Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:38]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:37][N:21]4[N:22]=[C:23]5[C:28]([CH:27]=[CH:26][C:25]([C:29]6[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[CH:30]=6)=[CH:24]5)=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.C(C1C=C(C2C(C3C=CC=CC=3)=CN3N=C4C(C=CC(C5C=C(C=CC=5)C#N)=C4)=C3N=2)C=CC=1)#N>Cl.O1CCOCC1>[NH2:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:38]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:37][N:21]4[N:22]=[C:23]5[C:28]([CH:27]=[CH:26][C:25]([C:29]6[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=6)[C:35]#[N:36])=[CH:24]5)=[C:20]4[N:19]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5ccc(-c6cccc(C#N)c6)cc5nn4cc3-c3ccccc3)cc2)CCC1
Agent: Cl
Agent: N#Cc1cccc(-c2ccc3c(c2)nn2cc(-c4ccccc4)c(-c4cccc(C#N)c4)nc32)c1
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2ccc3c(c2)nn2cc(-c4ccccc4)c(-c4ccc(C5(N)CCC5)cc4)nc32)c1
Temperature: 25 °C
Yield: 9.2 %

Procedure:
239.4 mg (1-{4-[8-(3-Cyanophenyl)-3-phenylpyrimido[1,2-b]indazol-2-yl]phenyl}-cyclobutyl)carbamic acid tert-butyl ester jointly with the byproduct 3-[2-(3-cyanophenyl)-3-phenylpyrimido[1,2-b]indazol-8-yl]benzonitrile were dissolved in 17 mL 4M hydrogen chloride in dioxane. After stirring over night at room temperature the solvent was evaporated to dryness and the residue was treated with saturated sodium bicarbonate solution. This aqueous solution was extracted three times with ethyl acetate. The combined organic extracts were worked up as already described. The residue was purified by column chromatography on silicagel (eluents: dichloromethane/methanol) and additional HPLC yielding 18.2 mg of the title compound.
Reaction SMILES: Br[C:2]1[C:3]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH3:26])[CH:21]=[CH:20]3)=[N:4][C:5]([F:16])=[C:6]([C:14]=1[F:15])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH:27]([B-](F)(F)F)=[CH2:28].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[F:16][C:5]1[N:4]=[C:3]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH3:26])[CH:21]=[CH:20]3)[C:2]([CH:27]=[CH2:28])=[C:14]([F:15])[C:6]=1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: C=C[B-](F)(F)F
Reactant: Cn1ccc2cc(-c3nc(F)c(C(=O)OC(C)(C)C)c(F)c3Br)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: C=Cc1c(-c2ccc3c(ccn3C)c2)nc(F)c(C(=O)OC(C)(C)C)c1F
Temperature: 70 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
A mixture of tert-butyl 5-bromo-2,4-difluoro-6-(1-methyl-1H-indol-5-yl)nicotinate (128 mg, 0.30 mmol), potassium vinyltrifluoroborate (80 mg, 0.60 mmol), Pd(OAc)2 (4.7 mg, 0.012 mmol), SPhos (17 mg, 0.024 mmol), aqueous K2CO3 (2.0 M×0.45 mL, 0.9 mmol) and dioxane (2.0 mL) were stirred at 70° C. under Ar overnight. The mixture was cooled and extracted with ethyl acetate. The organic layers were combined, dried, evaporated and purified by silica chromatography (0-5% ethyl acetate in hexanes) to give tert-butyl 2,4-difluoro-6-(1-methyl-1H-indol-5-yl)-5-vinylnicotinate (72 mg, 64%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=3)[C:10]([C:18]([OH:21])([CH3:20])[CH3:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1.N1CCCCC1.[CH3:28][C:29]1[O:33][N:32]=[C:31]([C@:34]([OH:38])([C:36]#[CH:37])[CH3:35])[CH:30]=1>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.[Cu]I>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:37]#[C:36][C@:34]([C:31]4[CH:30]=[C:29]([CH3:28])[O:33][N:32]=4)([OH:38])[CH3:35])[CH:15]=3)[C:10]([C:18]([OH:21])([CH3:20])[CH3:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Reactant: CC(C)(O)c1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(C(C)(C)O)nn(-c4ccnc(N)n4)c3c2)no1
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
