Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]=[C:9]2[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C([Li])CCC.CN([CH:23]=[O:24])C>C1COCC1>[CH:12]([C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([CH:23]=[O:24])[CH:11]=2)[CH2:6][CH2:7][N:8]=1)([CH3:14])[CH3:13]
Reactant: CC(C)C1=NCCc2ccc(Br)cc21
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)C1=NCCc2ccc(C=O)cc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of Example 1I (4.7 g, 18.7 mmol) in THF (80 mL) at −78° C. was treated dropwise with 2.5M n-butyllithium in hexanes (9.0 mL, 22.4 mmol), stirred for 20 minutes, treated dropwise with DMF (2.2 mL, 28.0 mmol), stirred for 20 minutes, quenched with saturated NH4Cl, warmed to room temperature, and extracted with diethyl ether. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated to provide the desired product.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)=[CH:3][C:2]=1[C:25]1[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:24]=1[F:23]
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: COc1ccc(-c2cc(-c3cnc4c(F)c(C(C)(C)O)ccn34)ccc2F)c(F)c1
Yield: 3 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 2-(2-fluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane were coupled in the same way as in Example 30 to give 2-[3-(2,2′-difluoro-4′-methoxybiphenyl-5-yl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (5 mg, 3%): m/z (ES+) 413 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:14]=[C:15]3[C:21]([C:22]([OH:24])=O)=[CH:20][NH:19][C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl.[O:26]1[CH2:31][CH2:30][CH2:29][CH:28]([NH2:32])[CH2:27]1>CN(C1C=CN=CC=1)C.C(N(CC)CC)C>[O:26]1[CH2:31][CH2:30][CH2:29][CH:28]([NH:32][C:22]([C:21]2[C:15]3[C:16](=[N:17][CH:18]=[C:13]([C:5]4[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=4)[N:14]=3)[NH:19][CH:20]=2)=[O:24])[CH2:27]1
Reactant: NC1CCCOC1
Reactant: COc1cc(-c2cnc3[nH]cc(C(=O)O)c3n2)cc(OC)c1OC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1cc(-c2cnc3[nH]cc(C(=O)NC4CCCOC4)c3n2)cc(OC)c1OC

Procedure:
2-(3,4,5-Trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (tetrahydro-pyran-3-yl)-amide was prepared starting from 2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid and tetrahydro-pyran-3-ylamine hydrochloride following the general procedures described in these Examples but with triethylamine and DMAP added. MP 191-192° C., M+H 413.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=2)[NH:10][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])=[CH:5][CH:4]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([NH:10][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:19]2[CH:20]=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(N[C@H](C)c2ccccc2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(N[C@H](C)c2ccccc2)c2cccc(N)c2)cc1

Procedure:
Following a procedure similar to that described in Example (59b), 2.06 g of N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]-N-[(R)-1-phenylethyl]amine [prepared as described in step (a) above], 2.70 g of nickel chloride hexahydrate and 860 mg of sodium borohydride were reacted, separated and purified, to obtain 510 mg of isomer A and 672 mg of isomer B of the title compound, each as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.Cl.[NH2:40][CH:41]1[CH2:46][CH2:45][CH2:44][C:43]([C:48]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[O:49])([OH:47])[CH2:42]1.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>CC(N(C)C)=O>[C:48]([C:43]1([OH:47])[CH2:44][CH2:45][CH2:46][CH:41]([NH:40][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:9]=[C:8]3[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:18])[CH2:42]1)(=[O:49])[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: NC1CCCC(O)(C(=O)c2ccccc2)C1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NC4CCCC(O)(C(=O)c5ccccc5)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (0.1 mmol, 49.5 mg), HCl salt of (3-amino-1-hydroxycyclohexyl)(phenyl)methanone (0.1 mmol, 25.5 mg), HATU (0.1 mmol, 38 mg) and DIEA (0.15 mL) in DMA (0.65 mL) was stirred at room temperature for overnight. The product, N-(3-benzoyl-3-hydroxycyclohexyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide, was obtained after rotary evaporation of solvent.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1)[CH3:14].[Br:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[CH2:33]Br>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[CH2:33][CH:13]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1)[CH3:14]
Reactant: COc1ccc(Br)c(CBr)c1
Reactant: CCc1ccc(C(=O)O)cc1
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc(Br)c(CC(C)c2ccc(C(=O)O)cc2)c1
Temperature: -5 °C
Reaction time: 8 h

