Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([S:10]([N:13]2[CH:26]([CH3:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=3)(=[O:12])=[O:11])=[CH:5][C:4]=1[CH3:28].C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[CH3:9][C:8]1[CH:7]=[C:6]([S:10]([N:13]2[CH:26]([CH3:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=3)(=[O:12])=[O:11])[CH:5]=[C:4]([CH3:28])[C:3]=1[OH:2]
Reactant: COc1c(C)cc(S(=O)(=O)N2c3ccccc3-c3ccccc3C2C)cc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: Cc1cc(S(=O)(=O)N2c3ccccc3-c3ccccc3C2C)cc(C)c1O
Yield: 81.9 %

Procedure:
The title compound was prepared from 5-[(4-methoxy-3,5-dimethylphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (1.0 g, 2.54 mmol), cyclohexene (0.64 mL, 6.36 mmol) and 1.0 M boron tribromide in dichloromethane (15.3 mL, 15.3 mmol) according to the procedure and in the same manner as described in Example 1, step b. The crude product was purified by flash column chromatography on silica gel, eluting with dichloromethane to yield 2,6-dimethyl-4-[(6-methylphenanthridin-5(6H)-yl)sulfonyl]phenol (0.79 g, 2.08 mmol, 82%) as a white solid, m.p. 211-213° C.;
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28](Cl)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:32]([CH:34]3[CH2:36][CH2:35]3)=[O:33])=[CH:16][N:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([Cl:54])[C:40]=1[OH:55]>>[C:1]([O:5][C:6](=[O:37])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:43]5[CH:44]=[C:39]([Cl:38])[C:40]([OH:55])=[C:41]([Cl:54])[CH:42]=5)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:32]([CH:34]3[CH2:36][CH2:35]3)=[O:33])=[CH:16][N:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Cl)nc34)cn2)C1
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)nc34)cn2)C1
Yield: 63.2 %

Procedure:
Following general procedure II, (R)-tert-butyl[1-(5-{[6-chloro-3-(cyclopropanecarbonyl)-1,5-naphthyridin-4-yl]amino}pyridin-2-yl)piperidin-3-yl]carbamate (150 mg, 0.29 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (120 mg, 0.43 mmol) to afford the product (119 mg, 64%) as an orange solid: ESI MS m/z 649 [M+H]+.
Reaction SMILES: C(OC(N1CC2C([CH2:11][N:12]([CH2:16][C:17]3[S:18][C:19]4[C:24]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[N:23][C:22]([Cl:31])=[N:21][C:20]=4[N:32]=3)[CH2:13]2)C1)=O)(C)(C)C.C1NC[CH2:36][N:35]2[CH2:39][CH2:40][CH2:41][C@@H:34]12>>[Cl:31][C:22]1[N:23]=[C:24]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:19]2[S:18][C:17]([CH2:16][N:12]3[CH2:13][CH2:36][N:35]4[CH2:39][CH2:40][CH2:41][C@H:34]4[CH2:11]3)=[N:32][C:20]=2[N:21]=1
Reactant: C1C[C@H]2CNCCN2C1
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3nc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCN4CCC[C@H]4C3)nc2n1

Procedure:
Prepared according to the method used in the preparation of 5-(5-chloro-7-morpholin-4-ylthiazolo[4,5-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using (S)-octahydro-pyrrolo[1,2-a]pyrazine in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as an orange solid (131 mg, 46%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(N(CC)CC)C>O1CCCC1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
To a solution of tert-butyl piperidin-4-ylcarbamate (200 mg, 1 mmol) in tetrahydrofuran (5 mL) were added 4-fluorobenzenesulfonyl chloride (195 mg, 1 mmol), triethylamine (0.2 mL) and the mixture was stirred at RT. After 2 h, the volatiles were removed in vacuo and the water was added to the residue. The solid formed was filtered, washed successively with water, 1N HCl, and water to afford tert-butyl 1-(4-fluorophenylsulfonyl)piperidin-4-ylcarbamate (350 mg, 98%) as a solid. LC/MS; (M+H)+=359.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][C:12]=1[O:19][CH3:20]>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:15]([C:14]3[CH:17]=[CH:18][C:11]([OH:10])=[C:12]([O:19][CH3:20])[CH:13]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: COc1cc(C=O)ccc1O
Product: COc1cc(-c2nc3cc(Br)cnc3[nH]2)ccc1O

