Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:58][CH:59]([CH3:61])[CH3:60])[C@@H:12]([CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37](=[O:57])[CH:38]([NH:52][C:53]([O:55][CH3:56])=[O:54])[CH:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:13][O:14][C:15](=[O:31])[C@@H:16]([NH:20]C(OCC2C=CC=CC=2)=O)[CH:17]([CH3:19])[CH3:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1>C1COCC1.[Pd]>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:58][CH:59]([CH3:61])[CH3:60])[C@@H:12]([CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37](=[O:57])[CH:38]([NH:52][C:53]([O:55][CH3:56])=[O:54])[CH:39]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:13][O:14][C:15](=[O:31])[C@@H:16]([NH2:20])[CH:17]([CH3:18])[CH3:19])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)NC(C(=O)NCCCC[C@@H](COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1)C(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)NC(C(=O)NCCCC[C@@H](COC(=O)[C@@H](N)C(C)C)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1)C(c1ccccc1)c1ccccc1
Yield: 47 %

Procedure:
To a stirred solution of (2S,2S)-2-benzyloxycarbonylamino-3-methyl-butyric acid 2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-(2-methoxy carbonylamino-3,3-diphenyl-propionylamino)-hexyl ester (step C, 120 mg, 0.14 mmol) in anhydrous THF (8 mL), under nitrogen atmosphere, was added palladium 10% wt. on activated carbon (160 mg). The mixture was reacted under hydrogen atmosphere overnight, at room temperature. The solution was filtered and the palladium on carbon was washed with THF (50 mL). The solvent was evaporated and the residue (110 mg) was purified by flash chromatography using ethyl acetate as the eluent. The clear oil was obtained in 47% yield (47 mg).
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[CH:14][C:15](O)=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.[CH3:48][O:49][C:50](=[O:53])[CH2:51][NH2:52]>[Cl-].[Na+].O.CN(C=O)C>[CH3:48][O:49][C:50](=[O:53])[CH2:51][NH:52][C:15](=[O:16])[CH:14]=[C:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COC(=O)CN
Reactant: O=C(O)C=C1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)C=C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.3 %

Procedure:
2-(9H-fluoren-9-ylidene)acetic acid (222 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxybenzo-triazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and glycine methyl ester hydrochloride (151.8 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (256 mg, 88% yield) as a white solid. LC-MS (m/z) 294 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:20][S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1)(=[O:23])=[O:22].F[C:32]1C=C(S(Cl)(=O)=O)C=C[CH:37]=1>>[CH2:32]([O:14][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[C:3]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)(=[O:22])=[O:23])[CH:4]=2)=[CH:10][CH:11]=1)[CH3:37]
Reactant: O=C(O)c1ccc(NC(=O)c2ccc(Cl)c(NS(=O)(=O)c3cccc(F)c3)c2)cc1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc(Cl)c(NS(=O)(=O)c3cccc(F)c3)c2)cc1

Procedure:
4-[4-Chloro-3-(3-fluoro-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=447.1 (M−H), was prepared in analogy to example 21, steps A to D. Step C was performed using 3-fluoro-benzenesulfonyl chloride and yielded 4-[4-chloro-3-(3-fluoro-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [C:1]([O:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(OC(C)(C)C)=O.OC1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][CH:23]=[N:24]2)=[CH:19][CH:18]=1>CN(C)C1C=CN=CC=1.CN(C)C=O.CCOC(C)=O>[C:9](=[O:10])([O:8][C:1]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][CH:23]=[N:24]2)=[CH:19][CH:18]=1)[O:11][C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: Oc1ccc2cccnc2c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Oc1ccc2cccnc2c1
Reaction time: 18 h
Yield: 96.7 %

