Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[O:34])[CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]([CH2:19][NH:20]C(=O)OC(C)(C)C)=[C:8]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.FC(F)(F)C(O)=O.[ClH:42]>O1CCCC1.C(OCC)(=O)C>[ClH:42].[ClH:42].[NH2:20][CH2:19][C:9]1[C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])=[N:11][C:12]2[C:7]([C:8]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:6][C:5]([O:4][CH2:3][C:2]([NH2:1])=[O:34])=[CH:14][CH:13]=2
Reactant: CC(C)Cc1nc2ccc(OCC(N)=O)cc2c(-c2ccccc2)c1CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Cc1nc2ccc(OCC(N)=O)cc2c(-c2ccccc2)c1CN
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of tert-butyl [6-(2-amino-2-oxoethoxy)-2-isobutyl-4-phenylquinolin-3-yl]methylcarbamate (0.10 g, 0.21 mmol) in tetrahydrofuran (5 ml) was added trifluoroacetic acid (5 ml), and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was partitioned between ethyl acetate (50 ml) and 10% aqueous potassium carbonate solution (100 ml). The aqueous layer was separated and extracted twice with ethyl acetate-isopropanol (10:1, 25 ml). The organic layer and the extract were combined and washed with saturated brine (10 ml), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give a colorless oil. The obtained colorless oil was dissolved in ethyl acetate (2 ml) and 4N solution of hydrogen chloride in ethyl acetate (1 ml) was added. The reaction mixture was concentrated and the obtained residue was crystallized from diisopropyl ether-methanol to give the title compound (0.062 g, yield 67%) as pale-yellow crystals.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][C:4]2([CH2:10][CH2:9][N:8](C(OCC3C=CC=CC=3)=O)[CH2:7][CH2:6]2)[CH2:3]1.[BrH:21].[CH2:22]([O:24]CC)[CH3:23]>C(O)(=O)C>[BrH:21].[C:22]([O:1][CH:2]1[CH2:3][C:4]2([CH2:6][CH2:7][NH:8][CH2:9][CH2:10]2)[CH2:5]1)(=[O:24])[CH3:23]
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CC(O)C2
Reactant: CCOCC
Agent: Br
Solvent: CC(=O)O
Product: CC(=O)OC1CC2(CCNCC2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.800 g (2.91 mmoles) of benzyl 2-hydroxy-7-aza-spiro-[3.5]nonane-7-carboxylate (WO 9222550) is slowly added to 5 ml of a 5.7N solution of hydrobromic acid in acetic acid cooled to 0° C. After stirring for 1 hr at 0° C., 50 ml of diethyl ether are added and the medium is stirred for 1 hr. The precipitate formed is filtered on a fritted filter and copiously rinsed with diethyl ether. After drying overnight under vacuum at 80° C., 0.380 g of the expected product are obtained in the form of a white solid.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:5]2[CH:14]=[CH:15][C:16]([C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[C:20]#[N:21])=[CH:17][C:4]=2[S:3]1.CCN(C(C)C)C(C)C.[CH:35]1[CH:40]=[CH:39][C:38]([CH2:41][O:42][C:43](Cl)=[O:44])=[CH:37][CH:36]=1>O1CCOCC1.CO>[C:20]([C:19]1[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=1[C:16]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:7][CH:8]3[CH2:9][CH2:10][N:11]([C:43]([O:42][CH2:41][C:38]4[CH:39]=[CH:40][CH:35]=[CH:36][CH:37]=4)=[O:44])[CH2:12][CH2:13]3)[C:2](=[O:1])[S:3][C:4]=2[CH:17]=1)#[N:21]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N#Cc1ccccc1-c1ccc2c(c1)sc(=O)n2CC1CCNCC1
Solvent: C1COCCO1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccccc1-c1ccc2c(c1)sc(=O)n2CC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a microwave vial was added 2-[2-oxo-3-(piperidin-4-ylmethyl)-2,3-dihydro-1,3-benzothiazol-6-yl]benzonitrile (11-3) (HCl salt) (0.025 g, 0.065 mmol), dissolved in 3 mL of anhydrous 1,4 Dioxane, then added DIPEA (0.034 mL, 0.194 mmol), followed by benzyl chloridocarbonate (0.014 mL, 0.097 mmol). The reaction mixture was then stirred at room temperature for 1 hour. The crude reaction mixture was then diluted with methanol, filtered and concentrated. Purification of crude reaction mixture by reverse phase chromatography (Waters Sunfire MSC18, 10% acetonitrile/0.1% trifluoroacetic acid/water→100% acetonitrile/0.1% trifluoroacetic acid/water) gave benzyl 4-{[6-(2-cyanophenyl)-2-oxo-1,3-benzothiazol-3(2H)-yl]methyl}piperidine-1-carboxylate (12-1) as waxy solid. HRMS (M+H)+: observed=484.1700, calculated=484.1689.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:14]=[CH:13][C:12]=2[N+:24]([O-])=O)=[CH:9][C:6]([C:7]#[N:8])=[CH:5][N:4]=1>CO.[Pd]>[NH2:24][C:12]1[CH:13]=[N:14][N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:23])[CH3:22])[C:11]=1[C:10]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: COc1ncc(C#N)cc1-c1c([N+](=O)[O-])cnn1COCC[Si](C)(C)C
Agent: [Pd]
Solvent: CO
Product: COc1ncc(C#N)cc1-c1c(N)cnn1COCC[Si](C)(C)C

