Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1.[C:14]([O-])(O)=[O:15].[Na+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[N:11]([C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:12])([F:13])[F:1])=[CH:10][CH:9]=1)=[C:14]=[O:15]
Reactant: O=C([O-])O
Reactant: Nc1ccc(OCC(F)(F)F)cc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(OCC(F)(F)F)cc1
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 73.3 %

Procedure:
2,2,2-Trifluoro-ethanol (7.09 g, 70.09 mmol) and stirred for 30 min. A solution of 1-Fluoro-4-nitro-benzene (10 g, 70.09 mmol) in DMF (25 mL) was added at 5-15° C., allowed to rt, stirred for 2 h, quenched with ice-water, filtered, washed with water and dried under high vacuum to obtain 14 g (89%) 1-Nitro-4-(2,2,2-trifluoro-ethoxy)-benzene as yellow solid. Subsequently, a solution of 1-Nitro-4-(2,2,2-trifluoro-ethoxy)-benzene (50 g, 226.2 mmol) in methanol (400 mL) was purged with nitrogen and 10% Pd—C (4.6 g) was added under nitrogen. This was stirred at rt under hydrogen atmosphere (balloon pressure) for 24 h. The reaction mixture was filtered through a celite bed and washed with methanol and the filtrate was removed under reduced pressure and washed with hexane to get 37 g (87%) 4-(2,2,2-Trifluoro-ethoxy)-phenylamine as a brown liquid. LC-MS: 192.4 [M+1]+. To a solution of 4-(2,2,2-Trifluoro-ethoxy)-phenylamine (12 g, 62.82 mmol) in DCM (1000 mL) was added solid NaHCO3 (52.77 g, 628.2 mmol). After 10 min, triphosgene (27.96 g, 94.24 mmol) dissolved in toluene (30 mL) was added to the reaction mixture under cooling at 10° C. and stirred for 10 min. The reaction mixture was filtered and the filtrate was concentrated, azeotroped twice with dry toluene to give 10 g 1-Isocyanato-4-(2,2,2-trifluoro-ethoxy)-benzene as yellow oily liquid which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[N:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].[C:25]([O-])(O)=O.[Na+].S(OC)(OC)(=O)=O>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[N:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([O:13][CH3:25])=[O:12]
Reactant: O=C([O-])O
Reactant: O=C(O)c1cccnc1Nc1ccc(-c2cccc(O)c2)cc1F
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)c1cccnc1Nc1ccc(-c2cccc(O)c2)cc1F
Yield: 38.4 %

Procedure:
To a mixture of 2-(3-fluoro-3′-hydroxybiphenyl-4-ylamino)nicotinic acid (1 g, 3.08 mmol) and NaHCO3 (0.5 g, 6.17 mmol) in acetone (20 ml) was added dropwise dimethyl sulphate (0.47 g, 3.70 mmol). The mixture was heated to reflux overnight and then concentrated. Ethyl acetate was added to the crude and washed twice with 4% solution of NaHCO3 and brine. The organic phase was then dried over MgSO4 and concentrated in vacuo to afford 0.4 g of solid beige pure enough for the next synthetic step. Yield=36%
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=1)[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[N-:25]=[N+:26]=[N-:27].[Na+].[Cl-].[NH4+].[Cl-].[Li+]>O.CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=1)[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:27][N:26]=[N:25][N:17]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(OCc2ccc(C#N)cc2)cc(C(C)(C)C)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc(OCc2ccc(-c3nnn[nH]3)cc2)cc(C(C)(C)C)c1
Temperature: 120 °C
Yield: 74.1 %