Procedure:
Butyl lithium (1.6M hexanes, 35 mL, 56 mmol) was added dropwise to a THF (50 mL)/HMPA (10 mL) solution of diisopropylamine (7.9 mL, 56 mmol) cooled to −5° C. After stirring 10 minutes a THF solution (17 mL) of 4-ethylbenzoic acid (3.36 g, 22.4 mmol) was added dropwise. The red solution was kept at 5° C. overnight. A THF solution (17 mL) of 1-bromo-2-(bromomethyl)-4-methoxybenzene (60.27 g, 22.4 mmol) was added dropwise. The reaction solution was then allowed to warm to room temperature. The solution was then partitioned between ethyl acetate and aqueous 1N HCl. The organic phase was washed with water, brine and dried over MgSO4. The filtered solution was concentrated and the residue purified by silica gel chromatography using hexanes/ethyl acetate (with 1% AcOH) gradient to give the title compound. LCMS1 3.72 min. (M−17)=331
Reaction SMILES: C(NC(C)C)(C)C.[CH3:8][S@@:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:10].C([O:26][C:27](=O)[C@@H:28]1[CH2:32][CH2:31][CH2:30][N:29]1[C:33](=[O:49])[C@@H:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:39](=[O:48])[CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)C1C=CC=CC=1>C1COCC1>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([S@:9]([CH2:8][C:27]([C@@H:28]2[CH2:32][CH2:31][CH2:30][N:29]2[C:33](=[O:49])[C@@H:34]2[CH2:38][CH2:37][CH2:36][N:35]2[C:39](=[O:48])[CH2:40][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[O:26])=[O:10])=[CH:12][CH:13]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CCc1ccccc1
Reactant: COc1ccc([S@](C)=O)cc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc([S@@](=O)CC(=O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)CCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.7 %

Procedure:
To diisopropylamine (0.13 ml) in THF (8 ml) was dropwise added 1.62M n-butyllithium-hexane solution (1.2 ml) at -78° C., followed by stirring at 0° C. for 0.5 hour. The reaction mixture was cooled to -30° C., dropwise added with (S)-(-)-4methoxyphenyl methyl sulfoxide (157 mg) in THF (8 ml), and stirred at 0° C. for 0.5 hour. The reaction mixture was cooled to -78° C., added with N-(3-phenylpropionyl)-L-prolyl-L-proline benzyl ester (400 mg) in THF (8 ml) quickly, and stirred for 0.5 hour. The reaction mixture was treated as in Example 13-A) and the residue obtained was purified by medium pressure liquid chromatography (silica gel, eluate; chloroform:methanol=99:1) to give 195 mg of the title compound (See Table 5).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH:24]=O>>[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH2:24][N:11]1[CH2:12][CH2:13][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10]1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(Cc2ccc3ccccc3c2)C1

Procedure:
This compound was prepared via the reductive amination method described in 49.2, by reaction of (R)-3-tert-butyloxycarbonylaminopyrrolidine with 2-naphthaldehyde. The residue is purified on a column of silica (eluent: from 100/0 to 90/10 (v/v) dichloromethane/methanol).
Reaction SMILES: Cl[C:2]1([S:8](Cl)(=[O:10])=[O:9])[NH:6][C:5]([Cl:7])=[CH:4][S:3]1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>C1(C)C=CC=CC=1.C(O)C>[CH:12]1([N:15]([NH:15][CH:12]2[CH2:14][CH2:13]2)[S:8]([C:2]2[S:3][CH:4]=[C:5]([Cl:7])[N:6]=2)(=[O:10])=[O:9])[CH2:14][CH2:13]1
Reactant: NC1CC1
Reactant: O=S(=O)(Cl)C1(Cl)NC(Cl)=CS1
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=S(=O)(c1nc(Cl)cs1)N(NC1CC1)C1CC1

Procedure:
In analogy to Example 13, the N-cyclopropyl-2-N-cyclopropylamino-4-chlorothiazolesulphonamide was prepared by reacting 2,4-dichlorothiazole-sulphonyl chloride from Example 1 with cyclopropylamine. Following chromatography on silica gel using toluene/ethanol (5:1) as the eluent, 15.0 g of product were obtained (51% of the theoretical yield), m.p. 176°-177° C.
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6](=[O:37])[CH2:7][CH:8]([S:33][C:34](=O)C)[CH:9]1[O:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[C:24]([CH3:32])[CH:23]=3)=[CH:16][CH:15]=2)[CH2:10]1.CI>CO>[CH3:4][O:5][C:6](=[O:37])[CH2:7][CH:8]([CH:9]1[O:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[C:24]([CH3:32])[CH:23]=3)=[CH:16][CH:15]=2)[CH2:10]1)[S:33][CH3:34]
Reactant: COC(=O)CC(SC(C)=O)C1CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: COC(=O)CC(SC)C1CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1
Reaction time: 0.75 h
Yield: 98.6 %