Procedure:
A solution of 6-methoxy-5-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)nicotinonitrile (11 mg, 0.029 mmol, 1 equiv) in methanol (4 mL) was circulated through a H-Cube® continuous-flow hydrogenation reactor (ThalesNano) fitted with a palladium on carbon catalyst cartridge at 30° C. The resulting solution was concentrated in vacuo to provide product (7.1 mg, 70% crude yield). 1H NMR (400 MHz, CDCl3), δ: 8.52 (d, J=2.2 Hz, 1H), 8.09 (d, J=2.2 Hz, 1H), 5.21 (s, 2H), 4.06 (s, 3H), 3.58 (m, 2H), 0.85 (m, 2H), −0.04 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:25]5[C:26](Br)=[N:27][CH:28]=[CH:29][CH:30]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[C:35]=1B(O)O.BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:32])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:25]5[C:26]([C:35]6[C:36]([CH3:40])=[CH:37][CH:38]=[CH:39][C:34]=6[CH3:33])=[N:27][CH:28]=[CH:29][CH:30]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1cccc(C)c1B(O)O
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccnc5Br)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccnc5-c5c(C)cccc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-(2-bromo-pyridin-3-yl)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2,6-dimethyl-phenylboronic acid following a procedure analogous to that described in Step 5 of Intermediate 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH2:8][CH2:7]2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1cc(Br)c2c(c1)CCN2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cc(Br)c2[nH]ccc2c1
Yield: 91.1 %

Procedure:
To a solution of 7-bromo-5-nitroindoline (3.0 g, 12.3 mmol) in 200 mL of acetone was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone until color of the solution turns to dark green. The reaction mixture was concentrated in vacuo and subjected to column chromatography (CHCl3, neat) to yield 2.7 g (11.2 mmol, 91%) of the indole.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].CC(C)(C)CCN.[O:17]=[C:18]1[C:26]2([CH2:30][O:29][C:28]3[CH:31]=[C:32]4[C:36](=[CH:37][C:27]2=3)[CH2:35][CH2:34][O:33]4)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]1[CH2:38][C:39](N)=[O:40]>>[CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH:4][C:39](=[O:40])[CH2:38][N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26]2([CH2:30][O:29][C:28]3[CH:31]=[C:32]4[C:36](=[CH:37][C:27]2=3)[CH2:35][CH2:34][O:33]4)[C:18]1=[O:17]
Reactant: NC(=O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Reactant: Cc1ccc(C)c(N)c1
Agent: CC(C)(C)CCN
Product: Cc1ccc(C)c(NC(=O)CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1