Procedure:
A mixture of 3.21 g (0.01 mole) of 4-(3,5-di-t-butylphenoxymethyl)-1-benzenecarbonitrile, 1.95 g (0.03 mole) of sodium azide, 1.60 g (0.03 mole) of ammonium chloride, 0.42 g (0.01 mole) of lithium chloride and 25 ml of dimethylformamide was heated at 120° C. in a stoppered flask for about sixty-four hours. The mixture was poured into 500 ml of water. The resulting precipitate was collected, rinsed with water and recrystallized from ethanol to give 2.7 g of white crystalline 5-{4-[(3,5-di-t-butylphenoxy)methyl]phenyl}tetrazole, m.p. 253°-255° C. Analysis: Calculated for: C22H28N4O: %C, 72.5; %H, 7.7; %N, 15.4; Found: %C, 72.5; %H, 7.9; %N, 15.0.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([O:21][CH3:22])=[O:20])[C:8]([CH3:28])=[CH:7][C:5]=2[N:6]=1.[CH3:29][N:30]1[C:38]2[C:33](=[N:34][C:35]([Sn](CCCC)(CCCC)CCCC)=[CH:36][CH:37]=2)[C:32]([C:52]2[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=2)=[N:31]1.[Li+].[Cl-]>O1CCOCC1.[Cu]I.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>[C:24]([O:23][C@@H:18]([C:9]1[C:8]([CH3:28])=[CH:7][C:5]2[N:6]=[C:2]([C:35]3[N:34]=[C:33]4[C:32]([C:52]5[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=5)=[N:31][N:30]([CH3:29])[C:38]4=[CH:37][CH:36]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH3:22])=[O:20])([CH3:27])([CH3:26])[CH3:25]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2c(n1)c(-c1cccnc1)nn2C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(n3)c(-c3cccnc3)nn4C)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a solution of (S)-methyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (8 mg, 0.018 mmol) in dioxane (2 mL), was added 1-methyl-3-(pyridin-3-yl)-5-(tributylstannyl)-1H-pyrazolo[4,3-b]pyridine (9 mg, 0.018 mmol), CuI (3.4 mg, 0.018 mmol), LiCl (3.8 mg, 0.09 mmol) and Pd(PPh3)4 (2 mg, 0.002 mmol). The reaction mixture was heated at 100° C. for 2 h. The reaction was cooled, washed with sat. NaHCO3, extracted by EtOAc, dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting with 0-100% EtOAc in hexanes to give the product. LCMS-ESI+: calc'd for C33H30ClN5O3S: 612.2 (M+H+); Found: 612.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:3]=1[O:4][CH:5]([CH2:17][CH3:18])[CH2:6][CH2:7][N:8](C)[C:9](=O)OC(C)(C)C>Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:3]=1[O:4][CH:5]([CH2:17][CH3:18])[CH2:6][CH2:7][NH:8][CH3:9]
Reactant: CCC(CCN(C)C(=O)OC(C)(C)C)Oc1cc(Cl)ccc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: CCC(CCNC)Oc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 178.8 %

Procedure:
[3-(2,5-Dichlorophenoxy)pentyl]methylcarbamic acid, 1,1-dimethylethyl ester (180 mg, 0.487 mmol) was dissolved in 4M hydrogen chloride in dioxane (6 ml). The resulting solution was stirred at room temperature for 3 h, then the solvent was evaporated. The residue was recrystallised from diethyl ether/ethanol to give 130 mg (88%) of the title compound as a white solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[C:20]([C:31]([NH2:33])=[O:32])=[CH:19][N:18]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:41](OC(=O)C)(=[O:43])[CH3:42]>C(#N)C>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH:25]4[CH2:30][CH2:29][N:28]([C:41](=[O:43])[CH3:42])[CH2:27][CH2:26]4)[C:20]([C:31]([NH2:33])=[O:32])=[CH:19][N:18]=3)=[CH:14][CH:15]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(C(N)=O)c(NCC4CCNCC4)n3)cc2)CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)N1CCC(CNc2nc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)ncc2C(N)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
To a solution of 2-(4-(4-acetylpiperazin-1-yl)phenylamino)-4-(piperidin-4-ylmethylamino)pyrimidine-5-carboxamide (22 mg, 0.049 mmol) and triethylamine (0.040 mL, 0.29 mmol) in acetonitrile (2 mL) at room temperature, acetic anhydride (0.020 mL, 0.21 mmol) was added. The solution was stirred at room temperature for 1 h. The mixture was then purified by HPLC to give the titled compound (8 mg). MS 495.41 (M+H).
Reaction SMILES: FC(F)(F)C([N:5]([CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([C:30]#[N:31])=[CH:22][CH:21]=1)[C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][CH:7]=1)=O.[OH-].[K+]>C(O)C>[C:30]([C:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20]([O:19][CH2:18][CH2:17][NH:5][C:6]2[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:15][CH:16]=2)=[CH:21][CH:22]=1)#[N:31]
Reactant: CCOC(=O)c1ccc(N(CCOc2ccc(C#N)c3ccccc23)C(=O)C(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1ccc(OCCNc2ccc(C(=O)O)cc2)c2ccccc12

