Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:7](Br)=[CH:6][C:3]=1[C:4]#[N:5].[Cl-].[NH4+:17]>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][C:7]([C:8]2[CH:7]=[N:17][CH:13]=[CH:14][C:10]=2[O:11][CH3:12])=[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: N#Cc1cc(Br)c(-c2ccco2)nc1N
Reactant: [NH4+]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccncc1-c1cc(C#N)c(N)nc1-c1ccco1
Yield: 56 %

Procedure:
A solution of 2-amino-5-bromo-6-(2-furyl)nicotinonitrile (1.80 g, 6.82 mmol), 2-methoxy-5-(1,1,1-tributylstannyl)pyridine (5.20 g, 13.1 mmol) and dichlorobis(triphenylphosphine) palladium (II) (480 mg, 0.634 mmol) in N,N-dimethylformamide (18 ml) was stirred at 80° C. for 2 hours in a nitrogen atmosphere. After cooling as it was, the reaction solution was diluted with ethyl acetate and an aqueous saturated solution of ammonium chloride. The organic layer was washed with an aqueous saturated solution of ammonium chloride (×2), then dried over anhydrous sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography (elution solvent; hexane, hexane:ethyl acetate=8:1, 4:1), and then suspended in diethyl ether. The resulting solid was collected by filtration and washed with diethyl ether, to give the title compound (1.12 g, 56%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][O:4][N:3]=1.COC(=O)[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1>>[O:16]([C:2]1[CH2:6][CH2:5][O:4][N:3]=1)[C:13]1[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=1
Reactant: BrC1=NOCC1
Reactant: COC(=O)c1ccc(O)cc1
Product: c1ccc(OC2=NOCC2)cc1

Procedure:
3-phenoxy-4,5-dihydroisoxazole I-177a and I-177b were prepared in 2 steps from racemic compound I-14. Bromo-4,5-dihydroisoxazole I-14 was reacted with 4-hydroxybenzoic acid methyl ester using Method 5 followed by hydroysis using the analogous conditions as in Example 94. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=368.0 m/z. Activity: B
Reaction SMILES: [IH:1].CS[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][N:5]=1.[CH3:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18]>C(O)C>[IH:1].[CH3:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH:18][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][N:5]=1
Reactant: CSC1=NCCc2ccccc21
Reactant: Cc1ccccc1CN
Agent: I
Solvent: CCO
Product: Cc1ccccc1CNC1=NCCc2ccccc21
Yield: 73 %

Procedure:
1-Methylthio-3,4-dihydroisoquinoline hydroiodide (1.52 g, 0.005 mol) was dissolved in a solution of ethanol (50 ml) containing 2-methylbenzylamine (0.61 g, 0.005 mol). The colourless solution was heated at reflux temperature for six hours with effluent gases being passed through a CHLOROS trap. The solution was then cooled and stood in the refrigerator overnight to give white crystals (1.38 g). This material was crystallised from methanol/ ethanol to give the title compound (1.06 g) as its hydroiodide salt, m.p. 241°-243°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C@H:8]3[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH3:16])[C@@H:9]3[CH2:17][O:18][C:4]=2[C:3]=1[O:19][CH3:20].C([Li])CCC.CN(C)[CH:28]=[O:29]>O1CCCC1>[OH:29][CH2:28][C:2]1[CH:7]=[CH:6][C:5]2[C@H:8]3[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH3:16])[C@@H:9]3[CH2:17][O:18][C:4]=2[C:3]=1[O:19][CH3:20]
Reactant: CN(C)C=O
Reactant: CCCN1CCC[C@@H]2c3ccc(Br)c(OC)c3OC[C@H]21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCN1CCC[C@@H]2c3ccc(CO)c(OC)c3OC[C@H]21
Reaction time: 0.17 h

