Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[CH3:19][S:20]([CH:23]=[CH2:24])(=[O:22])=[O:21]>O1CCOCC1>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:24][CH2:23][S:20]([CH3:19])(=[O:22])=[O:21])[CH2:15][CH2:14]1
Reactant: C=CS(C)(=O)=O
Reactant: COc1cc(N2CCNCC2)c(C)cc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 60 %

Procedure:
To 1-[2-methyl-5-(methyloxy)-4-nitrophenyl]piperazine (0.300 g, 1.2 mmol) in 10 mL of dioxane was added, ethenyl methyl sulfone (0.32 g, 3 mmol). The mixture was heated to 120° C. 1 hour. The solvent was rotovaped down and the crude product was purified by flash chromatography, followed by a wash of the solids with 30% ether in hexanes to give 1-[2-methyl-5-(methyloxy)-4-nitrophenyl]-4-[2-(methylsulfonyl)ethyl]piperazine (0.257 g, 0.72 mmol, 60%). 1H NMR (400 MHz, CDCl3) δ ppm 7.80 (s, 1 H), 6.54 (s, 1 H), 3.93 (s, 3 H), 3.18-3.30 (m, 2 H), 2.99-3.10 (m, 9 H), 2.71-2.82 (m, 4 H), 2.23 (s, 3 H).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH2:15]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23]O)=[CH:19][CH:18]=1)[CH3:16]>>[CH2:15]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:19][CH:18]=1)[CH3:16]
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: CCc1ccc(CO)cc1
Product: CCc1ccc(COc2ccnn2-c2cc(C#N)ccn2)cc1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-ethylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.26 (3H, t, J=6.0 Hz)), 2.66 (2H, q, J=6.0 Hz), 5.01 (2H, s), 5.75 (1H, d, J=2.0 Hz), 7.22-7.35 (4H, m), 7.39 (1H, dd, J=0.8 Hz, J=4.8 Hz), 7.57 (1H, d, J=2.0 Hz), 8.02 (1H, s), 8.71 (1H, d, J=4.8 Hz). [M+H] Calc'd for C18H16N4O, 305. Found, 305.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[CH2:20][OH:21])[CH3:2]>O=[Mn]=O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)(=[O:11])=[O:12])=[CH:6][C:5]=1[CH:20]=[O:21])[CH3:2]
Reactant: CCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1CO
Agent: O=[Mn]=O
Product: CCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1C=O
Reaction time: 3 h
Yield: 47.4 %

Procedure:
MnO2 (100 g, 1.15 mol) was loaded into a flask, followed by 1-(4-ethoxy-3-hydroxymethylphenylsulfonyl)-4-methylpiperazine (15 g, 0.05 mol, from step (b) above). This was washed with acetone (150 mL) and the suspension stirred for 3 hours. The MnO2 was filtered off onto Celite® and the filtrate concentrated under vacuum to give a pale yellow oil. This was recrystallised from toluene to give the title compound as a pale green solid (7.4 g, 47%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH:15]1[CH:19]=[C:18]([CH2:20][N:21]2[C:27]3[CH:28]=[CH:29][C:30]([C:32]#[N:33])=[CH:31][C:26]=3[CH2:25][N:24](S(C)(=O)=O)[C@H:23]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:22]2)[N:17]=[CH:16]1>>[C:32]([C:30]1[CH:29]=[CH:28][C:27]2[N:21]([CH2:20][C:18]3[N:17]=[CH:16][NH:15][CH:19]=3)[CH2:22][C@@H:23]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:24]([S:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)(=[O:12])=[O:11])[CH2:25][C:26]=2[CH:31]=1)#[N:33]
Reactant: CS(=O)(=O)N1Cc2cc(C#N)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: N#Cc1ccc2c(c1)CN(S(=O)(=O)c1ccc([N+](=O)[O-])cc1)[C@H](Cc1ccccc1)CN2Cc1c[nH]cn1
Yield: 3 %

Procedure:
Example 383 was prepared as a white solid in 3% yield from 4-nitrobenzene sulfonylchloride and Compound C of Example 248 by the following sequence: Compound C of Example 350, except that the reaction was run at room temperature and no purification was performed; Compound C of Example 380.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:12](N)[CH2:13][NH2:14]>>[NH:5]1[CH2:12][CH2:13][N:14]=[C:4]1[C:3]1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:2]=1[NH2:1]