Procedure:
Following the procedure as described in EXAMPLE 12.49 and making non-critical variations using 2,5-dimethylaniline to replace 3,3-dimethylbutylamine, dimethylphenyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3-indol]-1′(2′H)-yl)acetamide was obtained (63%) as a colorless solid: mp 250-252° C.; 1H NMR (300 MHz, DMSO-d6) δ9.63 (s, 1H), 7.33-7.25 (m, 1H), 7.21-6.97 (m, 6H), 6.91-6.85 (m, 1H), 6.53 (s, 1H), 6.38 (s, 1H), 4.74 (dd, J=23.9, 9.4 Hz, 2H), 4.60 (dd, J=29.3, 17.3 Hz, 2H), 4.49-4.41 (m, 2H), 2.92 (dd, J=8.6, 8.6 Hz, 2H), 2.20 (s, 3H), 2.14 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ177.7, 165.7, 161.6, 160.9, 143.1, 136.0, 135.5, 132.8, 130.7, 129.1, 126.6, 125.9, 123.9, 123.4, 121.3, 120.2, 119.7, 109.4, 92.8, 80.2, 72.5, 57.3, 43.3, 28.8, 21.0, 17.9; MS (ES+) m/z 441.2 (M+1).
Reaction SMILES: [Br-].C[O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[O:8][C:7]=1[CH2:21][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O.[CH3:41][C:42](=O)[CH3:43]>>[CH2:21]([C:7]1[O:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][CH:12]=2)=[CH:10][C:6]=1[CH2:4][OH:3])[CH:42]([CH3:43])[CH3:41]
Reactant: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)oc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)=O
Agent: [Br-]
Product: CC(C)Cc1oc(-c2ccc(C(F)(F)F)cc2)cc1CO

Procedure:
Prepared from intermediate 62 and propanone
Reaction SMILES: N#N.Br[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([CH2:14][N:15]1[C:21](=[O:22])[C@@H:20]([NH:23][C:24](=[O:36])[C@@H:25]([N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26])[CH2:19][O:18][C:17]3[CH:37]=[CH:38][CH:39]=[CH:40][C:16]1=3)=[C:9]([O:41][CH3:42])[CH:8]=[CH:7]2.[CH:43]1(B(O)O)[CH2:45][CH2:44]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:43]1([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[C:10]([CH2:14][N:15]2[C:21](=[O:22])[C@@H:20]([NH:23][C:24](=[O:36])[C@@H:25]([N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:32])[CH3:33])[CH3:26])[CH2:19][O:18][C:17]4[CH:37]=[CH:38][CH:39]=[CH:40][C:16]2=4)=[C:9]([O:41][CH3:42])[CH:8]=[CH:7]3)[CH2:45][CH2:44]1
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc2ccccc21
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc2cc(C3CC3)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc2ccccc21
Yield: 12.8 %

Procedure:
For a duration of 5 min., N2 was bubbled through a mixture of tert-butyl (S)-1-((S)-5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (200 mg, 327 μmol, Eq: 1.00), cyclopropylboronic acid (33.7 mg, 392 μmol, Eq: 1.20), Na2CO3 (408 μl, 816 μmol, Eq: 2.50) in 1,4-dioxane (2 mL) then Pd(Ph3P)4 (18.9 mg, 16.3 μmol, Eq: 0.05) was added. The mixture was heated to reflux overnight, cooled and diluted with EtOAc. The mixture was washed with water, brine, dried over Na2SO4 and concentrated to give tert-butyl (S)-1-((S)-5-((6-cyclopropyl-2-methoxynaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (24 mg, 41.8 μmol, 12.8%) which was used without purification.
Reaction SMILES: I[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([I:8])[N:3]=1.[CH3:9][NH:10][CH3:11]>CO>[I:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:10]([CH3:11])[CH3:9])[N:3]=1
Reactant: CNC
Reactant: Ic1cncc(I)n1
Solvent: CO
Product: CN(C)c1cncc(I)n1

Procedure:
A solution of 2,6-diiodopyrazine (6 g, 18.1 mmol) in methanol (50 ml) and dimethylamine (40% aqueous solution, 200 ml) was heated at reflux for 1 h. The methanol was removed under vacuum, the aqueous saturated with potassium carbonate and extracted with dichloromethane (3×100 ml). The combined extracts were dried (Na2SO4), evaporated and the residue purified by chromatography through silica-gel eluting with dichloromethane. The product (4 g) was obtained as a low melting solid, m.p. 46°-48° C., m/e 249 (M+); δ (360 MHz, CDCl3) 3.10 (6H, s, 2×Me); 7.87 (1H, s, pyrazine-H); 8.01 (1H, s, pyrazine-H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:15]([CH3:16])[C:14](=[O:17])[C:9]2=[CH:10][N:11]=[CH:12][CH:13]=[C:8]2[C:7]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[O:5])C.[OH-].[Na+]>>[F:24][C:21]1[CH:20]=[CH:19][C:18]([C:7]2[C:8]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:14](=[O:17])[N:15]([CH3:16])[C:6]=2[C:4]([OH:5])=[O:3])=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)c2ccncc2c(=O)n1C
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(C(=O)O)c(-c2ccc(F)cc2)c2ccncc2c1=O