Procedure:
Di-tert-butyl dicarbonate (7.40 g, 33.92 mmol) and 4-(dimethylamino)pyridine (222 mg, 1.81 mmol) were added in sequence to 7-hydroxyquinoline (2.00 g, 13.75 mmol) in anhydrous N,N-dimethylformamide (20.0 mL) at room temperature. After 18 hours, the reaction was diluted with EtOAc (250 mL). The organic layer was washed with 1.0 M NaOH (250 mL), water (3×250 mL), saturated aqueous NaCl solution (250 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 1:1 Hexanes:EtOAc) to give 28 as a colorless amorphous solid (3.26 g, 97%): 1H NMR (CDCl3, 500 MHz) δ 8.93 (dd, J=4.2, 1.7 Hz, 1H), 8.17 (bd, J=8.4 Hz, 1H), 7.90 (d, J=2.2 Hz, 1H), 7.84 (d, J=8.9 Hz, 1H), 7.43 (dd, J=8.8, 2.3 Hz, 1H), 7.40 (dd, J=8.3, 4.3 Hz, 1H), 1.60 (s, 9H); 13C NMR (CDCl3, 125 MHz) δ 151.7, 151.7, 148.9, 135.9, 129.0, 126.3, 122.0, 121.0, 120.2, 84.2, 27.8 (3C); IR (film) νmax 1759, 1277, 1240, 1142, 768, 750 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C14H11NO3, 246.1130; found, 246.1113.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:2]2[C:7]([C:8]3[CH:13]=[CH:12][N:11]=[CH:10][N:9]=3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23]
Reactant: Clc1ncccc1-c1ccncn1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1cc(Nc2ncccc2-c2ccncn2)ccc1F

Procedure:
4-(2-Chloro-pyridin-3-yl)-pyrimidine (60 mg, 0.30 mmol), 4-fluoro-3-nitrobenzenamine (56 mg, 0.36 mmol), Pd(OAc)2 (4 mg, 0.012 mmol), rac-BINAP (8 mg, 0.012 mmol) and K2CO3 (829 mg, 6.0 mmol) in toluene (3.0 mL) were reacted overnight at 130° C. The reaction was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filter, concentrated and purified by silica gel chromatography (0-100% EtOAc/hexanes) yielding the title compound. MS m/z=312 [M+1]+. Calc'd for C15H10FN5O2: 311.28.
Reaction SMILES: C(C1C=CC(C2SC=CC=2CO)=CC=1)C.OC1C=CC(CCC(OCC)=O)=C(C)C=1C.[CH2:32]([C:34]1[CH:39]=[CH:38][C:37]([C:40]2[S:41][CH:42]=[CH:43][C:44]=2[CH2:45][O:46][C:47]2[CH:52]=[CH:51][C:50]([CH2:53][CH2:54][C:55]([O:57]CC)=[O:56])=[C:49]([CH3:60])[C:48]=2[CH3:61])=[CH:36][CH:35]=1)[CH3:33]>>[CH2:32]([C:34]1[CH:35]=[CH:36][C:37]([C:40]2[S:41][CH:42]=[CH:43][C:44]=2[CH2:45][O:46][C:47]2[CH:52]=[CH:51][C:50]([CH2:53][CH2:54][C:55]([OH:57])=[O:56])=[C:49]([CH3:60])[C:48]=2[CH3:61])=[CH:38][CH:39]=1)[CH3:33]
Reactant: CCOC(=O)CCc1ccc(OCc2ccsc2-c2ccc(CC)cc2)c(C)c1C
Agent: CCOC(=O)CCc1ccc(O)c(C)c1C
Agent: CCc1ccc(-c2sccc2CO)cc1
Product: CCc1ccc(-c2sccc2COc2ccc(CCC(=O)O)c(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 207 by coupling of (2-(4-ethylphenyl)thiophen-3-yl)methanol and ethyl 3-(4-hydroxy-2,3-dimethyl phenyl)propanoate followed by hydrolysis of ethyl 3-(4-((2-(4-ethylphenyl)thiophen-3-yl)methoxy)-2,3-dimethylphenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=7.5 Hz, 2H), 7.24 (m, 4H), 6.95 (d, J=6.5 Hz, 1H), 6.65 (d, J=6.5 Hz, 1H), 4.98 (s, 2H), 2.96 (t, J=5.0 Hz, 2H), 2.70 (q, J=5.1 Hz, 2H), 2.62 (t, J=5.2 Hz, 2H), 2.28 (s, 3H), 2.22 (s, 3H), 1.26 (t, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[O:4].[Cl:8][C:9]1[C:19]2[CH2:18][CH2:17][NH:16][CH2:15][CH:14]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[C:13]=2[CH:12]=[C:11]([OH:27])[C:10]=1[OH:28].[F-].[K+].Br[CH2:32]Br>CN(C)C=O>[F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[O:4].[Cl:8][C:9]1[C:19]2[CH2:18][CH2:17][NH:16][CH2:15][CH:14]([C:20]3[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=3)[C:13]=2[CH:12]=[C:11]2[O:27][CH2:32][O:28][C:10]=12
Reactant: BrCBr
Reactant: Oc1ccc(C2CNCCc3c2cc(O)c(O)c3Cl)cc1
Agent: NC(=O)C(F)(F)F
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Oc1ccc(C2CNCCc3c2cc2c(c3Cl)OCO2)cc1
Reaction time: 0.08 h
Yield: 67.9 %