Procedure:
A solution of 4.3 g. of ethyl 4-[N-trifluoroacetyl-2-(4-cyano-1-naphthyloxy)ethylamino]benzoate and 4.3 g. of potassium hydroxide in 100 ml. of 95% ethanol is refluxed for 3 hours. After cooling, diluting with 100 ml. of water and acidification to pH 4 with concentrated hydrochloric acid, the white solid is collected, washed with water and dried, m.p. 254°-256° C.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:19]5[CH2:22][O:21][CH2:20]5)[CH:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:25][C:26]([OH:43])([CH3:42])[CH2:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1>[Pd]>[CH3:25][C:26]([OH:43])([CH3:42])[CH2:27][N:28]1[CH:32]=[C:31]([C:2]2[CH:24]=[CH:23][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH:19]6[CH2:22][O:21][CH2:20]6)[CH:16]=[CH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:30]=[N:29]1
Reactant: Brc1ccc2c(c1)OCCc1sc(-c3nccn3C3COC3)nc1-2
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4nccn4C4COC4)nc2-3)cn1

Procedure:
Following the procedure for 355, 8-Bromo-2-(1-oxetan-3-yl-1H-imidazol-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene and 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol were reacted under Suzuki palladium conditions to give 420. MS: (ESI+)=464.1. 1H NMR (400 MHz, DMSO) δ 8.36 (d, J=8.3 Hz, 1H), 8.15 (s, 1H), 7.94 (d, J=1.4 Hz, 2H), 7.47 (dd, J=8.3, 1.7 Hz, 1H), 7.28 (d, J=1.7 Hz, 1H), 7.19 (d, J=1.0 Hz, 1H), 6.38 (p, J=6.8 Hz, 1H), 5.10 (t, J=7.3 Hz, 2H), 4.86 (t, J=6.6 Hz, 2H), 4.72 (s, 1H), 4.36 (t, J=5.0 Hz, 2H), 4.04 (s, 2H), 3.38 (t, J=5.0 Hz, 2H), 1.10 (s, 6H)
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:6]2[S:14][CH:13]=[C:12]([CH3:15])[C:7]=2[N:8]=[C:9](Cl)[N:10]=1)[CH:2]=[CH2:3].[CH3:16][O:17][CH2:18][CH2:19][NH2:20].C(=O)([O-])O.[Na+]>>[CH2:1]([NH:4][C:5]1[C:6]2[S:14][CH:13]=[C:12]([CH3:15])[C:7]=2[N:8]=[C:9]([NH:20][CH2:19][CH2:18][O:17][CH3:16])[N:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(Cl)nc2c(C)csc12
Reactant: COCCN
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NCCOC)nc2c(C)csc12
Yield: 82 %

Procedure:
287 mg (1.2 mmol) of 4-allylamino-2-chloro-7-methylthieno[3,2-d]pyrimidine and 1.44 mg (19.2 mmol) of 2-methoxyethylamine were heated in a sealed tube at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate solution thereto and extraction with ethyl acetate (50 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 274 mg (yield: 82.3%) of the title compound.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[F:21][C:22]([F:32])([F:31])[C@H:23]([NH2:30])[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>>[F:32][C:22]([F:21])([F:31])[C@H:23]([NH:30][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: N[C@H](c1cccnc1)C(F)(F)F
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Product: O=C(N[C@H](c1cccnc1)C(F)(F)F)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and (R)-2,2,2-trifluoro-1-pyridin-3-yl-ethylamine (CAN 1212813-98-3) as starting materials. MS (EI): m/e=443.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([F:16])[CH:10]=2)[N:5]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[CH:3]=1.[I:21](O)(=O)(=O)=O.II>CO.ClCCl>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([F:16])[CH:10]=2)[N:5]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:3]=1[I:21]
Reactant: COC(=O)c1cc(N)c(F)c(-c2ccc(Cl)c(F)c2)n1
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1nc(-c2ccc(Cl)c(F)c2)c(F)c(N)c1I
Yield: 236.6 %

