Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[CH:13]2[CH2:16][CH2:17][CH2:18][C:12]2=[N:11][C:10]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OC(=O)C)C.CCCCCC>[CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[NH:11][C:10]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C2CCCC2=Nc2ccc(Cl)cc2N1Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1[C@H]2CCC[C@H]2Nc2ccc(Cl)cc2N1Cc1ccccc1
Yield: 53 %

Procedure:
Using 9-benzyl-7-chloro-2,3,9,10a-tetrahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one, the titled compound was synthesized in substantially the same manner as in Working Example 26 in a yield of 53%, m.p. 160°-163° C. (ethylacetate-hexane).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:28])[C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([NH2:20])=[N:13][C:12]=2[O:21][CH2:22][CH2:23][O:24][CH:25]([F:27])[F:26])[CH2:5][CH2:4]1>[Ni].[H][H]>[F:29][C:2]([F:1])([F:30])[C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10](=[O:28])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH2:20])=[N:13][C:12]=2[O:21][CH2:22][CH2:23][O:24][CH:25]([F:26])[F:27])[CH2:7][CH2:8]1
Reactant: [H][H]
Reactant: Nc1nc(OCCOC(F)F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Agent: [Ni]
Product: Nc1cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(OCCOC(F)F)nc1N

Procedure:
The sub-title compound is prepared from N-(trans-4-trifluoromethyl-cyclohexyl)-2-(2-difluoromethoxy-ethoxy)-6-amino-5-nitro-nicotinamide (150 mg, 0.339 mmol), Ra—Ni/H2 (3 bar) in analogy to example 7b.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([N:12]([C:22]1[C:27]([O:28][CH3:29])=[N:26][C:25](Cl)=[CH:24][N:23]=1)COCCO[Si](C)(C)C)(=[O:11])=[O:10].[CH2:31]([OH:34])[C:32]#[CH:33].[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:22]1[C:27]([O:28][CH3:29])=[N:26][C:25]([O:34][CH2:31][C:32]#[CH:33])=[CH:24][N:23]=1)(=[O:10])=[O:11]
Reactant: COc1nc(Cl)cnc1N(COCCO[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Reactant: C#CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OC)n1

Procedure:
Procedure as for Example 115 using 2,3-dichloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-N-({2-[(trimethylsilyl)oxy]ethoxy}methyl)benzenesulphonamide (Example 115a) (0.25 g), propargyl alcohol (0.025 mL) and sodium hydride (0.035 g of a 60% dispersion in oil) in N,N-dimethylformamide (5 mL). Yield 0.05 g.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:17](=[O:18])[C:16]3[NH:15][CH:14]=[N:13][C:12]=3[N:11]([CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:9]2=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:27][C:28](=[O:30])[CH3:29]>>[CH:1]1([CH2:7][N:8]2[C:17](=[O:18])[C:16]3[N:15]([CH2:27][C:28](=[O:30])[CH3:29])[CH:14]=[N:13][C:12]=3[N:11]([CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:9]2=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=c1c2[nH]cnc2n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Reactant: CC(=O)CCl
Product: CC(=O)Cn1cnc2c1c(=O)n(CC1CCCCC1)c(=O)n2CC1CCCCC1

Procedure:
1,3-Di-cyclohexylmethyl-7-(2-oxopropyl)-xanthine was prepared from 1,3-di-cyclohexylmethyl xanthine and chloroacetone using an analogous procedure to that described in Example 5. The title compound was isolated as a crystalline solid, m.p. 153° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10]([N:17]1C=CN=C1)([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[S:11]>C(Cl)(Cl)Cl>[NH:1]=[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]1[NH:17][C:10]([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[S:11]
Reactant: Cc1cc(C)nc(N)c1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)n(NC(=S)n2ccnc2)c(=N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.4 %

