Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH2:21][C:22]([OH:24])=O)[CH:18]=[CH:19][CH:20]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:65][N:66]([CH3:70])[CH2:67][CH2:68][NH2:69]>CN(C=O)C.CCOCC>[CH3:65][N:66]([CH3:70])[CH2:67][CH2:68][NH:69][C:22](=[O:24])[CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:12]2[N:11]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH3:31])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=3)[O:14][N:13]=2)[CH:16]=1
Reactant: COCc1cc(-c2nc(-c3cccc(CC(=O)O)c3)no2)ccc1-c1ccccc1C
Reactant: CN(C)CCN
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: CN(C)C=O
Solvent: CCOCC
Product: COCc1cc(-c2nc(-c3cccc(CC(=O)NCCN(C)C)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution (3-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}phenyl)acetic acid (preparation described in Example 24 Step 1, 100 mg, 0.24 mmol) in DMF (2 mL) at 0° C., was added DIEA (126 4, 0.72 mmol) and HATU (92 mg, 0.24 mmol). After 10 min, a solution of 2-dimethylaminoethylamine (21 mg, 0.24 mmol) in DMF (2 mL) was added and the reaction mixture stirred at RT overnight. Et2O was added and the mixture was washed with water. The organic phase was then dried over MgSO4, filtered and concentrated in vacuo. The crude was purified by preparative HPLC affording the title compound as a colorless oil. LC/MS (Method B): 485.0 (M+H)+. HPLC (Method A) Rt 4.59 min (Purity: 91.3%).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:49][C:50]1[CH:51]=[C:52]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([NH2:63])[CH:58]=2)[CH:53]=[C:54]([F:56])[CH:55]=1>CN(C=O)C>[F:49][C:50]1[CH:51]=[C:52]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([NH:63][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:58]=2)[CH:53]=[C:54]([F:56])[CH:55]=1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Nc1cccc(-c2cc(F)cc(F)c2)c1
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: CN(C)C=O
Product: O=C(Nc1cccc(-c2cc(F)cc(F)c2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 35.2 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3′,5′-difluoro-biphenyl-3-ylamine (0.013 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.009 g of product in 35% yield: LCMS (ESI) m/z 394 (MH+).
Reaction SMILES: [C:1]([O:4][CH:5]=[CH:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:23])[CH:11]2[NH:15]C(OC(C)(C)C)=O)[C:8]=1[C:24]([O:26][CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])(=[O:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(#N)C>[C:1]([O:4][CH:5]=[CH:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:23])[CH:11]2[NH2:15])[C:8]=1[C:24]([O:26][CH:27]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])(=[O:3])[CH3:2]
Reactant: CC(=O)OC=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)OC=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)C2SC1
Temperature: 20 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
A mixture of 3-(2-acetoxy-vinyl)-2-benzhydryloxycarbonyl-7-tert.-butoxycarbonylamino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (E-form) (1.65 g) (obtained as described above in Example 5), p-toluenesulphonic acid monohydrate (1.14 g) and acetonitrile (50 cc) is stirred for 16 hours at 20° C. It is then taken up in a 5% strength sodium bicarbonate solution (50 cc) and extracted with ethyl acetate (50 cc) and the organic phase is washed with a saturated sodium chloride solution (2×20 cc), dried over sodium sulphate and then concentrated to dryness under reduced pressure (20 mm Hg) at 20° C. 3-(2-Acetoxy-vinyl)-7-amino-2-benzhydryloxycarbonyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (E-form) (1.26 g) is obtained in the form of a crude red oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[CH:17]=[O:18].I[CH2:20][CH:21]([CH3:23])[CH3:22].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O.O>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[CH:17]=[O:18])[CH:21]([CH3:23])[CH3:22]
