Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][C:5]1[C:9]2[C:10]([Cl:23])=[CH:11][C:12]([O:14][CH2:15][C:16]3[N:20]([CH3:21])[N:19]=[C:18]([CH3:22])[CH:17]=3)=[CH:13][C:8]=2[S:7][CH:6]=1.[OH-].[Na+]>CCO>[Cl:23][C:10]1[C:9]2[C:5]([CH2:4][C:3]([OH:24])=[O:2])=[CH:6][S:7][C:8]=2[CH:13]=[C:12]([O:14][CH2:15][C:16]2[N:20]([CH3:21])[N:19]=[C:18]([CH3:22])[CH:17]=2)[CH:11]=1
Reactant: COC(=O)Cc1csc2cc(OCc3cc(C)nn3C)cc(Cl)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(COc2cc(Cl)c3c(CC(=O)O)csc3c2)n(C)n1
Yield: 90.5 %

Procedure:
To a mixture of methyl(4-chloro-6-((1,3-dimethyl-1H-pyrazol-5-yl)methoxy)-1-benzothiophen-3-yl)acetate (162 mg) and EtOH (3 mL) was added 1N NaOH (1 mL) at room temperature, and the mixture was refluxed for 1 h. The mixture was concentrated in vacuo, neutralized with 1N HCl at 0° C. and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was crystallized from EtOAc-hexane to give the title compound (141 mg).
Reaction SMILES: C([O:4][C:5]1[C:6]([O:31][CH3:32])=[C:7]([CH:11]([O:27][C:28](=[O:30])[CH3:29])[CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)[CH:8]=[CH:9][CH:10]=1)(=O)C.C([O-])(O)=O.[Na+].CO>O>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][N:15]2[CH2:14][CH2:13][CH:12]([CH:11]([O:27][C:28](=[O:30])[CH3:29])[C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([OH:4])[C:6]=3[O:31][CH3:32])[CH2:17][CH2:16]2)=[CH:21][CH:22]=1
Reactant: COc1c(OC(C)=O)cccc1C(OC(C)=O)C1CCN(CCc2ccc(F)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1c(O)cccc1C(OC(C)=O)C1CCN(CCc2ccc(F)cc2)CC1
Reaction time: 8 h

Procedure:
Stir overnight a mixture of the acetic acid -(3-acetoxy-2-methoxy-phenyl)-{1-[2-(4-fluoro-phenyl)-ethyl]-piperidin-4-yl}-methyl ester, Example 1F (5.2 g, 1.1 mmol), NaHCO3 (11 g, 130 mmol), methanol (100 mL) and water (50 mL). Add water (100 mL) and dichloromethane (100 mL), and separate the layers. Extract the aqueous layer with dichloromethane (100 mL), and combine the organic layers. Dry over Na2SO4 and filter. Remove the solvent under vacuum and obtain 5.1 g of product.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21]([CH3:23])C)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.[CH3:29]O.[BH4-].[Li+].Cl>O1CCCC1.O>[CH2:20]([NH:19][N:16]1[C:17](=[O:18])[C:12]([C:4]2[NH:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[S:2](=[O:1])(=[O:28])[N:3]=2)=[C:13]([OH:27])[C:14]2[S:26][CH:25]=[CH:24][C:15]1=2)[CH2:21][CH2:23][CH3:29]
Reactant: CO
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCNn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.075 g, 0.18 mmol) in tetrahydrofuran (4 mL) and methanol (0.029 mL, 0.5 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.150 mL, 0.3 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 2% methanol in chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (t, J=7.17 Hz, 3 H) 1.39 (dd, J=15.08, 7.35 Hz, 2 H) 1.50 (m, 2 H) 3.02 (t, J=6.43 Hz, 2 H) 6.65 (s, 1 H) 7.43 (d, J=5.15 Hz, 1 H) 7.55 (t, J=7.72 Hz, 1 H) 7.64 (d, J=8.09 Hz, 1 H) 7.77 (t, J=7.72 Hz, 1 H) 7.92 (d, J=8.09 Hz, 1 H) 8.34 (d, J=5.15 Hz, 1 H) 14.21 (s, 1 H) 14.83 (s, 1 H). MS (ESI−)m/z 417 (M−H)−.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[CH:8].[C:11]([C:15]1([CH2:19]O)[CH2:18][O:17][CH2:16]1)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([C:15]12[CH2:16][O:17][C:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[CH:8])([O:10][CH2:19]1)[O:9][CH2:18]2)([CH3:14])([CH3:13])[CH3:12]
Reactant: C#CCCCCCC(=O)O
Reactant: CC(C)(C)C1(CO)COC1
Product: C#CCCCCCC12OCC(C(C)(C)C)(CO1)CO2