Procedure:
A solution of 600 mg of trans-8-bromo-7-methoxy-4-propyl-1,2,3,4a,5,10b-hexahydro-4H-[1]-benzopyrano[3,4-b]pyridine in 10 ml of tetrahydrofuran is treated with 1.68 ml of 2.1M n-butyllithium at -78°. After 10 minutes, 27 ml of dimethylformamide is added. After 30 minutes at 0°, the reaction mixture is poured onto water and the products are extracted with ether. After drying the solvent is removed. The residue is treated with 35 mg of sodium borohydride in 5 ml of methanol. After 10 minutes the solvent is removed and the residue is chromatographed on 10 g silica gel with acetone/hexane 1:2 as the eluent to afford trans-8-hydroxymethyl-7-methoxy-4-propyl-1,2,3,4a,5,10b-hexahydro-4H-[1]-benzopyrano[3,4-b]pyridine.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].Cl.Cl.[NH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]1.C(N(CC)CC)C>O1CCCC1>[OH:29][CH:26]1[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][NH:20][S:2]([C:5]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:6]=2[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3])[CH2:24][CH2:25]1
Reactant: NCCN1CCC(O)CC1
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCN1CCC(O)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of methyl 2-chlorosulfonyl-6-nitrobenzoate (1.5 g, 5.4 mmol) in tetrahydrofuran (100 ml) was added over 1 hour to a stirred mixture of 1-(2-aminoethyl)-4-hydroxypiperidine dihydrochloride (1.2 g, 5.4 mmol) and triethylamine (2.3 ml, 16.5 mmol) in tetrahydrofuran (75 ml) cooled in an ice bath. After stirring at room temperature for 6 hours, solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and saturated sodium chloride solution. The ethyl acetate extract was dried (Na2SO4), filtered and concentrated. The residue was flash chromatographed on silica gel and eluted with 5% methanol-95% chloroform to give pure product, 1.0 g, as an oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.Br[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N:25]2[CH:29]=[CH:28][CH:27]=[N:26]2)[N:20]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N:25]4[CH:29]=[CH:28][CH:27]=[N:26]4)[N:20]=3)[C:6]3[CH:11]4[CH2:12][CH2:13][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:17]4
Reactant: Brc1cccc(-n2cccn2)n1
Reactant: Fc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Product: Fc1ccc2c(c1)c1c(n2-c2cccc(-n3cccn3)n2)C2CCN(CC2)C1

Procedure:
The reaction of 9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (230 mg, 1.0 mmol; Example 161) and 2-bromo-6-(1H-pyrazol-1-yl)pyridine (336 mg, 1.5 mmol; Maybridge) was performed as described in Example 68 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.99-2.14 (m, 2H) 2.15-2.30 (m, 2H) 3.09-3.29 (m, 5H) 4.29 (s, 2H) 6.52-6.57 (m, 1H) 6.90 (td, J=9, 3 Hz, 1H) 7.11 (dd, J=9, 3 Hz, 1H) 7.37 (d, J=8 Hz, 1H) 7.43 (dd, J=9, 4 Hz, 1H) 7.80 (s, 1H) 7.97 (d, J=8 Hz, 1H) 8.16 (t, J=8 Hz, 1H) 8.50 (d, J=3 Hz, 1H); MS (DCI/NH3) m/z 374 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH2:7][CH2:8][NH:9][CH2:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1>[Pd]>[F:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c3c([nH]c2c1)CNCC3
Agent: [Pd]
Product: Fc1ccc2c(c1)[nH]c1cnccc12
Yield: 87.5 %

