Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C)(C)CN1C=C[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:5]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH2:55]([C:57]1N=C(N)[S:59][N:58]=1)[CH3:56]>ClCCl>[CH2:55]([C:57]1[N:5]=[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:14])[CH3:15])[S:59][N:58]=1)[CH3:56]
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(CC(C)(C)O)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Reactant: CCc1nsc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCc1nsc(NC(=O)[C@H](CC(C)C)N2CC(Oc3ccccc3Cl)=CC2=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
To a solution of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 64, 104 mg, 0.32 mmol) in dichloromethane (1.00 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (69 mg, 0.36 mmol) and 1-hydroxybenzotriazole (46 mg, 0.34 mmol). The resulting solution was stirred for 5 min before 3-ethyl-[1,2,4]thiadiazol-5-ylamine (50 mg, 0.39 mmol) was added and the resulting mixture stirred at 25° C. overnight. The mixture was washed with saturated ammonium chloride (1 mL), evaporated and the crude product purified by HPLC (Gilson semi-prep; Supelcosil ABZ+Plus 12 μM 25 cm×21.2 mm column 20-95% acetonitrile/water gradient) which afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (3-ethyl-[1,2,4]thiadiazol-5-yl)-amide (83 mg, 59%) as a light yellow solid: HR-ES-MS m/z calculated for C20H23ClN4O3S [M+H]+ 435.1252, observed 435.1252; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.4 Hz, 3H), 0.91 (d, J=6.4 Hz, 3H), 1.45 (br. s., 1H), 1.53-1.72 (m, 1H), 1.83 (br. s., 1H), 3.69 (s, 3H), 4.04 (s, 2H), 4.26 (d, J=18.4 Hz, 1H), 4.48 (d, J=18.4 Hz, 1H), 4.80 (s, 1H), 4.96 (dd, J=11.2, 4.5 Hz, 1H), 6.84 (d, J=8.5 Hz, 2H), 7.17 (d, J=8.5 Hz, 2H), 7.35 (td, J=7.8, 1.5 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.64 (d, J=7.8 Hz, 1H), 13.28 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH2:23])[S:11][C:12]=2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:23][C:10]2[S:11][C:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=2)=[O:30])=[CH:27][CH:26]=1
Reactant: Nc1nc(-c2ccc(F)cc2)c(Cc2ccc([N+](=O)[O-])cc2)s1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: O=C(Nc1nc(-c2ccc(F)cc2)c(Cc2ccc([N+](=O)[O-])cc2)s1)c1ccc(F)cc1
Yield: 69.6 %

