Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([OH:19])=O)[C:13]([CH3:16])([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.C([Li])CCC.C(NC(C)C)(C)C.[C:44]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])(=[O:46])[CH3:45].N1C=CN=C1>C1COCC1>[C:48]([O:47][C:44](=[O:46])[CH2:45][C:17](=[O:19])[CH:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:51])([CH3:50])[CH3:49]
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(=O)OC(C)(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li]CCCC
Agent: c1c[nH]cn1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)C(NC(=O)OCc1ccccc1)C(C)(C)C
Temperature: 23 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
To a solution of CBZ-L-tert-leucine (20.53 g, 77.4 mmol, 1 equiv) in THF (150 mL) was added 1,1′-carbonyldiimidazole (13.81 g, 85.14 mmol, 1.1 equiv) at 23° C. The resulting solution was stirred at 23° C. for 1 h. In a separate flask, n-butyllithium (101.59 mL of a 1.6 M solution in hexanes, 162.54 mmol, 2.1 equiv) was added to a solution of diisopropylamine (22.78 mL, 162.54 mmol, 2.1 equiv) in THF (100 mL) at −78° C. The reaction mixture was stirred for 15 min at −78° C., warmed to 0° C. for 5 min, then cooled back to −78° C. A solution of tert-butyl acetate (21.9 mL, 162.54 mmol, 2.1 equiv) in THF (10 mL) was added via cannula, and the resulting mixture was stirred at −78° C. for 10 min. The above imidazole solution was then added dropwise to the lithium enolate at −78° C. The resulting mixture was stirred at −78° C. for 1 h, quenched with 1 M HCl (100 mL), and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel (10% EtOAc in hexanes) to afford 4-benzyloxycarbonylamino-5,5-dimethyl-3-oxo-hexanoic acid tert-butyl ester as a pale yellow oil (12.06 g, 44%): IR (cm−1) 1717, 1508, 1265, 739; 1H NMR (CDCl3) δ 1.09 (s, 9H), 1.44 (s, 9H), 3.50 (s, 2H 4.29 (d, 1H, J=9.3), 5.03 (s, 2H), 5.35-5.42 (m, 1H), 7.34 (s, 5H).
Reaction SMILES: [OH:1][CH:2]([CH:4]([CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])[C:5]([OH:7])=O)[CH3:3].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[NH2:42][CH:43]([C:45]1[C:46](=[O:62])[NH:47][C:48]([CH2:51][C:52]2[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[C:54]([O:60][CH3:61])[CH:53]=2)=[N:49][N:50]=1)[CH3:44]>>[CH3:61][O:60][C:54]1[CH:53]=[C:52]([CH:57]=[CH:56][C:55]=1[O:58][CH3:59])[CH2:51][C:48]1[NH:47][C:46](=[O:62])[C:45]([CH:43]([NH:42][C:5](=[O:7])[CH:4]([CH:2]([OH:1])[CH3:3])[CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])[CH3:44])=[N:50][N:49]=1
Reactant: COc1ccc(Cc2nnc(C(C)N)c(=O)[nH]2)cc1OC
Reactant: C=CCCCC(C(=O)O)C(C)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: C=CCCCC(C(=O)NC(C)c1nnc(Cc2ccc(OC)c(OC)c2)[nH]c1=O)C(C)O

Procedure:
742 mg (4.31 mmol) of 2-(1-hydroxyethyl)-6-heptenoic acid (Example 22A) are reacted analogously to Example 23A with 580 mg (4.31 mmol) of 1-hydroxy-1H-benzotriazole, 870 mg (8.61 mmol) of 4-methylmorpholine, 830 mg (4.31 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and 500 mg (1.72 mmol) of 6-(1-aminoethyl)-3-(3,4-dimethoxybenzyl)-1,2,4-triazin-5(4H)-one (Example 12A) to give N-{1-[3-(3,4-dimethoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}-2-(1-hydroxyethyl)-6-heptenamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH2:11][CH2:12]Cl)[CH2:8][CH2:9]Cl)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[CH2:23][C:24]#[N:25].[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:7]1[CH2:11][CH2:12][C:23]([C:24]#[N:25])([C:17]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=2[Cl:15])[CH2:9][CH2:8]1)=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CCc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.9 %

