Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([NH2:19])[C:17]#[N:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31])([O-])=O>>[CH2:1]([O:8][C:9](=[O:20])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([NH:19][S:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:24]=1)(=[O:32])=[O:31])[C:17]#[N:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: N#CC(N)CCCCCNC(=O)OCc1ccccc1
Product: N#CC(CCCCCNC(=O)OCc1ccccc1)NS(=O)(=O)c1ccccc1
Yield: 40.9 %

Procedure:
Using the general procedure described in step A of scheme 1, (6-amino-6-cyano-hexyl}-carbamic acid benzyl ester (2.8 g, 10 mmol) was sulfonylated with 2-nitrobenzenesulfonyl chloride (2.5 g, 11 mmol) at 0° C. to yield the titled compound (1.7 g, 36%); yellow oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]([C:16]3[CH2:23][S:22][CH:21]4[N:18]([C:19](=[O:32])[CH:20]4[NH:24][C:25]([O:27]C(C)(C)C)=O)[C:17]=3[C:33]([O:35][CH:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:34])=[CH:14][N:15]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].CS(O)(=O)=O.[S:54]1[CH:58]=[CH:57][CH:56]=[C:55]1[CH2:59]C(Cl)=O>C(#N)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]([C:16]3[CH2:23][S:22][CH:21]4[N:18]([C:19](=[O:32])[CH:20]4[NH:24][C:25](=[O:27])[CH2:59][C:55]4[S:54][CH:58]=[CH:57][CH:56]=4)[C:17]=3[C:33]([O:35][CH:36]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:34])=[CH:14][N:15]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(-c2ncc(C3=C(C(=O)OC(c4ccccc4)c4ccccc4)N4C(=O)C(NC(=O)OC(C)(C)C)C4SC3)s2)cc1
Reactant: O=C(Cl)Cc1cccs1
Agent: CS(=O)(=O)O
Solvent: CC#N
Product: CC(=O)Nc1ccc(-c2ncc(C3=C(C(=O)OC(c4ccccc4)c4ccccc4)N4C(=O)C(NC(=O)Cc5cccs5)C4SC3)s2)cc1

Procedure:
On treating 3-[2-(4-acetamido-phenyl)-thiazol-5-yl]-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (3.4 g) with methanesulphonic acid (3.4 cc) in acetonitrile (15 cc), in accordance with the working method described in Example 15, crude 7-amino-3-[2-(4-acetamido-phenyl)-thiazol-5-yl]-2-benzhydryloxycarbonyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (2.9 g) is obtained, and this is acylated with (thien-2-yl)-acetyl chloride (0.62 cc) in accordance with the working method described in Example 1. The crude product obtained is purified by crystallisation from acetonitrile (200 cc). 3-[2-(4-Acetamido-phenyl)-thiazol-5-yl]-2-benzhydryloxycarbonyl-8-oxo-7-[(thien-2-yl)-acetamido]-5-thia-1-azabicyclo[4.2.0]oct-2-ene (1.33 g) is obtained in the form of a beige crystalline powder.