Procedure:
The title compound was prepared from 5-bromo-2,3-diaminopyridine and 4-hydroxy-3-methoxybenzaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH:13]([C:17]3[N:18]=[C:19]([C:22]([F:25])([F:24])[F:23])[S:20][CH:21]=3)[CH2:12]2)=[CH:5][CH:4]=1.Br.C(=O)([O-])[O-].[K+].[K+].BrC[C:35]([O:37][CH3:38])=[O:36]>CC(C)=O>[C:35]([CH2:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH:13]([C:17]3[N:18]=[C:19]([C:22]([F:25])([F:24])[F:23])[S:20][CH:21]=3)[CH2:12]2)=[CH:5][CH:4]=1)([O:37][CH3:38])=[O:36]
Reactant: COc1ccc(CCN2CCOC(c3csc(C(F)(F)F)n3)C2)cc1
Reactant: COC(=O)CBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(CCN2CCOC(c3csc(C(F)(F)F)n3)C2)cc1

Procedure:
0.6 g (1.6 mmol) of N-[2-(4-Methoxyphenyl)ethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine are heated on a steam bath with 6 ml of 48% strength aqueous hydrobromic acid for 3 hours. The mixture is then concentrated, toluene is added, and the mixture is again evaporated to dryness. The foamy residue is boiled under reflux in 15 ml of acetone with 1.2 g (8.7 mmol) of potassium carbonate and 0.3 ml (1.65 mmol) of methyl bromoacetate for 1 hour. The mixture is then filtered, the filtrate is concentrated, and the residue is purified on a silica gel column using toluene/acetone =4:1.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[CH:21]=[CH:20][C:11]2[NH:12][C:13]([NH:15][C:16]([O:18][CH3:19])=[O:17])=[N:14][C:10]=2[CH:9]=1)(O)=[O:6]>C1C=CC=CC=1>[Cl:3][C:5]([C:8]1[CH:21]=[CH:20][C:11]2[NH:12][C:13]([NH:15][C:16]([O:18][CH3:19])=[O:17])=[N:14][C:10]=2[CH:9]=1)=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)Nc1nc2cc(C(=O)O)ccc2[nH]1
Solvent: c1ccccc1
Product: COC(=O)Nc1nc2cc(C(=O)Cl)ccc2[nH]1
Temperature: 23 °C

Procedure:
7.4 mL (12.069 g, 101.4 mmol) thionyl chloride and 1.80 g (7.66 mmol) methyl 5-carboxy-1H-benzimidazole-2-carbamate in 37 mL dry benzene were heated to reflux under argon for 3.5 hours. The mixture was then cooled to 23° C. and the solvent and excess thionyl chloride were distilled under reduced pressure. The resulting brown solid was stored under vacuum to remove all traces of thionyl chloride and used in the following Examples without further purification.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([NH:7][NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)=O>O=P(Cl)(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]([C:5]2[O:18][C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=3)=[N:8][N:7]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: COc1cccc(C(=O)NNC(=O)c2cccc(I)c2)c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc(-c2nnc(-c3cccc(I)c3)o2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-Iodo-N′-(3-methoxybenzoyl)benzohydrazide (11.0 g, 27.77 mmol) was suspended in POCl3 (60.0 ml) and heating was started. During heating white solid of starting materials dissolved into a clear solution. The reaction was kept at 100° C. and the reaction was monitor by thin layer chromatography. After 2 h, the reaction mixture was brought to room temperature and was carefully dropped into ice-water (1000.0 ml). White solid precipitated out was collected by filtration and washed with water. After dried, the crude product was purified by silica gel column chromatography eluting with dichloromethane and ethyl acetate in 9.5:0.5 ratio. After evaporating solvent the white solid was recrystallized from acetone/water and finally dried under vacuum. Pure product was obtained as white solid in 6.4 g (61.0%) yield. 1H NMR (400 MHz, CDCl3, δ): 8.47 (t, J=1.6 Hz, 2H), 8.12 (dt, J1=8.0 Hz, J2=1.6 Hz, 1H), 7.88 (m, 1H), 7.70 (dt, J1=8.0 Hz, J2=1.6 Hz, 1H), 7.67 (m, 1H), 7.45 (t, J=8.0 Hz, 1H), 7.28 (t, J=8.0 Hz, 1H), 7.10 (m, 1H), 3.92 (s, 3H, OCH3). 33C NMR (100 MHz, CDCl3, δ): 164.79, 163.07, 159.94, 140.58, 135.46, 130.68, 130.26, 126.03, 125.68, 124.69, 119.36, 118.36, 111.59, 94.39, 55.56.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[CH2:7]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CS(O)(=O)=[O:35].C(=O)(O)[O-].[Na+]>O>[CH2:7]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([NH2:30])=[O:29])=[CH:31][CH:32]=2)=[O:35])=[CH:19][CH:18]=1)[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NC(=O)c1ccc(Sc2ccc(CNCCc3ccccc3)cc2)cc1
Reactant: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: NC(=O)c1ccc(S(=O)c2ccc(CNCCc3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 34.3 %