Procedure:
An adaptation of the method described in WO 96/01826 was used. To a solution of ethyl O-mesitylsulfonylacetohydroxamate 7 (1.7 g, 6.0 mmol) in 1,4-dioxane (10 mL) cooled in an ice bath (freezes at 8-9° C.) was added 70% perchloric acid (7.5 mL) dropwise over 15 minutes, maintaining internal temperature below 15° C. The mixture was then diluted with ice water (100 mL) to precipitate the product O-(mesitylsulfonyl)hydroxylamine 8 which was filtered off, washed thoroughly with water, and immediately dissolved in chloroform (10 mL) while still wet (CAUTION! 8 is explosive when dry!). The organic layer was separated and was passed through a plug of Na2SO4 in a fritted syringe to remove water. The so obtained solution of O-(mesitylsulfonyl)hydroxylamine 8 was added dropwise to a solution of 2-amino-4,6-dimethylpyridine 9 (0.611 g, 5.00 mmol) in chloroform (10 mL) cooled in an ice bath. The mixture was then warmed to room temperature and was stirred for 2 hours to effect conversion to intermediate 10. Into the reaction mixture was then added 1,1′-thiocarbonyldimidazole 11 (1.16 g, 6.5 mmol) and the resulting mixture was stirred at 40° C. overnight. Volatiles were evaporated and the residue was chromatographed on silica gel (gradient elution with heptane:ethyl acetate 100:0→0:100) to yield imidazole-1-carbothioic acid (2-imino-4,6-dimethyl-2H-pyridin-1-yl)-amide 12 as an off-white solid (0.50 g, 40%) containing a minor amount of residual imidazole. 1H NMR (500 MHz, DMSO-d6): δ7.88 (s, 1H), 7.64 (s, 1H), 7.42 (br s, 2H), 6.93 (s, 1H), 6.69 (s, 1H), 6.67 (s, 1H), 2.28 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8](Br)=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:6](=[O:15])[N:5]=1)[CH3:2].[NH3:16]>C(#N)C>[CH2:1]([O:3][C:4]1[C:8]([NH2:16])=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:6](=[O:15])[N:5]=1)[CH3:2]
Reactant: CCOC(=O)C1=C(Br)C(OCC)=NS1=O
Reactant: N
Solvent: CC#N
Product: CCOC(=O)C1=C(N)C(OCC)=NS1=O
Temperature: 0 °C
Yield: 78 %

Procedure:
3-Ethoxy-4-bromo-5-ethoxycarbonylisothiazole-1-oxide (1.48 g, 5.0 mmol) was dissolved in fifteen ml of dry acetonitrile. The solution was cooled in ice and a solution of anhydrous ammonia in cold acetonitrile (0.105 mol in 5 ml) was added dropwise in excess. After stirring in the ice bath for 41/4 hours the reaction was complete. The title compound (1.16 g 78%, mp 153.5°-155° C.) was obtained as a yellow solid by chromatography on silica gel (chloroform).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=3[NH2:22])[CH:10]=[CH:11][CH:12]=2)=[N:3][CH:2]=1.[CH:23](O)=O>>[C:20]([C:17]1[CH:18]=[CH:19][C:14]2[N:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][N:3]=4)[CH:8]=3)[CH:23]=[N:22][C:15]=2[CH:16]=1)#[N:21]
Reactant: O=CO
Reactant: N#Cc1ccc(Nc2cccc(-c3ccncn3)c2)c(N)c1
Product: N#Cc1ccc2c(c1)ncn2-c1cccc(-c2ccncn2)c1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A mixture of (39) (3.0 g, 10 mmol) and HCO2H (20 ml) was stirred at 110° C. for 1 hr. The mixture was concentrated in vacuo. The residue was partitioned between a 5% aqueous NaHCO3 solution and CH2Cl2. The organic phase was dried over MgSO4 and the solvent was removed by evaporation. The residue was triturated with ethyl acetate to afford crystalline (40). (2.6 g, 85%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:20][C@H:12]2[CH2:13][N:14]([CH2:16][C:17](O)=[O:18])[CH2:15][C@@:11]2([C:21]([N:23]2[CH2:32][CH2:31][C:30]3[N:29]=[CH:28][C:27]([C:33]([F:36])([F:35])[F:34])=[CH:26][C:25]=3[CH2:24]2)=[O:22])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:37][NH:38][CH3:39].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[CH2:20][C@H:12]2[CH2:13][N:14]([CH2:16][C:17]([N:38]([CH3:39])[CH3:37])=[O:18])[CH2:15][C@@:11]2([C:21]([N:23]2[CH2:32][CH2:31][C:30]3[N:29]=[CH:28][C:27]([C:33]([F:36])([F:35])[F:34])=[CH:26][C:25]=3[CH2:24]2)=[O:22])[CH2:10]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]2CN(CC(=O)O)C[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)CN1C[C@@H]2C[C@@H](NC(=O)OC(C)(C)C)C[C@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1