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[CH3:14][C:15]1[CH:16]=[C:17]([Mg]Br)[CH:18]=[C:19]([CH3:21])[CH:20]=1>>[CH3:14][C:15]1[CH:16]=[C:17]([CH:2]2[C:9]3[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=3[CH2:4][CH2:3]2)[CH:18]=[C:19]([CH3:21])[CH:20]=1
Reactant: Cc1cc(C)cc([Mg]Br)c1
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Product: COC(=O)c1cc2c([nH]1)CCC2c1cc(C)cc(C)c1

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.5 g, 2.79 mmol) and 3,5-dimethylphenylmagnesium bromide (14 mL, 6.97 mmol, 0.5 M in THF, 2.5 equiv) were reacted according to General Procedure 3 to give the endo olefin-containing compound methyl 4-(3,5-dimethylphenyl)-1,6-dihydrocyclopenta[b]pyrrole-2-carboxylate, which was then hydrogenated according to General Procedure 6 (with 5% Pd/C), and was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-100% EtOAc/heptane to afford the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.20-2.36 (m, 7H), 2.71-2.98 (m, 3H), 3.83-3.86 (m, 3H), 4.17 (t, J=7.35 Hz, 1H), 6.49 (s, 1H), 6.67 (d, J=1.42 Hz, 1H), 6.82-6.88 (m, 2H), 9.02 (br. s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:45]([N+:49]1[N:53]=[C:52]([CH3:54])[S:51][C:50]=1[CH3:55])[CH2:46][CH2:47][CH3:48]>>[CH2:45]([N:49]1[N:53]=[C:52]([CH3:54])[S:51]/[C:50]/1=[CH:55]\[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])=[O:6])[CH2:46][CH2:47][CH3:48]
Reactant: CCCC[n+]1nc(C)sc1C
Reactant: O=C(O)c1ccccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 2-chlorobenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.89 (t, 3 H) 1.25-1.36 (m, 2 H) 1.66-1.75 (m, 2 H) 2.49-2.50 (m, 3 H) 4.14 (t, 2 H) 6.20 (s, 1 H) 7.35-7.44 (m, 2H) 7.45-7.49 (m, 1 H) 7.50-7.55 (m, 1 H); MS (ESI) m/z 309 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[CH2:34]([NH2:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]2[CH2:10][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:39][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:22])(=[O:16])=[O:15])[CH2:12]2)=[CH:32][CH:31]=1
Reactant: O=C(O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Reactant: CC(C)(C)CN
Product: CC(C)(C)CNC(=O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1

Procedure:
The operation is carried out under the conditions described in Example 124 starting with 110 mg of activated 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (121 μM) and 0.023 cm3 of neopentylamine. 69 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2,2-dimethylpropyl)benzamide are thus obtained in the form of a pale yellow powder [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 0.90 (s, 9H), 2.98 (s, 3H), 3.11 (d, J=6.5 Hz, 2H), 3.82 (mt, 2H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8 Hz, 4H), 7.46 (d, J=8 Hz, 4H), from 7.45 to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.86 (broad d, J=8 Hz, 1H), 8.37 (t, J=6.5 Hz, 1H)].
Reaction SMILES: CCN(CC)CC.O[C@@H:9]([CH3:29])[C@@H:10]([NH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:16])[C:11]([OH:13])=[O:12]>C(Cl)Cl>[C:23]1([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:15](=[O:16])[NH:14][C@H:10]2[C:11](=[O:13])[O:12][C@H:9]2[CH3:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[C@H](O)[C@@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1OC(=O)[C@@H]1NC(=O)OCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 45.3 %

Procedure:
In a two necked round bottom flask, Et3N (0.34 ml, 2.42 mmol) was added to a solution of (2R,3S)-3-hydroxy-2-({[(5-phenylpentyl)oxy]carbonyl}amino)-butanoic acid (0.25 g, 0.81 mmol) in dry CH2Cl2 (10 mL) under argon. After cooling at 0° C., HTBU (0.46 g, 1.21 mmol) was added and the mixture stirred 3 h at 0° C., then 16 h at rt. The obtained solid was filtered-off and the solvent removed under vacuum. The crude was purified by typical silica gel column chromatography eluting with Cy/AcOEt (from 98:2 to 80:20). The title compound (0.107 g, 45%), was obtained as white solid, which was further triturated with cyclohexane. MS (ESI) m/z: 290.21 [M−H]−. FTIR (cm−1): 3330, 3064, 3027, 2936, 2858, 1849, 1695, 1540, 1387, 1333, 1262, 1129, 1076, 1023, 985, 921, 845, 822, 741, 697. 1H NMR (CDCl3): δ 1.38 (m, 2H); 1.44 (d, 3H); 1.62-1.67 (m, 4H); 2.62 (t, 2H); 4.05-4.13 (m, 2H); 4.86 (m, 1H); 5.44 (t, 1H); 5.33 (d, 1H); 7.16-7.19 (m, 3H); 7.25-7.29 (m, 2H).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:7]([N:12]=1)=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:2][CH3:3].[C:13]1([C:19]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:20]2[C:24]([C:25]3[C:30]([C:31]4[CH:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33][CH:32]=4)=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:23][N:22]=[N:21]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+]>>[CH2:1]([C:4]1[N:12]([CH2:37][C:34]2[CH:33]=[CH:32][C:31]([C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:24]3[N:20]([C:19]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:21]=[N:22][N:23]=3)=[CH:36][CH:35]=2)[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ncccc2[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCCc1nc2cccnc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
2-propyl-3-(2'-(N-triphenylmethyltetrazol-5-yl)-biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine was prepared according to the procedure described in Example 7, Part A from 2-propylimidazo[4,5-b]pyridine (19 mg, 0.118 mmol), N-triphenylmethyl-5-(4'-bromomethylbiphen-2-yl)tetrazole (60 mg, 0.108 mmol), and NaH (0.236 mmol).