Procedure:
4-t-Butyl-1-(hept-6-ynyl)-2,6,7-trioxabicyclo[2.2.2]octane was prepared from oct-7-ynoic acid and 3-t-butyl-3-hydroxymethyloxetane using methodology described in Example I.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH2:15])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[Br:17][C:18]1[CH:19]=[C:20]([S:28](Cl)(=[O:30])=[O:29])[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1>O1CCCC1.CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:15][S:28]([C:20]3[CH:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=[C:18]([Br:17])[CH:19]=3)(=[O:30])=[O:29])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: O=S(=O)(Cl)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2N
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2NS(=O)(=O)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
To a solution of ((R)-4-amino-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (446 mg, 2.0 mmol) and 3-bromo-5-trifluoromethyl-benzenesulfonyl chloride (970 mg, 3.0 mmol) in tetrahydrofuran (5 mL) was added a solution of dimethyl-pyridin-4-yl-amine (489 mg, 4.0 mmol) in tetrahydrofuran (5 mL) dropwise. After being stirred at room temperature overnight, the mixture was concentrated. The residue was purified by column chromatography (gradient elution, 0-5% methanol in dichloromethane) to afford [(R)-4-(3-bromo-5-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (750 mg, 63.6%) as a white solid. MS calcd. for C18H19BrF3N3O4S 509, obsd. (ESI+) [(M+H)+] 510.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1Cl.[C:15]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[H-].[Na+]>C1COCC1>[Br:1][C:2]1[C:7]([CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15]([O:23][CH2:24][CH3:25])=[O:22])=[N:6][CH:5]=[C:4]([S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:3]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CN(C)S(=O)(=O)c1cnc(Cl)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)c1ncc(S(=O)(=O)N(C)C)cc1Br
Reaction time: 48 h

Procedure:
A solution of 5-bromo-6-chloro-N,N-dimethylpyridine-3-sulfonamide (400 mg; 1.34 mmol) and diethyl malonate (204 μl; 1.34 mmol) in anhydrous THF (2 ml) was added to a suspension of sodium hydride (53 mg; 1.34 mmol) in anhydrous THF (2 ml). The resulting mixture was stirred for 48 hours, then quenched by careful addition of a saturated solution of NH4Cl in water. EtOAc was added and the phases separated. The organic phase was washed with brine, dried on MgSO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc to give the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][CH:14]3[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15]3)=[CH:10][N:11]=2)[C:6](=[O:23])[C:5]([C:24]([O:26]CC)=[O:25])=[CH:4]1)[CH3:2].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][CH:14]3[CH2:15][C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:22]3)=[CH:10][N:11]=2)[C:6](=[O:23])[C:5]([C:24]([OH:26])=[O:25])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2ncc(NC3Cc4ccccc4C3)cc2c1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCn1cc(C(=O)O)c(=O)c2cc(NC3Cc4ccccc4C3)cnc21
Temperature: 52.5 °C
Yield: 90 %

