1H); 8.41 (m, 2H); 9.70 (brs, 1H); Mass Spectrum: (M+H)+ 463.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])[NH2:2].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[C@H:31]3[C@H:26]([CH2:27][CH2:28][CH2:29][CH2:30]3)[C:25](=[O:32])N(CCO)N=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[C@H:31]3[C@H:26]([CH2:27][CH:28]=[CH:29][CH2:30]3)[C:25](=[O:32])[N:1]([C:3]3[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=3)[C:6]([OH:8])=[O:7])[N:2]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(C2=NN(CCO)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: NNc1cccc(C(=O)O)c1
Product: COc1ccc(C2=NN(c3cccc(C(=O)O)c3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound C and 3-hydrazinobenzoic acid as described for compound 35. Crystallized from ethyl acetate/petroleum ether (60°-80° C.). M.p. 185°-186° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:12][CH2:13][CH3:14])[C:5](/[CH:15]=[C:16](\[CH3:20])/[C:17]([OH:19])=[O:18])=[CH:4][C:3]=1[O:21][CH3:22].[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:12][CH2:13][CH3:14])[C:5](/[CH:15]=[C:16](/[CH3:20])\[C:17]([OH:19])=[O:18])=[CH:4][C:3]=1[O:21][CH3:22])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CCCc1cccc2c(/C=C(\C)C(=O)O)cc(OC)c(O)c12
Solvent: c1ccncc1
Product: CCCc1cccc2c(/C=C(/C)C(=O)O)cc(OC)c(OC(C)=O)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.1 g of (E)-3-(4-hydroxy-3-methoxy-5-propyl-1-naphthyl)-2-methylpropenoic acid was dissolved in 20 ml of pyridine and 2 ml of acetic anhydride was added, followed by stirring at room temperature overnight. The reaction mixture was concentrated in vacuo and the resultant crystals were filtered and washed with ethyl acetate to obtain 7.5 g of the titled compound as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:4][C:3]=1[N:16]1[CH2:20][CH:19]2[CH2:21][C:22]3([CH2:27][CH:18]2[CH2:17]1)[O:26][CH2:25][CH2:24][O:23]3.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][O:14][S:36]([CH3:35])(=[O:38])=[O:37])[O:10][C:9]2=[O:15])[CH:5]=[CH:4][C:3]=1[N:16]1[CH2:20][CH:19]2[CH2:21][C:22]3([CH2:27][CH:18]2[CH2:17]1)[O:26][CH2:25][CH2:24][O:23]3
Reactant: O=C1O[C@@H](CO)CN1c1ccc(N2CC3CC4(CC3C2)OCCO4)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CN(c2ccc(N3CC4CC5(CC4C3)OCCO5)c(F)c2)C(=O)O1
Reaction time: 1 h

Procedure:
21.4 g (56.6 mmol) of 2-[2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-3-oxazolidinyl]phenyl]-hexahydro-1H-spiro[cyclopenta[c]pyrrol-5,2′-[1,3]dioxolane] prepared in the step 7 was dissolved in 200 ml of methylene chloride, 19.7 ml (141.5 mmol) of triethylamine was added, the temperature was lowered to 0° C., and then, 8.76 ml (113.2 mmol) of methansulfonyl chloride was added dropwise over 15 minutes, and the mixture was stirred for 1 hour. After the reaction was completed, the reaction mixture was diluted with 200 mL of methylene chloride, washed with water and a saturated aqueous solution of sodium chloride, and then, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[N:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([O:17][C:18]3[N:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:14]=[C:15]([CH3:16])[C:7]=2[CH:6]([CH2:5][C:4]([OH:24])=[O:3])[O:10]1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cccnn3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Oc2cccnn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Yield: 47.2 %