Procedure:
Sodium periodate (43 mg) was added to a solution of 4-[4-(phenethylamino-methyl)-phenylsulfanyl]-benzamide (73 mg, 0.2 mmol), water (10 mL), and methane sulfonic acid (39 mg, 0.4 mmol) while stirring at room temperature. After 1 and 2 hours, and an additional equivalent of sodium periodate (43 mg) and continue to stir at room temperature. Pour the reaction into saturated aqueous sodium bicarbonate solution then extract with ethyl acetate (3×50 mL). The combined ethyl acetate extracts were dried over sodium chloride/magnesium sulfate, filtered, and concentrated on a rotary evaporator to yield the crude product (60 mg). The crude product was purified by flash column chromatography on silica gel eluting with 10% aqueous ammonium hydroxide in ethanol and chloroform to yield 4-[4-(Phenethylamino-methyl)-benzenesulfinyl]-benzamide (26 mg): 1H NMR (DMSO-D6, 300.00 MHz): 8.98 (d, 1H, J=1.3 Hz), 8.46 (dd, 1H, J=7.9, 2.2 Hz), 8.23 (s, 1H), 8.09 (d, 1H, J=8.3 Hz), 7.75-7.66 (m, 4H), 7.49 (d, 2H, J=8.3 Hz), 7.30-7.15 (m, 5H), 3.76 (s, 2H), 2.75-2.70 (m, 4H); m/z=380.04(M+1); HPLC=100% @ 5.67 minutes (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH2:12][OH:13])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)[CH3:2].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([N:3]([CH2:11][CH2:12][O:13][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][O:14]1)[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCN(CCO)c1ccc(Br)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCN(CCOC1CCCCO1)c1ccc(Br)cc1
Temperature: 70 °C

Procedure:
14.7 g (60.3 mmols) of N-ethyl-N-(2-hydroxyethyl)-4-bromoaniline, 90 ml of chloroform, 10.68 ml (2.0-fold equivalent weight) of 3,4-dihydro-2H-pyran and 0.76 g (0.05-fold equivalent weight) of pyridine p-toluenesulfonate were mixed, and the mixture obtained was heated at 70° C. for 1.5 hours in an atmosphere of argon. Thereafter, a saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution obtained, which was then extracted with chloroform (200 ml×2). The organic layer thus formed was washed with a saturated aqueous sodium hydrogencarbonate solution, which was then dried with anhydrous magnesium sulfate and thereafter concentrated. The residue thus obtained was purified by silica gel column chromatography (developing system: chloroform) to obtain 18.90 g of N-ethyl-N-[2-(tetrahydropyran-2-yl)oxyethyl]-4-bromoaniline (yield: quantitative; a colorless oily liquid).
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[CH2:8][NH:7][C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].[CH:52](O)=O.C=O.[OH-].[Na+]>C(#N)C>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[CH2:8][N:7]([CH3:52])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: O=CO
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)CN[C@H](C)[C@@H](O)[C@]1(C)O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)CN(C)[C@H](C)[C@@H](O)[C@]1(C)O

