Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:12][CH2:13][C:14](Cl)=[O:15]>ClC(Cl)C>[CH:6]([C:2]1[NH:1][CH:5]=[C:4]([C:14](=[O:15])[CH2:13][Cl:12])[CH:3]=1)=[O:7]
Reactant: O=C(Cl)CCl
Reactant: O=Cc1ccc[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: O=Cc1cc(C(=O)CCl)c[nH]1
Temperature: 0 °C
Yield: 93.6 %

Procedure:
A mixture of 35 g (0.37 mole) pyrrole-2-carboxaldehyde in 325 ml dichloroethane was stirred under nitrogen in a three-necked, one-liter, round-bottomed flask fitted with an overhead stirrer and addition funnel. To this was added, in portions over a one-hour period, 294 g (2.21 mole) aluminum chloride. After the addition was completed, the mixture was stirred at room temperature for 10 minutes, then 124.7 g (88 ml, 1.10 mole) of chloroacetyl chloride was added dropwise over a one-hour period. The mixture was stirred at room temperature for 16 hours, then carefully poured into one liter of ice-water. The resulting precipitate (purple) was collected, washed well with water, and dried in vacuo. The dry solid was placed in a Soxhlet extractor and extracted with ethyl acetate for 20 hours. Concentration of the ethyl acetate solution afforded 59.4 g (94%) of the title compound as a yellow-green solid; m.p. 178°-179° C. This intermediate was used immediately in the next step. An analytical sample could be prepared by recrystallization from acetone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([NH:20][CH3:21])[C:17]([N+:22]([O-])=O)=[CH:16][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13](=[O:15])[CH3:14])[CH:7]=1>CO.[Pd]>[NH2:22][C:17]1[C:18]([NH:20][CH3:21])=[CH:19][C:3]([O:2][CH3:1])=[C:4]([CH:16]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13](=[O:15])[CH3:14])[CH:7]=1
Reactant: CNc1cc(OC)c(Oc2ccnc(NC(C)=O)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CNc1cc(OC)c(Oc2ccnc(NC(C)=O)c2)cc1N

Procedure:
The mixture containing N-(4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)pyridin-2-yl)acetamide in methanol with a catalytic amount of 10% Pd/C poisoned with lead was hydrogenated until the disappearance of the yellow color. The reaction was then filtered to remove the catalyst and concentrated to yield N-(4-(5-amino-2-methoxy-4-(methylamino)phenoxy)pyridin-2-yl)acetamide. HPLC=2.25 min; MS: MH+=303.
Reaction SMILES: B(Cl)(Cl)Cl.[NH2:5][C:6]1[C:11]([Cl:12])=[CH:10][N:9]([C@H:13]2[C@H:17]([OH:18])[C@H:16]([O:19]CC3C=CC=CC=3)[C@:15]([CH2:30][O:31]CC3C=CC=CC=3)([CH:27]([F:29])[F:28])[O:14]2)[C:8](=[O:39])[N:7]=1.N1C=CC=CC=1.CO>ClCCl>[NH2:5][C:6]1[C:11]([Cl:12])=[CH:10][N:9]([C@H:13]2[C@H:17]([OH:18])[C@H:16]([OH:19])[C@@:15]([CH:27]([F:28])[F:29])([CH2:30][OH:31])[O:14]2)[C:8](=[O:39])[N:7]=1
Reactant: Nc1nc(=O)n([C@@H]2O[C@@](COCc3ccccc3)(C(F)F)[C@@H](OCc3ccccc3)[C@H]2O)cc1Cl
Agent: ClB(Cl)Cl
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: Nc1nc(=O)n([C@@H]2O[C@@](CO)(C(F)F)[C@@H](O)[C@H]2O)cc1Cl
Temperature: 0 °C
Yield: 43.4 %