Procedure:
A procedure similar to that in Example 4 was used. 4-(4-fluoro-phenyl)-5-(4-nitro-benzyl)-thiazol-2-ylamine prepared in Example 9 and p-fluorobenzoyl chloride were used as starting materials, allowed to react at 35-40° C. for 24 hours, followed by post-treatment to obtain a crude product, which was purified by a silica gel column chromatography eluted with petroleum ether and ethyl acetate (4:1) to obtain a product as a pale yellow solid in a yield of 69.6%, mp: 120-122 └. 1H-NMR (CDCl3, 400 MHz) δ: 4.33 (2H, s, CH2), 7.12 (2H, t, 3JFH=3JHH=8.44 Hz, ArH), 7.18 (2H, t, 3JFH=3JHH=8.40 Hz, ArH), 7.38 (2H, d, J=8.68 Hz, ArH), 7.49 (2H, dd, 3JHH=8.72, 4JFH=5.32 Hz, ArH), 7.99 (2H, dd, 3JHH=8.96, 4JFH=5.32 Hz, ArH); 8.20 (2H, d, J=8.68 Hz, ArH); EI-MS m/e (%): 451.0 (M+, 32), 123.0 (100); HREI-MS Calcd. for C23H15F2N3O3S: 451.0802. found: 451.0818. Anal. Calcd. for C23H15F2N3O3S: C, 61.19; H, 3.35; N, 9.31. found: C, 61.16; H, 3.08; N, 9.35.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:24])([F:23])[C:9]1[CH:10]=[C:11]([C:15]2[N:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1.[OH-].[Na+]>O1CCCC1>[F:23][C:8]([F:7])([F:24])[C:9]1[CH:10]=[C:11]([C:15]2[N:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: O=Cc1ccc(-c2cccc(C(F)(F)F)c2)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(-c2cccc(C(F)(F)F)c2)nc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
261 mg (6.87 mmol) lithium aluminium hydride were given to 20 ml tetrahydrofuran (THF) and stirred at room temperature (r.t.) for 20 min. A solution of 1.15 g (4.58 mmol) 6-(3-Trifluoromethyl-phenyl)-pyridine-3-carbaldehyde in 20 ml THF was added drop by drop within 15 min., and the mixture stirred for 3 h. 1.5 ml ice water and 0.6 ml 2 M NaOH were added slowly at 0° C. and stirred continued for 30 min. A formed salt precipitate was isolated by filtration and washed with THF. The combined THF-solutions were evaporated, the residue extracted twice with ethyl acetate, the organic phase dried (sodium sulphate), evaporated, and the obtained material (0.98 g, 85%) used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([C@@H:16]([NH:21][C:22](=[O:33])[O:23][C:24]2C=CC([N+]([O-])=O)=C[CH:25]=2)[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:10]=1.C(O)C[OH:42]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([C@@H:16]([NH:21][C:22](=[O:33])[O:23][CH2:24][CH2:25][OH:42])[C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[C@H:11]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:10]=1
Reactant: OCCO
Reactant: CC(C)(C)[C@H](NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Product: CC(C)(C)[C@H](NC(=O)OCCO)C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 4-nitrophenyl (1S)-1-{[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}-2,2-dimethylpropylcarbamate (36-1, 500 mg, 0.93 mmol, 1.0 equiv) and ethylene glycol (3 mL, excess) was heated at 100° C. for 1 h. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel. Elution with 20% ethyl acetate/dichloromethane to 50% ethyl acetate/dichloromethane gave 2-hydroxyethyl (1S)-1-{[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}-2,2-dimethylpropylcarbamate (36-2) as a colorless foam. 1H NMR (500 MD, CDCl3) major rotamer: δ 7.38-7.21 (m, 5H), 7.11-6.94 (m, 3H), 6.40 (s, 1H), 5.92 (m, 1H), 5.51 (m, 1H), 5.07 (d, 1H, J=13 Hz), 4.91 (m, 1H), 4.37 (d, 1H, J=10 Hz), 4.20 (m, 2H), 3.81 (t, 2H, J=4.5 Hz), 3.64 (t, 1H, J=4 Hz),) 0.91 (s, 9H). LRMS m/z (M+H) 459.3 found, 459.2 required.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:38]([O:55][CH2:56][CH2:57][N:58]([CH2:88][CH3:89])[CH2:59][CH2:60][C@@H:61]([NH:70][C:71]1[CH:76]=[CH:75][C:74]([S:77]([NH2:80])(=[O:79])=[O:78])=[CH:73][C:72]=1[S:81]([C:84]([F:87])([F:86])[F:85])(=[O:83])=[O:82])[CH2:62][S:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)([C:51]([CH3:54])([CH3:53])[CH3:52])([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C>[Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:11][CH2:12][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:80][S:77]([C:74]3[CH:75]=[CH:76][C:71]([NH:70][C@H:61]([CH2:60][CH2:59][N:58]([CH2:57][CH2:56][O:55][Si:38]([C:51]([CH3:53])([CH3:54])[CH3:52])([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH2:88][CH3:89])[CH2:62][S:63][C:64]4[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=4)=[C:72]([S:81]([C:84]([F:87])([F:85])[F:86])(=[O:83])=[O:82])[CH:73]=3)(=[O:78])=[O:79])=[O:21])=[CH:18][CH:17]=2)[CH2:14][CH2:15]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: CCN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O[Si](C)(C)C(C)(C)C)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
(R)-4-(4-((tert-butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 13, 160 mg, 0.3 mmol), (R)-4-(4-((2-(tert-butyldiphenylsilyloxy)ethyl)(ethyl)amino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 25, 216 mg, 0.27 mmol), DMAP (100 mg, 0.82 mmol), and EDC (104 mg, 0.54 mmol) were placed in a 50 ml flask and flushed with nitrogen. DCM (3 ml) was added, and the solution was stirred at room temperature overnight. The reaction mixture was diluted with DCM (40 ml) and washed with 1N aq. sodium bisulfate (35 ml) followed by a saturated aq. sodium bicarbonate (40 ml). The organic layer was dried (Na2SO4), filtered, and evaporated under reduced pressure to give a residue, which was purified by column chromatography (ISCO, 40 g silica gel column, eluting with 0→25% EtOAc/hexanes) to give 4-(4-((R)-(tert-butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)-N-(4-((R)-4-((2-(tert-butyldiphenylsilyloxy)ethyl)(ethyl)amino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethyl sulfonyl)phenylsulfonyl)benzamide (EXAMPLE 4A, STEP 1, 140 mg), that was used in the preparation of EXAMPLE 4A, STEP 2, without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:27]([N:34]1[CH:38]=[C:37]([C:39]2[C:40](Cl)=[N:41][CH:42]=[CH:43][CH:44]=2)[CH:36]=[N:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O)(C(F)(F)F)=O>CCOC(C)=O.O>[CH2:27]([N:34]1[CH:38]=[C:37]([C:39]2[C:40]([O:1][C:2]3[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=3[CH3:20])[C:5]([NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=3)=[O:6])=[N:41][CH:42]=[CH:43][CH:44]=2)[CH:36]=[N:35]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(C)C)c2)cc1O
Reactant: Clc1ncccc1-c1cnn(Cc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2cccc(C(C)C)c2)cc1Oc1ncccc1-c1cnn(Cc2ccccc2)c1
Temperature: 130 °C