Procedure:
9-Deoxo-9a-aza-9a-homoerythromycin A (73.5 g —0.1 mole) was dissolved in 250 ml acetonitrile. To this solution, formic acid (19 ml, 0.5 mole) followed by formaldehyde (37%, 20 ml, 0.25 mole) were added and refluxed for 24 hours. The pH of the reaction mixture was adjusted with alkali (NaOH solution) to 10.5 and filtered to remove particles. To the filtered acetonitrile solution, an equal volume of water was added to precipitate Azithromycin monohydrate as cube shaped crystals. The crystals were filtered and dried under vacuum at 50° C. to give 65 g of Azithromycin monohydrate having water content of 5% (water content measured by the Karl Fischer titration method). This sample of Azithromycin monohydrate crystals has a characteristic solid state (KBr pellet) IR spectrum (FIG. 1) and a characteristic X-ray diffraction pattern (FIG. 2).
Reaction SMILES: [CH3:1][CH2:2][C:3](=[N:6][CH2:7][CH3:8])[CH2:4][CH3:5].[Cl:9][CH:10]([Cl:14])[C:11](Cl)=[O:12].C(OCC)C>C(N(CC)CC)C>[CH2:7]([N:6]([C:3](=[CH:4][CH3:5])[CH2:2][CH3:1])[C:11](=[O:12])[CH:10]([Cl:14])[Cl:9])[CH3:8]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CCN=C(CC)CC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC=C(CC)N(CC)C(=O)C(Cl)Cl

Procedure:
In a similar procedure as Example I, 5.9 g. (0.052 mole) N-3-pentylidene ethylamine was reacted with 4.8 ml. (0.05 mole) dichloroacetyl chloride in 100 ml. diethyl ether and 7.2 ml. triethylamine. There was obtained 7.7 g. of the title compound, an oil, nD30 = 1.4826.
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=[O:6])[NH:4]1)(=[O:3])=[O:2].[Na].Cl[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>CN(C)C=O>[S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=[O:6])[N:4]1[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])(=[O:2])=[O:3]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)c2ccccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 22.6g (0.11 mole) of sodium saccharin and 15g (0.1 mole) of tert-butyl α-chloroacetate in 150 ml of dimethylformamide is heated on a steam bath for 1 hour, allowed to stir at room temperature for 16 hours and poured into ice-water. The solution is dried over magnesium sulfate and the solvent is evaporated to give 24.9g of tert-butyl N-saccharinylacetate, m.p. 130°-132.5° C. This is refluxed with 300 ml of benzene and 1.4g (0.01 mole) of p-toluenesulfonic acid monohydrate to cause quantitative precipitation of 2-carboxymethylsaccharin, m.p. 212°-215° C. The completion of the reaction is established by passing a slow stream of nitrogen through the reaction mixture and into a solution of bromine in carbon tetrachloride. Failure to decolorize the bromine indicates that no more isobutylene is being evolved.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:15]=3[O:27][CH2:28][CH3:29])[CH3:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:30][C:31]([CH3:33])=O>>[NH2:1][C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:24][N:25]([CH:31]([CH3:33])[CH3:30])[CH2:26]4)[C:15]=3[O:27][CH2:28][CH3:29])[CH3:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCOc1c(C(C)n2cc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CNC1
Reactant: CC(C)=O
Product: CCOc1c(C(C)n2cc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C(C)C)C1
Yield: 65 %

Procedure:
The desired compound was prepared according to the procedure of Example 213 using 4-[1-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile instead of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile and acetone instead of formaldehyde as the starting materials in 65% yield. The product was isolated as a single enantiomer. 1H NMR (300 MHz, dmso) δ 7.95 (s, 1H), 7.19 (s, 1H), 7.16-7.13 (m, 1H), 6.58 (s, 2H), 6.11 (q, J=7.1 Hz, 1H), 4.04-3.67 (m, 5H), 3.04-2.92 (m, 2H), 2.36 (s, 3H), 2.27-2.12 (m, 1H), 1.69 (d, J=7.1 Hz, 3H), 1.30 (t, J=6.9 Hz, 3H), 0.85 (dd, J=6.1, 1.8 Hz, 6H). LCMS for C24H30ClN6O (M+H)+: m/z=453.2; Found: 453.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=O)=[N:6][CH:7]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:11][C:12]([OH:14])=[O:13])=[N:6][CH:7]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(Br)cn1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc(Br)cn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
5-Bromo-pyridin-2-carbaldehyde (2.0 g, 10.6 mmol), malonic acid (2.5 g, 24.2 mmol), and piperidine (0.9 mL, 9.0 mmol) were added to pyridine (6.5 mL). The reaction mixture was stirred at 100° C. for 1 hour and then concentrated under reduced pressure. Distilled water was added to the reaction mixture, which was then filtered. The resulting solid was dried under reduced pressure to give 1.3 g of the titled compound as a brown solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH:8]2[CH2:9][CH:3]1[CH2:4][CH2:5][C:6]2=[CH2:7].C(O)(=[O:13])C>>[CH3:1][C:2]([C@@H:3]1[CH2:9][CH:8]=[C:6]([CH2:7][OH:13])[CH2:5][CH2:4]1)=[CH2:10]
Reactant: C=C1CCC2CC1C2(C)C
Reactant: CC(=O)O
Product: C=C(C)[C@@H]1CC=C(CO)CC1
Yield: 40 %