Procedure:
Methyl 4-amino-6-(4-chloro-3-fluorophenyl)-5-fluoropicolinate (3.1 g, 10.38 mmol) was dissolved in methanol (40 mL). Periodic acid (0.946 g, 4.15 mmol) and iodine (2.371 g, 9.34 mmol) were added. The reaction mixture was heated at reflux overnight. The cooled reaction mixture was diluted with dichloromethane and washed with 1N sodium sulfite. The organic phase was washed with 1N sodium sulfite, washed with saturated sodium chloride, dried over magnesium sulfate, fitered, and concentrated onto celite. The product was purified by flash chromatography (SiO2, 100% dichloromethane) to provide the title compound 4.17 g, 9.82 mmol, 95% yield) as a pink solid: 1H NMR (400 MHz, DMSO-d6) d 3.88 (s, 3H), 6.80 (s, 2H), 7.65-7.77 (m, 2H), 7.77-7.84 (m, 1H); 19F NMR (376 MHz, DMSO-d6) d −140.15 , −115.85. ESIMS m/z 426 ([M+H]+).
Reaction SMILES: [OH-].[Na+:2].[F:3][CH:4]([F:42])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]1[N:17]2[CH:18]=[C:19]([C:23]3[CH:24]=[N:25][C:26]([N:29]4[CH2:35][CH2:34][CH:33]5[C:31]([C:36]([O:38]CC)=[O:37])([CH2:32]5)[CH2:30]4)=[N:27][CH:28]=3)[C:20]([F:22])=[CH:21][C:16]2=[N:15][C:14]=1[CH3:41]>C1COCC1.CO.O>[F:42][CH:4]([F:3])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]1[N:17]2[CH:18]=[C:19]([C:23]3[CH:24]=[N:25][C:26]([N:29]4[CH2:35][CH2:34][CH:33]5[C:31]([C:36]([O-:38])=[O:37])([CH2:32]5)[CH2:30]4)=[N:27][CH:28]=3)[C:20]([F:22])=[CH:21][C:16]2=[N:15][C:14]=1[CH3:41].[Na+:2]
Reactant: CCOC(=O)C12CC1CCN(c1ncc(-c3cn4c(Cc5ccccc5OC(F)F)c(C)nc4cc3F)cn1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2cc(F)c(-c3cnc(N4CCC5CC5(C(=O)[O-])C4)nc3)cn2c1Cc1ccccc1OC(F)F
Temperature: 70 °C
Reaction time: 3 h
Yield: 97.5 %