Procedure:
7-fluoro-2,3,4,9-tetrahydro-1H-β-carboline (3.5 g, 18.42 mmol) was suspended in xylenes (60 ml) in a 250 ml round-bottom flask equipped with a condenser that was open to the atmosphere, and heated. To this hot reaction mixture was added Pd/C (10 wt %, 0.2 eq, 700 mg) and the mixture refluxed in xylenes overnight (12-14 hours). The solution was then filtered through a pad of celite and the collected filtrate was then evaporated on a rotary evaporator to give the desired product as a brown/tan solid (3.0 g, 88% yield). 1H-NMR (300 MHz, DMSO-d6): δ 7.10 (m, 1H), 7.37 (dd, 1H), 8.10 (d, 1H), 8.28 (dd, 1H), 8.35 (dd, 1H), 8.89 (s, 1H), 11.74 (s, 1H). Retention Time (LC, method: ammonium acetate standard): 1.88 min. MS (M+H+): 187.1.
Reaction SMILES: [C:1]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C:15]=1[C:23]([O:25]CC)=[O:24])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CC(C)([O-])C.Br[CH2:34][C:35]1[CH:47]=[CH:46][C:38]([O:39][CH2:40][C:41]([O:43]CC)=[O:42])=[CH:37][CH:36]=1.[Na+].[Cl-]>O.CS(C)=O>[C:41]([CH2:40][O:39][C:38]1[CH:46]=[CH:47][C:35]([CH2:34][N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14]([C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[C:15]2[C:23]([OH:25])=[O:24])=[CH:36][CH:37]=1)([OH:43])=[O:42]
Reactant: CCCCCCCCCCCC(=O)c1c(C(=O)OCC)[nH]c2ccccc12
Reactant: CCOC(=O)COc1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCCCCC(=O)c1c(C(=O)O)n(Cc2ccc(OCC(=O)O)cc2)c2ccccc12

Procedure:
A mixture of 223 mg (0.6 mmol) of ethyl 3-dodecanoylindole-2-carboxylate, 81 mg (0.72 mmol) of potasisum t-butoxide and 2 ml of absol. DMSO is stirred in an oil bath at 110° C. for 5 min. Then 197 mg (0.72 mmol) of ethyl 2-[4-(bromomethyl)phenoxy]acetate are added, and the mixture is heated at the same temperature for a further 10 min. Cooling and addition of water and NaCl are followed by extraction with ether. The organic phase is dried over Na2SO4, the solvent is distilled off, and the residue is chromato-graphed on silica gel with petroleum ether/ethyl acetate (9+1). The resulting ethyl 3-dodecanoyl-1-{4-[(ethoxycarbonyl)methoxy]benzyl}indole-2-carboxylate is hydrolyzed in analogy to Example 2E. The product is precipitated from ether.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([NH:16][CH3:17])[N:10]=[C:9]2Cl>>[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([NH:16][CH3:17])[N:10]=[C:9]2[O:1][CH2:2][CH3:3]
Reactant: CNc1nc(Cl)c2cc(Br)ccc2n1
Reactant: CC[O-]
Agent: [Na+]
Product: CCOc1nc(NC)nc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.8 %

Procedure:
To a solution of sodium ethoxide (8.11 g, 119.3 mmol) in absolute alcohol (150 mL) was added powder (6-bromo-4-chloro-quinazolin-2-yl)-methyl-amine (13 g, 47.7 mmol) in one portion and the mixture was stirred for 3 hours at room temperature under N2 atmosphere. The excess of alcohol was removed in vacuo and the residue was purified by column to afford (6-bromo-4-ethoxy-quinazolin-2-yl)-methyl-amine (4 g, 14.2 mmol, 29.8%) as a light yellow solid. 1H NMR (DMSO-d6): δ 7.90-7.89 (d, 1H), 7.70-7.67 (dd, 1H), 7.33-7.31 (m, 1H), 7.21-7.20 (dd, 1H), 4.45-4.44 (q, 2H), 2.83-2.82 (d, 3H), 1.40-1.37 (t, 3H).
Reaction SMILES: C([O:4][C@@H:5]([C:7]1[N:12]=[C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:15][CH2:14]2)[CH:10]=[CH:9][N:8]=1)[CH3:6])(=O)C.[OH-].[K+]>O1CCOCC1.C(OCC)(=O)C>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][N:16]1[CH2:15][CH2:14][N:13]([C:11]2[CH:10]=[CH:9][N:8]=[C:7]([C@H:5]([OH:4])[CH3:6])[N:12]=2)[CH2:18][CH2:17]1
Reactant: CC(=O)O[C@H](C)c1nccc(N2CCN(Cc3ccccn3)CC2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@@H](O)c1nccc(N2CCN(Cc3ccccn3)CC2)n1
Reaction time: 3 h