Reactant: O=Cc1nn(C2CCCCO2)c2ccc(O)cc12
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COc1ccc2c(c1)c(C=O)nn2C1CCCCO1
Temperature: 70 °C
Reaction time: 5 h
Yield: 67.4 %

Procedure:
A mixture of (R/S) 5-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (200 mg, 0.81 mmol, 1.00 equiv), 1-iodo-2-methylpropane (300 mg, 1.63 mmol, 2.01 equiv) and Cs2CO3 (270 mg, 0.83 mmol, 1.02 equiv) in N,N-dimethylformamide (10 mL) was stirred under nitrogen at 70° C. for 5 h. The resulting solution was cooled to room temperature and diluted with 10 mL of H2O. The mixture was extracted with 3×20 mL of ethyl acetate. The combined organic layers were washed with 3×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-15% of ethyl acetate in petroleum ether to give 0.165 g (67%) of (R/S) 5-iso-butoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde as a white solid. 1H-NMR (300 MHz, DMSO-d6): δ 10.16 (s, 1H), 7.83 (d, J=9.3 Hz, 1H), 7.51 (d, J=2.1 Hz, 1H), 7.22 (dd, J=9.3 Hz, 2.4 Hz, 1H), 6.04-6.01 (m, 1H), 4.07-4.00 (m, 1H), 3.92-3.75 (m, 4H), 2.12-2.00 (m, 2H), 1.63-1.62 (m, 2H), 1.24-1.16 (m, 2H), 1.04 (d, J=6.6 Hz, 6H) ppm. LCMS (method A, ESI): RT=1.71 min, m/z=218.9 [M+H−THP]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH:13]1([CH2:19]C2C=CN=CC=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([CH2:19][C:4]2[CH:5]=[CH:6][N:1]=[C:2]([C:7]3[CH:12]=[C:11]([CH2:19][CH:13]4[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]4)[CH:10]=[CH:9][N:8]=3)[CH:3]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: c1cc(CC2CCCCC2)ccn1
Reactant: c1ccc(-c2ccccn2)nc1
Product: c1cc(CC2CCCCC2)cc(-c2cc(CC3CCCCC3)ccn2)n1

Procedure:
The mixture was then cooled to room temperature and hydrolyzed with 50 cc of water. The oil layer was separated, and the aqueous phase was extracted with 50 cc additional xylene. The oil layer and extract were combined and distilled to give 82.4 g of unreacted 4-cyclohexylmethylpyridine (0.47 mole) and 9.0 g (0.03 mole) of 4,4'-di-(cyclohexylmethyl)-2,2'-bipyridyl boiling at 273°-276° C. at 2.5 mm Hg. The yield of 2,2'-bipyridyl product was calculated at 43.3% based on the amount of 4-cyclohexylmethylpyridine consumed. This 2,2'-bipyridyl compound (recrystallized from isopropanol) gave a melting point of 117°-119° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=3)[NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]1[C:31](B(O)O)=[C:30]([CH3:35])[O:29][N:28]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:31]4[C:27]([CH3:26])=[N:28][O:29][C:30]=4[CH3:35])[CH:17]=3)[NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)N=C(c1cccc(Br)c1)NC2=O
Reactant: Cc1noc(C)c1B(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1noc(C)c1-c1cccc(C2=NC3(CCN(C(=O)OC(C)(C)C)CC3)C(=O)N2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-carboxylic acid tert-butyl ester (100 mg, 0.245 mmol), 3,5-dimethyl-isoxazole-4-boronic acid (51.8 mg, 0.367 mmol), tetrakis-(triphenylphosphine)palladium(0) (28 mg, 0.0245 mmol) and K3PO4 (104 mg, 0.490 mmol) in dioxane (1.2 mL) was heated with stirring at 100° C. for one hour in a nitrogen atmosphere. The reaction mixture was cooled, and then quenched with water and extracted with ethyl acetate (×3). The organic layers were combined and sequentially washed with water (×2) and saturated brine, and then dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to give 2-[3-(3,5-dimethyl-isoxazol-4-yl)-phenyl]-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-carboxylic acid tert-butyl ester as a pale yellow solid (88.3 mg, 85%).