Procedure:
To bis(2-chloroethyl)-carbamic acid tert-butyl ester (1.0 g, 3.8 mmol) and 2,4-dichlorophenyl acetonitrile (0.708 g, 3.8 mmol) in DMF (35 ml), NaH (95%) (0.258 g, 9.68 mmol) was added in one batch at 0° C. The solution was stirred for 10 minutes at room temperature. When foaming subsided, the solution was heated at 60° C. for 24 hours. It was then quenched with water at 0° C. and concentrated. The residue was extracted with ethyl acetate (25 mL) and washed three times with water (15 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (hexane:ethyl acetate 4:1) yielded 0.620 g (45%) of the product as a syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:20][C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5].NC1C=C(C(N2CCOCC2)=[O:42])C=CC=1N>>[Cl:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([C:21]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[O:42])=[CH:20][C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5]
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1N
Reactant: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)c1c(Cl)cccc1Cl
Product: O=C(Nc1c[nH]nc1-c1nc2cc(C(=O)N3CCOCC3)ccc2[nH]1)c1c(Cl)cccc1Cl

Procedure:
The compound was prepared in a manner analogous to 2,6-dichloro-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (Example 94E), but using (3,4-diamino-phenyl)-morpholin-4-yl-methanone (Example 94B) to give 2,6-dichloro-N-{3-[5-(morpholine-4-carbonyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}-benzamide (17 mg) as a beige solid. (LC/MS: Rt 2.98, [M+H]+ 485.13).
Reaction SMILES: [Li]C(C)(C)C.[CH3:6][C:7]([O:10][C:11]([N:13]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:14]1[C:19]2[C:20]([C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27][CH2:26]4)=[CH:21][O:22][C:18]=2[C:17](I)=[CH:16][N:15]=1)=[O:12])([CH3:9])[CH3:8].[Cl:47]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[CH3:6][C:7]([O:10][C:11]([N:13]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:14]1[C:19]2[C:20]([C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27][CH2:26]4)=[CH:21][O:22][C:18]=2[C:17]([Cl:47])=[CH:16][N:15]=1)=[O:12])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(-c3coc4c(I)cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c34)ccc21
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2cc(-c3coc4c(Cl)cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c34)ccc21
Reaction time: 0.25 h
Yield: 30.5 %

Procedure:
tBuLi (1.7 M in pentane) (0.59 mL, 1.003 mmol) was added dropwise to a solution of 1,1-dimethylethyl 5-[4-(bis{[(1,1-dimethylethyl)oxy]carbonyl}amino)-7-iodofuro[3,2-c]pyridin-3-yl]-2,3-dihydro-1H-indole-1-carboxylate (307 mg, 0.453 mmol) in THF (7 mL) at −78° C. under Nitrogen. The mixture was stirred at that temperature for 15 minutes, then a solution of hexachloroethane (217 mg, 0.917 mmol) in THF (3 mL) was added dropwise. The reaction was stirred and allowed to slowly warm from −78° C. to room temperature for 16 hours. The mixture was then quenched with saturated NH4Cl (25 mL), and extracted with ethyl acetate (2×20 mL). The extracts were washed with brine (1×20 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Analogix, 40 g SiO2 [RediSep Gold column], 0%-25% EtOAc in hexanes gradient over 45 minutes). The second peak (1st big one) was collected to give 1,1-dimethylethyl 5-[4-(bis{[(1,1-dimethylethyl)oxy]carbonyl}amino)-7-chlorofuro[3,2-c]pyridin-3-yl]-2,3-dihydro-1H-indole-1-carboxylate (81 mg, 0.138 mmol, 30.5% yield) as a colorless oil. LC/MS (ES) m/z=586, 588 [M+H]+. The third peak to elute was also collected and found to be 1,1-dimethylethyl 5-[7-chloro-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)furo[3,2-c]pyridin-3-yl]-2,3-dihydro-1H-indole-1-carboxylate (33 mg, 0.068 mmol, 14.99% yield), also as a colorless oil. LC/MS (ES) m/z=486, 488 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].I[CH:22]([CH3:24])[CH3:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:22]([CH3:24])[CH3:23])[N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: COc1ccc(-c2n[nH]c3c(Cl)cccc23)cc1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2nn(C(C)C)c3c(Cl)cccc23)cc1
Yield: 28.6 %