Reactant: NCCN
Reactant: COc1ccc(C#N)c(N)c1
Product: COc1ccc(C2=NCCN2)c(N)c1

Procedure:
The procedure used for the preparation of Intermediate C, Step 3 was used to prepare the title compound from 2-amino-4-methoxybenzonitrile (Step 1) and ethylene diamine. High vacuum drying gave the title compound (44 g, 92%). HPLC MS RT=1.04 min, MH+=192.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([C:13]1[CH:34]=[CH:33][C:16]([C:17]([NH:19][C:20]2[N:25]=[CH:24][C:23]3[C:26]([Cl:32])=[CH:27][N:28]([CH:29]4[CH2:31][CH2:30]4)[C:22]=3[CH:21]=2)=[O:18])=[CH:15][CH:14]=1)([CH3:12])[CH3:11])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[NH4+].[Cl-]>C1COCC1>[Cl:32][C:26]1[C:23]2[CH:24]=[N:25][C:20]([NH:19][C:17](=[O:18])[C:16]3[CH:15]=[CH:14][C:13]([C:10]([CH3:12])([CH3:11])[CH2:9][OH:8])=[CH:34][CH:33]=3)=[CH:21][C:22]=2[N:28]([CH:29]2[CH2:31][CH2:30]2)[CH:27]=1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)c1ccc(C(=O)Nc2cc3c(cn2)c(Cl)cn3C2CC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(CO)c1ccc(C(=O)Nc2cc3c(cn2)c(Cl)cn3C2CC2)cc1
Temperature: 60 °C
Yield: 84.7 %

Procedure:
To 4-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-N-(3-chloro-1-cyclopropyl-1H-pyrrolo[3,2-c]pyridin-6-yl)benzamide (20 mg, 0.040 mmol) was added THF (800 μA). At room temperature, TBAF (1.0M solution in THF, 50 μl) was added. The mixture was heated to 60° C. for 1 hr. After reaction was completed, 2 ml saturated NH4Cl was added and the mixture was extracted with EtOAc (3×2 ml). Organic layers were combined, dried, filtered and concentrated. The crude product was purified by preparatory HPLC (TFA mode, 20-45% ACN in water). Product containing fractions were combined, and then extracted with EtOAc to remove residual TBAF to give the title compound as a white solid (13 mg, 84%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98-1.05 (m, 1H) 1.05-1.12 (m, 1H) 1.26 (d, J=1.52 Hz, 7H) 3.44-3.55 (m, 3H) 4.77 (br. s., 1H) 7.50 (dd, J=8.59, 2.27 Hz, 2H) 7.62 (d, J=6.06 Hz, 1H) 7.96-8.05 (m, 2H) 8.34 (d, J=1.01 Hz, 1H) 8.51 (d, J=1.01 Hz, 1H) 8.61 (d, J=1.01 Hz, 1H) 8.57 (d, J=0.76 Hz, 1H) 10.64 (d, J=9.09 Hz, 1H); ESI-MS: m/z 384 (M+H)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:32][C:33]1[CH:51]=[C:50]([I:52])[CH:49]=[CH:48][C:34]=1[CH2:35][N:36]1[C:40]2=[CH:41][N:42]=[CH:43][CH:44]=[C:39]2[CH:38]=[C:37]1[C:45]([O-:47])=O.[Na+].Cl.[CH:55]1([CH2:58][O:59][NH2:60])[CH2:57][CH2:56]1>CN(C=O)C.C(OCC)(=O)C>[CH:55]1([CH2:58][O:59][NH:60][C:45]([C:37]2[N:36]([CH2:35][C:34]3[CH:48]=[CH:49][C:50]([I:52])=[CH:51][C:33]=3[F:32])[C:40]3=[CH:41][N:42]=[CH:43][CH:44]=[C:39]3[CH:38]=2)=[O:47])[CH2:57][CH2:56]1
Reactant: O=C([O-])c1cc2ccncc2n1Cc1ccc(I)cc1F
Reactant: NOCC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(NOCC1CC1)c1cc2ccncc2n1Cc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.9 %

Procedure:
HATU (67 mg, 0.18 mmol) and triethylamine (50 μL, 0.35 mmol) were added to a solution of sodium 1-(2-fluoro-4-iodo-benzyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (49 mg, 0.12 mmol) and O-cyclopropylmethyl-hydroxylamine hydrochloride (21.8 mg, 0.178 mmol) in DMF (500 μL). The reaction mixture was stirred at room temperature for 18 h, then a further 11 mg (0.09 mmol) of O-cyclopropylmethyl-hydroxylamine hydrochloride, 33 mg (0.09 mmol) of HATU, and 50 μL (0.35 mmol) of triethylamine was added. Stirring was continued for a further 18 h, then the reaction mixture was poured into ethyl acetate (15 mL). The organic layer was washed with a 1:1 solution of saturated NaHCO3 and brine (10 mL), dried over Na2SO4, filtered and concentrated to afford a yellow oil. The crude product was purified by reversed phase HPLC to afford the title compound as a white powder (TFA salt, 39 mg, 57%). LCMS (Method C): RT=3.17 min, M+H+=466. 1H NMR (DMSO-D6): δ=0.21 (m, 2H), 0.51 (m, 2H), 1.00 (m, 1H), 3.60 (d, J=7.2 Hz, 2H), 5.96 (s, 2H), 6.61 (t, J=8.0 Hz, 1H), 7.33 (s, 1H), 7.47 (dd, J=8.0, 1.2 Hz, 1H), 7.68 (dd, J=9.6, 1.6 Hz, 1H), 8.24 (d, J=6.4 Hz, 1H), 8.43 (d, J=6.4 Hz, 1H), 9.52 (s, 1H).