Procedure:
3-Hydroxy-N-(3-isopropylphenyl)-4-methylbenzamide (100 mg, 0.371 mmol), cesium carbonate (220 mg, 0.676 mmol) and 3-(1-benzyl-1H-pyrazol-4-yl)-2-chloropyridine (91.0 mg, 0.338 mmol) were combined in an argon-purged sealed tube. DMSO (1.5 mL) was added and the mixture was heated to 130° C. for 23 hours. The cooled reaction was diluted with EtOAc and water and then neutralized with TFA (pH˜7). The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified first by silica gel chromatography (1:1 MTBE/benzene) followed by trituration of the resulting solid with 20:1 hexanes/EtOAc to yield 3-(3-(1-benzyl-1H-pyrazol-4-yl)pyridin-2-yloxy)-N-(3-isopropylphenyl)-4-methylbenzamide as an off-white solid. MS m/z=503 [M+1]+. Calc'd for C32H30N4O2: 502.62.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=3)[N:4]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[N:3]=2)=[CH:22][CH:21]=1
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)c(-c1ccc(Cl)cc1)nn2C1CCCCO1
Yield: 80 %

Procedure:
The title compound was prepared as described in Example 161, using 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.400 g, 1.30 mmol), in ethylene glycol dimethyl ether (10 mL), 4-chlorophenyl boronic acid (0.306 g, 1.96 mmol), [1,1′-bis(diphenylphosphino)-ferrocene] complex with dichloromethane (1:1) (0.150 g, 0.130 mmol), and potassium phosphate (1.38 g, 6.5 mmol): (0.351 g, 80% yield): ES-MS (m/z) 338 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C=O)C.C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl>[Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:23])=[O:5]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc(C(F)(F)F)c1Cl