Procedure:
Ethanol (42.0 L) was added to reactor at 25-30° C., followed by ethyl 1-ethyl-6-(indan-2-ylamino)-4-oxo-1,8-naphthyridine-3-carboxylate (4.20 kg) with stirring. Aqueous sodium hydroxide solution (prepared by dissolving 3.4 kg of sodium hydroxide into 42.0 L of water) was added to reaction mixture at 25-30° C. and reactor temperature was raised to 50-55° C. The reaction mixture was stirred at 50-55° C. for 2 h and reaction progress was monitored by TLC. After completion of hydrolysis (˜3 h), the reaction mass was, cooled to 25-30° C. and pH was adjusted to 5-6 by addition of citric acid solution (prepared by dissolving 5.2 kg of citric acid in 47.0 L of water). The reaction mass was stirred for 20-25 minutes at 25-30° C. and filtered, the solid mass was washed with water (42.0 L) and acetone (21.0 L). The material was transferred to drying trays and dried with hot-air dryer at 70-75° C. until the water content decreased to 1.0%, yielding the desired compound (90%) as a solid. 1H NMR (DMSO-d6, 500 MHz): 1.40(3H, t, J=7.0 Hz), 2.86-2.90(2H, m), 3.37-3.41(2H, m), 4.38(1H, d, J=5.5 Hz), 4.62 (2H, q, J=7.0 Hz), 7.06(1H, d, J=6.0 Hz), 7.17-7.18(2H, m), 7.26-7.27(2H, m), 7.60(1H, d, J=2.5 Hz), 8.52(1H, d, J=2.0 Hz), 9.00 (1H, s), 15.30(1H, s). 13C NMR (DMSO-d6, 125 MHz): 15.19, 46.92, 52.92, 107.12, 109.42, 121.58, 124.63, 126.41, 140.11, 141.12, 143.33, 143.43, 145.93, 166.12, 177.53.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:9])[C:5](=[CH:7][CH:8]=1)[OH:6].[Li]CCCC.[B:15](OC)([O:18]C)[O:16]C.Cl>C1COCC1>[OH:9][C:4]1[CH:3]=[C:2]([B:15]([OH:18])[OH:16])[CH:8]=[CH:7][C:5]=1[OH:6]
Reactant: COB(OC)OC
Reactant: Oc1ccc(Br)cc1O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
4-Bromocatechol (T-1) (18.8 g; made by Tokyo Chemical Industry Co., Ltd.) was dissolved in dry THF (200 ml), which was cooled to −70° C. n-BuLi (72 ml) was added under an atmosphere of nitrogen and the stirring was continued at −70° C. for 2 hours. Trimethyl borate (15.6 g) in a THF solution was then slowly added dropwise at −70° C., and the mixture was warmed to room temperature and stirred for 16 hours. After the completion of the reaction, 2N HCl (100 ml) was added and the mixture was extracted with toluene. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure to give pale brown solids. The solids were recrystallized (heptane:toluene=4:1 by volume) to give 3,4-dihydroxyphenylboronic acid (T-2; 9.7 g; yield 63%) as colorless crystals.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([C:18]2[O:19][C:20]([C:23]3[N:28]=[C:27]([C:29]([O:31]C)=[O:30])[CH:26]=[CH:25][CH:24]=3)=[CH:21][N:22]=2)=[O:17])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C1COCC1.O.CCOC(C)=O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]([C:18]2[O:19][C:20]([C:23]3[N:28]=[C:27]([C:29]([OH:31])=[O:30])[CH:26]=[CH:25][CH:24]=3)=[CH:21][N:22]=2)=[O:17])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(Oc4ccccc4)cc3)o2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc(-c2cnc(C(=O)CCc3ccc(Oc4ccccc4)cc3)o2)n1
Yield: 91.2 %