To a pressure tube was added 2-[1-(2-aminopyrimidin-4-yl)-6-bromoindazol-3-yl]propan-2-ol followed by piperidine (2.5 mL), tetrakis(triphenylphosphine)palladium (102.88 mg, 0.09 mmol), copper(I) iodide (16.96 mg, 0.09 mmol) and (2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (269.16 mg, 1.78 mmol). The reaction was capped and stirred at 65° C. for 1.5 hr and then concentrated in vacuo. DCM (5 mL) was added to the reaction mixture and the concentration was repeated (×2). The crude product was purified by flash chromatography (Biotage, 1-10% methanol in DCM) gave the title compound: 1H NMR (500 MHz, DMSO) delta 1.63 (6H, s), 1.85 (3H, s), 2.41 (3H, s), 5.57 (1H, s), 6.41 (1H, s), 6.56 (1H, s), 7.00 (2H, s), 7.05 (1H, d, J=5.5 Hz), 7.33 (1H, dd, J=8.3, 1.2 Hz), 8.13 (1H, d, J=8.3 Hz), 8.27 (1H, d, J=5.2 Hz), 8.88 (1H, s); LC-MS: m/z=+419.10 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][C:8]([F:58])([F:57])[C:9]1[CH:10]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[C:31]([C:32]4[CH:33]=[C:34]([C:40]5[C:49]([CH3:50])=[CH:48][C:43]([C:44]([O:46]C)=[O:45])=[CH:42][C:41]=5[CH3:51])[CH:35]=[N:36][C:37]=4[O:38][CH3:39])=[CH:30][N:29]=[C:28](S(C)(=O)=O)[N:27]=3)[C@H:20]2[CH3:56])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1>C1COCC1>[F:17][C:15]([F:16])([F:18])[C:13]1[CH:12]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[C:31]([C:32]4[CH:33]=[C:34]([C:40]5[C:41]([CH3:51])=[CH:42][C:43]([C:44]([OH:46])=[O:45])=[CH:48][C:49]=5[CH3:50])[CH:35]=[N:36][C:37]=4[O:38][CH3:39])=[CH:30][N:29]=[C:28]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[N:27]=3)[C@H:20]2[CH3:56])[CH:10]=[C:9]([C:8]([F:7])([F:58])[F:57])[CH:14]=1
Reactant: COC(=O)c1cc(C)c(-c2cnc(OC)c(-c3cnc(S(C)(=O)=O)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: COc1ncc(-c2c(C)cc(C(=O)O)cc2C)cc1-c1cnc(N2CCOCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
Morpholine (206 μl, 2.358 mmol), methyl 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfonyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3,5-dimethylbenzoate (INTERMEDIATE 44, 355 mg, 0.472 mmol), and THF (2.4 mL) were stirred at 100° C. for 10 minutes in the microwave reactor, at which time LCMS showed complete conversion to target. The reaction was partitioned between water and ethyl acetate. The organic was then washed with brine, dried over sodium sulfate, filtered and evaporated. The crude isolate was purified by silica gel chromatography, eluting with 25-100% ethyl acetate/hexanes to give the titled compound. 1H NMR (CDCl3, 500 MHz): δ 8.16 (s, 1H), 8.01 (d, 1H), 7.89 (s, 1H), 7.80 (d, 2H), 7.73 (s, 2H), 7.27 (d, 1H), 5.66 (d, 1H), 4.72 (d, 1H), 4.32 (m, 1H), 4.00 (m, s, 4H), 3.93 (s, 3H), 3.84 (m, 4H), 3.80 (m, 4H), 2.15 (s, 3H), 2.13 (s, 3H), 0.72 (d, 3H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[C@H:13]2[CH2:14][CH:8]([CH2:9][CH2:10][CH2:11][CH2:12]2)[N:7]1[S:15]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)(=[O:17])=[O:16])=[O:5])C.[OH-].[Li+]>O1CCCC1.O>[CH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[CH:27][C:18]=1[S:15]([N:7]1[CH:6]([C:4]([OH:5])=[O:3])[C@H:13]2[CH2:14][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12]2)(=[O:17])=[O:16]
Reactant: CCOC(=O)C1[C@@H]2CCCCC(C2)N1S(=O)(=O)c1ccc2ccccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1[C@@H]2CCCCC(C2)N1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 80 °C
Yield: 98 %

Procedure:
To a solution of (R)-7-(naphthalene-2-sulfonyl)-7-aza-bicyclo[4.2.1]nonane-8-carboxylic acid ethyl ester (0.55 g, 1.42 mmol) in tetrahydrofuran (15 mL) is added a solution of lithium hydroxide (1.2 g, 28.6 mmol) in water (15 mL). The reaction is heated to 80° C. for 16 h, and the solvent is removed in vacuo. The residue is dissolved in water and washed with diethyl ether. The aqueous layer is then acidified with 6 N hydrochloric acid to pH less than 4 and extracted three times with ethyl acetate. The combined organic extracts are washed with brine, dried over magnesium sulfate, and concentrated to afford the title compound as a yellow solid (0.50 g, 98% yield). LCMS (m/z): 360.07 (M+1), 358.12 (M−1).