Reaction SMILES: C([O:5][C:6](=[O:73])[C@H:7]([CH2:64][CH2:65][C:66]([O:68]C(C)(C)C)=[O:67])[NH:8][C:9](=[O:63])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:62])[CH2:18][CH2:19][S:20][CH2:21][CH:22]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>>[CH2:44]([O:43][CH:22]([CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:21][S:20][CH2:19][CH2:18][C:17]([NH:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]([NH:8][C@H:7]([C:6]([OH:73])=[O:5])[CH2:64][CH2:65][C:66]([OH:68])=[O:67])=[O:63])=[CH:15][CH:14]=1)=[O:62])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61]
Reactant: CCCCCCCCCCCCCCCCCCOCC(CSCCC(=O)Nc1ccc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1)OCCCCCCCCCCCCCCCCCC
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCCCCOCC(CSCCC(=O)Nc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)OCCCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
To (4-(6,7-bis(stearyloxy)-4-thiaheptanoylamino)benzoyl)glutamic acid di-t-butyl ester as obtained in Example 25 (75 mg), trifiuoroacetic acid (5 ml) was added, followed by stirring at room temperature for 24 hours. The mixture was concentrated to yield the title compound (64 mg, yield 94%) as a colorless crystal.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[CH:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][O:27][CH:28]4[CH2:33][O:32][C:31]5=[N:34][C:35]([N+:37]([O-:39])=[O:38])=[CH:36][N:30]5[CH2:29]4)=[CH:22][N:21]=3)=[C:16]([F:40])[CH:15]=2)[CH2:9]1)(C)(C)C.BrC1N=CC(COC2COC3=NC([N+]([O-])=O)=CN3C2)=CC=1.C([SiH2]OC(C)(C)C1OC(=O)N(C2C=CC(B3OC(C)(C)C(C)(C)O3)=C(F)C=2)C1)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:40][C:16]1[CH:15]=[C:14]([N:10]2[CH2:9][CH:8]([CH2:7][OH:6])[O:12][C:11]2=[O:13])[CH:19]=[CH:18][C:17]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][O:27][CH:28]2[CH2:33][O:32][C:31]3=[N:34][C:35]([N+:37]([O-:39])=[O:38])=[CH:36][N:30]3[CH2:29]2)=[CH:22][N:21]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)C1CN(c2ccc(-c3ccc(COC4COc5nc([N+](=O)[O-])cn5C4)cn3)c(F)c2)C(=O)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[SiH2]OC(C)(C)C1CN(c2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)C(=O)O1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1OC(CO)CN1c1ccc(-c2ccc(COC3COc4nc([N+](=O)[O-])cn4C3)cn2)c(F)c1
Temperature: 80 °C

Procedure:
5-(tert-Butyl-dimethyl-silanyloxymethyl)-3-{3-fluoro-4-[5-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxymethyl)-pyridin-2-yl]-phenyl}-oxazolidin-2-one: To a suspension of 6-(6-bromo-pyridin-3-ylmethoxy)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (150 mg, 0.40 mmol), 5-(tert-butyl-dimethyl-silanyloxymethyl)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazolidin-2-one (198 mg, 0.44 mmol), Pd(Ph3P)4 (58 mg, 0.05 mmol) and K2CO3 (121 mg, 0.88 mmol) in DMF/H2O (10/1. 5.5 mL) was degassed. The mixture was heated to 80° C. for 2.5 h, diluted with EtOAc, washed with brine and concentrated in vacuo to give a crude product. The crude product was purified by flash chromatography (5% MeOH in EtOAc) to afford the title product (170 mg). ESI MS m/z 600.5 (M+H+).