Procedure:
Methyl 6-(2-(3-(4-phenoxyphenyl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate (356 mg, 0.831 mmol) was dissolved in THF/H2O (3:2, 75 mL) and LiOH (59 mg, 2.5 mmol) was added. The reaction solution was stirred at room temperature under an atmosphere of Ar for 2 h before the addition of 1 N HCl to adjust the solution to an acidic pH to quench the reaction. The reaction solution was diluted with EtOAc and the organic and aqueous layers were separated. The aqueous layer was extracted with EtOAc (3×). The organic phases were combined and washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 1% AcOH/EtOAc) to provide 6-(2-(3-(4-phenoxyphenyl)propanoyl)oxazol-5-yl)pyridine-2-carboxylic acid as a light yellow solid (314 mg, 91%): 1H NMR (THF-d8, 500 MHz) δ 8.11-8.03 (m, 4H), 7.30-7.25 (m, 4H), 7.03 (t, 1H, J=8.0 Hz), 6.94 (d, 2H, J=8 Hz), 6.91 (d, 2H, J=8.5 Hz), 3.43 (t, 2H, J=7.5 Hz), 3.04 (t, 2H, J=7.5 Hz); 13C NMR (THF-d8, 500 MHz) δ 187.3, 165.7, 158.9, 156.7, 153.6, 150.1, 147.2, 139.7, 137.1, 130.7, 130.6, 128.7, 125.5, 123.8, 123.7, 120.0, 119.4, 41.7, 29.8; HR ESI-TOF m/z 415.1284 (M+H+, C24H18N2O5, requires 415.1288).
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].Br[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([CH2:11][O:8][C:7]2[C:2]([CH3:1])=[C:3]([OH:9])[CH:4]=[CH:5][CH:6]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: BrCC1CCCCC1
Reactant: Cc1c(O)cccc1O
Product: Cc1c(O)cccc1OCC1CCCCC1

Procedure:
Alkylation of 2-methylbenzene-1,3-diol using (bromomethyl)cyclohexane following the method used in Example 154 gave 3-(cyclohexylmethoxy)-2-methylphenol. Yield (0.58 g, 37%): 1H NMR (400 MHz, CDCl3) δ 6.98 (t, J=8.0 Hz, 1H), 6.42 (t, J=7.6 Hz, 2H), 4.60 (bs, 1H), 3.72 (d, J=6.4 Hz, 2H), 2.12 (s, 3H), 1.68-1.89 (m, 6H), 1.16-1.35 (m, 3H), 1.01-1.11 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=1)\[C:13](O)=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:63]/[C:64](/[CH2:77][C@@H:78]1[C@H:81]([NH2:82])[C:80](=[O:83])[NH:79]1)=[CH:65]\[C:66](=[O:76])[CH2:67][NH:68][C:69](=[O:75])[O:70][C:71]([CH3:74])([CH3:73])[CH3:72]>C(Cl)Cl.CN(C=O)C>[NH2:63]/[C:64](=[CH:65]\[C:66](=[O:76])[CH2:67][NH:68][C:69]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:75])/[CH2:77][C@@H:78]1[C@H:81]([NH:82][C:13](=[O:14])/[C:12](=[N:11]\[O:10][C:7]([CH3:9])([CH3:8])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:29])/[C:16]2[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=2)[C:80](=[O:83])[NH:79]1
Reactant: CC(C)(C)OC(=O)NCC(=O)/C=C(\N)C[C@H]1NC(=O)[C@H]1N
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)/C=C(\N)C[C@H]1NC(=O)[C@H]1NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c1csc(NC(=O)OC(C)(C)C)n1