Procedure:
BCl3 (2.46 mL, 2.46 mmol) was added to a cooled (−78° C.) solution of compound 30 (0.125 g, 0.246 mmol) in dry dichloromethane (10 mL). The mixture was cooled to 0° C. and pyridine (0.5 mL) and MeOH (2 mL) were added. The reaction mixture was evaporated to dryness under reduced pressure. Purification by prep-HPLC provided 31 (0.035 g, 44%) as a white solid. LC-MS (M+H)+=328.1
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])(OCC)OCC.C(O[C@@H:15]1[C@H:21]2[C@H:22]3[C@H:31]([CH2:32][CH2:33][C@:18]2([CH2:19][CH3:20])[C:17](=[O:35])[CH2:16]1)[C@@H:30]1[C:25](=[CH:26]C(=O)[CH2:28][CH2:29]1)[CH2:24][CH2:23]3)(=O)C.N.C(OCC)(=O)C>CCO.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH2:9]([O:8][C:1]1[CH2:28][CH2:29][C@H:30]2[C:25](=[CH:24][CH2:23][C@@H:22]3[C@@H:31]2[CH2:32][CH2:33][C@@:18]2([CH2:19][CH3:20])[C@H:21]3[CH:15]=[CH:16][C:17]2=[O:35])[CH:26]=1)[CH3:10]
Reactant: CCOC(OCC)OCC
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(CC)C(=O)C=C[C@@H]34)[C@H]2CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
Triethyl orthoformate (3 ml, 18 mmol) and p-Toluenesulfonic acid (30 mg, 0.16 mmol) were added to a suspension of 15α-acetoxy-18-methyl-estr-4-en-3,17-dione (3 g, 8.8 mmol) in EtOH (18 ml). The mixture was stirred at room temperature for 1 h. Ammonia 32% (15.4 ml, 145 mmol) was added, and the mixture was heated at 40° C. for 48 h, cooled to 10° C., and ethyl acetate and water (15 ml) were then added. The extract was washed with water and concentrated. The crude product was purified by flash chromatography, eluting with heptane and ethyl acetate (8:2), crystallized from heptane, and dried under vacuum to afford 3-ethoxy-18-methyl-estra-3,5,15-trien-17-one (1.54 g, yield: 56%).
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH2:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][C:41](OCC)=[O:42])=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)[C:23]([OH:25])=[O:24])[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1.C(O)(C(F)(F)F)=O.Cl>[O-]CC.[Na+].C(O)C>[CH:1]1([NH:7][C:8](=[O:9])[NH:10][C:41](=[O:42])[CH2:40][CH2:39][C:36]2[CH:35]=[CH:34][C:33]([O:32][C:29]3[CH:28]=[CH:27][C:26]([C:22](=[CH:21][C:15]4[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]([O:12][CH3:11])[CH:14]=4)[C:23]([OH:25])=[O:24])=[CH:31][CH:30]=3)=[CH:38][CH:37]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)NC1CCCCC1
Reactant: CCOC(=O)CCc1ccc(Oc2ccc(C(=Cc3cc(OC)cc(OC)c3)C(=O)O)cc2)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: COc1cc(C=C(C(=O)O)c2ccc(Oc3ccc(CCC(=O)NC(=O)NC4CCCCC4)cc3)cc2)cc(OC)c1
Temperature: 75 °C
Reaction time: 0.08 h

Procedure:
Cyclohexylurea (1.3 g, 9 mmol) was dissolved in sodium ethoxide in ethanol (21% w/w, 3 mL) at 75° C. To this solution 5 was added (0.5 g, 1.1 mmol) in one lot. The resulting mixture was stirred at 75° C. for 5 min, then cooled quickly to 40-50° C. TFA (0.5 mL) was added and then 5% aqueous HCl (1N, 0.6 mL). After stirring at room temperature for 1 hr, the mixture was left overnight at 4° C. The solid separated was filtered and refluxed in ethyl acetate (4 mL) for 20 min. The mixture was allowed to cool to room temperature, filtered and the crude product was purified by silica gel chromatography using hexane-ethyl acetate (1:1). Yield: 0.27 g, 45%.
Reaction SMILES: FC(F)(F)C(O)=O.CC([NH:12][S:13]([C:16]1[C:21]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1)(=[O:15])=[O:14])(C)C>>[CH2:25]([S:22]([C:21]1[C:16]([S:13]([NH2:12])(=[O:14])=[O:15])=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:24])=[O:23])[CH3:26]
Reactant: CCS(=O)(=O)c1cccnc1S(=O)(=O)NC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)c1cccnc1S(N)(=O)=O
Yield: 57.9 %