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH:22]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:22]1([NH:28][C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NC1CCCCC1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(NC3CCCCC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), cyclohexanamine (131.03 mg, 1.32 mmol, 3.00 equiv), potassium carbonate (304.41 mg, 2.21 mmol, 5.00 equiv), and N,N-dimethylformamide (2 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of 20 mL of water. The resulting aqueous solution was extracted with 3×50 mL of ethyl acetate. The organic layers were combined and washed with 5×30 mL of aq. sodium chloride. The organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:50). This resulted in 80 mg (46%) of methyl 3-(cyclohexylamino)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: Cl.[CH3:2][O:3][C@@H:4]([C@@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1)[C@@H:5]([CH3:17])[C:6](=[S:16])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH:23]1[C:35]2[CH:34]([CH2:36][O:37][C:38]([N:40]([CH3:68])[C@H:41]([C:45]([NH:47][C@H:48]([C:52]([N:54]([C@@H:56]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:57]([O:62][CH3:63])[CH2:58][C:59](O)=[O:60])[CH3:55])=[O:53])[CH:49]([CH3:51])[CH3:50])=[O:46])[CH:42]([CH3:44])[CH3:43])=[O:39])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C)C=O>[CH:23]1[C:35]2[CH:34]([CH2:36][O:37][C:38]([N:40]([CH3:68])[C@H:41]([C:45]([NH:47][C@H:48]([C:52]([N:54]([C@@H:56]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:57]([O:62][CH3:63])[CH2:58][C:59]([N:19]3[CH2:20][CH2:21][CH2:22][C@H:18]3[C@H:4]([O:3][CH3:2])[C@@H:5]([CH3:17])[C:6]([NH:7][CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[S:16])=[O:60])[CH3:55])=[O:53])[CH:49]([CH3:51])[CH3:50])=[O:46])[CH:42]([CH3:44])[CH3:43])=[O:39])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: CO[C@@H]([C@@H]1CCCN1)[C@@H](C)C(=S)NCCc1ccccc1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)NCCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
To a mixture of #23 (337 mg, 0.983 mmol, 1 eq.) in dichloromethane (8 mL, 0.1 M) and N,N-dimethylformamide (1 mL) were added #8 (564 mg, 0.885 mmol, 0.9 eq.), diisopropylethylamine (383 mg, 2.95 mmol, 3 eq.) and HATU (472 mg, 1.18 mmol, 1.2 eq.). After 2 hours, the mixture was diluted with dichloromethane, washed sequentially with 0.1 M aqueous hydrochloric acid and with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase chromatography (Method G) to give #35 (600 mg, 66%); LC-MS: m/z 926.6 [M+H+], retention time=1.16 minutes; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [9.94 (br t, J=5 Hz) and 10.16-10.23 (br m), total 1H], 7.90 (d, J=7.2 Hz, 2H), [7.71 (br d, J=7 Hz) and 8.06 (br d, J=8 Hz), total 1H], 7.60-7.65 (m, 2H), 7.41 (br dd, J=7, 7 Hz, 2H), 7.15-7.36 (m, 7H), 3.29 (s, 3H), 1.16-1.22 (m, 3H).
