Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:36]([O:38][C:39]1[CH:45]=[C:44]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][CH3:54])[CH2:48][CH2:47]2)[CH:43]=[CH:42][C:40]=1[NH2:41])[CH3:37].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:41][C:40]3[CH:42]=[CH:43][C:44]([N:46]4[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][CH3:54])[CH2:48][CH2:47]4)=[CH:45][C:39]=3[O:38][CH2:36][CH3:37])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: CCCN1CCN(c2ccc(N)c(OCC)c2)CC1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Product: CCCN1CCN(c2ccc(Nc3nccc(-c4c(-c5ccc(OC)c(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)c(OCC)c2)CC1
Temperature: 130 °C
Yield: 40 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.2 mmol), 2-(ethyloxy)-4-(4-propyl-1-piperazinyl)aniline (48 mg, 0.18 mmol), and p-toluenesulfonic acid (93 mg, 0.49 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 130° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 3 mL of 0.5 N sodium methoxide 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (52 mg, 0.072 mmol, 40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.78 (s, 1H), 9.32 (s, 1H), 8.35 (s, 1H), 8.21 (d, J=5.31 Hz, 1H), 8.09 (d, J=2.01 Hz, 1H), 7.76 (dd, J=8.61, 2.01 Hz, 1H), 7.68 (d, J=8.97 Hz, 1H), 7.35-7.45 (m, 3H), 7.26 (d, J=8.79 Hz, 1H), 7.17 (t, J=8.06 Hz, 2H), 6.92 (t, J=6.87 Hz, 1H), 6.64 (d, J=2.20 Hz, 1H), 6.53 (d, J=5.31 Hz, 1H), 6.46 (dd, J=8.79, 2.38 Hz, 1H), 4.04 (q, J=6.96 Hz, 2H), 3.97 (s, 3H), 3.07-3.13 (m, 4H), 2.43-2.51 (m, 4H), 2.26 (t, J=7.23 Hz, 2H), 1.40-1.50 (m, J=7.36, 7.36, 7.36, 7.36, 7.36 Hz, 2H), 1.22 (t, J=6.96 Hz, 3H), 0.85 (t, J=7.42 Hz, 3H). MS (ESI): 719 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24](I)[CH:25]=[CH:26][C:17]=4[C:16]=3[N:28]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[CH3:36][Si:37]([C:40]#[CH:41])([CH3:39])[CH3:38].O>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:41]#[C:40][Si:37]([CH3:39])([CH3:38])[CH3:36])[CH:25]=[CH:26][C:17]=4[C:16]=3[N:28]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(Nc2ncc3c(n2)-c2ccc(I)cc2NC(=O)C3)cc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(C#C[Si](C)(C)C)cc2NC(=O)C3)cc1OC
Temperature: 22 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(3,4-dimethoxy-phenylamino)-9-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-30) (300 mg, 0.614 mmol) in 4 mL DMF at 22° C. was added dichlorobis(triphenylphosphine)palladium (15 mg, 0.02 mmol), copper iodide (9 mg, 0.05 mmol), and triethylamine (0.34 mL, 2.45 mmol). The solution was degassed with argon, and stirred at 22° C. for 1 h. (Trimethylsilyl)acetylene (120 mg, 1.22 mmol) was added and the solution was stirred at 22° C. for 2 h. Water was added to the reaction mixture, and the resulting precipitate was filtered and purified by silica gel chromatography (ISCO, elution with 30-100% ethyl acetate in hexanes) to give I-33-a (180 mg, 64%): MS m/z═459 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](/[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)\[C:10]#[N:11])=[CH:4][CH:3]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([O:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[C:10]#[N:11])/[C:12]2[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)=[CH:4][CH:3]=1)(=[O:26])[CH3:25]
Reactant: COc1cc(/C(C#N)=C/c2ccc(O)cc2)cc(OC)c1OC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1cc(/C(C#N)=C/c2ccc(OC(C)=O)cc2)cc(OC)c1OC
Yield: 93 %

Procedure:
Compound 15 (1.20 g) was acetylated with acetic anhydride and pyridine in accordance with a customary method, to thereby produce the target product (1.27 g, yield: 93%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([OH:8])=[N:6][CH:7]=1.[OH-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH2:12]([O:9][C:4]1[C:5]([OH:8])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1cc(Br)cnc1O
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Oc1ncc(Br)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.2 %

