Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]([CH3:18])[CH:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[NH:11][C:10]([CH3:17])([CH3:16])[CH2:9]2)=[N:4][N:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[C:22]([O:29][CH3:30])[CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.CCOC(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>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[S:6][C:5]([N:7]([CH3:18])[CH:8]3[CH2:13][C:12]([CH3:15])([CH3:14])[NH:11][C:10]([CH3:17])([CH3:16])[CH2:9]3)=[N:4][N:3]=2)=[C:22]([O:29][CH3:30])[CH:21]=1
Reactant: COc1cc(Cl)ccc1B(O)O
Reactant: CN(c1nnc(Br)s1)C1CC(C)(C)NC(C)(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(Cl)ccc1-c1nnc(N(C)C2CC(C)(C)NC(C)(C)C2)s1
Temperature: 80 °C
Yield: 88.7 %

Procedure:
Nitrogen was bubbled through a stirred solution of 5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine [Intermediate 4] (1 g, 3.00 mmol) and (4-chloro-2-methoxyphenyl)boronic acid (0.615 g, 3.30 mmol) in dioxane (20 mL). To this mixture was added Pd(PPh3)4 (0.173 g, 0.150 mmol) followed by a solution of Na2CO3 (0.954 g, 9.00 mmol) in water (5 mL). The reaction was heated at 80° C. for 18 hours. The reaction mixture was cooled to RT, diluted with EtOAc (150 mL) and washed with water (100 mL). The organic phase was separated, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to afford the crude product as a dark red/brown oil which solidified on standing. The crude material was purified by flash chromatography using an 80 g silica cartridge running a gradient of [2M NH3 in MeOH]/DCM to afford the title compound as an off-white solid (1.051 g, 89% yield). LC-MS: Rt 1.04 min; MS m/z 395.2 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.09 (d, J=8.59 Hz, 1H), 7.32 (d, J=2.02 Hz, 1H), 7.15 (dd, J=8.59, 2.02 Hz, 1H), 4.35 (tt, J=12.38, 3.54 Hz, 1H), 3.97 (s, 3H), 2.98 (s, 3H), 1.60 (dd, J=11.87, 3.28 Hz, 2H), 1.41 (t, J=12.13 Hz, 2H), 1.27 (s, 1H), 1.21 (s, 6H), 1.08 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:16][C:17]#[CH:18])[O:12]C(C)(C)[O:10][C:9]2=[O:15])=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:12])([CH2:16][C:17]#[CH:18])[C:9]([OH:15])=[O:10])=[CH:6][CH:7]=1
Reactant: C#CCC1(c2ccc(Cl)cc2)OC(C)(C)OC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C#CCC(O)(C(=O)O)c1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
A solution of 530 mg 5-(4-chloro-phenyl)-2,2-dimethyl-5-prop-2-ynyl-(1,3)dioxolan-4-one in 10 ml tetrahydrofurane and 5 ml methanol is treated with 2 ml of 1N NaOH and heated at 60° C. for 1 hour. Then the solution is cooled down, diluted with water and washed with ether. Then the aqueous solution is acidified with 1N HCl and extracted with ethyl acetate. The extracts are dried over sodium sulfate and evaporated to obtain the 2-(4-chlorophenyl)-2-hydroxy-pent-4-ynoic acid of a brownish thick oil which is used for the next step.
