Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:26](=O)[CH2:27][C:28]2[C:29]([C:34]([F:37])([F:36])[F:35])=[N:30][CH:31]=[CH:32][CH:33]=2)[CH:12]=[C:13]([N+:23]([O-:25])=[O:24])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]([O:43][CH2:44][CH3:45])(=[O:42])[NH:40][NH2:41].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[C:26](=[N:41]\[NH:40][C:39]([O:43][CH2:44][CH3:45])=[O:42])/[CH2:27][C:28]2[C:29]([C:34]([F:36])([F:35])[F:37])=[N:30][CH:31]=[CH:32][CH:33]=2)[CH:12]=[C:13]([N+:23]([O-:25])=[O:24])[C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)NN
Reactant: O=C(Cc1cccnc1C(F)(F)F)c1cc(OCc2ccccc2)c(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)N/N=C(/Cc1cccnc1C(F)(F)F)c1cc(OCc2ccccc2)c(OCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A mixture of 1-(3,4-bis(benzyloxy)-5-nitrophenyl)-2-(2-(trifluoromethyl)pyridin-3-yl)ethanone (0.485 g, 0.93 mmol), ethyl carbazate (0.11 g, 1.06 mmol) and p-toluene sulfonic acid (4 mg) in toluene (10 mL) was refluxed until distillation of water ceased. The reaction mixture was cooled to room temperature, the solvents were evaporated to dryness, and the crude solid was triturated with diethyl ether (15 mL), filtered and dried yielding (Z)-ethyl 2-(1-(3,4-bis(benzyloxy)-5-nitrophenyl)-2-(2-(trifluoromethyl)pyridin-3-yl)ethylidene)hydrazinecarboxylate, 0.475 g (84%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2.O[C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:11]=[C:10]1[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]1[CH2:3][CH2:2][O:1][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1cccc(O)c1
Reactant: O=C1c2ccccc2Oc2ccccc2N1CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(OCCN2C(=O)c3ccccc3Oc3ccccc32)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Title compound 462 (0.300 g, 1.18 mmol), methyl 3-hydroxybenzoate (0.179 g, 1.18 mmol) and triphenylphosphine (0.401 g, 1.53 mmol) were dissolved in THF (5 mL) then diethylazodicarboxylate (0.222 mL, 1.41 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The solvent was evaporated to provide title compound 463.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[NH:22][CH:21]=[C:20]([C:23](O)=[O:24])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([NH:39][C:23]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:7]4[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:15]=3[NH:22][CH:21]=2)=[O:24])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1ccc(-c2ncnc3c(C(=O)O)c[nH]c23)c(OCC2CC2)c1
Product: COc1ccc(-c2ncnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A73) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].[CH3:22]I.O>CN(C)C=O>[CH3:22][CH:11]1[CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][S:13]([C:16]([F:19])([F:17])[F:18])(=[O:15])=[O:14])[CH:5]=[CH:4][C:3]=2[C:2]1=[O:1]
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CCc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under nitrogen atmosphere, 200 mg of trifluoromethanesulfonate 5-oxo-5,6,7,8-tetrahydro-naphthalene-2-ylester was dissolved in 3 ml of dimethylformamide. 54 mg of 60% sodium hydroxide and 1.0 ml of methyl iodide were added and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate. Ethyl acetate layer was washed with saturated saline solution, and dried with anhydrous sodium sulfate. The solvents were distilled outunder reduced pressure, and the residues were separated and purified by preparative thin-layer chromatography (ethyl acetate/hexane=1/2) to obtain 42 mg of the above compound as a yellow oily matter.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[C:32]1([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:41]4[CH2:40][CH2:39][CH:38]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH2:43][CH2:42]4)=[O:22])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCC(c2ccccc2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-phenylpiperidine as in General Procedure 10 to give the title compound. LCMS: m/z=590.98 (M+H+); retention time=1.03 minutes.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C@@H:6]([NH2:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:15][C:16]([F:31])([F:30])[C:17]1[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[N:19]([CH2:26][C:27](O)=[O:28])[N:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C@@H:6]([NH:14][C:27](=[O:28])[CH2:26][N:19]1[C:20]2[CH2:21][CH2:22][CH2:23][CH2:24][C:25]=2[C:17]([C:16]([F:30])([F:15])[F:31])=[N:18]1)[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N[C@@H](Cc1ccccc1)c1ncc[nH]1
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1nc(C(F)(F)F)c2c1CCCC2)N[C@@H](Cc1ccccc1)c1ncc[nH]1
Reaction time: 0.25 h