Reaction SMILES: C([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:32]([NH:34][C@@H:35]([C:37]1[CH:42]=[CH:41][C:40]([Br:43])=[CH:39][CH:38]=1)[CH3:36])=[O:33])[NH:16][C:17](=[O:31])[CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(OCC1C=CC=CC=1)=O.C(#N)C.C[Si](I)(C)C>C(Cl)Cl>[C:19]1([CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]([NH:16][C@H:15]([C:32]([NH:34][C@@H:35]([C:37]2[CH:42]=[CH:41][C:40]([Br:43])=[CH:39][CH:38]=2)[CH3:36])=[O:33])[CH2:14][CH2:13][CH2:12][NH2:11])=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[C@@H](NC(=O)[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)C(c1ccccc1)c1ccccc1)c1ccc(Br)cc1
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: ClCCl
Product: C[C@@H](NC(=O)[C@H](CCCN)NC(=O)C(c1ccccc1)c1ccccc1)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
(R)-N5 -(Cbz)-N2 -(diphenylacetyl)-(S)-N-[1-(4-bromophenyl)ethyl]ornithine amide (0.50 g; 0.78 mmol; from step (c) above) was suspended in CH2Cl2 :acetonitrile (20 mL; 1:3) and was cooled to 0° C. Trimethylsilyl iodide (0.17 g, 0.86 mmol) was added at 0° C. and the reaction stirred for 2 hours at 0° C. (solids dissolving as the reaction proceeded). When the deprotection was complete, as determined by TLC analysis, the reaction was quenched with water and diluted with EtOAc. The organic layer was separated and washed with water (1×), 1 N sodium thiosulfate (1×) and brine (2×). The combined aqueous washings were extracted with CH2Cl2. The organics were combined and triethylamine (5 mL) was added. The mixture was allowed to stand for 18 hours, transferred to a separating funnel, washed with brine (3×), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product as a yellow solid (0.40 g). The crude product was chromatographed on silica gel eluting with MeOH:CH2Cl2 (3:7), then MeOH:CH2Cl2 (1:1), to give sub-title compound (free base) as an off-white solid (0.25 g).