Procedure:
A solution of 44 g (0.104 mole) of 6-chloro-7,8-dihydroxy-1-(p-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine trifluoroacetamide in 700 ml of dry dimethylformamide was treated with 45.5 g (0.784 mole) of potassium fluoride. After five minutes, 11.2 ml (27.6 g, 0.109 mole) of dibromomethane was added. The mixture was heated at 115° and held at 115° for 6 hours. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate and washed several times with water. The dried, concentrated product was chromatographed over 800 g of silica gel with a 1 to 3% methanol in chloroform gradient. The homogeneous fractions gave 30.4 g (71%) of 6-chloro-7,8-methylenedioxy-1-(p-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine trifluoroacetamide. A sample was crystallized from acetonitrile to give white crystals, m.p. 191°-193°.
Reaction SMILES: C(OC(N(C)[C@@H](C)C(N[C@@H](C(C)(C)C)C(N1[C@H](C(=O)N[C@H]2C3C(=CC=CC=3)CCC2)CC2C(=CC(C(O)=O)=CC=2)C1)=O)=O)=O)(C)(C)C.[C:48]([O:52][C:53]([N:55]([CH3:132])[C@@H:56]([CH3:131])[C:57]([NH:59][C@@H:60]([C:127]([CH3:130])([CH3:129])[CH3:128])[C:61]([N:63]1[CH2:67][C@@H:66]([C:68]2[CH:77]=[C:76]3[C:71]([CH2:72][C@@H:73]([C:99](=[O:111])[NH:100][C@H:101]4[C:110]5[C:105](=[CH:106][CH:107]=[CH:108][CH:109]=5)[CH2:104][CH2:103][CH2:102]4)[N:74]([C:78](=[O:98])[C@@H:79]([NH:84][C:85](=[O:97])[C@@H:86]([N:88]([C:90]([O:92][C:93]([CH3:96])([CH3:95])[CH3:94])=[O:91])[CH3:89])[CH3:87])[C:80]([CH3:83])([CH3:82])[CH3:81])[CH2:75]3)=[CH:70][CH:69]=2)[CH2:65][C@H:64]1[C:112]([NH:114][C@@H:115]([CH2:120][C:121]1[CH:126]=[CH:125][CH:124]=[CH:123][CH:122]=1)[C:116]([O:118]C)=[O:117])=[O:113])=[O:62])=[O:58])=[O:54])([CH3:51])([CH3:50])[CH3:49]>>[C:48]([O:52][C:53]([N:55]([CH3:132])[C@@H:56]([CH3:131])[C:57]([NH:59][C@@H:60]([C:127]([CH3:130])([CH3:129])[CH3:128])[C:61]([N:63]1[CH2:67][C@@H:66]([C:68]2[CH:77]=[C:76]3[C:71]([CH2:72][C@@H:73]([C:99](=[O:111])[NH:100][C@H:101]4[C:110]5[C:105](=[CH:106][CH:107]=[CH:108][CH:109]=5)[CH2:104][CH2:103][CH2:102]4)[N:74]([C:78](=[O:98])[C@@H:79]([NH:84][C:85](=[O:97])[C@@H:86]([N:88]([C:90]([O:92][C:93]([CH3:94])([CH3:96])[CH3:95])=[O:91])[CH3:89])[CH3:87])[C:80]([CH3:82])([CH3:81])[CH3:83])[CH2:75]3)=[CH:70][CH:69]=2)[CH2:65][C@H:64]1[C:112]([NH:114][C@@H:115]([CH2:120][C:121]1[CH:126]=[CH:125][CH:124]=[CH:123][CH:122]=1)[C:116]([OH:118])=[O:117])=[O:113])=[O:62])=[O:58])=[O:54])([CH3:49])([CH3:50])[CH3:51]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1C[C@H](c2ccc3c(c2)CN(C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)(C)C)[C@H](C(=O)N[C@@H]2CCCc4ccccc42)C3)CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)(C)C
Agent: C[C@@H](C(=O)N[C@H](C(=O)N1Cc2cc(C(=O)O)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Product: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](c2ccc3c(c2)CN(C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)(C)C)[C@H](C(=O)N[C@@H]2CCCc4ccccc42)C3)C[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Yield: 96.2 %