Procedure:
Using the second half of the procedure of Example 4 (i.e., the trifluoroacetic acid reaction), 9.0 g (0.029 mol) of the product from Example 9 was converted to 4.2 g (58%) of the title compound: m.p. 211°-212.5°; NMR (DMSO-d6, 200 MHz) 1.15 (3H, t, J=7 Hz), 3.4 (NH2), 3.7 (2H, q, J=7 Hz), 7.9 (1H, m), 8.5 (1H, m), 8.95 (1H, m); IR (nujol) 3370, 3190, 1350, 1310, 1180 cm-1.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)([CH3:3])=[CH2:2].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[OH-].[Na+].OO>C1COCC1.C(Cl)Cl.O.C(O)C>[C:1]([C@@H:4]1[CH2:9][CH2:8][C@H:7]([OH:10])[CH2:6][CH2:5]1)([CH3:3])=[CH2:2]
Reactant: C=C(C)C1CCC(=O)CC1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: C=C(C)[C@H]1CC[C@@H](O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4.7 g (0.034 mol) of 4-isopropenylcyclohexanone dissolved in 35 ml of THF were added dropwise to 39 ml of a 1 molar solution at -78° C. of L-Selectride in THF. The mixture was subsequently stirred at -78° for 3 hours and then heated to room temperature, and 5 ml of H2O, 20 ml of ethanol, 15 ml of 6N NaOH and 17 ml of 35% strength H2O2 solution were added in succession. Water was added to the reaction solution, and extraction was carried out with methylene chloride. The combined methylene chloride phases are dried and concentrated. 37 g (78% of theory) of product remained as a colorless oil. The cis/trans mixture produced (>90% cis) was reacted further without additional purification.
Reaction SMILES: Cl.[CH:2]([C:5]1[S:14][C:13]2[NH:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[N:9]=[C:8]([NH2:19])[C:7]=2[CH:6]=1)([CH3:4])[CH3:3].[CH3:20][O:21][CH2:22][CH2:23][C@H:24]1[CH2:29]N[CH2:27][CH2:26][NH:25]1>N1C=CC=CC=1>[CH3:20][O:21][CH2:22][CH2:23][C@@H:24]1[NH:25][CH2:26][CH2:27][N:19]([C:8]2[C:7]3[CH:6]=[C:5]([CH:2]([CH3:4])[CH3:3])[S:14][C:13]=3[NH:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[N:9]=2)[CH2:29]1
Reactant: COCC[C@H]1CNCCN1
Reactant: CC(C)c1cc2c(s1)Nc1ccccc1N=C2N
Agent: Cl
Solvent: c1ccncc1
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(C)C)cc32)CCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Combine 2-isopropyl-4H-3-thia-4,9-diaza-benzo[f]azulene-10-ylamine hydrochloride (0.31 g, 1.04 mmol) and (S)-2-(2-methoxy-ethyl)-piperazine (0.30 g, 2.08 mmol) with anhydrous pyridine (4 mL), heat to 110° C. and stir overnight. Cool to ambient temperature to give crude material. Purification by cation exchange chromatography, eluting with solutions of 2M ammonia in methanol, in dichloromethane, (2%, 5%, 10%), and 2M ammonia in methanol, followed by flash chromatography, eluting with a gradient of solutions of 2M ammonia in methanol, in dichloromethane (2-4%), to give the title compound: mass spectrum (APCI, m/e): 385 (M+1); NMR (1H, 300 MHz, DMSO-d6),δ (ppm): 7.60 (s, 1H), 6.86-6.73 (m, 3H), 6.67 (m, 1H), 6.30 (s, 1H), 3.78 (m, 2H), 3.38-3.33 (m, 2H), 3.19 (s, 3H), 3.01-2.60 (m, 6H), 2.39 (m, 1H), 1.51 (m, 2H), 1.17 (d, 6H, J=7.5 Hz).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([Cl:34])[C:27]=1[CH3:35])[C:11]([NH:13][NH:14][C:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1)=[O:12])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:34][C:28]1[C:27]([CH3:35])=[C:26]([NH:25][C@@H:10]([C:11]2[O:12][C:15]([C:16]3[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=3)=[N:14][N:13]=2)[CH2:9][OH:8])[CH:31]=[CH:30][C:29]=1[C:32]#[N:33]
Reactant: Cc1c(N[C@H](CO[Si](C)(C)C(C)(C)C)C(=O)NNC(=O)c2ccc(C#N)cc2)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(N[C@H](CO)c2nnc(-c3ccc(C#N)cc3)o2)ccc(C#N)c1Cl