Procedure:
Employing the compound obtained in Step 3 and an aqueous solution of sodium hydroxide, substantially the same reaction and process as in Reference Example 2, Step 4 were conducted to give the above-titled compound as colorless crystals.
Reaction SMILES: [BH4-].[K+].[OH:3][C:4]1([CH3:16])[CH2:8][S:7][C:6](=[S:9])[N:5]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.Cl>O.CO>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:5][C:6](=[S:9])[S:7][CH2:8][CH:4]([OH:3])[CH3:16]
Reactant: CC1(O)CSC(=S)N1c1ccccn1
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(O)CSC(=S)Nc1ccccn1
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
A solution of potassium borohydride (5.4 g) in distilled water (80 cc) is added, at a maximum of 35° C., to a solution of 4-hydroxy-4-methyl-3-(pyrid-2-yl)-thiazolidine-2-thione (22.6 g) in methanol (320 cc). The reaction is allowed to proceed for 30 minutes at 25°-35° C. A 3 N aqueous solution of hydrochloric acid (33.2 cc) is added. The methanol is evaporated off under reduced pressure (20 mm Hg) at 45° C. The aqueous phase is extracted with ethyl ether (800 cc). The ether solution is washed twice with distilled water (300 cc in total), treated with decolourising charcoal (1 g), dried over sodium sulphate and evaporated. The resulting product (23.0 g) is purified by recrystallisation from a mixture of ethyl ether (100 cc) and isopropyl ether (100 cc). 2-Hydroxypropyl pyrid-2-yldithiocarbamate (11.1 g), which melts at 78° C., is obtained.
Reaction SMILES: C(OCC)(=O)CC(C)=O.C(CC(N)=O)#N.[C:16]([C:18]1[C:19](=[O:27])[NH:20][C:21]([OH:26])=[C:22](C)[C:23]=1[CH3:24])#[N:17].CCC(=O)CC(OCC)=O>>[C:16]([C:18]1[C:19](=[O:27])[NH:20][C:21]([OH:26])=[CH:22][C:23]=1[CH3:24])#[N:17]
Reactant: Cc1c(O)[nH]c(=O)c(C#N)c1C
Agent: CCOC(=O)CC(=O)CC
Agent: N#CCC(N)=O
Solvent: CCOC(=O)CC(C)=O
Product: Cc1cc(O)[nH]c(=O)c1C#N