Procedure:
To a solution of 10.68 g (56.2 mmol) 5-bromopyridine-2,3-diol in 290 mL MeOH was added 1(N) aqueous NaOH solution (56.2 mL). A solution of benzyl bromide (5.07 mL, 42.6 mmol) in MeOH (20 mL) was added dropwise to this mixture. After stirring at room temperature for 6 h, the reaction mixture was partitioned between water and EtOAc. Layers were separated and the aqueous phase was extracted with EtOAc (3×). Combined organic solutions were washed with brine (1×), dried over Na2SO4 and concentrated in vacuo. The resulting solid was recrystallized from MeOH-EtOAc to give 3-(benzyloxy)-5-bromopyridin-2-ol as a white solid (7.9 g, 50%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[NH:34]1[CH2:41][CH2:40][CH2:39][C@@H:35]1[C:36]([OH:38])=[O:37]>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:34]5[CH2:41][CH2:40][CH2:39][CH:35]5[C:36]([OH:38])=[O:37])[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(O)[C@H]1CCCN1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Agent: OC1CCNC1
Product: O=C(O)C1CCCN1c1cc(-c2ccc(Sc3ccc4c(c3)OCCO4)c(C(F)(F)F)c2)ccn1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with (D)-proline. A yellow solid 121 was obtained (0.035 g, 70%). MS (APCI) m/z 503 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:12]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])[C:10]=1F)[C:5]([OH:7])=[O:6].[CH3:20][O:21][CH2:22][CH2:23][NH2:24]>[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:12]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])[C:10]=1[NH:24][CH2:23][CH2:22][O:21][CH3:20])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc(Br)c(F)c(S(=O)(=O)N2CCCC2)c1
Reactant: COCCN
Agent: [Na+]
Agent: [OH-]
Product: COCCNc1c(Br)cc(C(=O)O)cc1S(=O)(=O)N1CCCC1

Procedure:
A solution of 3-Bromo-4-fluoro-5-(pyrrolidine-1-sulfonyl)-benzoic acid (500 mg) in 2-methoxy-ethylamine was heated at 80° C. for 3 h. The mixture was dissolved in 2 M aq. NaOH and washed with EtOAc. The aqueous layer was acidified with 2 M HCl and extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated in vacuo. Yield: 543 mg.
Reaction SMILES: ClC1C(C(O)=O)=CN=C(Cl)C=1C.BrC1C=CC(NC2C(C(O)=O)=CN3C=CN=C3C=2C)=C(Cl)C=1.[N-:35]=[N+:36]=[N-:37].[Na+].[CH3:39][O:40][C:41](=[O:59])[C:42]1[C:47]([NH:48][C:49]2[CH:54]=[CH:53][C:52]([Br:55])=[CH:51][C:50]=2[Cl:56])=[C:46]([CH3:57])[C:45](Cl)=[N:44][CH:43]=1>>[CH3:39][O:40][C:41](=[O:59])[C:42]1[C:47]([NH:48][C:49]2[CH:54]=[CH:53][C:52]([Br:55])=[CH:51][C:50]=2[Cl:56])=[C:46]([CH3:57])[C:45]([N:35]=[N+:36]=[N-:37])=[N:44][CH:43]=1
Reactant: COC(=O)c1cnc(Cl)c(C)c1Nc1ccc(Br)cc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: Cc1c(Cl)ncc(C(=O)O)c1Cl
Agent: Cc1c(Nc2ccc(Br)cc2Cl)c(C(=O)O)cn2ccnc12
Agent: [Na+]
Product: COC(=O)c1cnc(N=[N+]=[N-])c(C)c1Nc1ccc(Br)cc1Cl
Temperature: 50 °C