Procedure:
A solution the product from Step A (37 mg, 0.072 mmol), dimethylamine (0.0433 mL, 0.0866 mmol, 2 M in THF), EDAC (18 mg, 0.0938 mmol), HOBt (19.51 mg, 0.144 mmol) and DIPEA (0.0252 mL, 0.144 mmol) in DMF (3 mL) was stirred at rt over the weekend. The reaction was quenched by addition of brine, extracted with EtOAc, dried over Na2SO4 and purified by CombiFlash (eluent: 8% methanol in DCM) to give the product as a yellowish gel. 1H-NMR (400 MHz, CDCl3): δ 1.29-1.43 (m, 9H), 1.75-2.09 (m, 4H), 2.20-2.35 (m, 1H), 2.55-2.71 (m, 3H), 2.86-3.00 (m, 4H), 3.05-3.22 (m, 6H), 3.60-3.93 (m, 2H), 4.25 (d, J=5.6 Hz, 1H), 4.59-4.92 (m, 3H), 7.70 (s, 1H), 8.70 (s, 1H); LC/MS: C26H36F3N5O4: m/z 540.3 (M+H).
Reaction SMILES: [O:1]=[C:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])[C:3]([OH:5])=[O:4].[BH4-].[Na+]>C(O)C>[OH:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])[C:3]([OH:5])=[O:4]
Reactant: O=C(O)C(=O)Cc1ccccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)C(O)Cc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 50 %

Procedure:
To a magnetically stirred solution of α-oxo-2-nitrobenzenepropanoic acid (40.00 g) in absolute ethanol (500 ml) cooled in ice water was added sodium borohydride (20.0 g) in portions at such a rate as to maintain the temperature between 25 and 30°. The temperature of the solution was maintained between 25°-30° for a further 4 hours after the addition. The solution was evaporated to near dryness, and the residue was dissolved in water. The solution was acidified with concentrated hydrochloric acid and extracted four times with ethyl acetate. The organic extract was washed twice with water and dried over magnesium sulfate. Evaporation gave a syrup which was crystallized (seeding) from dichloromethane-cyclohexane; yield 28.26 g (70%), m.p. 87°-90°. Recrystallization with decolorization from water gave 20.31 g. (50%) of the titled compound; m.p. 104°-105°; MH+ 212 (CI mode), λmaxKBr 1715 (COOH), 3445 (OH) cm-1 ; pmr (CDCl3, DMSO-d 6) δ3.04-3.72 (8 lines, AB part of an ABX system, --CH2 --), 4.34-4.54 (q centered at 4.45, width 12 Hz, symmetrically spaced, X part of ABX system, --CH(OH)), 7.28-7.68 (m, 3 aromatic protons and exchangeable OH), 7.80-8.00 ("d" centered at 7.95, "J" 8 Hz, 1 aromatic proton).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[C:14]3=[N:15][C:16]([Sn](C)(C)C)=[CH:17][N:18]=[C:13]3[NH:12][CH2:11][C:10]2=[O:23])[CH2:3][CH2:2]1.Br[C:25]1[CH:26]=[C:27]2[CH:33]=[CH:32][NH:31][C:28]2=[N:29][CH:30]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C)C=O>[NH:31]1[C:28]2=[N:29][CH:30]=[C:25]([C:16]3[N:15]=[C:14]4[N:9]([CH2:8][CH2:7][CH:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)[C:10](=[O:23])[CH2:11][NH:12][C:13]4=[N:18][CH:17]=3)[CH:26]=[C:27]2[CH:33]=[CH:32]1
Reactant: C[Sn](C)(C)c1cnc2c(n1)N(CCC1CCOCC1)C(=O)CN2
Reactant: Brc1cnc2[nH]ccc2c1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CNc2ncc(-c3cnc4[nH]ccc4c3)nc2N1CCC1CCOCC1
Temperature: 100 °C
Yield: 11.2 %