Reaction SMILES: S(=O)(=O)(O)O.C([C:9]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][C:15](C(=O)C)=[CH:16][CH:17]=3)[CH:12]([CH3:25])[C:11]=2[CH:10]=1)(=O)C.C([O:29][C:30](=[O:32])[CH3:31])(=O)C.OO>O.ClCCl>[C:30]([O:32][C:16]1[CH:15]=[CH:14][C:13]2[C:12]3[C:11](=[CH:10][C:9]([O:29][C:30](=[O:32])[CH3:31])=[CH:21][CH:25]=3)[CH:19]([CH3:20])[C:18]=2[CH:17]=1)(=[O:29])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1ccc2c(c1)C(C)c1cc(C(C)=O)ccc1-2
Agent: O=S(=O)(O)O
Agent: OO
Solvent: ClCCl
Solvent: O
Product: CC(=O)Oc1ccc2c(c1)C(C)c1cc(OC(C)=O)ccc1-2
Temperature: 24 °C
Reaction time: 7 h
Yield: 36.9 %

Procedure:
36M-sulfuric acid (12 mL) was slowly dropwise added to a mixture of 2,7-diacetyl-9-methylfluorene (30 g), dichloromethane (30 mL), acetic anhydride (35 g) and a 34% hydrogen peroxide aqueous solution (34.6 g) while maintaining 3° C. or lower. The resulting mixture was stirred at 24° C. for 7 hours and then poured into water. The separated organic layer was sufficiently washed in order with saturated sodium hydrogencarbonate, 10% saturated sodium hydrogensulfite and water, and then dried on anhydrous magnesium sulfate. The solvent was distilled off from this organic layer under reduced pressure, and the resulting residue was purified by means of column chromatography (silica gel, eluting solvent: heptane/toluene [6/4]) and recrystallization (ethanol) to obtain 2,7-diacetyloxy-9-methylfluorene (12.4 g) of colorless crystal. Melting point: 138.6-139.7° C.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[F:11].[B:12]1(B2OC(C)(C)C(C)(C)O2)[O:16]C(C)(C)C(C)(C)[O:13]1.C([O-])(=O)C.[K+]>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:11][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[CH:8][S:9][C:10]=2[C:2]=1[B:12]([OH:16])[OH:13]
Reactant: Fc1ccc2ncsc2c1Br
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: OB(O)c1c(F)ccc2ncsc12
Temperature: 85 °C
Yield: 71.8 %

Procedure:
A mixture of 7-bromo-6-fluorobenzothiazole (90.7 mg, 0.391 mmol), bis(pinacolato)diboron (149 mg, 0.587 mmol), (1,1′bis-(diphenylphosphino)-ferrocene) palladium dichloride (15.9 mg, 0.0217 mmol), and potassium acetate (76.7 mg, 0.782 mmol) in 1,4-dioxane (1.9 mL) was heated to 85° C. for 24 h. The reaction mixture was concentrated and was then purified by ISCO chromatography (0 to 50% EtOAc:hexane) to give afford 55.3 mg of the title compound as an off-white solid. MS (ESI): 198.02 [M+H]+; HPLC tR=1.18 min (TOF: polar—3 min).
Reaction SMILES: [CH2:1]([N:8]([CH2:25][C@H:26]([O:39][CH:40]([O:42][CH2:43][CH3:44])[CH3:41])[CH2:27]OS(C1C=CC(C)=CC=1)(=O)=O)[C@@H:9]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>O1CCCC1>[CH2:1]([N:8]1[CH2:25][C@H:26]([O:39][CH:40]([O:42][CH2:43][CH3:44])[CH3:41])[CH2:27][C@H:20]([C:21]([O:23][CH3:24])=[O:22])[C@H:9]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)O[C@H](COS(=O)(=O)c1ccc(C)cc1)CN(Cc1ccccc1)[C@@H](CC(=O)OC)C(=O)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(C)O[C@@H]1C[C@H](C(=O)OC)[C@@H](C(=O)OCc2ccccc2)N(Cc2ccccc2)C1
Temperature: -78 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