Procedure:
3-Cyano-6-hydroxy-4-methylpyrid-2-one was prepared from ethyl acetoacetate and cyanoacetamide following the procedure of Bobbitt and Scola (J. Org. Chem. 25, 560, 1960). 3-Cyano-4,5-dimethyl-6-hydroxypyrid-2-one was similarly prepared from ethyl methylacetoacetate and cyanoacetamide.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH3:22][C:23]([CH3:28])([CH3:27])[C:24](Cl)=[O:25].O>CN(C)C=O>[CH3:22][C:23]([CH3:28])([CH3:27])[C:24]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)=[O:25]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(OCc1ccccc1)c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)n1ccc2cc(C(=O)OCc3ccccc3)ccc21
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
Sodium hydride (53 mg) was added to a solution of benzyl 1H-indole-5-carboxylate (276 mg) in N,N-dimethylformamide (2 ml) with ice cooling, and the mixture was stirred for 30 minutes. 2,2-Dimethylpropionyl chloride (162 mg) was added thereto, and the mixture was stirred for 2 hours. Water was added thereto, and the aqueous phase was neutralized, extracted with dichloromethane, and the extract was dried over sodium sulfate anhydrous. The resulting product was concentrated under reduced pressure to give benzyl 1-(2,2-dimethylpropionyl)-1H-indole-5-carboxylate (320 mg, Y.:87%) as pale orange crystals.
Reaction SMILES: [CH:1]([CH:13]1[CH2:18][C:17](=[O:19])[O:16][C:14]1=[O:15])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]CCCC.[CH2:20]([NH:23][CH2:24][CH:25]=[CH2:26])[CH:21]=[CH2:22].C1(C)C=CC=CC=1>O>[CH2:20]([N:23]([CH2:24][CH:25]=[CH2:26])[C:17](=[O:19])[CH2:18][CH:13]([CH:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:14]([OH:16])=[O:15])[CH:21]=[CH2:22]
Reactant: C=CCNCC=C
Reactant: CCCCCCCCCCC=CC1CC(=O)OC1=O
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCN(CC=C)C(=O)CC(C=CCCCCCC)C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A 500 ml, two-neck flask was charged with 105.2 g (500 mmol) dodecenylsuccinic anhydride 100 ml toluene. The flask was equipped with a thermometer and immersed in a water bath. Diallylamine (48.6 g, 500 mmol) was then dripped into the magnetically stirred anhydride plus toluene solution over a 15-minute period. Ice was added to the water bath as required to prevent temperature of the reaction mixture from getting above 35° C. The mixture was then stirred for another 45 minutes at room temperature. The toluene was then removed via rotary evaporator and air sparge to yield 153.4 g (99.8% of theory) of a red, oily liquid. An FTIR trace on this compound was found to have significant absorptions at 2924, 1726, 1605, 1440, 1221, 1174, 972, and 922 wavenumbers.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Cl.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23]Cl)[CH:18]=1>CCO>[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][S:15][C:13]2[O:14][C:10]([C:7]3[CH:8]=[CH:9][C:4]4[NH:3][CH:2]=[N:1][C:5]=4[CH:6]=3)=[N:11][N:12]=2)[CH:18]=1
Reactant: ClCc1cccnc1
Reactant: Sc1nnc(-c2ccc3nc[nH]c3c2)o1
Agent: Cl
Solvent: CCO
Product: c1cncc(CSc2nnc(-c3ccc4[nH]cnc4c3)o2)c1

Procedure:
1 (0.33 g, 1.5 mmol), TEA (0.418 mL, 3.0 mmol) and (pyridin-3-yl)methylchloride hydrochloride (0.246 g, 1.5 mmol) were dissolved in 10 mL of EtOH and kept under reflux overnight. The solvent was removed and the remaining oil was purified by flash-chromatography on silica gel, applying a CHCl3/MeOH gradient.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](COCC[Si](C)(C)C)[C:9]([CH3:11])=[CH:10][C:3]=12.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([CH3:11])=[CH:10][C:3]=12
Reactant: Cc1cc2c(Cl)ccnc2n1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: Cc1cc2c(Cl)ccnc2[nH]1
Yield: 60.6 %