Procedure:
To (S)-1-(1H-imidazol-2-yl)-2-phenylethanamine from the previous reaction was added DMF (10 mL), 2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid (288 mg, 1.18 mmol), and HATU (530 mg, 1.4 mmol). Diisopropylethylamine (452 μL, 2.6 mmol) was added and the reaction was stirred for 15 min. The reaction was partitioned between EtOAc and H2O. The organics were separated, washed with saturated aqueous NaHCO3, and saturated aqueous NaCl. Solvents were removed in vacuo and the residue purified by column chromatography on silica to provide the desired product: MS (m/z) 418.3 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](Cl)=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[CH3:33].[F-].[Cs+]>COCCOC.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>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:29]2[CH:30]=[CH:31][C:32]([CH3:33])=[C:27]([CH3:26])[CH:28]=2)=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(Cc3ccccc3)c(=O)c2Cl)cc1
Reactant: Cc1ccc(B(O)O)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(-c2c(-c3ccc(S(C)(=O)=O)cc3)cnn(Cc3ccccc3)c2=O)cc1C
Temperature: 25 °C
Yield: 56 %

Procedure:
2-Benzyl-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (150 mg, 0.4 mmol) prepared in Example 78 was dissolved in anhydrous DME (10 mL) and heated to reflux with 3,4-dimethylbenzeneboronic acid in presence of CsF (146 mg, 0.96 mmol) and tetrakis(triphenylphosphine)palladium (14 mg, 0.012 mmol) for 6 hours. After cooling to room temperature the reaction mixture was diluted with water and extracted with ethyl acetate (100 mL). The organic layer was washed with brine, dried over MgSO4, and evaporated in vacuo. The compound was purified on a silica gel column, eluting with 30% ethyl acetate in pentanes, providing the desired compound (yield: 100 mg, 56%). 1H NMR (300 MHz, CDCl3) δ 2.15, 2.20 (2s, 3H), 2.25, 2.30 (2s, 3H), 3.05, 3.08 (2s, 3H), 5.35, 5.40 (2s, 2H), 6.60–7.1 (m, 3H), 7.30–7.40 (m, 4H), 7.42–7.60 (m, 2H), 7.70–8.02 (m, 4H). MS (DCI/NH3) m/z 445 (M+H)+. Anal. calc. for C26H24N2O3S.H2O: C, 67.51; H, 5.66; N, 6.05. Found: C, 67.45; H, 5.56; N, 5.85.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH:11]=[CH:10]1.[OH-].[Li+:17]>O1CCCC1.O>[NH2:7][C:4]1[CH:5]=[CH:6][C:1]([NH:8][C:9](=[O:15])/[CH:10]=[CH:11]\[C:12]([O-:14])=[O:13])=[CH:2][CH:3]=1.[Li+:17]
Reactant: Nc1ccc(N)cc1
Reactant: O=C1C=CC(=O)O1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(NC(=O)/C=C\C(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.3 %