Procedure:
Prepared in analogous manner to example 4 step 4, using (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (100 mg, 0.23 mmol), HATU (89 mg, 0.23 mmol), DIPEA (68 μl, 0.39 mmol), tert-butyl ((Z)-4-amino-5-((2R,3S)-3-amino-4-oxoazetidin-2-yl)-2-oxopent-3-en-1-yl)carbamate (58 mg, 0.19 mmol) and DCM:DMF (3:1, 2 mL). 79 mg. LCMS: Rt=0.98 min, m/z=710.4 (M+1). Method 2m_acidic.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][N:6]1[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)([CH3:11])[C:9](=[O:20])[NH:8][C:7]1=[O:21])C.C(=O)([O-])[O-].[K+].[K+].I[CH2:30][CH3:31].[OH-].[Na+]>CN(C=O)C.CS(C)=O>[F:19][C:14]1[CH:13]=[C:12]([C:10]2([CH3:11])[N:6]([CH2:5][C:4]([OH:3])=[O:22])[C:7](=[O:21])[N:8]([CH2:30][CH3:31])[C:9]2=[O:20])[CH:17]=[C:16]([F:18])[CH:15]=1
Reactant: CCI
Reactant: CCOC(=O)CN1C(=O)NC(=O)C1(C)c1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CCN1C(=O)N(CC(=O)O)C(C)(c2cc(F)cc(F)c2)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of ethyl[5-(3,5-difluorophenyl)-5-methyl-2,4-dioxoimidazolidin-1-yl]acetate, isomer A from Step D (50.0 mg, 0.160 mmol) in DMF (1 mL) was added potassium carbonate (33.0 mg, 0.192 mmol) and iodoethane (0.015 mL, 0.192 mmol). The reaction was stirred at ambient temperature for 18 h and then a solution of 1 N NaOH (0.480 mL, 0.480 mmol) was added and stirring continued for 3 h. The reaction mixture was diluted with DMSO (1 mL), filtered, and purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the racemic title compound. MS: m/z=313 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([NH:34][CH3:35])=[CH:32][CH:31]=1>>[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([N:34]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])(=[O:17])=[O:18])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=2)[CH3:35])=[CH:32][CH:31]=1
Reactant: CNc1ccc(Cl)cc1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Product: CN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2C(F)(F)F)cc1)c1ccc(Cl)cc1
Yield: 72 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 4-chloro-N-methylaniline, the title compound was isolated as a yellow solid in 72% yield (94% purity by HPLC).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[CH2:7]2)[CH2:3][CH2:2]1.Cl[C:17]1[N:18]=[N:19][C:20]([C:23]2[S:27][N:26]=[C:25]([CH3:28])[N:24]=2)=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:28][C:25]1[N:24]=[C:23]([C:20]2[N:19]=[N:18][C:17]([N:1]3[CH2:6][CH2:5][C:4]4([C:14]5[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=5)[C:8](=[O:15])[CH2:7]4)[CH2:3][CH2:2]3)=[CH:22][CH:21]=2)[S:27][N:26]=1
Reactant: O=C1CC2(CCNCC2)c2ccccc21
Reactant: Cc1nsc(-c2ccc(Cl)nn2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nsc(-c2ccc(N3CCC4(CC3)CC(=O)c3ccccc34)nn2)n1

Procedure:
The object product (106 mg, 40%) was obtained in the same manner as in Example 1 and using spiro[indene-1,4′-piperidin]-3(2H)-one (190 mg), 3-chloro-6-(3-methyl-1,2,4-thiadiazol-5-yl)pyridazine (150 mg) and potassium carbonate (150 mg).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:4]=[N:5][C:6]([C:9]([OH:11])=[O:10])=[CH:7][CH:8]=1.Cl.[CH2:13](O)[CH3:14]>>[CH3:1][NH:2][C:3]1[N:4]=[N:5][C:6]([C:9]([O:11][CH2:13][CH3:14])=[O:10])=[CH:7][CH:8]=1
Reactant: CNc1ccc(C(=O)O)nn1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc(NC)nn1