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:38]=[C:20]4[CH:21]([C:27]5[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=5)[CH2:22][C:23](=[O:26])[CH2:24][CH2:25][N:19]4[N:18]=3)=[CH:12][C:11]=2[O:39][CH3:40])[CH:9]=1>C1COCC1.[Cu]I>[Cl:4][C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:38]=[C:20]4[C@@H:21]([C:27]5[CH:28]=[CH:29][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:31][CH:32]=5)[CH2:22][C@@:23]([CH3:1])([OH:26])[CH2:24][CH2:25][N:19]4[N:18]=3)=[CH:12][C:11]=2[O:39][CH3:40])[CH:9]=1
Reactant: C[Mg]Br
Reactant: COc1cc(Nc2nc3n(n2)CCC(=O)CC3c2ccc(OC(F)(F)F)cc2)ccc1-n1cnc(Cl)c1
Agent: [Cu]I
Solvent: C1CCOC1
Product: COc1cc(Nc2nc3n(n2)CC[C@](C)(O)C[C@@H]3c2ccc(OC(F)(F)F)cc2)ccc1-n1cnc(Cl)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 4 %

Procedure:
A 25 mL round bottom flask was charged with copper (I) iodide (53.1 mg, 0.279 mmol) in THF (5 mL), and cooled to 0° C. A solution of methyl magnesium bromide (9.96 mL, 14.0 mmol) was added. The resulting mixture was stirred for 20 min. To the solution of methyl cuprate was added 2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-9-(4-(trifluoromethoxy)phenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-7(6H)-one (743 mg, 1.39 mmol) in THE (1 mL). The mixture was stirred at 0° C. for 2 h. The reaction mixture was quenched with saturated ammonium chloride and diluted with EtOAc. The organic layer was collected and washed sequentially with H2O (100 mL), aq sat. NaHCO3 solution (100 mL), and brine (100 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product was purified using reverse phase preparatory HPLC (MeOH/water/trifluoroacetic acid) to afford rel-(7R,9R)-2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-methyl-9-(4-(trifluoromethoxy)phenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-7-ol (43 mg, 4% yield, Example 152, first isomer to elute) and rel-(7S,9R)-2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-methyl-9-(4-(trifluoromethoxy)phenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-7-ol (39.6 mg, 4% yield, Example 153, second isomer to elute). Data for Example 152: LC-MS (M+H)+ 549.3. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 10.09 (1 H, br. s.), 8.02 (1 H, d, J=1.5 Hz), 7.26-7.38 (5 H, m), 7.08-7.20 (3 H, m), 4.63-4.75 (2 H, m), 4.40 (1 H, ddd, J=14.9, 5.1, 2.3 Hz), 3.86 (3 H, s), 2.23-2.31 (1 H, m), 2.14-2.21 (1 H, m), 2.05-2.12 (1 H, m), 1.94-2.03 (1 H, m), 1.48 (3 H, s). Data for Example 153: LC-MS (M+H)+ 549.3. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.76 (1 H, s), 7.32 (1 H, d, J=2.4 Hz), 7.22-7.30 (5 H, m), 7.15 (1 H, d, J=8.5 Hz), 7.02-7.09 (2 H, m), 4.60 (1 H, ddd, J=14.7, 8.3, 2.6 Hz), 4.30 (1 H, ddd, J=14.9, 7.4, 2.4 Hz), 4.21 (1 H, dd, J=10.1, 1.8 Hz), 3.83-3.87 (3 H, m), 2.54 (1 H, dd, J=14.3, 10.4 Hz), 2.11-2.22 (3 H, m), 1.52 (3 H, s).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14]([C:16]2[C:17]([O:22][C:23]3[CH:31]=[CH:30][C:26]4[O:27][CH2:28][O:29][C:25]=4[CH:24]=3)=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:15])=[C:8]([F:32])[CH:7]=1.[OH-].[Li+]>O1CCCC1.CO>[O:27]1[C:26]2[CH:30]=[CH:31][C:23]([O:22][C:17]3[C:16]([C:14]([NH:13][CH2:12][C:9]4[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:33])=[O:2])=[CH:7][C:8]=4[F:32])=[O:15])=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:24][C:25]=2[O:29][CH2:28]1