Procedure:
To a solution of [1-hydroxy-4-methyl-6-(pyridazin-3-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.35 g, 1.06 mmol) in THF:H2O (1:1, 6 mL) at 0° C. was added a solution of LiOH (0.076 g, 3.2 mmol) in water (1 mL). The solution was allowed to warm to room temperature over 3 hours then acidified to pH 2 with 1N HCl and extracted with EtOAc (2×10 mL). The organic extracts were washed with water (10 mL), dried and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (DCM:MeOH 90:10) to give [1-hydroxy-4-methyl-6-(pyridazin-3-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid (0.15 g, 47%). 1H NMR (400 MHz, DMSO): δ 9.23 (s, 1H), 9.01 (dd, J=1.2, 4.4 Hz, 1H), 7.79-7.76 (m, 1H), 7.47 (dd, J=1.2, 9.2 Hz, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.14 (d, J=2.0 Hz, 1H), 5.54 (dd, J=2.4 Hz, 1H), 3.10 (dd, J=2.4, 15.6 Hz, 1H), 2.32 (s, 3H), 2.19-2.12 (m, 1H). MS (ESI) m/z=299 [M−H]−.
Reaction SMILES: [O:1]=[C:2]1[O:3][CH2:4][CH2:5]/[C:6]/1=[CH:7]/[C:8]1[CH:13]=[C:12]([NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH:11]=[CH:10][C:9]=1[S:21](Cl)(=[O:23])=[O:22].[NH2:25][C:26]1[CH:27]=[CH:28][C:29]2[CH2:33][O:32][B:31]([OH:34])[C:30]=2[CH:35]=1.N1C=CC=CC=1>O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>[F:17][C:16]([F:19])([F:18])[C:15]([NH:14][C:12]1[CH:11]=[CH:10][C:9]([S:21](=[O:23])(=[O:22])[NH:25][C:26]2[CH:27]=[CH:28][C:29]3[CH2:33][O:32][B:31]([OH:34])[C:30]=3[CH:35]=2)=[C:8](/[CH:7]=[C:6]2\[C:2](=[O:1])[O:3][CH2:4][CH2:5]\2)[CH:13]=1)=[O:20]
Reactant: O=C1OCC/C1=C/c1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)B(O)OC2
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: c1ccncc1
Product: O=C1OCC/C1=C/c1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.5 %

Procedure:
The crude intermediate (Z)-2-((2-oxodihydrofuran-3(2H)-ylidene)methyl)-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride (2.85 g, 10 mmol) and 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (1.5 g, 10 mmol) was suspended in CAN (50 ml), followed by the addition of pyridine (3 ml) dropwise. After stirred at rt for 3 hrs, the mixture was poured into ice-H2O and extracted with EtOAc, washed with H2O, brine, dried over MgSO4, filtered, concentrated in reduced pressure to dryness. The crude product was treated with DCM to give (Z)-2,2,2-trifluoro-N-(4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-3-((2-oxodihydrofuran-3(2H)-ylidene)methyl)phenyl)acetamide as a solid (3.4 g). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 11.63 (s, 1H), 10.34 (s, 1H), 9.18 (s, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.87 (s, 1H), 7.87 (dd, J=8.4, 1.6 Hz, 1H), 7.82 (t, J=2.8 Hz, 1H), 7.34 (d, J=1.6 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.07 (dd, J=8.4, 1.6 Hz, 1H), 4.85 (s, 2H), 4.28 (t, J=7.2 Hz, 2H), 2.88 (dt, J=2.8, 7.2 Hz, 2H). MS (ESI) m/z=495 (M−1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10]NC=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[Se].[CH2:34]([N:41]=[C:42]=[Se:43])[C:35]1C=CC=CC=1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:35][CH2:34][N:41]=[C:42]=[Se:43])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [Se]=C=NCc1ccccc1
Reactant: O=CNCCCCc1ccccc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Se]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [Se]=C=NCCCCCCc1ccccc1
Yield: 95 %

Procedure:
A mixture of phenylbutyl formamide (g, 1.5 mmol), triethylamine (6.4 mmol), 4 Å molecular sieves (g), triphosgene (0.8 mmol), and selenium powder (3.0 mmol) in CH2Cl2 was refluxed and worked up as mentioned for 2a. The crude residue thus obtained was purified by silica gel column chromatography (EtOAc/hexanes 2:98) to give 0.96 g (95%) of 2d as an oil. 1H NMR (CDCl3) δ 1.37-1.43 (m, 2H), 1.45-1.51 (m, 2H), 1.67 (dt, 2H, J=15.2 and 7.6 Hz), 1.75 (dt, 2H, J=14.9 and 6.7 Hz), 2.64 (t, 2H, J=7.6 Hz), 3.60 (t, 2H, J=6.7 Hz), 7.19-7.25 (m, 3H), 7.32-7.40 (m, 2H); HRMS (EI) calcd for C13H17NSe, 267.0521. found, 267.0529.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](Cl)=[N:6][CH:7]=1.[CH2:9]([SH:13])[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:13][CH2:9][CH2:10][CH2:11][CH3:12])=[N:6][CH:7]=1
Reactant: CCCCS
Reactant: Clc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCSc1ccc(Br)cn1
Temperature: 60 °C

Procedure:
A mixture of 5-bromo-2-chloro-pyridine (2.0 g), 1-butanethiol (1.3 mL), cesium carbonate (4.5 g) and DMF (5 mL) was heated to 60° C. for 3 hours. The mixture was diluted with water and extracted three times with EA. The combined organic phases were washed with brine, dried (Na2SO4) and concentrated to provide the subtitle compound. MS ESI+: m/z=246 [M+H]+.