Procedure:
Sodium methoxide (28% in methanol) (0.050 mL, 0.22 mmol) was added to a suspension of the product from step 11b (0.085 g, 0.18 mmol) in methanol (1.5 mL) at room temperature. The reaction turned clear and was stirred for 45 minutes, and then methyl iodide (0.05 mL, 0.80 mmol) was added. The reaction was stirred an additional 45 minutes, quenched with aqueous ammonium chloride, concentrated to remove the methanol, and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried with magnesium sulfate, and concentrated to give 3-{3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-3-methylsulfanyl-propionic acid methyl ester (0.08 g, 99%) as an oil. MS found: (M+H)+=451.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C(NB)(C)(C)C.[CH2:11]([N:18]1[CH2:26][CH:25]2[CH:21]([C:22](=O)[C:23]3[CH:29]=[CH:28][S:27][C:24]=32)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Al+3].[Cl-].[Cl-].[Cl-].B.Cl.[OH-].[Na+]>C(Cl)Cl>[CH2:11]([N:18]1[CH2:26][CH:25]2[CH:21]([CH2:22][C:23]3[CH:29]=[CH:28][S:27][C:24]=32)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1c2ccsc2C2CN(Cc3ccccc3)CCC12
Agent: B
Agent: BNC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: c1ccc(CN2CCC3Cc4ccsc4C3C2)cc1
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A slurry of AlCl3 (946 mg, 7.11 mmol) in CH2Cl2 (7 ml) was treated with tert-butylaminoborane (1.24 g, 14.22 mmol) at 0° C. and stirred for 30 minutes. Next, a solution of the product from step e) (671 mg, 2.37 mmol) in CH2Cl2 (5 ml) was added dropwise to the AlCl3/borane solution. After 2 hours at 0° C., the crude reaction mixture was poured into cold 10% HCl, treated with 2 M NaOH to pH 12 and extracted with CH2Cl2 (3×75 ml). The combined organic extracts were washed with brine (75 ml), dried (MgSO4), and solvent evaporated in vacuo leaving the crude product that was purified by silica-gel chromatography using a ethyl acetate/hexanes gradient (0% to 75% ethyl acetate) to give the subtitle compound (409 mg, 64%). MS calculated for C17H19NS+H 270, observed 270.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([N:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:18]=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]#[N:34])[C:16]2=[O:35])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.CO>[H][H].[C].[Pd]>[C:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:17]1[C:16](=[O:35])[N:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=2)[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH:18]=1)#[N:34]
Reactant: [H][H]
Reactant: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(-c2cccc(OCc3ccccc3)c2)c1=O
Agent: [Pd]
Solvent: CO
Product: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(-c2cccc(O)c2)c1=O
Yield: 62.3 %

Procedure:
52 mg of 1-(3-benzyloxyphenyl)-3-(2-cyanophenyl)-5-(2-pyridyl)-1,2-dihydropyridin-2-one and 20 mg of 5% palladium-carbon were added to 3 ml of methanol, followed by stirring at room temperature in hydrogen atmosphere overnight. After the resulting insoluble matters were filtered off, the filtrate was evaporated. The residue was purified by silica gel chromatography (ethyl acetate/hexane system), to give 26 mg the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=2)[NH2:10])=[C:5]([CH3:14])[O:4][N:3]=1.C(O[CH:18]=[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])C>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH:10][CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:11]=[CH:12][CH:13]=2)=[C:5]([CH3:14])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1cccc(N)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1cccc(-c2c(C)noc2C)c1)C(=O)OCC
Temperature: 130 °C
Yield: 52 %

Procedure:
3-(3,5-Dimethyl-4-isoxazolyl)aniline (for a preparation see Intermediate 2, 80 g, 420 mmol) and diethyl ethoxymethylenemalonate (92 g, 425 mmol) were mixed together and heated to 130° C. for 20 minutes, liberating ethanol, which was evaporated under reduced pressure. The reaction mixture was poured into iPr2O (1 L) and the resulted precipitate filtered off and washed with iPr2O. The resulting solid was recrystallised from acetonitrile to give the title compound as a brown solid (78 g, 52%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:19])=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:19][S:31]([C:27]2[S:26][CH:30]=[CH:29][CH:28]=2)(=[O:33])=[O:32])=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)ccc1N
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(OCc2ccccc2)ccc1NS(=O)(=O)c1cccs1
Reaction time: 1 h