Procedure:
4,6-Dichloro-5-methyl-nicotinic acid (J. Heterocyclic Chemistry 1999, 36, 953–957) was converted to 7-(4-bromo-2-chloro-phenylamino)-8-methyl-imidazo[1,2-a]pyridine-6-carboxylic acid according to the steps described in the alternate synthesis of Step D, Example 9. It was determined that addition of sodium azide to the 4-(4-bromo-2-chloro-phenylamino)-6-chloro-5-methyl-nicotinic acid methyl ester intermediate required heating to 50° C., which results in a separable mixture of the desired methyl ester, 6-azido-4-(4-bromo-2-chloro-phenylamino)-5-methyl-nicotinic acid methyl ester, and the corresponding carboxylic acid. MS ESI (+) m/z 380, 382 (M+, Cl, Br pattern) detected. 1H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 9.40 (br s, 1H), 8.25 (d, 1H), 8.12 (d, 1H), 7.79 (m, 1H), 7.42 (dd, 1H), 6.80 (d, 1H), 2.07 (s, 3H).
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:26]2[N:27]=[C:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[S:29][CH:30]=2)\[C:23](O)=[O:24])[CH2:19][CH2:18]1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:39][C@@H:40]1[C:43](=[O:44])[NH:42][C@@H:41]1[CH2:45][N:46]1[N:50]=[C:49]([C@@H:51]([N:53]([CH2:61][CH2:62][CH2:63][NH:64][C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[C:54](=[O:60])[O:55][C:56]([CH3:59])([CH3:58])[CH3:57])[CH3:52])[CH:48]=[N:47]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[C:56]([O:55][C:54]([N:53]([CH2:61][CH2:62][CH2:63][NH:64][C:65]([O:67][C:68]([CH3:70])([CH3:69])[CH3:71])=[O:66])[C@H:51]([C:49]1[CH:48]=[N:47][N:46]([CH2:45][C@@H:41]2[C@H:40]([NH:39][C:23](=[O:24])/[C:22](=[N:21]\[O:20][C:17]3([C:15]([O:14][CH:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)=[O:16])[CH2:19][CH2:18]3)/[C:26]3[N:27]=[C:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[S:29][CH:30]=3)[C:43](=[O:44])[NH:42]2)[N:50]=1)[CH3:52])=[O:60])([CH3:57])([CH3:58])[CH3:59]
Reactant: C[C@@H](c1cnn(C[C@H]2NC(=O)[C@H]2N)n1)N(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](c1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)/C(=N\OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)c2csc(NC(=O)OC(C)(C)C)n2)n1)N(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a mixture of (Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (416 mg, 0.736 mmol), tert-butyl ((S)-1-(2-(((2R,3S)-3-amino-4-oxoazetidin-2-yl)methyl)-2H-1,2,3-triazol-4-yl)ethyl)(3-((tert-butoxycarbonyl)amino)propyl)carbamate (0.736 mmol) and DIPEA (193 μl, 1.10 mmol) in DCM/DMF (5:1, 7.3 mL) at 0° C. was added HATU (308 mg, 0.810 mmol). After stirring at 0° C. for 1 h it was diluted with EtOAc, washed with water, brine, dried over sodium sulfate and concentrated in vacuo. Purification via silica gel chromatography (EtOAc-Heptane, 50-90%) afforded the desired compound (700 mg, 96%) as a red solid. LCMS: Rt=1.17 min, m/z=987.7 (M+1) Method 2m_acidic. Chiral SFC analysis (SFC-X5, CO2/EtOH=90/10, SFC=5 ml/min, AD column, Rt=12.28 min) confirmed it was a single diastereomer.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[CH2:28][CH2:27][CH2:26][S:25]2(=[O:30])=[O:29])[CH:3]=1.[CH3:31][N:32]1[CH2:36][CH2:35][NH:34][C:33]1=[O:37]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:34]4[CH2:35][CH2:36][N:32]([CH3:31])[C:33]4=[O:37])=[CH:3][C:4]=3[N:24]3[CH2:28][CH2:27][CH2:26][S:25]3(=[O:30])=[O:29])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CN1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 13.6 %

Procedure:
Using [4-bromo-2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl][4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (247 mg) described in Preparation Example 166 and 1-methylimidazolidin-2-one (60 mg) and by the reaction and treatment in the same manner as in Example 536, the title compound (35 mg) was obtained.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[NH2:16][CH2:17][C@@H:18]1[O:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[S:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=3)=[C:26]([F:37])[CH:25]=2)[CH2:19]1.C(N(CC)C(C)C)(C)C.[C:47](O)(=[O:50])[CH2:48][CH3:49]>CN(C=O)C>[F:37][C:26]1[CH:25]=[C:24]([N:20]2[CH2:19][C@H:18]([CH2:17][NH:16][C:47](=[O:50])[CH2:48][CH3:49])[O:22][C:21]2=[O:23])[CH:29]=[CH:28][C:27]=1[C:30]1[S:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=1
Reactant: CCC(=O)O
Reactant: NC[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)NC[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
1,3-Dicyclohexylcarbodiimide (0.153 g, 0.740 mmol) is added to a mixture of 2-[4-(5(S)-aminomethyl-2-oxo-oxazolidin-3-yl)-2-fluorophenyl]-4H-[1,3,4]thiadiazin-5-one (0.200 g, 0.617 mmol), N,N-diisopropylethylamine (0.161 ml, 0.927 mmol) and propionic acid (0.051 ml, 0.680 mmol) in DMF (3 ml). The mixture is stirred overnight at room temperature and then partially evaporated under vacuum. The residue is diluted with water (5 ml) and the resulting precipitate is filtered and dried under vacuum. Purification by PTLC (10% MeOH/DCM) gives pure product as a white solid (0.21 g, 90%); 1HNMR (300 MHz, DMSO-d6) δ 0.94 (t, J=7.7 Hz, 3H), 2.08 (q, J=7.7 Hz, 2H), 3.40-3.48 (m, 2H), 3.59 (s, 2H), 3.77 (dd, J=6.0, 9.1 Hz, 1H), 4.14 (t, J=9.1 Hz, 1H), 4.74-4.78 (m, 1H), 7.41 (dd, J=2.2, 8.8 Hz, 1H), 7.52 (dd, J=2.2, 14 Hz, 1H), 7.69 (t, J=8.5 Hz, 1H), 8.16 (t, J=5.8 Hz, 1H), 11.6 (s, 1H); mp 192-3; MS (m/z): [M+H]+=381.
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[CH3:13]O.S(=O)(=O)(O)O>>[O:1]1[C:5]2[C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CO
Reactant: O=C(O)c1cccc2c1OCC2
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc2c1OCC2
Temperature: 80 °C