Procedure:
Sodium hydroxide (7.5 mg, 0.188 mmol) was added to a solution of Example 177 (0.104 g, 0.188 mmol) in THF-MeOH-water, 1:1:1 (4 mL). The mixture was stirred at 70° C. for 3 h. The reaction mixture was concentrated, diluted with water and washed with diethyl ether, then the aqueous layer was freeze-dried, to give the title compound (100 mg, 100%) as a white lyophilised solid. δH (400 MHz, DMSO-d6) 8.21 (d, J 1.3 Hz, 2H), 8.12 (d, J 7.5 Hz, 1H), 7.22 (m, 1H), 7.08 (m, 1H), 7.05 (t, J 72, 76 Hz, 1H), 6.97 (m, 1H), 6.92 (m, 1H), 6.81 (dd, J 7.5, 1.1 Hz, 1H), 4.12 (s, 2H), 4.04 (m, 1H), 3.96 (m, 1H), 3.43 (m, 1H), 3.07 (m, 1H), 2.07 (s, 3H), 1.76 (m, 1H), 1.50 (m, 1H), 1.15 (m, 1H), 0.72 (dd, J 8.7, 2.9 Hz, 1H), 0.00 (dd, J 5.4, 3.2 Hz, 1H). LCMS (pH 10): MH+ 524, RT 1.56 minutes.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:6][NH:5][CH2:4]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:60]1[CH:61]=[CH:62][C:63]([C:71]([OH:73])=[O:72])=[N:64][C:65]=1[O:66][CH2:67][CH:68]1[CH2:70][CH2:69]1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:68]1([CH2:67][O:66][C:65]2[N:64]=[C:63]([C:71]([OH:73])=[O:72])[CH:62]=[CH:61][C:60]=2[N:5]2[CH2:6][CH:3]([O:2][CH3:1])[CH2:4]2)[CH2:69][CH2:70]1
Reactant: O=C(O)c1ccc(Br)c(OCC2CC2)n1
Reactant: COC1CNC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC1CN(c2ccc(C(=O)O)nc2OCC2CC2)C1
Temperature: 110 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
Under a nitrogen atmosphere, 3-methoxyazetidine (38 mg, 0.44 mmol), BINAP (23 mg, 0.037 mmol), Pd2(dba)3 (17 mg, 0.02 mmol) and Cs2CO3 (240 mg, 0.735 mmol) were added to a solution of 5-bromo-6-(cyclopropylmethoxy)pyridine-2-carboxylic acid (CAN 1415898-37-1, 100 mg, 0.37 mmol) in toluene (4 mL). The reaction mixture was stirred overnight at 110° C. and then concentrated under reduced pressure. The residue was dissolved in water and extracted with ethyl acetate (30 mL). The aqueous layer was adjusted to pH 2 by addition of 1N HCl. The resulting precipitate was collected by filtration and dried in vacuo. Chromatographical purification over silica gel using petroleum ether/ethyl acetate=1/2 provided the title compound (35 mg, 34%) as a yellow solid, LC-MS: 265.2 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14]([CH3:15])=[C:13]([Cl:16])[C:12]([CH3:17])=[N:11]1.[NH2-].[Na+].N.Cl[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>O1CCCC1.O.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:4][C:3]=1[N:10]1[C:14]([CH3:15])=[C:13]([Cl:16])[C:12]([CH3:17])=[N:11]1
Reactant: CCOC(=O)CCl
Reactant: Cc1nn(-c2cc(O)c(Cl)cc2F)c(C)c1Cl
Agent: N
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)COc1cc(-n2nc(C)c(Cl)c2C)c(F)cc1Cl
Reaction time: 3 h
Yield: 93.9 %

Procedure:
1-(2-fluoro-4-chloro-5-hydroxyphenyl)-3,5-dimethyl-4-chloropyrazole (27.5 g) was dissolved in tetrahydrofuran (200 ml), and to the resultant solution was added sodium amide (4.0 g). When the evolution of ammonia gas from the reaction mixture ceased, ethyl monochloroacetate (12.3 g) was added dropwise to the reaction mixture. After the completion of addition, the reaction mixture was heated under reflux, with stirring for further 3 hours. To the reaction mixture, after cooling, were added toluene and water to form two layers. The organic layer as separated was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent by distillation in vacuo gave the titled compound (33.9 g) as a pale brown crystalline solid. Recrystallization of this solid from cyclohexane afforded a white crystalline solid. m.p. 101°-104° C.
Reaction SMILES: [OH:1][CH:2]([C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[CH2:3][C:4]1[N:5]=[N:6][NH:7][N:8]=1.[C:17]([CH:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)([CH3:20])([CH3:19])[CH3:18].C(O)(=O)C.C([BH3-])#N.[Na+]>C(Cl)Cl.C[C@H](NC([C@H]1N(C([C@@H](NC([C@@H](N)CC2C=CC(O)=CC=2)=O)CC(O)=O)=O)CCC1)=O)C(N1[C@H](C(N2[C@H](C(N3[C@H](C(N4[C@H](C(N5[C@H](C(N6[C@H](C(O)=O)CCC6)=O)CCC5)=O)CCC4)=O)CCC3)=O)CCC2)=O)CCC1)=O.CN(C=O)C.CO>[C:17]([CH:21]1[CH2:22][CH2:23][CH:24]([NH:27][CH2:13][C:12]2[CH:15]=[CH:16][C:9]([CH:2]([OH:1])[CH2:3][C:4]3[N:5]=[N:6][NH:7][N:8]=3)=[CH:10][CH:11]=2)[CH2:25][CH2:26]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: O=Cc1ccc(C(O)Cc2nn[nH]n2)cc1
Reactant: CC(C)(C)C1CCC(N)CC1
Agent: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(=O)O)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)C1CCC(NCc2ccc(C(O)Cc3nn[nH]n3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Resin bound 4-[1-hydroxy-2-(2H-tetrazol-5-yl)ethyl]benzaldehyde (50 mg) was swelled in DCM for 30 min. Solvent was removed, and the resin was washed once with DMF. A solution of 4-tert-butylcyclohexyl amine (25 mg, 0.164 mmol) in 50% TMOF in DMF (1 ml,) was added followed by acetic acid (50 μl). The mixture was shaken at room temperature for 3 hours, then a solution of sodium cyanoborohydride (13 mg, 0.20 mmol) in 50% MeOH in DMF (1 ml) was added. The resin-mixture was shaken overnight at room temperature, then drained and washed with DMF (3×2 ml) and DCP (3×2 ml).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[NH:13][C:12]([C:14]([C:46]4[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=4)=[C:15]4[N:45]=[C:18]([C:19]([C:38]5[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=5)=[C:20]5[NH:37][C:23](=[C:24]([C:30]6[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=6)[C:25]6[CH:26]=[CH:27][C:28]=2[N:29]=6)[CH:22]=[CH:21]5)[CH:17]=[CH:16]4)=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.ClCCl.C1(C)C=CC=CC=1.C(O)C>[OH:52][C:49]1[CH:48]=[CH:47][C:46]([C:14]2[C:12]3[NH:13][C:9]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([O:1][CH2:25][CH2:26][CH2:27][CH2:28][CH2:8][CH2:5][CH2:4][CH2:3][CH2:2][CH2:7][CH3:6])=[CH:3][CH:4]=4)=[C:28]4[N:29]=[C:25]([C:24]([C:30]5[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=5)=[C:23]5[NH:37][C:20](=[C:19]([C:38]6[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=6)[C:18]6[CH:17]=[CH:16][C:15]=2[N:45]=6)[CH:21]=[CH:22]5)[CH:26]=[CH:27]4)=[CH:10][CH:11]=3)=[CH:51][CH:50]=1
Reactant: Oc1ccc(-c2c3nc(c(-c4ccc(O)cc4)c4ccc([nH]4)c(-c4ccc(O)cc4)c4nc(c(-c5ccc(O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCOc1ccc(-c2c3nc(c(-c4ccc(O)cc4)c4ccc([nH]4)c(-c4ccc(O)cc4)c4nc(c(-c5ccc(O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Reaction time: 1.5 h