Procedure:
To a suspension of 2-chloro-3-(trifluoromethyl)benzoic acid (15 g, 67 mmol) and catalytic DMF (0.06 mL, 0.67 mmol) in DCM (150 mL) was added oxalyl chloride (6.8 mL, 80 mmol) dropwise. The reaction was let stir (vigorous bubbling) for 4 h and concentrated to an oily solid which became solid after overnight drying on high vacuum.
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][O:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]([S:18][C@H:19]2[NH:22][C:21](=[O:23])[C@@H:20]2[O:24][CH3:25])=[O:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:28]([C:31]1[CH:45]=[CH:44][C:34]([CH2:35][O:36][C:37](=[O:43])[CH:38](OCC)[OH:39])=[CH:33][CH:32]=1)([O-:30])=[O:29].C(Cl)Cl>C1(C)C=CC=CC=1.CN(C)C=O>[N+:28]([C:31]1[CH:32]=[CH:33][C:34]([CH2:35][O:36][C:37](=[O:43])[CH:38]([N:22]2[C@H:19]([S:18][C:16](=[O:17])[CH2:15][CH2:14][CH2:13][NH:12][C:10]([O:9][CH2:8][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:27][CH:26]=3)=[O:11])[C@@H:20]([O:24][CH3:25])[C:21]2=[O:23])[OH:39])=[CH:44][CH:45]=1)([O-:30])=[O:29]
Reactant: CO[C@H]1C(=O)N[C@@H]1SC(=O)CCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CO[C@H]1C(=O)N(C(O)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1SC(=O)CCCNC(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
Analogously to Example 23, 400 mg of (3S,4R)-4-(4-p-nitrobenzyloxycarbonylaminobutyrylthio)-3-methoxy-2-oxoazetidine in 15 ml of absolute toluene and 3.7 ml of absolute dimethylformamide are reacted with 565 mg of 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester in the presence of freshly dried molecular sieves. After working up and chromatography over silica gel, the title compound with the following IR spectrum (CH2Cl2) is obtained:
Reaction SMILES: [CH2:1]=[CH:2][CH3:3].[CH:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>>[C:4]1([CH:2]([CH3:3])[CH3:1])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: c1ccccc1
Reactant: C=CC
Product: CC(C)c1ccccc1

Procedure:
When benzene is alkylated with propylene to produce cumene, the reaction may also take place under liquid phase conditions including a temperature of up to about 250° C., e.g., up to about 150° C., e.g., from about 10° C. to about 150° C.; a pressure of about 3000 psig or less, (about 20875 kPa abs.) e.g., from about 100 to 3000 kPa; and an aromatic hydrocarbon weight hourly space velocity (WHSV) of from about 5 hr-1 to about 250 hr-1, e.g., from 5 hr-1 to about 50 hr-1.
Reaction SMILES: CO.[CH:3]1([NH:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:29])[C:15]([O:25][CH2:26][C:27]#[N:28])=[CH:16][N:17]3[CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][C:11]=2[F:30])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl.[NH2:32][OH:33]>C(N(CC)CC)C>[CH:3]1([NH:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:29])[C:15]([O:25][CH2:26][C:27](=[N:32][OH:33])[NH2:28])=[CH:16][N:17]3[CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][C:11]=2[F:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: N#CCOc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: NC(COc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O)=NO
Yield: 52.2 %

Procedure:
To a 30 ml methanol solution of 1.5 g of {[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]oxy}acetonitrile were added 1.1 ml of triethylamine and 540 mg of hydroxylamine hydrochloride, followed by heating under reflux for 27 hours. The solvent was evaporated under a reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 850 mg of 2-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]oxy}-N′-hydroxyethanimidamide.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.CCN(CC)CC.[C:16]1([O:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl.CCOC(C)=O>[O:22]([C:23]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NCc1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(NCc1ccncc1)Oc1ccccc1
Reaction time: 1 h
Yield: 42.5 %

Procedure:
To a solution of 4-(aminomethyl)pyridine (10.7 g, 98.5 mmol) in CH2Cl2 (245 mL) at 0°, was added Et3N (14.2 mL, 19.9 g, 197 mmol) followed by dropwise addition of phenylchloroformate (14.8 mL, 18.5 g, 118 mmol). After stirring for 1 h, the resulting mixture was diluted with EtOAc (1.5 L), the organic phase was washed twice with water and brine, dried over sodium sulfate and concentrated under vacuum. Chromatography (SiO2, gradient EtOAc to 10% MeOH/CHCl3) gave a yellow solid which was recrystallized from EtOAc:hexane (2:1), to yield the desired compound (9.55 g, 41.85 mmol, 42% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].[C:30]1([CH2:36][C:37](Cl)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:37](=[O:38])[CH2:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN2CCOC2=O)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)Cc3ccccc3)cc2CN2CCOC2=O)c1