Procedure:
2,3-Dihydrobenzofuran-7-carboxylic acid (8 g, 48.7 mmol) was dissolved in methanol (39.6 mL, 975 mmol) and concentrated sulfuric acid (2.6 mL, 48.7 mmol) was slowly added. The mixture was refluxed at 80° C. for 17 h. The solvent was evaporated and the residue was dissolved in ethyl acetate and washed with brine. The organic layer was evaporated to give the title compound as a beige solid. Yield: 8.6 g (99%). HPLC purity 93%, RT=1.72 min (System A; 10-97% MeCN over 3 min); 96%, RT=1.67 min (System B; 10-97% MeCN over 3 min). MS (ESI+) for C10H10O3 m/z 179 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:37])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[C@@H:17]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C@H:16]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:38][C:39]1[CH:44]=[C:43]([CH2:45][O:46][CH3:47])[CH:42]=[C:41]([F:48])[C:40]=1[C:49]1[N:54]=[C:53]([C:55](O)=[O:56])[CH:52]=[CH:51][C:50]=1[F:58].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>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:37][C:55]([C:53]3[CH:52]=[CH:51][C:50]([F:58])=[C:49]([C:40]4[C:39]([F:38])=[CH:44][C:43]([CH2:45][O:46][CH3:47])=[CH:42][C:41]=4[F:48])[N:54]=3)=[O:56])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[C@@H:17]([O:21][Si:22]([C:25]([CH3:27])([CH3:26])[CH3:28])([CH3:24])[CH3:23])[C@H:16]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: COCc1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C1
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: COCc1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C3)CCC4OC(C)=O)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-amino-4-((3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (324 mg, 0.606 mmol), 6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridine-2-carboxylic acid (180 mg, 0.606 mmol) and HATU (0.460 g, 1.21 mmol) in DMF (3.0 mL) and DIPEA (0.316 mL, 1.82 mmol) was stirred at room temperature for 2 h. After quenching the reaction with water, the mixture was extracted with EtOAc (2 times). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by purified by column chromatography on silica gel using CombiFlash® apparatus eluting with EtOAc/hexanes (50-100%) to give an amide intermediate, 4-((3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-1-yl)-3-[({6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate.
Reaction SMILES: [CH2:1]([C:3]1[NH:7][N:6]=[N:5][N:4]=1)[CH3:2].N([CH2:11][C@H:12]1[O:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[C:22]([F:24])[C:21]([C:25]3[CH2:26][CH2:27][S:28](=[O:32])(=[O:31])[CH2:29][CH:30]=3)=[C:20]([F:33])[CH:19]=2)[CH2:13]1)=[N+]=[N-].CC(OC(/N=N/C(OC(C)C)=O)=O)C>ClCCl>[O:32]=[S:28]1(=[O:31])[CH2:27][CH:26]=[C:25]([C:21]2[C:22]([F:24])=[CH:23][C:18]([N:14]3[CH2:13][C@H:12]([CH2:11][N:5]4[N:6]=[N:7][C:3]([CH2:1][CH3:2])=[N:4]4)[O:16][C:15]3=[O:17])=[CH:19][C:20]=2[F:33])[CH2:30][CH2:29]1
Reactant: CCc1nnn[nH]1
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2cc(F)c(C3=CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: ClCCl
Product: CCc1nnn(C[C@H]2CN(c3cc(F)c(C4=CCS(=O)(=O)CC4)c(F)c3)C(=O)O2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.4 %