Procedure:
Methyl 5-(benzyloxy)-2-(amino)benzoate ([116027-17-9], 1.3 g, 5.06 mmol) was stirred in DCM (20 mL) and pyridine (1.2 mL) at 0° C. Thiophene-2-sulfonyl chloride (1.02 g, 5.56 mmol) was added. After one hour, the cooling bath was removed and the reaction was stirred overnight. The mixture was washed once with 10% aqueous HCl. The organics were dried and concentrated. Chromatography (20 to 40% ethyl acetate in hexanes) gave the title compound. [M+H] calc'd for C19H17NO5S2, 404; found, 404.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:10]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:11][CH:12]([CH3:14])[CH3:13]>>[CH:12]([CH:11]([C:1]([OH:3])([CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]([O:16][CH2:17][CH3:18])=[O:15])([CH3:14])[CH3:13]
Reactant: CCOC(=O)CC(C)C
Reactant: CC(=O)c1ccccc1
Product: CCOC(=O)C(C(C)C)C(C)(O)c1ccccc1

Procedure:
The material undergoes smooth pyrolysis when injected into a gas chromatography column (at about 230° C.) to generate acetophenone and ethyl isovalerate.
Reaction SMILES: COC1C=CC2C(=CC(C(O)=O)=CC=2)N=1.[CH3:16][NH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28]([O:30]CC)=[O:29])[CH:26]=2)[CH:21]=[CH:20][N:19]=1>>[CH3:16][NH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28]([OH:30])=[O:29])[CH:26]=2)[CH:21]=[CH:20][N:19]=1
Reactant: CCOC(=O)c1ccc2ccnc(NC)c2c1
Agent: COc1ccc2ccc(C(=O)O)cc2n1
Product: CNc1nccc2ccc(C(=O)O)cc12

Procedure:
The title compound was prepared by a method analogous to that described in Step 3 of Intermediate 19, using ethyl 1-(methylamino)isoquinoline-7-carboxylate. +ESI (M+H) 203.1; 1H NMR (400 MHz, DMSO-d6, δ): 13.03 (br. s., 1H), 8.87 (s, 1H), 8.06 (dd, J=8.51, 1.47 Hz, 1H), 7.97 (d, J=5.67 Hz, 1H), 7.85 (d, J=4.50 Hz, 1H), 7.75 (d, J=8.41 Hz, 1H), 6.91 (d, J=5.87 Hz, 1H), 2.95 (d, J=4.50 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[F:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[O:20][CH2:19][CH2:18][C:17]2=[O:24].Cl>CCOCC>[F:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[O:20][CH2:19][CH:18]([C:3](=[O:5])[C:2]([F:1])([F:8])[F:9])[C:17]2=[O:24]
Reactant: CCOC(=O)C(F)(F)F
Reactant: O=C1CCOc2ccc(F)cc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: O=C1c2cc(F)ccc2OCC1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 19 h
Yield: 50.6 %

Procedure:
Ethyl trifluoroacetate (4.33 g, 30 mmol) was dissolved in ether (25 mL) and treated with sodium methoxide (25%, 7.08 g, 33 mmol). To the stirred solution was added 6-fluoro-4-chromanone (4.92 g, 30 mmol) and additional ether (10 mL). The reaction was stirred at room temperature overnight (19.0 hours) and treated with 3N hydrochloric acid (15 mL). The organic layer was collected, washed with brine, dried over MgSO4, concentrated in vacuo and recrystallized from ether/hexane to give a yellow solid (3.98 g, 51%): mp 107°-112° C.; 1H NMR (CDCl3) 300 MHz 14.95 (s, 1H) 7.52 (dd, 1H) 7.23 (m, 1H) 6.97 (m, 1H) 5.07 (s, 2H); 19F NMR (CDCl3) 300 MHz -72.60 (s), -119.93 (m). Mass spectrum: M+=262.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[H][H]>CO.ClCCl.[Pd]>[NH2:9][C:3]1[C:2]([OH:1])=[N:7][C:6]([CH3:8])=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: Cc1ccc([N+](=O)[O-])c(O)n1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(N)c(O)n1