To a solution of 1-benzyl 4-methyl (2S)-2-[benzyl((2S)-2-(1-ethoxyethoxy)-3-[(4-methylphenyl)sulfonyl]oxypropyl)amino]succinate (35.7 g, 0.0569 mol) in a mixture of tetrahydrofuran (95.5 mL, 1.18 mol) and toluene (490 mL, 4.6 mol) at −78 Celsius was added 1.00 M of Lithium hexamethyldisilazide in tetrahydrofuran (68.2 mL). The reaction was stirred at −78 Celsius overnight then allowed to warm up to −20 Celsius and stirred at −20 Celsius for 3 h. After quenched with aq. ammonium chloride, the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated to dry. The residue was applied on silica gel column, eluting with 0 to 20% EtOAc in hexane, to afford the product (18.1 g, 69.9%). MS (ESI): (M+H)+=456.2. The corresponding diastereoisomer was also obtained (4.52 g, 17.5%).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][C:13]([CH3:45])([CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:34]=[C:33]3[C:28]([C:29]([C:36](=[O:44])[NH:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:30][C:31]([CH3:35])=[N:32]3)=[CH:27][CH:26]=2)=[CH:21][N:20]=1)[C:14]([OH:16])=[O:15]>C(Cl)Cl>[C:14]([C:13]([CH3:45])([CH3:12])[CH2:17][O:18][C:19]1[N:20]=[CH:21][C:22]([C:25]2[CH:34]=[C:33]3[C:28]([C:29]([C:36](=[O:44])[NH:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:30][C:31]([CH3:35])=[N+:32]3[O-:6])=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)([OH:16])=[O:15]
Reactant: Cc1cc(C(=O)Nc2ccccc2)c2ccc(-c3ccc(OCC(C)(C)C(=O)O)nc3)cc2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(C(=O)Nc2ccccc2)c2ccc(-c3ccc(OCC(C)(C)C(=O)O)nc3)cc2[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
m-Chloroperoxybenzoic acid (30.0 mg, 0.20 mmol) was added at room temperature to a solution of 2,2-dimethyl-3-(5-(2-methyl-4-(phenylcarbamoyl)quinolin-7-yl)pyridin-2-yloxy)propanoic acid B-17 (45.5 mg, 0.10 mmol) in methylene chloride (7 mL). The reaction mixture was stirred at room temperature overnight, then concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography on C18 reverse phase (water:acetonitrile gradient with 0.05% formic acid) to give 7-(6-(2-carboxy-2-methylpropoxy)pyridin-3-yl)-2-methyl-4-(phenylcarbamoyl)quinoline 1-oxide B-23 (16.0 mg, Yield=40%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.28 (s, 6H), 2.66 (s, 3H), 4.34 (s, 2H), 7.17 (d, J=6.0 Hz, 1H), 7.40-7.46 (m, 3H), 7.80 (d, J=8.0 Hz, 2H), 7.93 (d, J=8.5 Hz, 1H), 7.99 (s, 1H), 8.14 (d, J=8.5 Hz, 1H), 8.41 (d, J=8.5 Hz, 1H), 8.83 (s, 1H), 8.87 (s, 1H), 10.78 (s, 1H). MS (ESI) [M+1]+ 474.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[CH:11]([O:20][C:21]1[CH:43]=[CH:42][C:24]2[C:25]3[N:29]([CH2:30][CH2:31][O:32][C:23]=2[CH:22]=1)[CH:28]=[C:27]([C:33]1[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=1)[N:26]=3)[CH2:12][CH:13]([CH3:19])[C:14](OCC)=[O:15])C.CCOC(C)=O.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1>[CH:39]([N:34]1[C:33]([C:27]2[N:26]=[C:25]3[N:29]([CH2:30][CH2:31][O:32][C:23]4[CH:22]=[C:21]([O:20][CH:11]([CH2:12][CH:13]([CH3:19])[CH2:14][OH:15])[CH2:10][OH:9])[CH:43]=[CH:42][C:24]=43)[CH:28]=2)=[N:37][C:36]([CH3:38])=[N:35]1)([CH3:41])[CH3:40]
Reactant: CCOC(=O)C(C)CC(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C(=O)OCC
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(CO)CC(C)CO)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 55.1 %

Procedure:
To a suspension of LiAlH4 (85 mg, 2.23 mmol) in THF (1 mL) at 0° C. was added a solution of 2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-4-methylpentanedioic acid diethyl ester (391 mg, 0.744 mmol) in THF (20 mL) and stirring at RT was continued for 2.5 h. To the reaction mixture was added EtOAc (2 mL) and stirring was continued for 30 min. An aqueous solution (10%) of Rochelle's salt was then added and the mixture was stirred for 5 min. Organic solvents were removed under reduced pressure and the resulting aqueous phase was extracted with EtOAc (×2). The combined organic phases were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 3-18% MeOH in DCM) affording 2-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-4-methylpentane-1,5-diol as a colorless gum (181 mg, 55%). LCMS: RT 2.49 min [M+H]+ 442.3