Procedure:
To a pre-cooled (−78° C.) solution of (R)—N′-(3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)propanoyl)-4-cyanobenzohydrazide (0.810 g, 1.64 mmol) in THF (160 mL) was added TBAF (1.64 mL, 1.64 mmol, 1 M solution in THF) dropwise over 10 min. Upon complete addition, the reaction mixture was concentrated under reduced pressure. The resulting residue was taken up in EtOAc (100 mL) and washed with H2O (80 mL). The biphasic mixture was separated and the aqueous layer extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (1×70 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a yellow oil, which was purified by flash chromatography over silica gel (50% EtOAc in hexanes then 100% EtOAc) to provide the title compound as an off-white solid. The resulting solid was diluted with CH2Cl2 (90 mL) and hexanes (70 mL) was added. Upon concentration of the suspension a white solid was provided (460 mg, 74%). 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.21 (d, J=8.8 Hz, 2H), 8.00 (d, J=9 Hz, 2H), 7.53 (d, J=9 Hz, 1H), 6.95 (d, J=9 Hz, 1H), 5.85 (d, J=8 Hz, 1H), 5.34-5.27 (m, 1H), 4.29 (br s, 2H) and 2.38 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29]>CN(C)C=O>[N+:28]([C:19]1[CH:20]=[C:21]([C:24]([F:25])([F:26])[F:27])[CH:22]=[CH:23][C:18]=1[O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])([O-:30])=[O:29]
Reactant: O=C(O)c1cccc(O)c1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cccc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])c1
Yield: 73.5 %

Procedure:
3-Hydroxybenzoic acid (13.8 g) in dry dimethylformamide (100 ml) was heated and stirred for 7 hours at 100° with anhydrous potassium carbonate (26 g) and 4-chloro-3-nitrobenzotrifluoride (22.5 g). The mixture was then evaporated to a small volume under reduced pressure and diluted with water. With warming, a dark solution was obtained. Acidification gave a white precipitate; this was washed with water and recrystallised from a mixture of methanol and water to give 3(2-nitro-4-trifluoromethylphenoxy) benzoic acid (24 g).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].Cl[C:8]1[N:13]=[CH:12][C:11](/[C:14](/[C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[C:15](\[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[CH2:16][CH3:17])=[CH:10][CH:9]=1>>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][O:5][C:8]1[N:13]=[CH:12][C:11](/[C:14](/[C:24]2[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=2)=[C:15](\[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[CH2:16][CH3:17])=[CH:10][CH:9]=1
Reactant: CC/C(=C(\c1ccc(O)cc1)c1ccc(Cl)nc1)c1ccccc1
Reactant: CN(C)CCO
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCN(C)C)nc1)c1ccccc1
Yield: 74.9 %

Procedure:
Following the same procedure as described in example 3, 2-(dimethylamino)ethanol (798 mg, 10 eq) and (Z)-4-(1-(6-chloropyridin-3-yl)-2-phenylbut-1-enyl)phenol (300 mg, 1 eq, prepared from example 1) were reacted to get the desired product (260 mg, 75% yield). 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.14-7.20 (m, 2H), 7.01-7.09 (m, 5H), 6.93 (d, J=8.0 Hz, 1H), 6.78 (d, J=8.0 Hz, 2H), 5.84 (d, J=8.8 Hz, 1H), 4.22 (t, J=5.2 Hz, 2H), 2.70 (t, J=5.2 Hz, 2H), 2.50 (q, J=7.2 Hz, 2H), 2.35 (s, 6H), 0.91 (t, J=7.6 Hz, 3H); m/z=389 [M+1]+.
Reaction SMILES: [CH2:1]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8].[CH2:20]=O>>[CH3:20][N:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH3:8])[CH3:9]
Reactant: C=O
Reactant: CC(C)CCCCCCNCCCCCCC(C)C
Product: CC(C)CCCCCCN(C)CCCCCCC(C)C
Yield: 97.8 %