Procedure:
5-Ethyl-1H-tetrazole (0.164 g, 1.67 mmol), (5R)-3-[4-(1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-(hydroxymethyl)oxazolidin-2-one (WO 01/81350 A1) (0.30 g, 0.84 mmol), and polystyrene-triphenylphosphine (1.73 mmol/g loading: Argonaut Technologies, Inc. Foster City, Calif. USA, 1.46 g, 2.53 mmol) were dissolved in dry dichloromethane (30 ml). Diisopropylazodicarboxylate (0.33 ml, 1.68 mmol) was added and the mixture was stirred at room temperature for 16 hours. The resin was filtered off and rinsed with dichloromethane. The filtrate was evaporated to dryness and purified by chromatography on silica gel with 10% acetonitrile in dichloromethane. The material obtained after chromatography was precipitated from dichloromethane with diethyl ether to yield the title compound as a white powder (0.26 g, 71%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[N:25]1[CH2:24][CH2:23][N:22]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:27][CH2:26]1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1
Yield: 99 %

Procedure:
Method 1 was followed using 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (1.0 eq), 1-Boc-piperazine (1.2 eq), and TEA (2.0 eq) at 55° C. for 1 hour yielding tert-butyl 4-(2-nitro-4-(trifluoro-methyl)phenyl)piperazine-1-carboxylate (99%). LCMS (m/z): 376.1 (MH+); LC Rt=3.58 min.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][NH:7][C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]2[CH:22]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:24]([CH3:26])=[CH:25][C:9]1=2.[CH2:40]=[C:41]1[O:45][C:43](=[O:44])[CH2:42]1>CN(C)C1C=CN=CC=1.O1CCCC1>[C:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:8]([N:7]([CH2:6][C:5]2[CH:31]=[C:32]([C:34]([F:35])([F:37])[F:36])[CH:33]=[C:3]([C:2]([F:1])([F:38])[F:39])[CH:4]=2)[C:43](=[O:44])[CH2:42][C:41](=[O:45])[CH3:40])[C:9]2[CH:25]=[C:24]([CH3:26])[C:23]([C:27]([F:30])([F:28])[F:29])=[CH:22][C:10]1=2)=[O:16])([CH3:19])([CH3:21])[CH3:20]
Reactant: C=C1CC(=O)O1
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1CCCN(C(=O)OC(C)(C)C)c2cc(C(F)(F)F)c(C)cc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 97.8 %

Procedure:
To a solution of (S)-5-(3,5-bis-trifluoromethyl-benzylamino)-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (Example 3, Step 14) (1.0 g, 1.75 mmol) and 4-dimethylaminopyridine (25 mg, 0.21 mmol) in dry tetrahydrofuran (10 mL) at 0° C. under a nitrogen atmosphere, add diketene (0.147 mL, 1.93 mmol). After stirring 1.5 h at 0° C., remove the solvent under reduced pressure. Purify the by flash chromatography, eluting with hexanes/ethyl acetate (20:1 to 1:2), to provide the title compound as an off-white solid (1.12 g, 97%). TLC Rf 0.40 (3:1 hexanes/ethyl acetate); 1H NMR (CDCl3, 300 MHz) δ 1.10-2.10 (m, 13H), 2.29 (s, 3H), 2.52 (s, 3H), 3.41-3.53 (m, 1H), 4.14-4.54 (m, 4H), 4.89-5.12 (m, 1H), 5.57-5.69 (m, 1H), 6.89 (s, 1H), 7.24-7.92 (m, 4H).
Reaction SMILES: C([O:3][C:4](=O)/[C:5](/[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1)=[CH:6]/[CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1>>[CH:7]1(/[CH:6]=[C:5](\[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH2:21][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)/[CH2:4][OH:3])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)/C(=C/C1CCCC1)c1ccc(S(=O)(=O)Cc2cccnc2)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: O=S(=O)(Cc1cccnc1)c1ccc(/C(=C\C2CCCC2)CO)cc1
Yield: 58 %

Procedure:
Following the method of example 54e, reduction of (E)-3-cyclopentyl-2-[4-(pyridin-3-ylmethanesulfonyl)-phenyl]-acrylic acid ethyl ester (2.43 g, 6.08 mmol) with DIBAL in toluene (12.61 mL, 15.2 mmol) gives the title compound as an amorphous solid (1.26 g).