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16](S(C2C=CC(C)=CC=2)(=O)=O)[CH:15]=[C:14]3[C:30]([OH:32])=[O:31])[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[C:30]([OH:32])=[O:31])[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(C(=O)O)c3cc(-c4cncc(OC(C)C)n4)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)Oc1cncc(-c2ccc3[nH]cc(C(=O)O)c3c2)n1
Temperature: 90 °C
Yield: 11.9 %

Procedure:
To a solution of 5-(6-isopropoxy-pyrazin-2-yl)-1-(toluene-4-sulfonyl)-1H-indole-3-carboxylic acid (450 mg, 0.99 mmol) in 1,4-dioxane (5 mL) was added of 10% aq. NaOH (5 mL) at RT and the reaction was heated at 90° C. for 1 h. The reaction was cooled to RT and washed with DCM (2×3 mL). The aqueous layer was neutralized with 1N HCl (4 mL) and was extracted with EtOAc (5 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 5-(6-isopropoxypyrazin-2-yl)-1H-indole-3-carboxylic acid (35 mg, 12%) as a brown solid. MS (ESI, pos. ion) m/z: 298.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH2:12][CH3:13])[C:9](O)=[O:10])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)C.O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:14])([CH2:12][CH3:13])[CH2:9][OH:10])=[CH:6][CH:7]=1
Reactant: CCC(C)(C(=O)O)c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCC(C)(CO)c1ccc(F)cc1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
A solution of 3.0 g of 2-(4-fluorophenyl)-2-methylbutyric acid in 10 ml of tetrahydrofuran was added dropwise to a mixture of 20 ml of tetrahydrofuran and 0.5 g of lithium aluminum hydride at 40° C. The temperature was then elevated and the mixture was refluxed for 30 minutes. The mixture was cooled to room temperature and ethanol was added dropwise to the mixture to decompose excessive lithium aluminum hydride. Then, water was added to the mixture to complete the decomposition. The formed precipitate was removed by filtration and tetrahydrofuran was removed from the filtrate by distillation under reduced pressure. The residue was extracted with benzene, and the benzene extract was washed with water direct, over Na2SO4, and evaporated under reduced pressure to give 2.6 g of 2-(4-fluorophenyl)-2-methylbutyl alcohol.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][C@H:9]([OH:28])[CH2:10][CH2:11][C@@H:12]2[C@@H:16]([CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C@@H:15]([OH:26])[CH2:14][C@H:13]2[OH:27])=[CH:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].I[CH:36]([CH3:38])[CH3:37].O>CN(C=O)C.C(OCC)(=O)C>[OH:27][C@@H:13]1[CH2:14][C@H:15]([OH:26])[C@H:16]([CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][C:23]([O:25][CH:36]([CH3:38])[CH3:37])=[O:24])[C@H:12]1[CH2:11][CH2:10][C@@H:9]([OH:28])[CH2:8][CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: O=C(O)CCC/C=C\C[C@@H]1[C@@H](CC[C@@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](CC[C@@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Reaction time: 2 h

Procedure:
Four samples (the product before crystallization, the product of the first crystallization, the filtrate of the first crystallization, and the product of the second crystallization) were hydrolyzed using methanol and 3N NaOH. After 2 h at 25° C., the mixture was acidified and extracted with ethyl acetate. After drying-concentration of the extracts, crude Latanoprost acid was obtained. The crude Latanoprost acid was esterified using K2CO3 and 2-iodopropane in DMF. After 2 h at 60° C., water and ethyl acetate were added and phase separated, the aqueous layer was extracted with ethyl acetate. After drying-concentration of the extracts, crude Latanoprost was obtained. HPLC (Phenomenex Luna 5 μm silica and Chiralcel OD-H) analysis of the crude product showed the following results:
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH:4]=O.[C:12]([O:16][C:17](=[O:40])[NH:18][C:19]1[N:28]([CH2:29][CH2:30][CH3:31])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([NH2:39])[CH:34]=3)[CH:25]=2)[N:20]=1)([CH3:15])([CH3:14])[CH3:13].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CO>ClCCCl>[C:12]([O:16][C:17](=[O:40])[NH:18][C:19]1[N:28]([CH2:29][CH2:30][CH3:31])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([NH:39][CH2:4][C:3]4[C:2]([CH3:1])=[CH:9][C:8]([CH3:10])=[CH:7][C:6]=4[CH3:11])[CH:34]=3)[CH:25]=2)[N:20]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: CCCN1Cc2cc(Oc3cccc(N)c3)ccc2N=C1NC(=O)OC(C)(C)C
Reactant: Cc1cc(C)c(C=O)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: CCCN1Cc2cc(Oc3cccc(NCc4c(C)cc(C)cc4C)c3)ccc2N=C1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2,4,6-Trimethyl-benzaldehyde (0.0005 mol) was added to a mixture of [6-(3-amino-phenoxy)-3-propyl-3,4-dihydro-quinazolin-2-yl]-carbamic acid tert-butyl ester (0.0005 mol) in DCE (3 mL) and the mixture was stirred for 5 min. at room temperature, and then NaBH(OAc)3 (0.0006 mol) was added and the reaction mixture was stirred overnight at room temperature. The excess NaBH(OAc)3 was decomposed with CH3OH, and the solvent was evaporated. The obtained residue was purified by Biotage column chromatography (eluent: 100% CH2Cl2). The purest product fractions were collected and then the solvent was evaporated and co-evaporated with toluene to yield the title compound as a residue.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:4]([N+:12]([O-])=O)[CH:3]=1.[Cl-].[NH4+].O>CO.[Zn]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:4]([NH2:12])[CH:3]=1
Reactant: CS(=O)(=O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(Br)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
A light brown suspension of 4-bromo-1-methanesulfonyl-2-nitro-benzene (8.65 g, 30.9 mmol) in methanol (300 mL, not completely dissolved in methanol even at hot condition) was treated sequentially with ammonium chloride (24.8 g, 463.5 mmol), zinc dust (20.2 g, 309 mmol), and water (100 mL). Initially, the reaction was exothermic, and the brown color disappeared. The reaction mixture was stirred for 1 h at 25° C. The reaction mixture was then filtered, and the residue was washed with methanol (50 mL) and ethyl acetate (100 mL). The filtrate was concentrated in vacuo, and the organic compound was extracted into ethyl acetate (3×100 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 8/1 to 6/1 to 4/1 hexanes/ethyl acetate) afforded 5-bromo-2-methanesulfonyl-phenylamine (5.7 g, 74%) as a white solid: mp 107-109° C.; EI-HRMS m/e calcd for C7H8BrNO2S (M+) 248.9459, found 248.9451.