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:11]=[CH:12][N:13]2[C:17]([C:18]3[CH2:19][C@@H:20]4[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]4[C:22]=3[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])=[CH:16][S:15][C:14]=12)(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])O.[Na+]>C1COCC1>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:18]([C:17]3[N:13]4[CH:12]=[N:11][C:10]([CH2:9][OH:8])=[C:14]4[S:15][CH:16]=3)[CH2:19][C@H:20]12)[CH3:39]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3csc4c(CO[Si](C)(C)C(C)(C)C)ncn34)C[C@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3csc4c(CO)ncn34)C[C@H]12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 47.2 %

Procedure:
To a solution of 848.8 mg of 848.8 mg of 4-nitrobenzyl (5R,6S)-2-(7-t-butyldimethylsilyloxymethylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate in 20 ml of THF was added 1.22 ml of acetic acid and 7.1 ml of a 1 M solution of tetra-n-butylammonium fluoride in THF, and the mixture was stirred at room temperature for 2.5 hours. After neutralizing the mixture with a saturated aqueous sodium hydrogen carbonate solution, it was extracted two times with ethyl acetate, washed with semi-saturated aqueous saline, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by column chromatography on silica gel (ethyl acetate:methanol=9:1) to give 324.3 mg of 4-nitrobenzyl (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxymethylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19]([OH:21])=O)=[CH:11][C:12]3[O:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:22])[CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:44][C:45]1([CH3:53])[O:49][CH:48]([CH2:50][O:51][NH2:52])[CH2:47][O:46]1.[NH4+].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19]([NH:52][O:51][CH2:50][CH:48]3[CH2:47][O:46][C:45]([CH3:53])([CH3:44])[O:49]3)=[O:21])=[CH:11][C:12]3[O:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:22])[CH:3]=1
Reactant: CC1(C)OCC(CON)O1
Reactant: O=C(O)c1cc2ocnc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)OCC(CONC(=O)c2cc3ocnc3c(F)c2Nc2ccc(Br)cc2Cl)O1
Reaction time: 1 h

Procedure:
To a solution of 5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]oxazole-6-carboxylic acid (463 mg, 1.20 mmol) in CH2Cl2 (10 mL) was added HOBt (254 mg, 1.63 mmol) followed by EDCI (314 mg, 1.63 mmol). The mixture was stirred for 1 h and O-((2,2-dimethyl-1,3-di-oxolan-4-yl)methyl)hydroxylamine (238 mg, 1.62 mmol) was added. After stirring for 4 h at ambient temperature, the reaction was treated with saturated NH4Cl (aq.). The resultant mixture was extracted with CH2Cl2 (30 mL×3). The combined organic extracts was washed by water (30 mL) and brine (30 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo. The crude product (473 mg) was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]3[NH:30][N:29]=[N:28][N:27]=3)[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(-c2oc(CCCCCC#N)nc2-c2ccc(Cl)cc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2oc(CCCCCc3nnn[nH]3)nc2-c2ccc(Cl)cc2)cc1
Yield: 44.9 %

Procedure:
4 g of 6-[4-(4-chlorophenyl)-5-(4-methoxyphenyl)-2-oxazolyl]hexanenitrile, twice 2 g of sodium azide and twice 1.7 g of ammonium chloride in 50 cm3 of dimethylformamide are heated according to Example 5. The product of the reaction is purified by chromatography on a column 2 cm in diameter containing 40 g of silica gel (50 to 200μ). The column is eluted, collecting 25 cm3 fractions, first with 0.2 liter of diisopropyl ether and then with 0.3 liter of ethyl acetate. The ethyl acetate eluates are concentrated to dryness and the solid residue is crystallised in 40 cm3 of ethanol. 2 g (45%) of 5-{5-[4-(4-chlorophenyl)-5-(4-methoxyphenyl)-2-oxazolyl]pentyl}tetrazole, white crystals, melting point 160° C., are obtained.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:27])[CH2:18][C:19]3[CH:20]=[N:21][C:22](Cl)=[C:23]([CH3:25])[CH:24]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:28][C:29]([F:40])([F:39])[C:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[CH:32][N:31]=1.C1(PC2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:27])[CH2:18][C:19]3[CH:24]=[C:23]([CH3:25])[C:22]([C:34]4[CH:33]=[CH:32][N:31]=[C:30]([C:29]([F:40])([F:39])[F:28])[CH:35]=4)=[N:21][CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)Cc3cnc(Cl)c(C)c3)nc2)CC1
Reactant: OB(O)c1ccnc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: C1CCC(PC2CCCCC2)CC1
Agent: CC(=O)[O-]
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3cnc(-c4ccnc(C(F)(F)F)c4)c(C)c3)nc2)CC1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a sealed tube were added N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(6-chloro-5-methylpyridin-3-yl)acetamide 148-1 (123 mg, 0.32 mmol), 2-(trifluoromethyl)pyridin-4-ylboronic acid (61 mg, 0.32 mmol), Pd(OAc)2 (3.6 mg, 0.016 mmol), 2,6-Dimethoxy-1,1′-biphenyl-2-yl)dicyclohexylphosphine (13.0 mg, 0.032 mmol) and K3PO4 (202 mg, 0.95 mmol). The tube and its contents were then purged with nitrogen. After degassed toluene (1.0 mL) was added, the mixture was stirred at 120° C. overnight. After cooling to room temperature, the mixture was poured into water and extracted with ethyl acetate (8 mL×3). The combined organic phases were dried over Na2SO4, and concentrated. The residue was purified by reverse phase HPLC to give to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(3-methyl-2′-(trifluoromethyl)-2,4′-bipyridin-5-yl)acetamide 222. MS m/z 498.8 (M+1); 1H NMR 400 MHz (CDCl3) δ 8.81 (d, 1H), 8.51 (d, 1H), 8.35 (s, 1H), 8.11 (d, 1H), 7.91 (s, 1H), 7.89 (s, 1H), 7.68-7.64 (m, 2H), 7.30 (dd, 1H), 3.80-3.75 (m, 4H), 3.63 (t, 2H), 3.14 (t, 2H), 3.11 (t, 2H), 2.39 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3([C:28]([NH2:30])=[O:29])[CH2:27][CH2:26]3)[C:14]([C:31]([F:34])([F:33])[F:32])=[CH:13][N:12]=2)=[CH:6][CH:5]=1)[CH3:3].N1C=CC=CC=1.[C:41](OC(=O)C)(=[O:43])[CH3:42]>C(Cl)Cl>[C:41]([NH:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3([C:28]([NH2:30])=[O:29])[CH2:26][CH2:27]3)[C:14]([C:31]([F:33])([F:34])[F:32])=[CH:13][N:12]=2)=[CH:8][CH:9]=1)[CH3:3])(=[O:43])[CH3:42]
Reactant: CC(=O)OC(C)=O
Reactant: CC(N)c1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3C3(C(N)=O)CC3)n2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NC(C)c1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3C3(C(N)=O)CC3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a solution of 1-(2-(2-(2-(4-(1-aminoethyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide 70A (0.015 g, 0.032 mmol) in DCM (1 mL) was added pyridine (0.0040 mL, 0.050 mmol) and acetic anhydride (0.0050 mL, 0.053 mmol) and the reaction mixture was stirred at ambient temperature overnight. The mixture was partitioned between water and EtOAc, the layers were separated and the water layer was extracted with EtOAc (2 times). The combined organic extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo to give the title compound 71 as a light brown solid (0.016 g, 98%). LCMS-C: rt 5.24 min; m/z 512 [M+H]+.