Procedure:
A mixture of 4-chloro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (296.5 mg, 1 mmol) and TBAF (5 mL, 1 M in THF, Aldrich) was refluxed overnight. The THF was removed under reduced pressure and the residue was diluted with water (5 mL). The precipitate that formed was collected, washed with water and dried (MgSO4) to afford the title compound (101 mg, 60%). 1H NMR (CD3OD) δ 7.99 (d, 1H, J=5.5 Hz), 7.06 (d, 1H, J=5.5 Hz), 6.23 (s, 1H), 2.46 (s, 3H); MS(ESI+) m/z 167 and 169 (M+H, 1 Cl)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.[H-].[Na+].CC1C=CC(S(O[CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]3[CH:35]=[C:34]([Br:36])[CH:33]=[CH:32][C:31]=3[Cl:37])=[CH:25][CH:24]=2)(=O)=O)=CC=1>O1CCCC1>[Br:36][C:34]1[CH:33]=[CH:32][C:31]([Cl:37])=[C:30]([CH:35]=1)[CH2:29][C:26]1[CH:25]=[CH:24][C:23]([O:22][CH2:21][CH2:20][O:6][C@@H:3]2[CH2:4][CH2:5][O:1][CH2:2]2)=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc(Cc3cc(Br)ccc3Cl)cc2)cc1
Reactant: O[C@@H]1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc(Br)cc1Cc1ccc(OCCO[C@@H]2CCOC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
To a stirred solution of (R)-tetrahydrofuran-3-ol (320 mg, 3.63 mmol) in dry tetrahydrofuran (10 mL) was added sodium hydride (145 mg, 3.63 mmol, 60%) slowly under 0° C. The reaction was stirred at this temperature for 30 min and then 2-(4-(5-bromo-2-chlorobenzyl)phenoxy)ethyl 4-methylbenzenesulfonate (intermediate AB) (300 mg, 0.61 mmol) was added. The reaction was warmed to room temperature and then heated to reflux overnight. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to a yellow oil. The crude oil was purified by flash chromatography to get 200 mg of colorless oil (80% yield).
Reaction SMILES: O=[C:2]1[CH:7]([C:8](OCC)=[O:9])[CH2:6][CH2:5][N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:3]1.O.[NH2:21][NH2:22]>C(O)C>[O:9]=[C:8]1[C:7]2[CH2:6][CH2:5][N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:3][C:2]=2[NH:22][NH:21]1
Reactant: NN
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1=O
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2c([nH][nH]c2=O)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution of 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate (5.0 g, 18.43 mmol) in ethanol (10 mL) was added hydrazine monohydrate (1.04 g, 20.27 mmol) via syringe. The resulting solution was heated to 80° C. and stirred overnight. A white precipitate formed after stirring overnight. The reaction was cooled to rt and solvent was decanted from the reaction mixture, the solids were dried under vacuum to provide the desired product (3.8 g, 86%). MS (ESI) mass calcd. C11H17N3O3, 239.2. m/z found, 240.2 [M+H]+. 1H NMR (500 MHz, MeOD) δ 4.40 (s, 2H), 3.67-3.54 (m, 2H), 2.40 (t, J=5.6 Hz, 2H), 1.48 (s, 9H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:31][CH2:30][C:11]2([O:19][C:18]3[C:14](=[N:15][N:16](CC4C=CC(OC)=CC=4)[CH:17]=3)[C:13](=[O:29])[CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCCl>[CH2:1]([N:8]1[CH2:31][CH2:30][C:11]2([O:19][C:18]3[CH:17]=[N:16][NH:15][C:14]=3[C:13](=[O:29])[CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cn2cc3c(n2)C(=O)CC2(CCN(Cc4ccccc4)CC2)O3)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: O=C1CC2(CCN(Cc3ccccc3)CC2)Oc2cn[nH]c21
Temperature: 25 °C
Yield: 91.7 %

Procedure:
Dissolved 1-benzyl-2′-(4-methoxybenzyl)-2′H-spiro[piperidine-4,5′-pyrano[3,2-c]pyrazol]-7′(6′H)-one (428 mg, 1.02 mmol) in 20 mL 1,2-dichloroethane and treated with 10 mL trifluoroacetic acid. The resultant mixture was heated for 18 h at 90° C. The reaction was cooled to ambient temperature and concentrated to dryness under reduced pressure. The resultant residue was taken up in 50 mL saturated aqueous sodium bicarbonate and extracted with 2×50 mL ethyl acetate. The organic extracts were combined and dried over sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was flash chromatographed (25 g silica, step gradient 5 column volumes 50% ethyl acetate/heptane, 10 CV 100% ethyl acetate) to yield 278 mg (91%) of 1-benzyl-1′H-spiro[piperidine-4,5′-pyrano[3,2-c]pyrazol]-7′(6′H)-one as a pale yellow solid. 1H NMR (400 MHz, CD3OD) δ ppm 7.27 (m, 6H), 3.55 (s, 2H), 2.64 (m, 4H), 2.45 (td, J=11.7, 2.5 Hz, 2H), 2.06 (d, J=12.1 Hz, 2H), 1.74 (m, 2H); m/z (M+1)=298.5.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1(C)C=CC=C[CH:19]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[C:1]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][CH2:18][CH3:19])=[O:14])=[CH:16][CH:17]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Reactant: Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1ccc(C(=O)c2ccccc2)cc1
Yield: 90.5 %

Procedure:
A mixture of 4-benzoylbenzoic acid (20 g, 88.4 mmole), toluene (5 mL), p-toluenesulfonic acid (1 g) and ethanol (20 mL) was refluxed for 12 hours, cooled, washed with 5% sodium carbonate, and neutralized by water wash. The organic layer was dried over anhydrous magnesium sulfate and concentrated to obtain 22 g ethyl 4-benzoylbenzoate in a yield 90.5%.