Procedure:
Prepared according to Method D step B from 7-chloro-3-(4-methoxyphenyl)-1H-indazole (0.129 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and 2-iodopropane (0.10 mL, 1.0 mmol) to give the title compound (0.043 g) as a white solid.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]2[CH:16]=[N:17][NH:18][C:10]=12>C1(C)C(C)=CC=CC=1>[CH:1]1([NH:7][C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]3[CH:16]=[N:17][NH:18][C:10]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(Cl)c2[nH]ncc2n1
Reactant: NC1CCCCC1
Solvent: Cc1ccccc1C
Product: Cc1cc(NC2CCCCC2)c2[nH]ncc2n1
Yield: 16.2 %

Procedure:
Cyclohexylamine (1.14 ml, 0.01 mole) and 7-chloro-5-methyl-1H-pyrazolo[4,3-b]pyridine (0.5 g, 0.003 mole) were heated at reflux in dry xylene (3 ml) for 48 h. The solvent was removed under reduced pressure and the residue crystallised from ethyl acetate/ether/pentane to give the title compound as a white solid (112 mg, 16%), m.p. 287°-289° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3([CH2:19][NH2:20])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[F:21][C:22]([F:38])([F:37])[C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31](O)=[O:32])[N:24]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3([CH2:19][NH:20][C:31](=[O:32])[C:30]4[CH:34]=[CH:35][CH:36]=[C:28]([C:25]5[N:24]=[C:23]([C:22]([F:38])([F:37])[F:21])[O:27][N:26]=5)[CH:29]=4)[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: NCC1(c2nc(-c3ccc(F)cc3)cs2)CCOCC1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCC1(c2nc(-c3ccc(F)cc3)cs2)CCOCC1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 27 %

Procedure:
This compound was synthesized from (4-(4-(4-fluorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (11 mg, 27% yield): 1H NMR (300 MHz, CDCl3) δ 8.45 (s, 1H), 8.23 (d, J=6.4 Hz, 1H), 7.98 (d, J=6.4 Hz, 1H), 7.85 (t, J=5.1 Hz, 2H), 7.55 (t, J=7.7 Hz, 1H), 7.25 (s, 1H), 7.04 (t, J=7.7 Hz, 2H) 3.94 (m, 2H), 3.87 (m, 2H), 3.21 (m, 2H), 2.28 (m, 2H), 2.04 (m, 2H). MS (ESI) m/z: Calculated for C25H20F4N4O3S: 532.12. found: 533.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[CH3:14][N:15]([CH3:32])[C:16]1[CH:17]=[C:18]([C:22]2[C:23]3[N:24]([N:28]=[C:29]([NH2:31])[N:30]=3)[CH:25]=[CH:26][CH:27]=2)[CH:19]=[CH:20][CH:21]=1>>[CH3:14][N:15]([CH3:32])[C:16]1[CH:17]=[C:18]([C:22]2[C:23]3[N:24]([N:28]=[C:29]([NH:31][CH:10]4[CH2:11][CH2:12][N:7]([C:5]5[S:4][N:3]=[C:2]([CH3:1])[N:6]=5)[CH2:8][CH2:9]4)[N:30]=3)[CH:25]=[CH:26][CH:27]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Reactant: CN(C)c1cccc(-c2cccn3nc(N)nc23)c1
Product: Cc1nsc(N2CCC(Nc3nc4c(-c5cccc(N(C)C)c5)cccn4n3)CC2)n1