Procedure:
Under a nitrogen atmosphere, into a reaction vessel were charged 13.23 g (122.4 mmol) of 1,4-phenylenediamine and 225 ml of tetrahydrofuran. A solution prepared by dissolving 8.00 g (81.6 mmol) of maleic anhydride in 24 ml of tetrahydrofuran was dropped into this under cooling with ice over a period of 2 hours, then, the mixture was stirred at room temperature for 3 hours. After completion of the reaction, a solution prepared by dissolving 1.99 g (81.6 mmol) of 98% lithium hydroxide in 17.95 g of water was dropped at room temperature over a period of 30 minutes, and the mixture was stirred at room temperature for 1 hour. Thereafter, the solvent was distilled off under reduced pressure to obtain a residue to which 200 ml of 2-propanol was added, and the mixture was stirred at room temperature overnight. Thereafter, the deposited solid was isolated by filtration, and washed with 50 ml of 2-propanol. The resultant solid was dried under reduced pressure at 45° C. for 5 hours, to obtain 13.03 g of lithium (2Z)-4-[(4-aminophenyl)amino]-4-oxo-2-butenoate as a pate brown-white solid. Yield: 75.3%
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]#[C:7][CH2:8][OH:9])=[CH:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11].Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:10]([O:9][CH2:8][C:7]#[C:6][C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)(=[O:12])[CH3:11]
Reactant: OCC#Cc1ccoc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)OCC#Cc1ccoc1
Reaction time: 1 h
Yield: 74.3 %

Procedure:
A mixture of 3-(3-furyl)-2-propynyl alcohol (1.45 g, 0.0118 mol), DMAP (1 mg), TEA (2.46 ml, 0.017 mol), and acetic anhydride (1.6 ml, 0.017 mol) in 25 ml of methylene chloride was stirred for 1 hour and the mixture was poured into cold 1N HCl solution. The mixture was extracted with ether (3×50 ml), the organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (hexane/ether, 2:1) to afford 1.44 g (57.5%) of 3-(3-acetyloxy-1-propynyl)furan as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH:12]([O:15][C:16]1[NH:20][N:19]=[C:18]([NH2:21])[CH:17]=1)([CH3:14])[CH3:13].C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:21][C:18]2[CH:17]=[C:16]([O:15][CH:12]([CH3:14])[CH3:13])[NH:20][N:19]=2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: CC(C)Oc1cc(N)n[nH]1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)Oc1cc(Nc2nc(Cl)ncc2[N+](=O)[O-])n[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.5 %

Procedure:
A mixture of 2,4-dichloro-5-nitropyrimidine (2 g) and 5-isopropoxy-1H-pyrazol-3-amine (Intermediate 6, 1.5 g) in acetonitrile (50 mL) with triethylamine (5 mL) was stirred at room temperature for 24 hours, The resulting mixture was concentrated, and the resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to afford 1 g of the title compound. MS (electrospray): 299 (M+1) for C10H12ClN6O3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]2[CH2:18][S:19][CH2:20][C:15]2=[N:14]1.C(Cl)Cl.C([O-])([O-])=[O:25].[Na+].[Na+]>>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[CH:17]=[C:16]2[CH2:18][S:19](=[O:25])[CH2:20][C:15]2=[N:14]1
Reactant: O=C([O-])[O-]
Reactant: FC(F)(F)c1cc(Cl)c(-n2cc3c(n2)CSC3)c(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: O=S1Cc2cn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)nc2C1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution of compound (3) (41 mg, 0.11 mmol) in CH2Cl2 (3 mL) m-CPBA (31.3 mg, 0.13 mmol) was added at −78° C. under N2. After 30 min. the reaction mixture was allowed to warm to −30° C. and stirred at −30° C. until the starting material disappeared completely. Aqueous Na2CO3 (10 mL) was then added and the organic phase was separated. The organic layer was washed with aq. Na2CO3 (10×4 mL), dried, concentrated to obtain a solid which was purified by flash chromatography on silica (20% EtOAc:hexane) to obtain the title compound (60%). 1H NMR (CDCl3) δ 7.78 (s, 2H), 7.45 (s, 1H), 7.53 (m, 2H), 4.01 (d, J=7.8 Hz, 1H), 3.88 (d, 7.8 Hz, 1H); MS (M+) 355.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]([CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N:11][C:12]=1[CH3:13])(=O)=O.[CH3:25][N:26](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.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:25]([C:7]1[CH:8]=[CH:9][C:10]([CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N:11][C:12]=1[CH3:13])#[N:26]
Reactant: Cc1nc(CCC(=O)OC(C)(C)C)ccc1OS(=O)(=O)C(F)(F)F
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1nc(CCC(=O)OC(C)(C)C)ccc1C#N
Temperature: 85 °C
Reaction time: 4 h