Procedure:
1-(2-(Tetrahydro-2H-pyran-4-yl)ethyl)-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1.0 g, 2.352 mmol), 5-bromo-1H-pyrrolo[2,3-b]pyridine (0.556 g, 2.82 mmol), tris(dibenzylideneacetone)palladium(0) (0.237 g, 0.259 mmol), tri-o-tolylphosphine (0.158 g, 0.518 mmol) and triethylamine (0.984 mL, 7.06 mmol) were combined in a sealed tube, dimethylformamide (5 mL) was added. The atmosphere in the vessel was removed under vacuum and replaced with nitrogen gas. The reaction was heated to 100° C. for 1 h. After cooling to room temperature, the reaction mixture was filtered through Celite. The filter cake was washed with ethyl acetate. The wash and filtrate were combined and concentrated nearly to dryness. The resulting solid was dissolved in hot methanol, filtered through Celite and purified by reverse-phase preparative HPLC (5-80% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min). The clean fractions were collected, neutralized with ammonium hydroxide and concentrated to dryness. The solid obtained was filtered, washed with water and dried under high vacuum to yield the title compound (0.10 g, 0.264 mmol, 11.2% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 11.71 (br. s., 1H), 8.81 (s, 1H), 8.44 (s, 1H), 8.26 (s, 1H), 7.49 (d, J=10.54 Hz, 2H), 6.48 (br. s., 1H), 4.18 (s, 2H), 4.13 (t, J=6.44 Hz, 2H), 3.82 (d, J=12.89 Hz, 2H), 3.27 (t, J=11.13 Hz, 2H), 1.71 (d, J=12.49 Hz, 2H), 1.60 (br. s., 3H), 1.24 (d, 2H); MS (ESI) m/z 379.2 [M+1]+; mp 255-258° C.
Reaction SMILES: [CH3:1][CH:2]([O:27][C:28](=[O:30])[CH3:29])[CH:3]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[C:18](=[O:26])[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)N1CCCCC1>C(#N)C>[CH3:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]2[C:12]=1[C:18](=[O:26])[N:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:3]([CH:2]([O:27][C:28](=[O:30])[CH3:29])[CH3:1])=[N:10]2
Reactant: CC(=O)OC(C)C(Nc1cccc(C)c1C(=O)Nc1ccccc1)N1CCCCC1
Solvent: CC#N
Product: CC(=O)OC(C)c1nc2cccc(C)c2c(=O)n1-c1ccccc1

Procedure:
Compound 179 (0.037 g, 0.09 mmol) was dissolved in acetonitrile (10 mL) and the reaction mixture was heated at reflux for 3 h. The solvent was removed under reduced pressure and the residue dissolved in a mixture of ethyl acetate (10 mL) and 1M HCl (5 mL). After separating the aqueous layer, the organic layer was washed with additional 1M HCl (2×5 mL), saturated sodium bicarbonate solution (3×5 ml), water (2×5 mL) and saturated brine (5 mL). The solution was dried (MgSO4), filtered, and the filtrate concentrated under reduced pressure to give compound 180. ESI-MS m/z=323 (MH+). The product had nearly totally racemized at this point (chiral purity was 46:54 S:R). The reaction described above and compound 180 are shown below.
Reaction SMILES: O1CCCCC1[N:7]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][N:9]=[CH:8]1.Br[C:22]1[CH:23]=[C:24]2[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:29][N:28](C3CCCCO3)[C:25]2=[CH:26][N:27]=1>>[NH:7]1[C:11]([C:22]2[CH:23]=[C:24]3[C:30]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:29][NH:28][C:25]3=[CH:26][N:27]=2)=[CH:10][N:9]=[CH:8]1
Reactant: CC1(C)OB(c2cncn2C2CCCCO2)OC1(C)C
Reactant: Brc1cc2c(-c3ccccc3)nn(C3CCCCO3)c2cn1
Product: c1ccc(-c2n[nH]c3cnc(-c4cnc[nH]4)cc23)cc1
Yield: 25 %