Procedure:
The solvent system must be polar. If the non-polar beta-pinene is used in excess as the solvent, the reaction products are only polymeric substances. For reasons not apparent, if the solvent is glacial acetic acid alone, a completely polar solvent system, perillyl alcohol is obtained in only about a 40% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1>S(=O)(=O)(O)O.O1CCCC1>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:16][CH2:15][C:10](=[O:11])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1
Reactant: c1cc(N2CCC3(CC2)OCCO3)ccn1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: O=C1CCN(c2ccncc2)CC1
Yield: 49.6 %

Procedure:
A solution of 8-(4-pyridyl)-1,4-dioxa-8-azaspiro[4,5]decane (10 g) in 2N sulphuric acid (140 ml) and tetrahydrofuran (70 ml) was stirred for 72 hr. The reaction was quenched with water (700 ml) and extracted with dichloromethane (400 ml). The organic extracts were dried (MgSO4) and evaporated to give a yellow solid which was purified by flash chromatography on silica, eluting with methanol/dichloromethane (10:90 v/v) to give 1-(4-pyridyl)-4-oxopiperidine as a solid (3.97 g); m.p. 101°-104° C.; NMR (d6 -DMSO) δ2.45 (4H, t), 3.75 (4H, t), 6.85 (2H, m), 8.20 (2H, m); m/e 177 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16].S(=O)(=O)([OH:19])N.[O-]Cl=O.[Na+]>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]([OH:19])=[O:8])=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16]
Reactant: COCCCCc1cc(C=O)ccc1OC
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(=O)O
Product: COCCCCc1cc(C(=O)O)ccc1OC
Reaction time: 3 h

Procedure:
To a stirred suspension of 4-methoxy-3-(4-methoxy-butyl)-benzaldehyde (300 mg, 1.35 mmol) and sulfamic acid (176 mg, 1.81 mmol) in 80% acetic acid (2.3 mL) is added dropwise a solution of 80% NaClO2 (127 mg, 1.40 mmol; dissolved in 170 μL of H2O) in water (0.65 mL) over 5 min and by keeping the temperature at 18-20° C. Stirring of the yellow slurry is continued over 3 hrs at 20° C. before adding another aliquot of 80% NaClO2 (151 mg, 1.67 mmol; dissolved in 205 μL of H2O), dissolved in water (0.8 mL), and sulfamic acid (130 mg, 1.34 mmol) in 80% aqueous acetic acid. After stirring overnight, the reaction mixture is diluted by adding water (2.3 mL), the resulting suspension is stirred for 30 min and filtered. The precipitate is dried to give the title product as white solid. TLC, Rf (CH2Cl2/MeOH 98:2)=0.5. MS: 239.0 [M+H]+. 1H-NMR (CD3OD): δ 1.55-1.7 (m, 4H), 2.65 (t, 2H), 3.31 (s, 3H), 3.41 (t, 2H), 3.89 (s, 3H), 4.87 (s, 1H+D2O), 6.98 (m, 1H), 7.78 (s, 1H), 7.87 (m, 1H) ppm.
Reaction SMILES: O.O.O.[O-:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Na+].Br[C:13]1[C:14]([NH2:20])=[N:15][CH:16]=[C:17]([Br:19])[N:18]=1.O>C(#N)C>[Br:19][C:17]1[N:18]=[C:13]([O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:14]([NH2:20])=[N:15][CH:16]=1
Reactant: [O-]c1ccccc1
Reactant: Nc1ncc(Br)nc1Br
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Nc1ncc(Br)nc1Oc1ccccc1

Procedure:
Sodium phenoxide trihydrate (0.5 g) and 3,5-dibromo-2-pyrazinamine (0.5 g) in acetonitrile (20 mL) were heated at reflux for 7 hours. After cooling, water was added and the reaction mixture extracted with ethyl acetate (x2). The combined extracts were dried (MgSO4) and the solvent evaporated to give the sub-title compound as a white solid.