Procedure:
In a similar manner to Example 1, 202.1 g (0.75 mol) of diisononylamine and 170.3 g (1.65 mol) of formaldehyde (29.1%) are reacted in a 1 l autoclave; a maximum pressure of 1.9 MPa is established at a temperature of 160° C. After the end of the reaction, the organic phase is removed from the aqueous phase; the remaining organic phase is subsequently distilled. 208.0 g of N-methyldiisononylamine having a purity of 85.0% are isolated, corresponding to a yield of 83.2% of theory.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[C:10]([OH:19])([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:3].Cl.[OH2:21]>>[CH3:3][N+:2]([O-:21])([CH2:4][CH:5]1[C:10]([OH:19])([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([O:17][CH3:18])[CH:16]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:1].[CH3:3][N:2]([CH2:4][CH:5]1[C:10]([OH:19])([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:1]
Reactant: O
Agent: COc1cccc(C2(O)CCCCC2CN(C)C)c1
Agent: Cl
Product: COc1cccc(C2(O)CCCCC2C[N+](C)(C)[O-])c1

Procedure:
First, tramadol N-oxide was prepared as set forth hereinafter. Tramadol hydrochloride (0.5 mol) was converted to its free base in basified water (pH >9) and then extracted with ether. The ether was evaporated to yield the crystalline hydrate of tramadol. The solid was then heated with steam under a high vacuum to remove as much water as possible to yield 131.5 g of material. The material was dissolved in methanol (500 mL) and 65 g of 30% H2O2 was added. The solution was stirred for 3 hours and then an additional 65 g of the 30% H2O2 was added. The reaction was stirred for 2.5 days at room temperature. Approximately 10 mg of PtO2 on carbon (use of Pt/C is suggested for its ease of removal) was added to the reaction mixture, and very gentle foaming took place. An additional 10 mg of PtO2 was added and the reaction mixture was stirred overnight and then filtered thru a filter aid. The filtrate was concentrated under vacuum while being heated to a temperature of <40° C. The residue was taken up in methylene chloride. Since the methylene chloride solution contained some colloidial platinum, the solution was diluted with ethyl acetate to 1 L and filtered through a nylon filter membrane (0.45μ pore size) to yield a clear colorless filtrate. The filtrate was concentrated to 600 mL, and then ethyl acetate was added continuously to maintain a volume of 800 mL while the solution was heated until a vapor temperature of 74° C. was reached. The solution was then cooled to room temperature. The solid was collected by filtration, washed with ethyl acetate and dried in vacuo to yield 126.6 g of the tramadol N-oxide (mp. 159.5°-160° C.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[O:30][CH2:31][CH3:32])=[CH:11][CH:10]=1)#[N:2].C[Sn]([N:37]=[N+:38]=[N-:39])(C)C>C1(C)C=CC=CC=1>[CH2:31]([O:30][C:17]1[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[NH:39][N:38]=[N:37][N:2]=3)=[CH:14][CH:13]=2)[C:20]2[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=1)[CH3:32]
Reactant: CCOC(=O)c1cccc2nc(OCC)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc2nc(OCC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of ethyl 1-[(2′-cyanobiphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7-carboxylate (0.7 g) and trimethyltin azide (0.7 g) in toluene (15 ml) was heated under reflux for 4 days. The reaction mixture was concentrated to dryness and to the residue were added methanol (20 ml) and 1N-HCl (10 ml). The mixture was stirred at room temperature for 30 minutes and adjusted to pH 3 to 4 with 1N NaOH. After removal of the solvent, the residue was partitioned between chloroform and water. The organic layer was washed with water and dried, and the solvent was evaporated to dryness to give a syrup. The syrup was purified by column chromatography on silica gel to give crystals. Recrystallization from ethyl acetate-benzene afforded colorless crystals (0.35 g, 45%), m.p. 158-159° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][NH:5][C:6](=[O:22])[C:7]([CH3:21])([CH3:20])[CH2:8][N:9]1C(=O)C2C(=CC=CC=2)C1=O.NN>CO>[NH2:9][CH2:8][C:7]([CH3:21])([CH3:20])[C:6]([NH:5][CH2:4][C:3]1[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=1[Cl:1])=[O:22]
Reactant: CC(C)(CN1C(=O)c2ccccc2C1=O)C(=O)NCc1ccccc1Cl
Agent: NN
Solvent: CO
Product: CC(C)(CN)C(=O)NCc1ccccc1Cl
Reaction time: 8 h