Procedure:
Prepared in analogy to example 1h employing 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (see example 1c) and 8-(3-dimethylamino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (prepared in analogy to example 66a-c). The title compound was obtained as light yellow foam. MS ISP (m/e): 435.3 (100) [(M+H)+].
Reaction SMILES: Cl[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:26]([NH:27][C:28](=[O:58])[C:29](=[N:55][O:56][CH3:57])[C:30]3[N:31]=[C:32]([NH:35]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:33][CH:34]=3)[C:25](=[O:59])[N:7]2[C:8]=1[C:9]([O:11]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:10].[I-].[Na+:61].[SH:62][C:63]1[O:64][C:65]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)=[CH:66][N:67]=1>>[NH2:35][C:32]1[S:33][CH:34]=[C:30]([C:29](=[N:55][O:56][CH3:57])[C:28]([NH:27][C@@H:26]2[C:25](=[O:59])[N:7]3[C:8]([C:9]([O-:11])=[O:10])=[C:3]([CH2:2][S:62][C:63]4[O:64][C:65]([C:68]5[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=5)=[CH:66][N:67]=4)[CH2:4][S:5][C@H:6]23)=[O:58])[N:31]=1.[Na+:61]
Reactant: Sc1ncc(-c2ccccc2)o1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [I-]
Agent: [Na+]
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CSc3ncc(-c4ccccc4)o3)CS[C@H]12)c1csc(N)n1
Yield: 7.1 %

Procedure:
The same operation as in EXAMPLE 65 was conducted by using 600 mg (0.71 mmol) of benzhydryl 3-chloromethyl-7β-[2-methoxyimino-2-( 2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn-isomer), 160 mg (1.07 mmol) of sodium iodide and 130 mg (0.72 mmol) of 2-mercapto-5-phenyloxazole, whereby 70 mg (yield: 7.1%) of the above identified compound was obtained.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][CH2:25][OH:26]>C(N(CC)CC)C>[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][CH2:25][O:26][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: OCCc1cccs1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)OCCc2cccs2)cc1
Temperature: 45 °C
Reaction time: 4 h

Procedure:
4-toluenesulfonyl chloride (162 g), toluene (363.3 g) and 2-(2-Thienyl)ethanol (104 g) are combined. Triethylamine (93 g) is added maintaining the temperature lower than 45° C. After 4 hrs, the mixture is washed with aqueous phosphoric acid, aqueous sodium hydroxide and then water. The organic phase is distilled off under vacuum. Isopropanol (314 g) and heptanes (365.9 g) are added. The batch is crystallized by cooling and isolated at −15° C. The crystals are filtered and washed with heptanes (175 mL). The crystals are then dried under vacuum at room temperature until a melting point of 30° C. is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][NH:11][C:10](=O)[CH:9]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:10]1[N:11]=[N:12][CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:9]=1
Reactant: O=c1cc(-c2ccc(F)cc2)cn[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccc(-c2cnnc(Cl)c2)cc1
Temperature: 110 °C

Procedure:
5-(4-Fluorophenyl)pyridazin-3(2H)-one (2.15 g, 11.3 mmol) was dissolved in POCl3 (133 ml) and the mixture was refluxed at 110° C. for 30 min. The reaction was cooled in an ice bath and slowly quenched with aqueous sodium hydrogen carbonate (200 mL). The mixture was extracted with ethyl acetate (3×200 mL). The combined organics were washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to afford the title compound. 1H NMR (500 MHz, CD3SOCD3) δ 9.67 (d, 1H); 8.28 (d, 1H); 8.07 (dd, 2H); 7.42 (t, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C@H:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16][CH2:15]3)=[C:5]([O:29][CH3:30])[CH:4]=1)#[N:2].[SH2:31].C(NCC)C>CN(C=O)C>[NH2:2][C:1]([C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C@H:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16][CH2:15]3)=[C:5]([O:29][CH3:30])[CH:4]=1)=[S:31]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(C#N)cc3OC)ccc21
Reactant: S
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(C(N)=S)cc3OC)ccc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
Into a solution of ethyl {(1S-5-[3-(4-cyano-2-methoxyphenoxy)propoxy]-2,3-dihydro-1H-inden-1-yl}acetate (2.2 g, 5.4 mmol) (Example 145) in DMF (anhydrous, 20 mL) under argon at rt was passed H2S gas at a moderate rate for 30 min. A solution of diethylamine (0.8 g, 8.1 mmol) in DMF (5 mL) was added in one portion, and the reaction was stirred at 60° C. for 3 h. Then the reaction was cooled to rt and argon was passed through the reaction mixture for 1 h to remove residual H2S. The reaction mixture was then concentrated under reduced pressure and the residue purified by silica gel flash chromatography (EtOAc/Hexane (v/v)=1:1) to afford 1.9 g (81%) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 1.21 (t, 3H), 1.60-1.68 (m, 1H), 2.15-2.22 (m, 2H), 2.23-2.34 (m, 1H), 2.38 (q, 1H), 2.70-2.86 (m, 3H), 3.38-3.44 (m, 1H), 3.80 (s, 3H), 4.05-4.16 (m, 4H), 4.19 (t, 2H), 6.70 (d, 1H), 6.80 (s, 1H), 6.97 (d, 1H), 7.06 (d, 1H), 7.56-7.64 (m, 2H), 9.33-9.40 (s, 1H), 9.65 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:17])[NH:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].[C:24]([O:28][C:29](=[O:40])[NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]Br)[CH:33]=1)([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C>[C:24]([O:28][C:29](=[O:40])[NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][N:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:2]([Br:1])[C:3]2=[O:17])[CH:33]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCc1cccc(CBr)c1
Reactant: O=c1[nH]ccc(OCc2ccc(F)cc2)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cccc(Cn2ccc(OCc3ccc(F)cc3)c(Br)c2=O)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 20.2 %