Reaction SMILES: [NH2:1][C@H:2]([CH3:18])[C@@H:3]([OH:17])[CH2:4][N:5]([CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[CH3:6].[CH3:19][N:20]1[C:24]([C:25]2[CH:26]=[C:27]([NH:31][C:32](=O)[O:33]C3C=CC=CC=3)[CH:28]=[CH:29][CH:30]=2)=[N:23][N:22]=[N:21]1>C(#N)C>[F:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][N:5]([CH3:6])[CH2:4][C@H:3]([OH:17])[C@H:2]([NH:1][C:32]([NH:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([C:24]3[N:20]([CH3:19])[N:21]=[N:22][N:23]=3)[CH:26]=2)=[O:33])[CH3:18])=[CH:15][CH:14]=1
Reactant: C[C@@H](N)[C@@H](O)CN(C)CCCc1ccc(F)cc1
Reactant: Cn1nnnc1-c1cccc(NC(=O)Oc2ccccc2)c1
Solvent: CC#N
Product: C[C@@H](NC(=O)Nc1cccc(-c2nnnn2C)c1)[C@@H](O)CN(C)CCCc1ccc(F)cc1
Yield: 3.7 %

Procedure:
The product of Step g (186 mg, 7.3 mmol, 1 eq.), phenyl 3-(1-methyl-1H-tetraazol-5-yl)phenylcarbamate (220 mg, 7.3 mmol, 1 eq.) and acetonitrile (10 mL) were mixed at 25° C. under N2 overnight. Worked up by stripping off the solvents then purifying the residue over silica gel in 1:1 Hexanes/EtOAc to 100% EtOAc to 4:1 EtOAc/MeOH. Obtained 123 mg of an amorphous solid. NMR (300 MHz, CDCl3) δ 7.88 (s, 1H); 7.60 (d, 1H, J=7 Hz); 7.42 (t, 1H, J=7 Hz); 7.30 (d, 1H, J=7 Hz); 7.20-7.00 (m, 2H); 6.91 (t, 2H, J=7 hz); 4.17 (s, 3H); 3.97 (m, 1H); 3.80 (m, 1H); 2.70-2.40 (m, 6H); 2.34 (s, 3H); 1.90-1.70 (m, 2H); 1.18 (d, 3H, J=7 Hz).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14](Cl)(=O)C>CO>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 75.5 %

Procedure:
A 1 L 3-necked round bottomed flask equipped with a nitrogen inlet, stirbar, addition funnel and thermocouple was charged with 4-fluoro-3-nitrobenzoic acid (50 g, 0.27 mol) and methanol (300 mL). The system was cooled to 0 C and acetyl chloride (27 mL, 0.37 mol) was added dropwise. The system was warmed to room temperature, the addition funnel was replaced with a reflux condenser, and was heated to reflux for 1.5 h. The reaction mixture was cooled to room temperature, quenched with saturated aqueous NaHCO3, and extracted with ethyl acetate. The organic extract was washed with brine, dried with Na2SO4 and concentrated in vacuo to give methyl 4-fluoro-3 nitrobenzoate as an orange solid (40.6 g, 75%). 1H NMR (400 MHz, CD3OD) δ 8.67 ((dd, J=2.2 and 6.8 Hz, 1H), 8.34 (dddd, J=2.2, 4.4, 6.4 and 8.8 Hz, 1H), 7.55 (dd, J=8.8 and 10.8 Hz, 1H), 3.94 (s, 3H) ppm. ES-HRMS m/z 200.02446 (M+H calcd for C8H7FNO4 requires 200.0354).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:12]1[CH:17]=[CH:16][C:15](/[C:18](/[C:35]2[CH:40]=[CH:39][C:38]([S:41][C:42]([F:45])([F:44])[F:43])=[CH:37][CH:36]=2)=[CH:19]\[CH2:20][O:21][C:22]2[CH:33]=[CH:32][C:25]([O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:24]([CH3:34])[CH:23]=2)=[CH:14][CH:13]=1.C(NC(C)C)(C)C>O1CCCC1.[Cu]I.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>[OH:10][CH:7]1[CH2:8][CH2:9][N:4]([CH2:1][C:2]#[C:3][C:12]2[CH:13]=[CH:14][C:15](/[C:18](/[C:35]3[CH:36]=[CH:37][C:38]([S:41][C:42]([F:44])([F:43])[F:45])=[CH:39][CH:40]=3)=[CH:19]\[CH2:20][O:21][C:22]3[CH:33]=[CH:32][C:25]([O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:24]([CH3:34])[CH:23]=3)=[CH:16][CH:17]=2)[CH2:5][CH2:6]1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(SC(F)(F)F)cc2)cc1C