Procedure:
Prepared according to the procedure described in Example 100, Step 1, using the following starting materials: {3-[4-amino-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and phenylacetyl chloride.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].[C:9]1([CH2:15][C:16](Cl)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCOCC>[OH-].[Na+]>[C:9]1([CH2:15][C:16]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[C@@H](O)[C@H](N)C(=O)O
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: C[C@@H](O)[C@H](NC(=O)Cc1ccccc1)C(=O)O
Reaction time: 16 h

Procedure:
L-Threonine (35.7 g) is dissolved in 1 N sodium hydroxide (1 liter) and chilled to -5° to -10° C. To the cold, mechanically stirred solution is added dropwise phenylacetyl chloride (46.3 g). The reaction mixture is stirred for about 16 hours as the temperature rises to 26° C. The mixture is washed with ether, acidified to pH 2 with hydrochloric acid, and extracted with ethyl acetate (two times). The combined extracts are dried over sodium sulfate and concentrated under reduced pressure until crystalline solids form. Ether is added to the mixture and the crystals are collected (34.8 g); melting point 161°-163° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B(O)O)[CH:5]=[CH:4][N:3]=1.Cl[C:12]1[CH:20]=[CH:19][N:18]2[C:14](=[N:15][C:16]3[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=32)[N:13]=1>>[F:1][C:2]1[CH:7]=[C:6]([C:12]2[CH:20]=[CH:19][N:18]3[C:14](=[N:15][C:16]4[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=43)[N:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: Clc1ccn2c(n1)nc1ccccc12
Product: Fc1cc(-c2ccn3c(n2)nc2ccccc23)ccn1

Procedure:
General experimental procedure (A) for Suzuki coupling with 2-fluoropyridin-4-ylboronic acid was followed. Reaction was performed on a 40 mg scale of 2-chloropyrimido[1,2-a]benzimidazole. The residue was purified by HPLC (acetonitrile/water) to give 6.2 mg (12%) of T732 as a white solid. 1H NMR (CD3OD): δ 9.91 (1H, d, J=7.2 Hz), 8.47-8.53 (2H, m, overlapped), 8.39 (PH, d, J=7.2 Hz), 8.25 (1H, m), 8.04 (1H, m), 7.95 (1H, d, J=8.4 Hz), 7.89 (1H, m), 7.76 (1H, m); MS: 265 (M+H+).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(OCC)(=O)C>CN(C=O)C>[N:32]1([CH2:31][CH2:30][N:2]2[CH2:3][CH2:4][CH2:5][C:6]3[CH:11]=[C:10]([O:12][C:13]4[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=4)[CH:9]=[CH:8][C:7]=3[CH2:1]2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCCN(CCN2CCOCC2)C3)nc1
Temperature: 90 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 4-(2-chloroethyl)morpholine hydrochloride (0.217 g, 1.16 mmol) in DMF (5.3 mL). Heat at 90° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (150 mL). Wash with 1.0 N NaOH (1× 50 mL), brine (1× 50 mL), dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 10% to 20% (2.0 M NH3 in methanol) in acetone to give the title compound: MS ES+ 397.2 (M+H)+, HRMS calcd for C22H29N4O3 397.2240 (M+H)+, found 397.2223, time 0.48 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=5.6 min, 99.0% purity.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH:10]2[CH:12]([CH:11]2[C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C2C(CN1Cc1ccccc1)C2c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccc(C2C3CN(Cc4ccccc4)CC32)cc1
Yield: 65.2 %

Procedure:
To a tetrahydrofuran solution (40 mL) of 3-benzyl-6-(4-fluorophenyl)-3-azabicyclo[3.1.0]hexan-2-one (956 mg, 3.40 mmol) synthesized in Reference Synthesis Example 238, lithium aluminum hydride (258 mg, 6.80 mmol) was added at 0° C. and the resultant mixture was stirred under reflux by heating for 30 minutes. After completion of the reaction, 1 M sodium hydroxide aqueous solution was added to the reaction solution at 0° C. and extraction from the resultant mixture with dichloromethane was performed. The organic layer was purified by silica gel (amino-based) column chromatography (hexane/ethyl acetate=15/1→10/1) to obtain the title compound (593 mg, yield 66%).