Reactant: COC(=O)COc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)COc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.5 %

Procedure:
To a stirred solution of [4-({[2-(benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-acetic acid methyl ester (0.40 g, 0.88 mmol) in tetrahydrofuran (10 mL) and methanol (2 mL) was added aqueous lithium hydroxide (2 mL, 1 M, 2 mmol). The reaction was stirred at room temperature 1 hour. The solvents were stripped in vacuo and the residue partitioned between dilute aqueous hydrochloric acid and ethyl acetate. The aqueous was extracted with 2 aliquots ethyl acetate and the pooled organics were washed with brine, dried over sodium sulfate and concentrated in vacuo to afford a yellow solid. The crude product was recrystallized from ethyl acetate to afford 80 mg of a white crystalline solid (0.18 mmol, 21% yield). mp 180° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.Cl.Cl.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:33])[CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:33])[CH2:26][N:27]2[CH2:28][CH2:29][N:30]([C:7]([C:5]3[N:4]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[N:3]=[C:2]([CH3:1])[CH:6]=3)=[O:9])[CH2:31][CH2:32]2)=[CH:21][CH:20]=1
Reactant: O=C(CN1CCNCC1)c1ccc(F)cc1
Reactant: Cc1cc(C(=O)O)n(-c2ccccc2)n1
Agent: Cl
Product: Cc1cc(C(=O)N2CCN(CC(=O)c3ccc(F)cc3)CC2)n(-c2ccccc2)n1
Yield: 78.5 %

Procedure:
The title compound was prepared in a similar manner as described in Example 1.2, using 3-methyl-1-phenyl-1H-pyrazole-5-carboxylic acid (30.3 mg), and 1-(4-fluorophenyl)-2-(piperazin-1-yl)ethanone dihydrochloride (29.5 mg) as starting materials, to afford the title compound (31.9 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ 2.35 (s, 3H), 2.60-2.67 (m, 2H), 2.69 (bs., 2H), 3.81 (s, 2H), 3.89 (bs, 2H), 4.16 (bs, 2H), 6.62 (s, 1H), 7.13 (t, J=8.46 Hz, 2H), 7.38-7.54 (m, 5H), 7.99-8.09 (m, 2H). Exact mass calculated for C23H23FN4O2: 406.2. Found: LCMS m/z=407.5 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[O:20][CH:19]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:18][CH2:17]2)([O-])=O.C1(C2CCC3C(=CC=C(OC4C=CC=CC=4N)C=3)O2)C=CC=CC=1>C(O)(=O)C.[Zn]>[NH2:10][C:8]1[CH:7]=[CH:6][C:5]([O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[O:20][CH:19]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:18][CH2:17]3)=[C:4]([CH:9]=1)[NH2:1]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)c([N+](=O)[O-])c1
Agent: Nc1ccccc1Oc1ccc2c(c1)CCC(c1ccccc1)O2
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)c(N)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,4-Dinitro-1-(2-phenylchroman-6-yloxy)-benzene (0.04 g) was dissolved in 12 ml of glacial acetic acid and zinc (0.131 g) was added. The reaction stirred at room temperature for 30 minutes. Workup was done as described for 2-(2-phenylchroman-6-yloxy)-aniline in Example 29. Product was purified by column chromatography (CH2Cl2:Et3N /96:4 as the eluant). 1H-NMR (300 MHz; d6-DMSO): δ 7.48-7.28 (m, 5H), 6.74 (d, 1H, J=8.8 Hz), 6.63 (dd, 1H, J=8.8 Hz, J=2.9 Hz), 6.57 (d, 1H, J=2.8 Hz), 6.49 (d, 1H, J=8.4 Hz), 6.02 (d, 1H, J=2.6 Hz), 5.81 (dd, 1H, J=8.4 Hz, J=2.6 Hz), 5.03 (dd, 1H, J=10.0 Hz, J=2.3 Hz), 4.62 (s, 2H), 4.48 (s, 2H), 2.99-2.82 (m, 1H), 2.71-2.57 (m, 1H), 2.20-2.06 (m, 1H), 2.03-1.86 (m, 1H)