Reaction SMILES: C(NCC)C.C(O)(C)(C)C.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][C:13]=1[N+:21]([O-:23])=[O:22].Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([N+:35]([O-:37])=[O:36])[CH:29]=1)=[O:27]>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH2:19][CH2:25][C:26]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([N+:35]([O-:37])=[O:36])[CH:29]=2)=[O:27])=[CH:14][C:13]=1[N+:21]([O-:23])=[O:22]
Reactant: O=C(CBr)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)(C)O
Solvent: c1ccccc1
Solvent: CCNCC
Product: O=C(CCC(=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
Zinc chloride (27.4 g, 201 mmol), diethylamine (15.6 mL, 151 mmol) and t-butanol (14.4 mL, 151 mmol) were combined in benzene (151 mL) at room temperature under a nitrogen atmosphere and stirred for 2 h. 1-(4-chloro-3-nitrophenyl)ethanone (30.1 g, 151 mmol) and 2-bromo-1-(4-chloro-3-nitrophenyl)ethanone (28 g, 101 mmol) were added. The mixture was stirred vigorously for 20 h, S and the solid product was collected by filtration and rinsed with benzene, water, methanol, and dichloromethane. The solid was dried in a vacuum oven.
Reaction SMILES: C([O:4][CH2:5][C:6]([CH3:35])([CH3:34])[CH2:7][C@H:8]([N:25]([C:27](OC(C)(C)C)=[O:28])[CH3:26])[CH2:9][O:10][C:11](=[O:24])[NH:12][C:13]1[N:14]=[CH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([F:23])=[CH:18][CH:17]=2)(=O)C.Cl.CCN(C(C)C)C(C)C.[Cl:46][C:47]1[C:66]([F:67])=[CH:65][CH:64]=[CH:63][C:48]=1[CH2:49][NH:50]C(=O)OC1C=CC([N+]([O-])=O)=CC=1>C1COCC1>[F:23][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[N:14][C:13]([NH:12][C:11](=[O:24])[O:10][CH2:9][C@@H:8]([N:25]([CH3:26])[C:27]([NH:50][CH2:49][C:48]1[CH:63]=[CH:64][CH:65]=[C:66]([F:67])[C:47]=1[Cl:46])=[O:28])[CH2:7][C:6]([CH3:35])([CH3:34])[CH2:5][OH:4])=[CH:22]2
Reactant: CC(=O)OCC(C)(C)C[C@@H](COC(=O)Nc1cc2cc(F)ccc2cn1)N(C)C(=O)OC(C)(C)C
Reactant: O=C(NCc1cccc(F)c1Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2cc(F)ccc2cn1)CC(C)(C)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
To a solution of (S)-4-(tert-butoxycarbonyl(methyl)amino)-5-(6-fluoroisoquinolin-3-ylcarbamoyloxy)-2,2-dimethylpentyl acetate (1.9 g, 3.8 mmol) in THF (50 mL) was added HCl (4 N in 1,4-dioxane, 19 mL, 76 mmol). The reaction mixture was stirred at RT for 1 h and concentrated to dryness. The residue was suspended in THF (100 mL). To the suspension were added DIEA (2.0 mL, 11.4 mmol) and 4-nitrophenyl 2-chloro-3-fluorobenzylcarbamate (1.2 g, 3.8 mmol). The reaction mixture was stirred at RT for 2 h and concentrated. The residue was purified on RP-HPLC using a mixture of acetonitrile and water to give (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-hydroxy-4,4-dimethylpentyl 6-fluoroisoquinolin-3-ylcarbamate (1.1 g, 53%). LRMS (M+H+) m/z 535.5