Procedure:
To a vigorously-stirred suspension of 5,10,15,20-tetrakis-(4-hydroxy-phenyl)-porphyrin (400 mg, 0.59 mmol) and K2CO3 (1.0 g, 7.1 mmol) in DMF (10 mL) is added dropwise at 50° C. during 30 mins and the mixture is stirred at the same temperature for 1.5 h. After removal by filtration of K2CO3 and removal under reduced pressure of DMF, the residue obtained is dissolved in dichloromethane (200 mL), washed with water (3×150 mL) and the solution dried (Na2SO4). The solvent is evaporated under reduced pressure and the residue obtained is dissolved in toluene:ethanol (5:1 by vol., ca. 10 mL) and purified by chromatography using a column (5×5 cm) of silica gel (Merck 60). The column is eluted with toluene followed by toluene:ethyl acetate (2:1 by vol.) and the desired material recovered by evaporation of solvent from the appropriate fractions is dried under high vacuum. The product is obtained as violet crystals.
Reaction SMILES: [NH2:1][NH2:2].C([Li])CCC.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.O>C1COCC1>[CH3:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[N:1][NH2:2])[NH2:22])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: NN
Reactant: Cc1ccc(-c2ccc(C#N)cc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2ccc(C(N)=NN)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
To a stirring solution of hydrazine (3.32 mL, 3.32 mmol, 1 M in THF) in THF (5 mL) at −78° C. was added butyllithium (1.28 mL, 3.05 mmol, 2.5 M in hexanes). After 30 min, a solution of 4′-methyl-[1,1′-biphenyl]-4-carbonitrile (535 mg, 2.77 mmol) in THF (5 mL) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured onto water (150 mL) and stirred vigorously for 1 h. The precipitate was isolated by filtration using water (2×20 mL) and isohexanes (3×20 mL) to wash the filter cake. The solid was dried under vacuum to yield 560 mg (90%) of 4′-methyl-[1,1′-biphenyl]-4-carbohydrazonamide INT-39 as a fine yellow solid. LCMS-ESI (m/z) calculated for C14H15N3: 225; found 226 [M+H]+, tR=1.15 min (Method 10).