Procedure:
Following a procedure analogous to that for the synthesis of Compound K of Example 1, (S)-methyl 2-((2S,4R)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)-4-((S)-2-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrrolidine-2-carboxamido)-3-phenylpropanoate (310 mg, 0.26 mmol) was converted to the title compound (291 mg, 95%). MS (ESI+) m/z 1016.7 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29](O)=[O:30])[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[CH3:32][CH:28]([N:26]1[CH:27]=[C:23]([C:21]2[CH:20]=[N:19][N:18]3[C:14]([C:10]4[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:34])([F:33])[F:1])=[O:6])[CH:13]=[CH:12][CH:11]=4)=[CH:15][N:16]=[C:17]3[CH:22]=2)[CH:24]=[N:25]1)[C:29]([N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)=[O:30]
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Reactant: C1COCCN1
Product: CC(C(=O)N1CCOCC1)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and morpholine. LCMS (M+H)+: m/z=543.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1.[CH3:26][N:27]1[C:31]([CH3:32])=[C:30]([S:33](Cl)(=[O:35])=[O:34])[C:29]([CH3:37])=[N:28]1>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:21][CH2:22][N:23]([S:33]([C:30]3[C:29]([CH3:37])=[N:28][N:27]([CH3:26])[C:31]=3[CH3:32])(=[O:34])=[O:35])[CH2:24][CH2:25]2)[N:3]=1
Reactant: Cc1nn(C)c(C)c1S(=O)(=O)Cl
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)c3c(C)nn(C)c3C)CC2)nc1N

Procedure:
The title compound was prepared from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone, Example 59, and 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride (Maybridge) by the procedure described in Example 152. HR-MS (ES, m/z) calculated for C23H28FN7O4S [(M+H)+] 518.1981, observed 518.1986.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH2:9]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[CH2:10][CH3:11]>O1CCOCC1>[O:6]=[C:5]([N:15]1[CH2:16][CH2:17][N:12]([CH2:9][CH2:10][CH3:11])[CH2:13][CH2:14]1)[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8]
Reactant: CCCN1CCNCC1
Reactant: O=C1CCCC(=O)O1
Solvent: C1COCCO1
Product: CCCN1CCN(C(=O)CCCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 78.7 %

Procedure:
1.5 g of glutaric anhydride and then 1.66 g of N-propylpiperazine in solution in 5 cm3of dioxane are added to 10 cm3 of dioxane in a round-bottomed flask kept under an argon atmosphere. After stirring for 2.5 hours at room temperature, the solvent is evaporated under reduced pressure and then the resulting oil is supplemented with 100 cm3 of diethyl ether. After stirring for one hour, the solid obtained is filtered, dried at 20° C. (90 Pa) to give 2.47 g of 5-oxo-5-(4-propylpiperazin-1-yl)pentanoic acid in the form of a white solid which is used as it is.
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:22]2[CH:23]=[N:24][C:25]([CH2:28]O)=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2].CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>C(Cl)Cl>[CH:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:22]2[CH:23]=[N:24][C:25]([CH2:28][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:26][CH:27]=2)=[CH:9][CH:10]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: C1COCCN1
Reactant: CCC(C)c1ccc(-n2c(-c3ccc(CO)nc3)nc3ccccc3c2=O)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)c1ccc(-n2c(-c3ccc(CN4CCOCC4)nc3)nc3ccccc3c2=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 984 %