Reaction SMILES: [OH-:1].[Na+].OO.[Cl:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][C@H:15]([C:17]1[N:21]([CH3:22])[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([F:32])([F:31])[F:30])=[N:19][N:18]=1)[CH3:16])[C:9]#[N:10].O>C(O)C.C(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][C@H:15]([C:17]1[N:21]([CH3:22])[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([F:30])([F:32])[F:31])=[N:19][N:18]=1)[CH3:16])[C:9]([NH2:10])=[O:1]
Reactant: C[C@H](Oc1ccc(C#N)cc1Cl)c1nnc(-c2ccccc2C(F)(F)F)n1C
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: C[C@H](Oc1ccc(C(N)=O)cc1Cl)c1nnc(-c2ccccc2C(F)(F)F)n1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 1M aqueous sodium hydroxide solution (0.74 ml) and a 30% aqueous hydrogen peroxide solution (0.56 ml) were added to a solution of 3-chloro-4-[(1S)-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy}benzonitrile (200 mg) in ethanol (6 ml) at 0° C., followed by stirring at room temperature for 3 hours. The reaction solution was added to a mixture of water and chloroform, followed by separation operation, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was washed with diisopropylether, to obtain, as a colorless solid, 3-chloro-4-[(1S)-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy}benzamide (135 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].ClC(Cl)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>>[C:19]([C:8]1[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)Nc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)Nc1ccc(C(=O)c2ccccc2)cc1
Temperature: 80 °C

Procedure:
An ice-cooled solution of 5 grams of acetanilide and 15 g. of aluminum chloride in 75 ml. of dichloroethane is treated with 5 g. of benzoyl chloride in portions. The mixture is then heated at 80° C for 3 hours, decomposed with ice and dilute hydrochloric acid and the resulting solid isolated by suction filtration and recrystallized from ethanol:water to give p-benzoylacetanilide.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:7][C:8]1[N:17]=[C:16]([C:18]([N:20]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:29]3[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:30]=3[CH2:37][OH:38])[CH:14]=2)[N:9]=1.C(OCC)(=O)C.O>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:1]([O:38][CH2:37][C:30]1[CH:31]=[C:32]([F:36])[C:33]([F:35])=[CH:34][C:29]=1[C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH2:7])[N:17]=[C:16]2[C:18]([N:20]1[CH2:21][C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:28]1)=[O:19])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)c(F)cc3CO)ccc2n1
Reactant: CC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
40 μl of isobutyryl chloride are added to a solution of 150 mg of [2-amino-6-(4,5-difluoro-2-hydroxymethylphenyl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone and 2 mg of 4-(dimethylamino)pyridine (DMAP) in 5 ml of dimethylformamide, and the mixture is stirred at 80° C. for 16 h. 8 ml of ethyl acetate and 8 ml of water are added, the organic phase is separated off and evaporated to dryness in vacuo. The residue is dissolved in 1 ml of dimethyl sulfoxide and purified by chromatography (reversed phase HPLC).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]([NH:22][S:23]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)(=[O:25])=[O:24])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CS(C)=[O:34].[OH-].[Na+].Cl>O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([NH:11][C:12]2[C:13]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29](=[O:34])[NH:28][CH:27]=3)(=[O:24])=[O:25])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccnc2)cc(OC)c1
Reactant: CS(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(=O)[nH]c2)cc(OC)c1
Temperature: 100 °C
Yield: 90 %

Procedure:
N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)pyridine-3-sulfonamide (220 mg, 0.47 mmol), prepared using procedures similar to those described above in Example 8, DMSO (5 mL), and 3N NaOH (5 mL) are combined and heated to 100° C. overnight with stirring. Upon cooling to room temperature, the reaction mixture was diluted with H2O and the pH was adjusted to 7.0 with 1N HCl. The resulting solid was filtered, washed with H2O, and air-dried. The solid was then sonicated in EtOAc, filtered, washed with EtOAc, and dried under high vacuum to give N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-6-oxo-1,6-dihydropyridine-3-sulfonamide (190 mg, 90%). 1H NMR (400 MHz, DMSO-d6) δ 12.23 (br s, 1H), 12.10 (br s, 1H), 8.97 (s, 1H), 8.23 (s, 1H), 7.95 (m, 2H), 7.59 (m, 1H), 7.37 (m, 4H), 6.43 (d, 1H), 6.25 (s, 1H), 3.77 (s, 6H). MS (EI) m/z for C21H19N5O5S: 454.0 (MH+).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[CH2:2][CH:3]=[CH2:4].B1C2CCCC1CCC2.[O-]P([O-])([O-])=O.[K+].[K+].[K+].FC(F)(F)S(O[C:31]1[C:32]([CH3:70])([CH3:69])[C@H:33]2[C@:46]([CH3:49])([CH2:47][CH:48]=1)[C@@H:45]1[C@:36]([CH3:68])([C@@:37]3([CH3:67])[C@H:42]([CH2:43][CH2:44]1)[C@H:41]1[C@H:50]([C:53]([CH3:55])=[CH2:54])[CH2:51][CH2:52][C@:40]1([NH:56][CH2:57][CH2:58][N:59]1[CH2:64][CH2:63][S:62](=[O:66])(=[O:65])[CH2:61][CH2:60]1)[CH2:39][CH2:38]3)[CH2:35][CH2:34]2)(=O)=O.C(Cl)Cl>C1COCC1.O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:66]=[S:62]1(=[O:65])[CH2:63][CH2:64][N:59]([CH2:58][CH2:57][NH:56][C@:40]23[CH2:52][CH2:51][C@@H:50]([C:53]([CH3:55])=[CH2:54])[C@@H:41]2[C@@H:42]2[C@@:37]([CH3:67])([CH2:38][CH2:39]3)[C@@:36]3([CH3:68])[C@@H:45]([C@:46]4([CH3:49])[C@@H:33]([CH2:34][CH2:35]3)[C:32]([CH3:69])([CH3:70])[C:31]([CH2:4][CH2:3][CH2:2][C:1]([O:6][CH3:7])=[O:5])=[CH:48][CH2:47]4)[CH2:44][CH2:43]2)[CH2:60][CH2:61]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: C=CCC(=O)OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B1C2CCCC1CCC2
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(CCCC(=O)OC)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
A solution of methyl but-3-enoate (16.7 mg, 0.167 mmol) in THF (3 mL) under argon was cooled to 0° C. and 9-BBN (0.5 M in THF) (0.356 mL, 0.178 mmol) was added dropwise. The reaction mixture was warmed to rt and was stirred for 2 h. A solution of potassium phosphate tribasic (1M) (59.0 mg, 0.278 mmol) was added to the reaction mixture followed by a solution of (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate (80 mg, 0.111 mmol) in dioxane (3.00 mL). PdCl2(dppf).CH2Cl2 adduct (4.5 mg, 5.6 μmol) was then added and the reaction mixture was stirred for 16 h at 85° C. The reaction mixture was cooled to room temperature and was diluted with water (10 mL). The aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried (sodium sulfate) and concentrated under vacuum. The product was purified by column chromatography on silica gel (0%->50% ethyl acetate in hexanes) to afford methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)butanoate (53 mg, 0.079 mmol, 71% yield). LC/MS: m/e 671.5 (M+H)+, 2.36 min (method 3).
Reaction SMILES: CS([Cl:5])(=O)=O.[Cl:6][C:7]1[C:8]([CH:22](O)[CH3:23])=[C:9]2[C:14](=[CH:15][C:16]=1[Cl:17])[N:13]=[C:12]([O:18][CH3:19])[C:11]([O:20][CH3:21])=[N:10]2.C(N(CC)CC)C>ClCCl.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Na+].O>[Cl:5][CH:22]([C:8]1[C:7]([Cl:6])=[C:16]([Cl:17])[CH:15]=[C:14]2[C:9]=1[N:10]=[C:11]([O:20][CH3:21])[C:12]([O:18][CH3:19])=[N:13]2)[CH3:23]
Reactant: COc1nc2cc(Cl)c(Cl)c(C(C)O)c2nc1OC
Reactant: CS(=O)(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1nc2cc(Cl)c(Cl)c(C(C)Cl)c2nc1OC
Reaction time: 0.5 h
Yield: 17 %

Procedure:
Methanesulphonyl chloride (239 mg, 2.09 mmol) was added to a solution of 6,7-dichloro-2,3-dimethoxy-5-(1-hydroxyethyl)quinoxaline (527 mg, 1.74 mmol) (Preparation 2) and triethylamine (264 mg, 2.61 mmol) in dry dichloromethane (20 mL) at 20° C. The mixture was stirred for 30 minutes, then tetra-n-butyl ammonium chloride (726 mg, 2.61 mmol) was added in portions. After a further 30 minutes at 20° C., brine (20 mL) was added and the organic layer separated. The aqueous layer was extracted with dichloromethane (2×20 mL), and the combined extracts were dried (MgSO4) and concentrated under reduced pressure. Purification by flash chromatography using hexane/dichloromethane (1:1) gave 5-(1-chloroethyl)-6,7-dichloro-2,3-dimethoxyquinoxaline (95 mg, 17%), as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([CH:14]3[CH2:19][CH2:18][CH:17]([CH:20]=[O:21])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:22]=[C:23]=[O:24]>C(OCC)(=O)C.[Fe](Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11]([CH:14]3[CH2:19][CH2:18][CH:17]([CH:20]4[O:21][C:23](=[O:24])[CH2:22]4)[CH2:16][CH2:15]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: C=C=O
Reactant: Cc1ccc([C@H]2CC[C@H](C3CCC(C=O)CC3)CC2)cc1
Agent: Cl[Fe]Cl
Solvent: CCOC(C)=O
Product: Cc1ccc([C@H]2CC[C@H](C3CCC(C4CC(=O)O4)CC3)CC2)cc1

Procedure:
4-(trans-4-(4-methylphenyl)cyclohexyl)cyclohexane-carbaldehyde (20.6 g, 72 mmol, ratio of trans-4-(trans-4-(4-methylphenyl)cyclohexyl)cyclohexanecarbaldehyde/cis-4-(trans-4-(4-methylphenyl)cyclohexyl)-cyclohexylcarbaldehyde=98/2) was dissolved in ethyl acetate (380 g), and iron chloride (FeCl3, 0.2 g, 1.2 mmol) was added thereto. 3.7 equivalents of ketene was introduced into the solution at 40° C. over 150 minutes. After completing the introduction of ketene, nitrogen was introduced for 30 minutes to eliminate the unreacted ketene. The resulting solution was concentrated to provide 4-(4-(trans-4-(4-methylphenyl)-cyclohexyl)cyclohexyl)-2-oxetanone (ratio of 4-(trans-4-(trans-4-(4-methylphenyl)cyclohexyl)cyclohexyl)-2-ox etanone/4-(cis-4-(trans-4-(4-methylphenyl)cyclohexyl)-cyclohexyl)-2-oxetanone=98/2) (27.8 g, 64 mmol, yield: 88%)).
Reaction SMILES: [C:1]1([C:7]2([C:10]3[N:15]=[C:14]4[S:16][C:17]([C:19]5[CH:20]=[C:21]6[C:25](=[CH:26][CH:27]=5)[CH2:24][N:23]([CH2:28][C:29]([O:31]C)=[O:30])[CH2:22]6)=[N:18][C:13]4=[CH:12][CH:11]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O.[OH-].[Li+]>C1COCC1>[C:1]1([C:7]2([C:10]3[N:15]=[C:14]4[S:16][C:17]([C:19]5[CH:20]=[C:21]6[C:25](=[CH:26][CH:27]=5)[CH2:24][N:23]([CH2:28][C:29]([OH:31])=[O:30])[CH2:22]6)=[N:18][C:13]4=[CH:12][CH:11]=3)[CH2:8][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CN1Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)cc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CN1Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)cc2C1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Methyl 2-(5-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)isoindolin-2-yl)acetate (17 mg, 0.039 mmol) was dissolved in THF (308 μL) and water (77 μL) before lithium hydroxide monohydrate (1 mg, 0.039 mmol) was added and stirred at 65° C. for 2 h. The reaction mixture was concentrated, acidified with 1 N HCl, and filtered. The solid was dissolved in DMSO and eluted through the frit to give the title compound after concentration. MS (ESI) m/z: Calculated: 427.1; Observed: 427.9 (M++H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[OH:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCOCC>[CH3:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[O:19][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: Cc1cccc(O)c1C
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1cccc(Oc2ccc([N+](=O)[O-])cn2)c1C
Temperature: 110 °C

Procedure:
In a 20 mL microwave vial 2-chloro-5-nitropyridine (500 mg, 3.15 mmol), 2,3-dimethylphenol (385 mg, 3.15 mmol) and potassium carbonate (1308 mg, 9.46 mmol) were dissolved in N,N-Dimethylformamide (10 mL) to give a dark brown suspension. The reaction vessel was sealed and heated in Biotage Initiator at 110° C. for 1 h. After cooling the reaction was diluted with 25 mL of Et2O. The organic phase was washed with 3×25 mL of water, 10 mL of brine, dried over sodium sulphate, filtered and evaporated under vacuum to afford the title compound as a pale orange oil. (640 mg). 1H NMR (400 MHz, CDCl3): δ ppm 9.07 (1H, d), 8.50 (1H, dd), 7.24-7.19 (1H, m), 7.18-7.14 (1H, m), 7.04 (1H, d), 6.95 (1H, d), 2.38 (3H, s), 2.09 (3H, s); UPLC: 0.81 min, 245 [M+H]+.