Procedure:
To a solution of 729 mg (1.97 mmol) of tert-butyl 3-(5-trifluoromethylsulfonyloxy-6-methylpyridin-2-yl)propanoate (from Step E) and 464 mg (3.95 mmol) of zinc cyanide in 10 mL of DMF was added 137 mg (0.12 mmol) of tetrakis(triphenylphosphine)palladium(0). After stirring at 85° C. for 4 h, the reaction mixture was diluted with 10 mL of EtOAc and filtered through a cake of Celite. Solid was washed with EtOAc (3×10 mL) and the filtrate was concentrated. Chromatography on a Biotage 40M cartridge using 3:17 v/v EtOAc/hexanes as the eluant afforded 487 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.42 (s, 9H), 2.71 (d, J=7.4, 2H), 2.73 (s, 3H), 3.09 (d, J=7.3, 2H), 7.12 (d, J=8.0, 1H), 7.77 (d, J=8.0, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1.C[CH2:14][N:15](CC)[CH2:16]C.CNC.C1COCC1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:15]([CH3:16])[CH3:14])(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Agent: CNC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
To 4-bromo-2-fluorobenzene-1-sulfonyl chloride (1.0 g, 3.7 mmol) and Et3N (1.5 mL, 11 mmol) in dichloromethane (10 mL) was added a solution of dimethylamine 2.0 M in THF (2.2 mL, 4.4 mmol). The reaction was stirred at ambient temperature for 30 minutes. The reaction was washed with 10 mL of 1N aqueous HCl and 10 mL of brine. Organics were dried over Na2SO4 and evaporated to dryness. Crude product was purified by chromatography on silica gel (eluting with 0-25% ethyl acetate in hexanes) to afford 4-bromo-2-fluoro-N,N-dimethylbenzenesulfonamide (780 mg, 75%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=2)[O:4][C:3]=1[C:26]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)=[O:27].Cl[C:35]([O:37][CH3:38])=[O:36].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:9]=[C:10]3[C:2]([NH:1][C:35](=[O:36])[O:37][CH3:38])=[C:3]([C:26]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[O:27])[O:4][C:5]3=[N:6][C:7]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:16][CH:15]=1
Reactant: Nc1c(C(=O)c2cccnc2)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Nc1c(C(=O)c2cccnc2)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 0.030 g (0.0607 mmol) of the product from Example 26 in CH2Cl2 (0.6 mL) at 0° C. was treated with methyl chloroformate (5 μL; 0.0607 mmol) followed by diisopropylethylamine (10 μL; 0.0607 mmol). After the addition, the reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction was quenched with saturated NaHCO3 solution. The reaction mixture was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was washed twice with saturated NaHCO3 solution, brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by MPLC (silica gel; 0% to 30% ethyl acetate:hexane gradient) gave the title compound. HPLC/MS: 551.9 (M+1), 553.9 (M+3); Rt=4.24 min.
Reaction SMILES: [NH2:1][C:2]1[C:10](I)=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1I.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>>[NH2:1][C:2]1[C:10]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:14]([F:25])([F:24])[F:13])[CH:20]=2)=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([C:14]([F:25])([F:24])[F:13])[CH:20]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Nc1c(I)cc(C(=O)O)cc1I
Product: Nc1c(-c2cccc(C(F)(F)F)c2)cc(C(=O)O)cc1-c1cccc(C(F)(F)F)c1