Procedure:
To a solution of 3-bromo-4-(4-fluorobenzyloxy)pyridine-2(1H)-one (from Step 3, synthesis EXAMPLE 59) (0.2 g, 0.67 mmol) in DMF (11 mL) was added K2CO3 (0.26 g, 1.3 mmol) and 3-(bromomethyl)benzylcarbamic acid tert-butyl ester (0.23 g, 0.80 mmol), and the reaction mixture was stirred at 80° C. for 3 hours. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was diluted with a 50% aqueous solution of brine (24 mL), and extracted with CHCL3 (4×50 mL). The combined organics was washed water and then brine, dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 3:7 EtOAc/hexanes) and recrystallization from MeOH afforded {3-[3-bromo-4-(4-fluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]benzyl}carbamic acid tert-butyl ester as an off-white solid (0.07 g, 20%): mp 136-138° C.; 1H NMR (300 MHz, CDCl3) δ 7.42-7.37 (m, 2H), 7.30-7.20 (m, 5H), 7.08 (t, J=9 Hz, 2H), 6.04 (d, J=9 Hz, 1H), 5.16 (s, 2H), 5.14 (s, 2H), 4.28 (d, J=6 Hz, 1H), 1.44 (s, 9H). ES HRMS m/z 517.1124 (M+H C25H27BrFN2O4 requires 517.1133).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]2[CH:13]=[CH:12][NH:11][C:6]=2[N:7]=[C:8]([NH2:10])[N:9]=1.Br[CH2:15][CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].O>CN(C=O)C>[Si:18]([O:17][CH2:16][CH2:15][N:11]1[C:6]2[N:7]=[C:8]([NH2:10])[N:9]=[C:4]([Cl:3])[C:5]=2[CH:13]=[CH:12]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: Nc1nc(Cl)c2cc[nH]c2n1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCn1ccc2c(Cl)nc(N)nc21
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (0.618 g, 15.45 mmol) in anhydrous DMF (15 mL) at 0° C. is added slowly a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-amine (2 g, 11.86 mmol) in 5 mL of anhydrous DMF. The mixture is stirred at this temperature under N2 for 15 min, then (2-bromoethoxy)-t-butyldimethylsilane (4.0 mL, 18.64 mmol) is added at 0° C. The mixture is stirred at RT overnight. The reaction mixture is poured into water and extracted with ethyl acetate (EtOAc; 4×). The organic layer is dried over anhydrous magnesium sulfate (MgSO4), filtered and concentrated in vacuo. The crude product is purified by flash cromatography using EtOAc/cyclohexane (1/1) as eluent to yield 7-[2-(t-butyldimethylsilanyloxy)ethyl]-4-chloro-7H-pyrrolo [2,3-d]pyrimidin-2-amine as white needles: LC/MS (M+1=327). 1H NMR (CDCl3, 400 MHz) δ-0.08 (s, 6H), 0.84 (s, 9H), 3.88 (t, 2H, J=5.2 Hz), 4.17 (t, 2H, J=5.2 Hz), 4.89 (s, 2H, NH2), 6.35 (d, 1H, J=3.6 Hz), 6.96 (d, 1H, J=16 Hz).
Reaction SMILES: C(C1NC=CN=1)(C1[NH:4]C=CN=1)=O.[CH3:13][C:14]1[CH:35]=[CH:34][CH:33]=[CH:32][C:15]=1[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:29]#[C:30][CH3:31])[CH2:25][C:26](O)=[O:27])=[CH:20][CH:19]=1.[NH4+].[OH-].Cl>C1COCC1.O>[CH3:13][C:14]1[CH:35]=[CH:34][CH:33]=[CH:32][C:15]=1[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:29]#[C:30][CH3:31])[CH2:25][C:26]([NH2:4])=[O:27])=[CH:20][CH:19]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CC#CC(CC(=O)O)c1ccc(OCc2ccccc2C)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC#CC(CC(N)=O)c1ccc(OCc2ccccc2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.9 %