Procedure:
6-hydroxy-5-nitro-2-picoline (500 mg, 3.247 mmol) was dissolved in methanol:dichloromethane (5:1, 60 ml) and 10% palladium on active carbon was added thereto slowly, and then stirred for 2 hours with adding hydrogen gas at room temperature. The reaction mixture was filtered by using celite and evaporated under reduced pressure to quantitatively obtain white solid (400 mg).
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([C@@H:16]([CH2:28][OH:29])[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C(=C)CC5[C@]4(C)CCCC5)[C@@H]2C3)C)O1.C1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@@H](CO)C5[C@]4(C)CCCC5)[C@@H]2C3)C)O1>>[CH2:11]1[CH2:10][O:9][C:8]23[O:13][CH2:14][CH2:1][O:2][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([C@H:16]([CH2:28][OH:29])[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:12]1
Reactant: C[C@]12CCCCC1C[C@H](CO)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Agent: C=C1CC2CCCC[C@]2(C)[C@H]2CC[C@@]3(C)[C@@H](CC45OCCOC43OCCO5)[C@H]12
Agent: C[C@]12CCCCC1[C@H](CO)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCCCC1C[C@@H](CO)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Yield: 70 %

Procedure:
17,17-Bis(ethylendioxy)-7β-hydroxymethylandrostane and 3,3:17,17-bis(ethylendioxy)-7α-hydroxymethylandrostane were prepared in 10% and 70% yield, respectively, from 3,3:17,17-bis(ethylendioxy)-7-methyleneandrostane (Prepn. 48) by the procedure described above for the preparation of 3,3:17,17-bis(ethylendioxy)-6β-hydroxymethylandrostane (Prepn. 9). The residue was purified by flash chromatography (SiO2, n-hexane/EtOAc 60/40). 3,3:17,17-Bis(ethylendioxy)-7β-hydroxymethylandrostane: 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.84 (m, 8H), 3.58 (m, 2H), 3.32 (t, 1H), 1.94-0.68 (m, 21H), 0.85 (s, 3H), 0.81 (s, 3H). 3,3:17,17-Bis(ethylendioxy)-7α-hydroxymethylandrostane: 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.83 (m, 8H), 3.67 (m, 2H), 3.34 (t, 1H), 1.97-0.91 (m, 21H), 0.87 (s, 3H), 0.81 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C@H:9]2[CH2:12][C@H:11]([N:13]3[C:17]4=[N:18][CH:19]=[CH:20][CH:21]=[C:16]4[C:15]([CH3:23])([CH3:22])[C:14]3=[O:24])[CH2:10]2)=[N:6][CH:7]=1.[CH:25]1(B(O)O)[CH2:27][CH2:26]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH:25]1([C:2]2[CH:3]=[N:4][C:5]([NH:8][C@H:9]3[CH2:12][C@H:11]([N:13]4[C:17]5=[N:18][CH:19]=[CH:20][CH:21]=[C:16]5[C:15]([CH3:23])([CH3:22])[C:14]4=[O:24])[CH2:10]3)=[N:6][CH:7]=2)[CH2:27][CH2:26]1
Reactant: CC1(C)C(=O)N([C@H]2C[C@H](Nc3ncc(Br)cn3)C2)c2ncccc21
Reactant: OB(O)C1CC1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)C(=O)N([C@H]2C[C@H](Nc3ncc(C4CC4)cn3)C2)c2ncccc21
Temperature: 80 °C
Reaction time: 18 h

Procedure:
1-(Trans-3-((5-bromopyrimidin-2-yl)amino)cyclobutyl)-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (example 60, 95 mg, 0.245 mmol), cyclopropyl boronic acid (31.5 mg, 0.367 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (17.33 mg, 0.024 mmol) were mixed in 1,4-dioxane (1 msL) under an argon atmosphere. Aqueous sodium carbonate (2 M, 0.367 mL, 0.734 mmol) was added via syringe and the reaction mixture was stirred at 80° C. for 18 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated to dryness under reduced pressure. The resulting crude product was purified via silica gel flash column chromatography eluting with 0 to 100% ethyl acetate in hexanes to yield 1-(trans-3-((5-cyclopropylpyrimidin-2-yl)amino)cyclobutyl)-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one as a light yellow solid. M+1: 350.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.59-0.66 (m, 2 H) 0.78-0.94 (m, 2 H) 1.31 (s, 6 H) 1.75 (tt, J=8.44, 5.16 Hz, 1 H) 2.25-2.37 (m, 2 H) 3.18 (m, 2 H) 4.47-4.57 (m, 1 H) 5.16 (quin, J=8.41 Hz, 1 H) 7.07 (dd, J=7.24, 5.28 Hz, 1 H) 7.51 (br. d, J=6.50 Hz, 1 H) 7.76 (dd, J=7.24, 1.56 Hz, 1 H) 8.12 (s, 2 H) 8.21 (dd, J=5.28, 1.56 Hz, 1 H).