Procedure:
Following the procedures in Example 204, 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole and 5-bromo-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine were reacted and the product was deprotected to give 213 as a yellow solid (30 mg, 25%) over two steps. 1H NMR (400 MHz, DMSO) δ 8.23 (s, 1H), 7.75 (s, 1H), 7.43 (m, 1H), 7.34 (m, 1H), 7.27 (m, 2H), 6.77 (m, 2H), 6.66 (m, 1H). ESI MS m/z=262 (M+1)
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[C:8](=[O:25])[CH2:9][CH:10]([C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][C:20](=[O:23])[NH:19][C:18]=3[CH:24]=2)[CH2:11][C:12]=1[OH:13])(=[O:6])[CH2:4][CH3:5].[CH2:26](Br)[CH:27]=[CH2:28]>CCCCCC>[C:3]([C:7]1[C:8](=[O:25])[CH2:9][CH:10]([C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][C:20](=[O:23])[N:19]([CH2:28][CH:27]=[CH2:26])[C:18]=3[CH:24]=2)[CH2:11][C:12]=1[OH:13])(=[O:6])[CH2:4][CH3:5]
Reactant: C=CCBr
Reactant: CCC(=O)C1=C(O)CC(c2ccc3c(c2)NC(=O)CO3)CC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: C=CCN1C(=O)COc2ccc(C3CC(=O)C(C(=O)CC)=C(O)C3)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sixty percent sodium hydride in mineral oil 0.60 g (15 mmol NaH) was washed once with 15 mL of hexane, decanting via pipette. To this was added 1.6 g (5.1 mmol) of 2-propionyl-3-hydroxy-5-(3-oxo-(2H, 4H)-1,4-benzoxazin-6-yl)cyclohex-2-en-1-one in solid portions. The mixture was stirred at room temperature for 15 minutes, treated with 1.4 g (12 mmol) of allyl bromide and stirred at room temperature for 30 minutes. The mixture was poured into 100 mL of ice cold 0.2N HCl and extracted twice with 30 mL portions of a 5:1 ether-ethyl acetate mixture. The extracts were combined, washed with water, an aqueous NaCl solution, dried over MgSO4, filtered and the solvent evaporated off to give the crude product, as a yellow solid. Recrystallization from ethanol afforded the above-named product in a yield of 1.4 g (77 percent of theoretical). The product melted at 129°-131.5° C.; 1 H NMR (CDCl3): d1.10 (t, J=7 Hz, 3H, --CH3), 2.55-3.56 (m, 7H), 4.52-4.73 (m including s at 4.50 for OCH2, 4H, --NCH2), 5.12-5.42 (m, 2H, --CH=CH2), 5.70-6.15 (m, 1H, --CH=CH2), 6.82-7.10 (m, 3H, aromatic H's), 18.10 (broad s, 1H, enol O--H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]1[CH2:16][C:15]2[N:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH2:13]1>CCOC(C)=O>[N+:17]1([O-:6])[CH:18]=[CH:19][CH:20]=[C:14]2[CH2:13][CH2:12][CH2:16][C:15]=12
Reactant: c1cnc2c(c1)CCC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: [O-][n+]1cccc2c1CCC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-Chloroperoxybenzoic acid (11.6 g, 67.1 mmol) was dissolved in EtOAc (70 mL, 6 ml/g). The reaction mixture was stirred for 10 minutes at room temperature, and then cooled to 0° C. 2,3-cyclopentenopyridine was dissolved in EtoAc (25 ml, 5 mL/g) which was added dropwise to reaction mixture over 15 minutes keeping the temperature constant below 10° C. The reaction mixture was stirred overnight at ambient temperature. The reaction mixture was quenched with Sat. NaHCO3 (50 mL). The organic layer was dried over sodium sulfate and filtered. Acqu layer was extracted with DCM (40 mL) twice. The organic layer was dried over sodium sulfate and filtered. Combined organic layer was concentrated in vacuo and purification of the crude material via Isco (0-5% Methanol/DCM) gave rise to the desired 6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide (1.4 g).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:22]=[CH:21][C:15]3[N:16]=[C:17]([S:19][CH3:20])[S:18][C:14]=3[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].C1C=C(Cl)C=C(C(OO)=[O:31])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:22]=[CH:21][C:15]3[N:16]=[C:17]([S:19]([CH3:20])=[O:31])[S:18][C:14]=3[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: CNC(=O)c1cc(Oc2ccc3nc(SC)sc3c2)ccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)sc3c2)ccn1
Reaction time: 1 h