Procedure:
Carbonyl diimidazole (0.46 g, 2.84 mmol) was added to a solution of 3-[4-(2-Methyl-benzyloxy)-phenyl]-hex-4-ynoic acid (See Example 13) (0.73 g, 2.37 mmol) in anhydrous THF (10 mL). The mixture was stirred at room temperature for 2 hours. Concentrated NH4OH (10 mL) was then added to the mixture, and the reaction was stirred at room temperature overnight. The reaction mixture was poured into water (300 mL) and the solution was adjusted to pH=7 with conc. HCl. The aqueous layer was then extracted with 3×25 mL ethyl acetate. The combined organic layers were washed with water, followed by brine. The organic layer was then dried (Na2SO4) and concentrated under reduced pressure to yield 0.48 g (70%) of 3-[4-(2-Methyl-benzyloxy)-phenyl]-hex-4-ynoic acid amide (23.2) as a light yellow solid. LC/MSD m/e: 308.4 (M+H)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[NH:21][C:12]3[N:13]=[CH:14][CH:15]=[C:16]([C:17]([NH:19][NH2:20])=[O:18])[C:11]=3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:22]#[C:23]Br>CN(C)C(=O)C.C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][C:9]2[NH:21][C:12]3=[N:13][CH:14]=[CH:15][C:16]([C:17]4[O:18][C:23]([NH2:22])=[N:20][N:19]=4)=[C:11]3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNC(=O)c1ccnc2[nH]c(CCc3ccccc3)cc12
Reactant: N#CBr
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Nc1nnc(-c2ccnc3[nH]c(CCc4ccccc4)cc23)o1
Reaction time: 8 h
Yield: 44.1 %

Procedure:
To a solution of 2-(2-phenylethyl)-1H-pyrrolo[2,3-b]pyridine-4-carbohydrazide (104 mg, 0.371 mmol) in N,N-dimethylacetamide (1 mL) was added a solution of cyanogen bromide (47 mg, 0.445 mmol) in N,N-dimethylacetamide (0.5 mL) at room temperature, and the resulting mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate), and recrystallized from N,N-dimethylformamide/water to give the title compound (50 mg, yield 44%) as pale-yellow crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([NH2:16])[CH2:13][C@H:12]1[C:17]1[O:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[C:37](O)=[O:38]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([NH:16][C:37]([C:28]2[CH:29]=[CH:30][C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:27]=2[OH:26])=[O:38])[CH2:13][C@H:12]1[C:17]1[O:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1C[C@@H](c2nc3ccccc3o2)N(C(=O)OCc2ccccc2)C1
Reactant: O=C(O)c1ccc2ccccc2c1O
Product: O=C(N[C@H]1C[C@@H](c2nc3ccccc3o2)N(C(=O)OCc2ccccc2)C1)c1ccc2ccccc2c1O

Procedure:
(2S,4S)-2-benzooxazol-2-yl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-1-carboxylic acid benzyl ester was prepared from (2S,4S)-4-amino-2-benzooxazol-2-yl-pyrrolidine-1-carboxylic acid benzyl ester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogous manner to example 1. MS calcd. for C30H26N3O5[(M+H)+] 508, obsd. 508.