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:15][C:16]1[C:17]([C:33]2[CH:34]=[N:35][N:36]([C:38]3([CH2:48][C:49]#[N:50])[CH2:41][N:40]([CH:42]4[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]4)[CH2:39]3)[CH:37]=2)=[C:18]2[CH:24]=[CH:23][N:22](COCC[Si](C)(C)C)[C:19]2=[N:20][CH:21]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.FC(F)(F)C(O)=O.C(N)CN>C(Cl)Cl>[F:15][C:16]1[C:17]([C:33]2[CH:34]=[N:35][N:36]([C:38]3([CH2:48][C:49]#[N:50])[CH2:41][N:40]([CH:42]4[CH2:43][CH2:44][N:45]([C:4](=[O:6])[C:3]5[CH:7]=[CH:8][N:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:2]=5[F:1])[CH2:46][CH2:47]4)[CH2:39]3)[CH:37]=2)=[C:18]2[CH:24]=[CH:23][NH:22][C:19]2=[N:20][CH:21]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)c(F)cnc21
Reactant: O=C(O)c1ccnc(C(F)(F)F)c1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: NCCN
Product: N#CCC1(n2cc(-c3c(F)cnc4[nH]ccc34)cn2)CN(C2CCN(C(=O)c3ccnc(C(F)(F)F)c3F)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-fluoro-2-(trifluoromethyl)isonicotinic acid (70.0 mg, 0.335 mmol), {3-[4-(5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-piperidin-4-ylazetidin-3-yl}acetonitrile.3[HCl] (207 mg, 0.335 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (148 mg, 0.335 mmol) and triethylamine (0.234 mL, 1.68 mmol) in methylene chloride (2 mL) was stirred at room temperature for 1 hour. To the mixture was added trifluoroacetic acid (2 mL, 20 mmol). The resulting solution was stirred at room temperature for 1 hour and concentrated. The residue was dissolved in methanol (2 mL) and ethylenediamine (0.5 mL, 7 mmol). After being stirred at room temperature for 2 hours, the mixture was purified by HPLC (method B) to give 11.2 mg of the title compound as a white solid. LC/MS found: 571.3 (M+H)+. 1H NMR (400 MHz, CDCl3): δ 11.85 (brs, 1H), 8.65 (d, J=4.4 Hz, 1H), 8.59 (s, 1H), 8.23 (d, J=3.2 Hz, 1H), 8.20 (s, 1H), 7.89 (s, 1H), 7.61 (s, 1H), 6.85 (s, 1H), 4.04 (m,1H), 3.72 (m, 2H), 3.58 (m, 2H), 3.53 (m, 2H), 3.53 (m, 2H), 3.40 (m, 1H), 3.25 (m, 1H), 3.06 (t, J=9.2 Hz, 1H), 2.54 (m, 1H), 1.75 (m, 1H), 1.62 (m, 1H), 1.26 (m, 1H), 1.21 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][C:17]([CH3:19])=[CH:18][N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1C(=O)N([I:27])C(=O)C1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][C:17]([CH3:19])=[C:18]([I:27])[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2nn3cc(C)nc3s2)cc1OC
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: COc1ccc(-c2nn3c(I)c(C)nc3s2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3,4-dimethoxyphenyl)-6-methylimidazo[2,1-b][1,3,4]thiadiazole (0.346 g, 1.257 mmol) was dissolved in DCM (4.2 mL), and NIS (0.283 mg, 1.257 mmol) was added. The reaction mixture was stirred at RT overnight, quenched with sat. aq. thiosulfate and extracted with DCM. The organic layers were combined and washed with sat. aq. NH4Cl, dried (MgSO4), filtered and concentrated. The residue was suspended in Et2O, and the solid was filtered off, washed with Et2O and dried in vacuo affording the desired product (brown solid (0.295 g, 58%). TLC (cyclohexane/EtOAc 1:1) Rf 0.46; HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.8 mL/min, 50° C.): tR=4.53 min, [M+H]+ m/z 402.0; 1H NMR (300 MHz, CDCl3) δ/ppm 7.37 (s, 1H), 7.32 (d, J=8.3, 1H), 6.86 (d, J=8.3, 1H), 3.91 (d, J=14.3, 6H), 2.31 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=1>[Pd].C(O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccccc2F)nc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(-c2ccccc2F)nc1
Reaction time: 3 h

Procedure:
50 mg of 10% palladium on carbon were added to a solution of 3.2 g (14.66 mmol) of 2-(2-fluoro-phenyl)-5-nitro-pyridine in 250 ml of ethanol, and the reaction mixture was hydrogenated at atmospheric pressure for 3 h. After filtration, the solution was evaporated. Yield: 2.5 g.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=2)=[CH:3][N:2]=1.[C:17]1([C:23]2[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:17]1([C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:14](=[O:16])[CH2:13][C:10]3[CH:9]=[CH:8][C:7]([C:4]4[CH:5]=[CH:6][N:1]=[N:2][CH:3]=4)=[CH:12][CH:11]=3)=[N:27][CH:28]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)Cc1ccc(-c2ccnnc2)cc1
Reactant: Nc1ccc(-c2ccccc2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(-c2ccnnc2)cc1)Nc1ccc(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-(4-(pyridazin-4-yl)phenyl)acetic acid 37-4 (43 mg, 0.2 mmol), 5-phenylpyridin-2-amine (41 mg, 0.24 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (117 mg, 0.3 mmol) in DMF (1 mL) was added DIEA (104 μL, 0.6 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The crude product was purified by reverse phase HPLC to give N-(5-phenylpyridin-2-yl)-2-2(4-pyridazin-4-yl)phenyl)acetamide 37 as white solid. MS m/z 367.1 (M+1); 1H NMR 400 MHz (CDCl3) δ 9.45-9.44 (m, 1H), 9.22 (dd, 1H, J1=1.2 Hz, J2=11.2 Hz), 8.44 (d, 1H, J=2.4 Hz), 8.29 (d, 1H, J=8.8 Hz), 7.92 (dd, 1H, J1=16.8 Hz, J2=2.4 Hz), 7.70-7.66 (m, 3H), 7.56-7.51 (m, 4H), 7.46-7.43 (m, 2H), 7.39-7.35 (m, 1H), 3.85 (s, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=[O:8].O[CH2:11][NH:12][C:13](=[O:15])[CH3:14]>FC(F)(F)C(O)=O>[C:13]([NH:12][CH2:11][C:5]1[S:1][C:2]([CH2:6][C:7]([OH:9])=[O:8])=[CH:3][CH:4]=1)(=[O:15])[CH3:14]
Reactant: O=C(O)Cc1cccs1
Reactant: CC(=O)NCO
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NCc1ccc(CC(=O)O)s1

Procedure:
1.42 g of 2-thienylacetic acid are added in portions to a solution, kept at 0°-5° C., of 1.34 g of N-hydroxymethyl acetamide (Einhorn, Ann. Chem., volume 343, page 264 (1905)) in 10 ml of trifluoroacetic acid, whilst stirring. The mixture is stirred for 2 hours at 0°-5° C. and the trifluoroacetic acid is distilled off under reduced pressure. 30 ml of water are added to the residue and the mixture is extracted with twice 50 ml of ethyl acetate. The organic extracts are washed with a saturated aqueous sodium chloride solution, dried over magnesium sulphate, concentrated under reduced pressure and filtered through silica gel. The residue is crystallised from ethyl acetate and gives 2-(5-acetylaminomethyl-2-thienyl)-acetic acid, thin layer chromatogram (silica gel): Rf=0.61 (system: butanol/acetic acid/water, 45:45:10); infrared absorption spectrum (mineral oil): characteristic bands at 2.95μ, 5.82μ, 6.23μ and 6.38μ.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][OH:19])[CH2:13][CH2:12]3)=[N:9][N:10]=2)[CH:7]=1.CCN(CC)CC.FC(F)(F)S(O[Si:33]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])(=O)=O>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19][Si:33]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])[CH2:13][CH2:12]3)=[N:9][N:10]=2)[CH:7]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: OCCN1CCN(c2nnc3ccc(F)cn23)CC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[Si](OCCN1CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Reaction time: 2.5 h
Yield: 89.7 %

Procedure:
To a solution of Intermediate 94a (169 mg, 0.64 mmol) and Et3N (265 μL, 1.91 mmol) in DCM (6 mL) was added triisopropylsilyl trifluoromethanesulfonate (189 μL, 0.70 mmol). The solution was stirred for 2.5 h, then diluted with water and extracted with DCM. The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-5% (2M NH3 in MeOH) in DCM, to give the title compound as a pale brown gum (242 mg, 90%). LCMS (Method 3): Rt 2.93 min, m/z 422 [MH+].