Procedure:
To a solution of (R)-1-[4-(4-pyridin-2-ylmethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl acetate (prepared according to the method of Example 182, Step A, 0.14 g, 0.33 mmol) in dioxane (6 mL) was added at ambient temperature 6 N aqueous potassium hydroxide (0.5 mL). After stirring for 3 h the solution was diluted with ethyl acetate and washed twice with water. The organic layer was separated, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give the title compound as a white solid, 0.09 g (69%). 1H NMR (CDCl3, 300 MHz) δ 1.52 (d, 3H), 2.38-2.59 (m, 4H), 3.72-3.77 (m, 6H), 4.69 (q, 1H), 6.37 (d, 1H), 7.22 (d, 1H), 7.41 (d, 1H), 7.69 (m, 1H), 8.21 (d, 1H) 8.58, (d, 1H); mp: 68-70° C.; MS (Cl) 300 (MH+); [α]D+16.2 (c, 1.0, MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[OH:10][CH2:11][CH:12]([CH2:14]O)[OH:13].O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:13][CH:12]1[CH2:11][O:10][CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)[O:6][CH2:14]1
Reactant: O=Cc1cccc(Cl)c1
Reactant: OCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: OC1COC(c2cccc(Cl)c2)OC1
Yield: 42.2 %

Procedure:
A mixture of 3-chlorobenzaldehyde (28.1 g, 0.2 mole), glycerol (18.4 g, 0.2 mole) and p-toluenesulfonic acid (0.1 g) in 150 ml of benzene was heated at reflux under a Dean-Stark apparatus until water was no longer collecting (3.6 ml). The solution was cooled, washed with 2% sodium bicarbonate solution (2 × 100 ml) and with water (2 × 100 ml). The washed solution was dried over magnesium sulfate and concentrated under reduced pressure. The oil remaining was distilled to give 18.1 g of colorless liquid which distilled at a pot temperature of 124°-128° C under 1 × 10-4 mm.
Reaction SMILES: C([NH:5][C:6](=[O:27])[C:7]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH3:20])=[CH:11][C:10]([N:21]2[CH2:26][CH2:25][S:24][CH2:23][CH2:22]2)=[N:9][CH:8]=1)(C)(C)C.CS(O)(=O)=O>C1(C)C=CC=CC=1>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[C:7]([C:6]([NH2:5])=[O:27])=[CH:8][N:9]=[C:10]([N:21]3[CH2:26][CH2:25][S:24][CH2:23][CH2:22]3)[CH:11]=2)=[C:14]([CH3:20])[CH:15]=1
Reactant: Cc1cc(F)ccc1-c1cc(N2CCSCC2)ncc1C(=O)NC(C)(C)C
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: Cc1cc(F)ccc1-c1cc(N2CCSCC2)ncc1C(N)=O
Temperature: 25 °C