Procedure:
2′-Amino-3,3″-bis-trifluoromethyl-[1,1′;3′1″]terphenyl-5′-carboxylic acid was prepared as an off white solid (0.992 g, 94%) from 4-amino-3,5-diiodobenzoic acid and 3-trifluoromethylphenyl boronic acid using a procedure similar to step 1 of Example 175. 1H NMR (CDCl3) δ 7.90 (s, 2H); 7.78 (m, 2H); 7.74-7.60 (m, 6H); 4.24 (bs, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:15]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH3:9])=[O:15])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cccc(Br)c1
Solvent: ClCCl
Product: CS(=O)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 169.2 %

Procedure:
3-Bromothioanisol (0.5 g, 2.46 mmol) was added to methylene chloride (12 mL) and chilled to 0° C. To this was added 3-chloroperoxybenzoic acid (0.467 g, 2.71 mmol). The m-CPBA did not dissolve completely. The mixture was stirred overnight. The reaction was quenched with a saturated sodium thiosulfate (30 mL) solution. The product was extracted with EtOAc (3×20 mL). The organic fractions were combined, washed with brine (20 mL), and dried with sodium sulfate. The organic was then concentrated to yield 0.912 g (81%) 1-bromo-3-methanesulfinyl-benzene. 1HNMR (methylene chloride-d2) δ 7.83 (t, J=2.0 Hz, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.44 (t, J=7.9 Hz, 1H), 2.77 (s, 3H); LC-MS RT: 1.28, [M+H]+: 219.0.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@@H:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[OH:6].[Cl-].O.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](O)(=[O:22])=[O:21])=[CH:16][CH:15]=1>CO>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O:6][C@H:5]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3][NH:2][CH3:1])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: CNCC[C@H](O)c1cccs1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: CNCC[C@H](OS(=O)(=O)c1ccc(C)cc1)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
A mixture of (S)-3-methylamino-1-thiophen-2-yl-propan-1-ol (5.0 g, 29.2 mmol), methylene to chloride (50 mL), p-toluenesulfonic acid hydrate (5.55 g, 29.2 mmol) and methanol (20 mL) is stirred 1 h at 25° C., then concentrated to dryness. The residue (10.8 g) which solidifies after a few hours is finally recrystallised from butanol (30 mL) affording a white powder (6.0 g, 60%);
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:9]2[C:10]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:15]([C:24]4[CH:29]=[CH:28][C:27]([C:30]5([NH:34]C(=O)OC(C)(C)C)[CH2:33][CH2:32][CH2:31]5)=[CH:26][CH:25]=4)=[N:14][C:11]=3[O:12][CH2:13][C:8]2=[N:7][N:6]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:9]2[C:10]3[CH:17]=[C:16]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:15]([C:24]4[CH:25]=[CH:26][C:27]([C:30]5([NH2:34])[CH2:31][CH2:32][CH2:33]5)=[CH:28][CH:29]=4)=[N:14][C:11]=3[O:12][CH2:13][C:8]2=[N:7][N:6]=1
Reactant: COCCc1nnc2n1-c1cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc1OC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCc1nnc2n1-c1cc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc1OC2
Reaction time: 0.01 h
Yield: 50.1 %

Procedure:
Tert-butyl (1-(4-(1-(2-methoxyethyl)-8-phenyl-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutyl)carbamate (12 mg, 0.022 mmol) was dissolved in dichloromethane (0.5 ml); TFA (0.5 ml) was added at room temperature and the resulting mixture was stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 ml) and concentrated to dryness under reduced pressure. This was repeated three times. The residue was then slurred in diethyl ether (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The residue was then slurred in n-hexane (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and dried to give the desired product as an off-white solid (5 mg, 50% yield). LCMS (Method D) RT=0.741 min, M+1=454. 1H-NMR (500 MHz, CD3OD) δ 8.40 (1H, s), 7.52-7.47 (2H, d), 7.46-7.41 (2H, d), 7.38-7.34 (3H, m), 7.32-7.26 (2H, dd), 5.65 (2H, s), 3.94 (2H, t), 3.49 (2H, t), 3.35 (3H, s), 2.82-2.74 (2H, m), 2.63-2.54 (2H, m), 2.30-2.19 (1H, m), 2.04-1.93 (1H, m).