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:14]([O:16]C)=[O:15])[CH:10]=[C:11]([F:13])[CH:12]=3)[N:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO>[CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:14]([OH:16])=[O:15])[CH:10]=[C:11]([F:13])[CH:12]=3)[N:8]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1cc(F)cc2oc(C3CC3)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(F)cc2oc(C3CC3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
A mixture of the ester from Step E (115 mg, 0.49 mmol), 2 N NaOH (2.0 mL, 4.0 mmol), and methanol (5 mL) was stirred at room temperature under nitrogen for 2 h. The reaction mixture was acidified with 1 N HCl, extracted with methylene chloride, washed with brine, dried over sodium sulfate, filtered and concentrated to afford 2-cyclopropyl-6-fluorobenzoxazole-4-carboxylic acid (105 mg, 97%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 12.90 (br s, 1H), 7.91 (dd, J=8.1, 2.4 Hz, 1H), 7.58 (dd, J=10.2, 2.4 Hz, 1H), 2.39-2.29 (m, 1H), 1.25-1.14 (m, 4H); 19F NMR (282 MHz, CDCl3) δ −116.79; MS (ESI+) m/z 222 (M+H).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:6]1[CH3:20])[CH:2]=[CH:3][CH3:4].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][OH:27])=[CH:24][CH:23]=1>>[CH2:1]([N:5]1[C:9]2=[C:10]([O:27][CH2:26][C:25]3[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=3)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:6]1[CH3:20])[CH:2]=[CH:3][CH3:4]
Reactant: CC=CCn1c(C)c(CCCCC)c2cnnc(Cl)c21
Reactant: OCc1ccc(F)cc1
Product: CC=CCn1c(C)c(CCCCC)c2cnnc(OCc3ccc(F)cc3)c21
Yield: 49.8 %

Procedure:
The title compound (cis/trans=14/86) was prepared as a white powder in 49.8% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2-methyl-3-pentylpyrrolo[2,3-d]pyridazine (cis/trans=20/80) and 4-fluorobenzyl alcohol.
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][NH:6][CH:7]=1.[N-:14]=[N+:15]=[N-:16].[Na+]>P(Cl)(Cl)(Cl)=O>[N:14]([C:3]1[C:2]([CH3:1])=[CH:7][N:6]=[CH:5][C:4]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1c[nH]cc(C)c1=O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cncc(C)c1N=[N+]=[N-]
Temperature: 95 °C
Yield: 74 %

Procedure:
A slurry of 14.1 g (78 mmol) of ethyl 1,4-dihydro-5-methyl-4oxo-3-pyridinecarboxylate (prepared according to Horvath, G.; Dvortsak, P. J. Heterocycl. Chem. 1980, 359) in 30 mL of phosphorous oxychloride was refluxed for 1 hour. After cooling, the volatiles were removed with a rotary evaporator. The residue was poured into cold saturated aqueous sodium bicarbonate. Dichloromethane was added and the mixture was filtered through celite. The layers were separated. The organic layer was dried (sodium sulfate) and the solvent was removed with a rotary evaporator. The residue was dissolved in 150 mL of dimethylformamide. 15.2 g (234 mmol) of sodium azide was added. The mixture was heated at 95° C. for 1 hour. After cooling, the solvent was removed with a rotary evaporator. The residue was partitioned between ethyl acetate and water. The organic layer was dried (sodium sulfate) and the solvent was removed with a rotary evaporator. The residue was passed through a plug of silica gel with 25% ethyl acetate in hexanes as eluant to afford 11.9 g of the title compound as a cream colored solid.