Procedure:
To a solution of N-(2-chlorobenzyl)-3-(1,3-dioxoisoindolin-2-yl)-2,2-dimethylpropanamide (0.50 g, 1.35 mmol) in methanol (5 mL) was added hydrazine (423 μL, 13.5 mmol, 10 equiv.). The reaction mixture was stirred overnight. The crude mixture was concentrated. The resulting residue was dried in vacuum to give 3-amino-N-(2-chlorobenzyl)-2,2-dimethylpropanamide, which was used without further purification. LRMS (M+H+) m/z 241.1.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[F:8][C@@H:9]1[C@@H](CO)[O:12][C@@H:11]([N:16]2[CH:23]=[CH:22][C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:10]1.C(O)C>N1C=CC=CC=1>[C:5]([O:4][CH2:1][C@H:2]1[O:12][C@@H:11]([N:16]2[CH:23]=[CH:22][C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:10][C@@H:9]1[F:8])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=O)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Acetic anhydride (1.2 ml, 13 mmol) was added to a solution of 2',3'-dideoxy-3'-fluorouridine (1 g, 4.34 mmol) in dry pyridine (10 ml) and the mixture was stirred at room temperature for 24 hours. Ethanol (2 ml) was added and the mixture was evaporated to dryness. Residual pyridine was removed by coevaporation with portions of ethanol and the final residue purified by silica gel column chromatography eluting with 5% MeOH/CH2Cl2 to give the title compound which was isolated following trituration with ether.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([CH:7]([F:9])[F:8])[S:4][C:3]=1[CH:10]=[O:11].[C:12]([Mg]Br)#[CH:13]>>[Cl:1][C:2]1[CH:6]=[C:5]([CH:7]([F:8])[F:9])[S:4][C:3]=1[CH:10]([OH:11])[C:12]#[CH:13]
Reactant: C#C[Mg]Br
Reactant: O=Cc1sc(C(F)F)cc1Cl
Product: C#CC(O)c1sc(C(F)F)cc1Cl

Procedure:
Using the procedure of Stage B of Preparation 2, 0.64 g of the product of Stage C above and 8.5 ml of ethynyl magnesium bromide were reacted to obtain 0.67 g of the expected product.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].O.[OH-].[Li+].Cl>C1COCC1.O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:13]=[C:5]2[C:3]([OH:4])=[O:2])=[CH:15][CH:16]=1
Reactant: COC(=O)c1cc2ccccc2n1-c1ccc(OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-n2c(C(=O)O)cc3ccccc32)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 3 g 1-(4-Methoxy-phenyl)-1H-indole-2-carboxylic acid methyl ester in 50 ml THF, 10 ml water and 0.58 g lithium hydroxide monohydrate were added. After stirring for 2 h at 60° C. the reaction was cooled to RT. The mixture was acidified with half concentrated hydrochloric acid and the precipitate was collected by filtration and was washed with 10 ml water The product was obtained as a white solid which was dried under reduced pressure. Yield: 520 mg.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.[CH:13]1([C:16]2[NH:20][N:19]=[C:18]([NH2:21])[CH:17]=2)[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C.CS(C)=O>O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([NH:21][C:18]2[CH:17]=[C:16]([CH:13]3[CH2:15][CH2:14]3)[NH:20][N:19]=2)[N:3]=1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(Nc2cc(C3CC3)[nH]n2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 111.5 %

Procedure:
A round-bottom flask was charged with methyl 2,6-dichloropyrimidine-4-carboxylate (6.9 g, 33.2 mmol), 5-cyclopropyl-1H-pyrazol-3-amine (4.13 g, 33.6 mmol), DIPEA (11.6 mL) and DMSO (40 mL). The reaction was stirred at RT for 4 h then H2O (150 mL) was added. The mixture was vigorously stirred for 20 min, the resulting precipitate was filtered and washed with water, then dried under high vacuum to afford 10.87 g (>100%) of methyl 2-chloro-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidine-4-carboxylate (212): MS (ESI) m/z=294.2 [M+1]+.