Procedure:
3-(4-sec-butylphenyl)-2-(6-(hydroxymethyl)pyridin-3-yl)quinazolin-4(3H)-one (0.176 g, 0.46 mmol) was dissolved in CH2Cl2 (30 mL) under nitrogen and cooled to 0° C. Hünig's base (0.160 mL, 0.92 mmol) was added, followed by MsCl (0.042 mL, 0.55 mmol), and the mixture was stirred for 15 min at 0° C. Morpholine (0.400 mL) was added, the reaction was warmed to room temperature, and stirred for 2 hours, before concentration and purification by flash chromatography on silica gel, eluting with 100% ethyl acetate to 10% methanol/ethyl acetate, afforded the title compound (0.175 g, 984%). 1H-NMR (300 MHz, DMSO-6): δ8.48 (s, 1H), 8.22 (d, J=7.9 Hz, 1H), 7.90-7.95 (m, 1H), 7.79 (d, J=8.1 Hz, 1H), 7.60-7.68 (m, 2H), 7.22-7.27 (m, 3H), 7.10-7.16 (m, 2H), 3.49-3.54 (m, 6H), 2.55-2.63 (m, 1H), 2.19-2.29 (m, 4H), 1.33-1.56 (m, 2H), 1.13 (d, J=6.8 Hz, 3H), 0.62 (t, J=7.2 Hz, 3H). MS (APCI) m/z: 455 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([C:18]#N)=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.ClCCl.[H-].C([Al+]CC(C)C)C(C)C.Cl.C([O-])(=[O:36])C.[K+]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH:18]=[O:36])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cc2ncccc2nc1-c1cccc(F)c1
Reactant: CC(=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Product: O=Cc1cc2ncccc2nc1-c1cccc(F)c1
Temperature: 15 °C
Reaction time: 26 h

Procedure:
To a solution of 2-(3-fluorophenyl)-1,5-naphthyridine-3-carbonitrile (0.175 g, 0.702 mmol) in dichloromethane (9.93 mL, 0.702 mmol) at −78° C. was added diisobutylaluminum hydride 1.0 M in dichloromethane (1.40 mL, 1.40 mmol, 2 eqv.) dropwise over 3 min with stirring and the mixture was allowed to warm to 15° C. with stirring over 24 h. The mixture was cooled to −78° C. To the cooled mixture was added diisobutylaluminum hydride 1.0 M in dichloromethane (0.702 mL, 0.702 mmol, 1 eqv.) dropwise and the mixture was stirred at −78° C. for further 2 h. After 26 h, the mixture was cooled in ice water bath and quenched by addition of 1 N aq. HCl (4.21 mL, 4.21 mmol) at 0° C. and stirred. After 1.5 h, to the mixture was added potassium acetate (0.413 g, 4.21 mmol). The organic layer was separated and the aq. layer was extracted with CH2Cl2 (50 mL×2). The combined organic layers were washed saturated NaHCO3 (50 mL×1), brine (50 mL×1), dried over Na2SO4, filtered, and concentrated at reduced pressure to give an orange solid. The orange solid was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexane over 14 min and then 100% isocratic of EtOAc for 5 min as eluent to give 2-(3-fluorophenyl)-1,5-naphthyridine-3-carbaldehyde as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.15 (1H, s), 9.17 (1H, dd, J=4.1, 1.8 Hz), 8.90 (1H, d, J=0.8 Hz), 8.54-8.59 (1H, m, J=8.6, 1.0, 0.8, 0.8 Hz), 7.98 (1H, dd, J=8.6, 4.1 Hz), 7.59-7.67 (2H, m), 7.53-7.58 (1H, m), 7.39-7.47 (1H, m); LC-MS (ESI) m/z 252.9 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C@@H:13]2[CH2:15][O:14]2)=[CH:5][C:4]=1[N:16]=[CH:17][N:18]([CH3:20])[CH3:19])#[N:2].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(Cl)(Cl)Cl.C(O)C>[C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C@@H:13]([OH:14])[CH2:15][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:5][C:4]=1[N:16]=[CH:17][N:18]([CH3:20])[CH3:19])#[N:2]
Reactant: COc1cc(C#N)c(N=CN(C)C)cc1OC[C@@H]1CO1
Reactant: C1CCNCC1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1cc(C#N)c(N=CN(C)C)cc1OC[C@@H](O)CN1CCCCC1
Yield: 85.7 %