Procedure:
To the solution of 4-(2-methylsulfanyl-benzothiazol-6-yloxy)-pyridine-2-carboxylic acid methylamide from step 3 (3.88 g, 11.72 mmol, 1.0 eq) in DCM (20 mL) at 0° C., was added MCPBA (77%, 2.88 g, 1.1 eq). The mixture was stirred at this temperature for one hour. Saturated sodium bicarbonate solution (100 mL) was added. The aqueous layer was extracted with DCM (3×150 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated in vacuo to yield 4-(2-methanesulfinyl-benzothiazol-6-yloxy)-pyridine-2-carboxylic acid methylamide as white powder in quantitative yields. The crude product was used in the next step without purification. M+H=348.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH3:11])[N+:3]=1[O-].[NH4+].[Cl-]>CCO.O.[Fe]>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1cc([N+](=O)[O-])cc(Cl)[n+]1[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1cc(N)cc(Cl)n1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A solution of 2-chloro-6-methyl-4-nitropyridine 1-oxide (52 g, 0.27 mol) in EtOH and H2O was treated with powdered iron (46 g, 0.83 mol) and NH4Cl (44 g, 0.83 mol). The mixture was stirred at 90° C. for 3 h. After cooling to room temperature the reaction mixture was filtered, and the filtrate was extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine (500 mL), dried over magnesium sulfate, filtered and concentrated to afford 2-chloro-6-methylpyridin-4-amine. 1H NMR (400 MHz, CDCl3) δ 6.36 (d, J=1.5 Hz, 1H), 6.28 (d, J=1.2 Hz, 1H), 4.30 (m, 2H), 2.34 (s, 3H). LRMS calc'd for (C6H7ClN2) [M+H]+, 143; found 143.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1)[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[CH3:17].Br[C:34]1[CH:39]=[N:38][C:37]([Br:40])=[CH:36][N:35]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[Br:40][C:37]1[N:38]=[CH:39][C:34]([C:21]2[CH:20]=[CH:19][C:18]([N:9]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=3[CH3:17])[C:3]3[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])=[CH:23][CH:22]=2)=[N:35][CH:36]=1
Reactant: Cc1ccc(N(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c2ccc(C)cc2C)c(C)c1
Reactant: Brc1cnc(Br)cn1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(N(c2ccc(-c3cnc(Br)cn3)cc2)c2ccc(C)cc2C)c(C)c1
Temperature: 80 °C

Procedure:
A mixture of N-(2,4-dimethylphenyl)-2,4-dimethyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)aniline (Compound 17) (6.0 g, 14 mmol), 2,5-dibromopyrazine (7.74 g, 30 mmol), Pd(PPh3)4 (0.5 g, 0.43 mmol), K2CO3 (4.14 g, 30 mmol) in dioxane/water (80 mL/17 mL) was degassed and heated at about 80° C. overnight. The resulting mixture was poured into ethyl acetate (200 mL), washed with brine, dried over Na2SO4, then loaded on silica gel and purified by flash column using eluents of hexanes to hexanes/dichloromethane 9:1 to 6:1 to 7:3. The desired yellow fraction was collected, and a yellow solid (Compound 18) was obtained after removal of solvents (3.83 g, 60% yield).
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10]C(C)=O>>[CH:1]1([C:7]([CH3:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)C1CCCCC1
Reactant: CC(C)=O
Product: CC(=O)C1CCCCC1

Procedure:
Using the apparatus, catalyst and method of Examples 16-18, cyclohexane carboxylic acid and acetone in a molar ratio of 1:2.76 was introduced into the system after purging with acetone. Methyl cyclohexyl ketone was produced and identified as in Examples 16-18.
Reaction SMILES: C([Li])(CC)C.[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[CH3:22])=[O:12])([CH3:9])([CH3:8])[CH3:7].CON(C)[C:26](=[O:29])[CH2:27][CH3:28]>C1CCCCC1.C1COCC1>[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[CH2:22][C:26](=[O:29])[CH2:27][CH3:28])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: COc1cccc(NC(=O)OC(C)(C)C)c1C
Reactant: CCC(=O)N(C)OC
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCC(=O)Cc1c(NC(=O)OC(C)(C)C)cccc1OC
Temperature: -60 °C
Reaction time: 0.08 h

Procedure:
A solution of 140 mL (0.18 mol) of 1.3M sec-butyl lithium in cyclohexane was added slowly to N-tert-butoxycarbonyl-3-methoxy-2-methylaniline (21.3 g, 0.09 mol) in 250 mL of THF keeping the temperature below -40° C. with a dry ice-ethanol bath. The bath was removed and the temperature allowed to rise to 0° C. and then the bath replaced. After the temperature had cooled to -60° C., 18.5 g (0.18 mol) of N-methoxy-N-methylpropanamide in an equal volume of THF was added dropwise. The reaction mixture was stirred 5 minutes, the cooling bath removed and stirred an additional 18 hours. It was then poured into a mixture of 300 mL of ether and 400 mL of 0.5N HCl. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated at reduced pressure to give 25.5 g of a crude of 1-[2-(tert-butoxycarbonylamino)-6-methoxyphenyl]-2-butanone. This material was dissolved in 250 mL of methylene chloride and 50 mL of trifluoroacetic acid and stirred for a total of 17 hours. The mixture was concentrated at reduced pressure and ethyl acetate and water added to the remaining oil. The ethyl acetate was separated, washed with brine, dried (MgSO4) and concentrated. The residue was chromatographed three times on silica eluting with 20% EtOAc/hexane to give 13.9 g of 2-ethyl-4-methoxy-1H-indole.