Procedure:
A solution of 3-methylaminopyridazine-6-carboxylic acid (0.58 g) in ethanol (50 ml) was saturated with HCl gas, refluxed 48 hours and evaporated. The residue was partitioned between EtOAc and aqueous NaHCO3, separated and the aqueous re-extracted with EtOAc. The organic was dried and evaporated to give title compound (0.61 g). MS(+ve ion chemical ionisation) m/z 182 (MH+, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:22]([NH:25][NH:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=1)([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[CH:22]([N:25]([C:19](=[O:21])/[CH:18]=[CH:17]/[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:9]=1)[NH:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=1)([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)O)c2ccccc21
Reactant: Cc1cccc(C(=O)NNC(C)C)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)NN(C(=O)/C=C/c2cn(C(=O)OC(C)(C)C)c3ccccc23)C(C)C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acrylic acid (150.0 mg, 0.52 mmol), N′-isopropyl-3-methylbenzohydrazide (150.0 mg, 0.78 mmol) and HATU (296.6 mg, 0.78 mmol) dissolved in DMF (3.0 ml), N,N-diisopropylethylamine (DIPEA)(0.14 ml, 0.78 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (30% EtOAc) for refinement and dried so that white (E)-tert-butyl 3-(3-(1-isopropyl-2-(3-methylbenzoyl)hydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (92.0 mg, 48.3%).
Reaction SMILES: [Cl-].[NH4+:2].C[Al](C)C.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[C:15]1[N:19]([CH3:20])[N:18]=[C:17]([C:21](OCC)=O)[CH:16]=1>C1(C)C=CC=CC=1>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[C:15]1[N:19]([CH3:20])[N:18]=[C:17]([C:21]#[N:2])[CH:16]=1
Reactant: CCOC(=O)c1cc(-c2c(F)cccc2F)n(C)n1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cn1nc(C#N)cc1-c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of ammonium chloride (0.42 g, 7.52 mmol) in toluene (10 mL) at 0° C. was added dropwise trimethyl aluminum (2 M in toluene, 3.76 mL, 7.52 mmol). After the addition was complete, the reaction mixture was stirred at 0° C. for 1 h, warmed to room temperature, and then a mixture of ethyl 5-(2,6-difluorophenyl)-1-methyl-1H-pyrazole-3-carboxylate (i.e. the product of Step A) (1 g, 3.76 mmol) in toluene (5 mL) was added and the mixture was heated at 110° C. for 4 h. The reaction mixture was allowed to cool to room temperature, partitioned between aqueous hydrochloric acid (1 N) and diethyl ether (about 20 mL) and the organic phase was separated. The aqueous phase was extracted with diethyl ether and the combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by silica gel column chromatography (10 to 20% gradient of ethyl acetate in hexanes) to provide the title compound as a solid (0.4 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C@H:5]2[O:7][C@H:8]([CH:10]([OH:13])[CH2:11][CH3:12])[CH2:9][C@H:4]2[O:3]1.N1C=CC=CC=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[C:21]([O:13][CH:10]([C@H:8]1[O:7][C@@H:5]2[O:6][C:2]([CH3:1])([CH3:14])[O:3][C@@H:4]2[CH2:9]1)[CH2:11][CH3:12])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCC(O)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(OC(=O)c1ccccc1)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a stirred solution of crude 1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propan-1-ol (compound 1e, 8.08 g, 40.0 mmol) and pyridine (16.1 mL, 200 mmol) in DCM was added benzoyl chloride (5.0 mL, 43.0 mmol) dropwise at 0° C. After the addition, the mixture was warmed to room temperature and stirred at room temperature overnight. The resulting mixture was washed with 1N hydrochloric acid, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:3 EtOAc in petroleum ether) to afford 6.86 g of 1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propyl benzoate (compound 26a).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].O.[CH3:13]O>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:13])=[O:10]
Reactant: CO
Reactant: O=C(O)Cc1ccccc1Br
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)Cc1ccccc1Br
Yield: 96 %

Procedure:
A solution of ortho-bromophenylacetic acid (5.14 g) in dry methanol (40 ml) containing 5 drops of concentrated sulphuric acid was heated at reflux for three hours. The reaction mixture was cooled, then poured into iced water (150 ml) and extracted (2×75 ml) with ether. The ether layers were combined, washed successively with water (×3), saturated sodium bicarbonate solution (×2), water (×1) and saturated brine and then dried. Filtration and evaporation gave methyl ortho-bromophenylacetate (5.23 g, 96%) as a pale yellow liquid, IR maximum 1742 cm-1, which was used without further purification.