Procedure:
N′-(2-cyano-5-(2S)-oxiranylmethoxy-4-methoxyphenyl)-N,N-dimethylimidoformamide (850 mg, 3.09 mmol) in chloroform (6 ml) and ethanol (12 ml) was irradiated with piperidine (0.46 ml, 4.6 mmol) in a microwave oven at reflux for 10 minutes. The solvent was evaporated and the residue was purified by silica gel chromatography, eluant CH2Cl2/MeOH 90/10 to give title compound (954 mg, 86%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.C[Li].[C:11](C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[OH-].[Na+]>C(OCC)C.C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH3:11])[C:5]([CH3:8])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)nc1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cnc(Cl)nc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 2-chloro-5-methylpyrimidine (EXAMPLE 144, STEP 1) (0.50 g, 0.00389 mol) in diethyl ether (12 mL) at −30° C. and under nitrogen was added dropwise 1.4M methyllithium (2.90 mL, 0.00405 mol) and the reaction allowed to stir at −30° C. for 30 min and at 0° C. for 30 min. The reaction was quenched with a solution of acetic acid (0.242 mL), water (0.039 mL, and THF (0.8 mL) and then a solution of DDQ (0.92 g, 0.00405 mol) in THF was added. The reaction was stirred 5 min at rt, recooled to 0° C. and 3N sodium hydroxide added. The reaction was allowed to stir at 0° C. for 30 min after which a thick oily precipitate formed. The organic supernatant was decanted and the residue washed with diethyl ether (2×20 mL). The organic layers were dried over sodium sulfate, filtered through a pad of silica and the silica pad washed with diethyl ether. The filtrate was concentrated in vacuo to give the title compound as an oil. M.S.(M+1): 143.
Reaction SMILES: O[CH2:2][CH:3]([NH:5]C(=O)OC(C)(C)C)[CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[Cl:44][C:45]1[C:50]([N+:51]([O-:53])=[O:52])=[CH:49][CH:48]=[CH:47][C:46]=1[OH:54]>C1C=CC=CC=1>[Cl:44][C:45]1[C:50]([N+:51]([O-:53])=[O:52])=[CH:49][CH:48]=[CH:47][C:46]=1[O:54][CH2:2][CH:3]([NH2:5])[CH3:4]
Reactant: O=[N+]([O-])c1cccc(O)c1Cl
Reactant: CC(CO)NC(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(N)COc1cccc([N+](=O)[O-])c1Cl
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 96.3 %

Procedure:
7.2 g (0.0414 mol) of 1,1-dimethylethyl 2-hydroxy-1-methylethylcarbamate and 10.8 g (0.0414 mol) 15 of triphenylphosphine are placed in a 500 ml, three-necked, round-bottomed flask containing 140 ml of benzene. The mixture is cooled in an ice bath and 6.5 ml (0.0414 mol) of diethyl azodicarboxylate are added dropwise. The mixture is left stirring for 15 minutes, 4.8 g (0.027 mol) of 2-chloro-3-nitrophenol are added, the temperature of the reaction mixture is left to return to room temperature and the reaction mixture is left stirring overnight. The precipitate obtained is then filtered and the filtrate evaporated. The residue is taken up in 100 ml of a 3N hydrochloric acid solution and is then heated at 80° C. in an oil bath for 2 hours. The phases are separated, the aqueous phase is recovered, the pH is adjusted to alkaline with a concentrated sodium hydroxide solution and extraction is carried out three times with ether. Washing is carried out with water and drying is carried out. There are obtained 6 g of product which is used as is in the following stage.