Reactant: C#CCN1CCC(O)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCC(O)CC3)cc2)c2ccc(SC(F)(F)F)cc2)cc1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1-Propargylpiperidin-4-ol (154 mg, 1.10 mmol) was added to a solution of methyl (Z)-[4-[3-(4-iodophenyl)-3-[4-(trifluoromethyl-sulfanyl)phenyl]allyloxy]-2-methylphenoxy]-acetate (340 mg, 0.553 mmol; prepared as described in example 56) and diisopropylamine (0.35 mL, 2.49 mmol) in tetrahydrofuran (9 mL). The mixture was degassed and copper(I) iodide (8.4 mg, 0.044 mmol) and bis(triphenylphosphine)palladium(II) dichloride (19.3 mg, 0.027 mmol) were added. The reaction mixture was stirred under argon at ambient temperature for 20 h, filtered and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, chloroform/methanol 97:3) yielding methyl (E)-[4-[3-[4-[3-(4-hydroxypiperidin-1-yl)propynyl]phenyl]-3-[4-(trifluoromethylsulfanyl)phenyl]-allyloxy]-2-methylphenoxy]acetate.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[C:10]1[N:15]=[CH:14][CH:13]=[CH:12][N:11]=1>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: Clc1ncccn1
Reactant: Nc1ccc(Br)cc1
Product: Brc1ccc(Nc2ncccn2)cc1
Temperature: 25 °C
Yield: 31 %

Procedure:
4-Bromoaniline (0.300 g, 1.74 mmol) and 2-chloropyrimidine (0.200 g, 1.74 mmol) were heated neat at 150° C. in a 25 mL flask for 2 h. The reaction mixture was cooled to ambient temperature, and purification of the residue by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 13.8-15.9 min) afforded N-(4-bromophenyl)-N-(2-pyrimidinyl)amine as a yellow solid (0.135 g, 0.54 mmol); RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 11.08 min; 1H NMR (DMSO-d6, 400 MHz) δ 9.78 (s, 1H), 8.50 (d, 2H), 7.76 (d, 2H), 7.45 (d, 2H), 6.87 (t, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[C:14]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:15]=[C:16](Br)[CH:17]=2)=[O:11])=[CH:4][CH:3]=1.[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O.CN(C)C=O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[C:14]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:15]=[C:16]([C:29]3[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=3)[CH:17]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccncc1
Reactant: Cc1ccc(-c2cc(Br)cc(C(=O)NCc3ccc(C)nc3)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(-c3ccncc3)c2)cc1

Procedure:
In a 5 mL microwave vial, 5-Bromo-4′-methyl-biphenyl-3-carboxylic acid (6-methyl-pyridin-3-ylmethyl)-amide (20 mg, 0.05 mmol), Pyridine-4-boronic acid (12.44 mg, 0.1012 mmol), cesium carbonate (82.42 mg, 0.2530 mmol), tetra-n-butylammonium iodide (18.69 mg, 0.05060 mmol), and POPd (2.538 mg, 0.005060 mmol) were dissolved in Water (0.04 mL, 2 mmol) and N,N-dimethylformamide (0.2 mL, 2 mmol). The reaction mixture was microwaved for 20 mins at 150 degrees. The reaction was purified directly by reversed phase HPLC (acetonitrile:water gradient) at pH 10. The combined pure fractions were reduced in vacuo to afford the title compound as an off white solid.
Reaction SMILES: N1C(=O)CC[C@H]1C(NCC(N[C@H](C([NH:24][C:25]1[CH:33]=[CH:32][C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=1)=O)CCCNC(=N)N)=O)=O>C(O)(=O)C>[N+:29]([C:28]1[CH:32]=[CH:33][C:25]([NH2:24])=[CH:26][CH:27]=1)([O-:31])=[O:30]
Reactant: N=C(N)NCCC[C@H](NC(=O)CNC(=O)[C@@H]1CCC(=O)N1)C(=O)Nc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Product: Nc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
Next, 50 μl of the synthetic peptide substrate (2 mM), pyroGlu-Gly-Arg-p-nitroanilide (S-2444, Kabi, Sweden) were added and the mixture was incubated for 30 minutes at room temperature. The reaction was stopped by the addition of 1 ml of 10% acetic acid. The amount of p-nitroaniline produced was measured by absorbance at 405 nm. The activity was expressed as International Standard Units (IU).