Procedure:
4-(4-Fluoro-2-methyl-phenyl)-6-thiomorpholin-4-yl-nicotinamide can be produced by suspending N-tert-Butyl-4-(4-fluoro-2-methyl-phenyl)-6-thiomorpholin-4-yl-nicotinamide in toluene. The suspension is heated with the dropwise addition of methanesulfonic acid to provide an emulsion, which is then stirred and cooled to room temperature. The phases are separated and the organic phase washed with deionized water. The combined aqueous phases are cooled to about 0° C., followed by the slow addition of 28% aqueous sodium hydroxide to increase the pH to about 12.5. The suspension obtained then can be extracted with dichloromethane. The combined organic extracts are dried and concentrated in a rotary evaporator. Propyl acetate is then added, and the solution concentrated in a rotary evaporator. A second portion of propyl acetate is added, and the solution concentrated to form a suspension. N-hexane is added to the suspension, followed by stirring. The resulting precipitate is filtered off, washed with n-hexane:propyl acetate 9:1, and dried in a vacuum oven to yield 4-(4-fluoro-2-methyl-phenyl)-6-thiomorpholin-4-yl-nicotinamide as a light yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8]2[CH:13]=[C:12](Cl)[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1.[CH3:17][O:18][C:19](=[O:34])[CH2:20][CH2:21][C:22]1[O:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[N:26]=1>>[CH3:17][O:18][C:19](=[O:34])[CH2:20][CH2:21][C:22]1[O:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:12]3[CH:13]=[C:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[CH3:16])[N:9]=[C:10]([NH2:15])[N:11]=3)=[CH:29][CH:28]=2)[N:26]=1
Reactant: Cc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Reactant: COC(=O)CCc1nc(-c2ccc(N)cc2)co1
Product: COC(=O)CCc1nc(-c2ccc(Nc3cc(-c4cc(Cl)ccc4C)nc(N)n3)cc2)co1

Procedure:
Following the method described in Example 26, 4-(5-chloro-2-methyl-phenyl)-6-chloro-pyrimidin-2-ylamine and 3-[4-(4-amino-phenyl)-oxazol-2-yl]-propionic acid methyl ester provided 3-(4-{4-[2-amino-6-(5-chloro-2-methyl-phenyl)-pyrimidin-4-ylamino]-phenyl}-oxazol-2-yl)-propionic acid methyl ester.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.Br[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18].C>C(O)C>[CH2:4]1[C:5]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:2][CH2:3]1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NCCc1c[nH]c2ccccc12
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1=CNCCc2c1[nH]c1ccccc21

Procedure:
A mixture of tryptamine hydrochloride (1.96 g, 10 mmol), ethyl 3-bromopyruvate (1.67 mL, 1.2 equiv) and decolorizing charcoal (0.5 g) in absolute ethanol was heated to reflux under nitrogen overnight. TEA was added and the reaction mixture was heated to reflux for another 7.5 hours. After cooling, charcoal was removed by filtration and washed with ethanol. The filtrate was concentrated under vacuum and diluted with water (20 mL). It was then extracted by EtOAc (3×30 mL) and the combined organic layers were washed with brine and dried over MgSO4. Evaporation of solvent and recrystallization from DCM-Hexane gave the title compound (1.17 g). 1H-NMR (CDCl3): δ 10.49 (1 H, br s), 7.79 (1H, d), 7.43 (1H, d), 7.43 (1 H, d), 7.06 (2H, m), 5.27 (1H, br s), 4.29 (2H, q) 3.58 (2H, m), 3.17 (2H, m), 1.36 (3H, t); MS (ES): 257 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18]Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=2)=[CH:4][CH:3]=1
Reactant: ClCc1ccccn1
Reactant: Sc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Clc1ccc(SCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 170 %

Procedure:
4-Chlorobenzenethiol (5 g) in warm ethanol (5 ml) was added to a solution of sodium hydroxide (2.8 g) in ethanol (50 ml). To the solution was added a solution of 2-picolyl chloride, hydrochloride (5.7 g) in ethanol (25 ml) and the mixture was stirred at ambient temperature for 6 hours. The mixture was filtered and evaporated and the residue was converted into the hydrochloride with ethereal HCl solution and this was recrystallised from ethanol-ether to give 2-(((4-chlorophenyl)thio)methyl)pyridine, hydrochloride (8 g) mp 196°-8° C. (Found: C, 52.95; H, 4.1; N, 5.15. C12H10ClNS.HCl requires C, 53.1; H, 4.2; N, 4.9%).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]([CH3:13])[CH2:9][C:10](O)=[O:11])=O)=[CH:4][CH:3]=1.O.[NH2:17][NH2:18]>CC(O)C>[OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]2[CH:8]([CH3:13])[CH2:9][C:10](=[O:11])[NH:17][N:18]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CC(CC(=O)O)C(=O)c1ccc(O)cc1
Solvent: CC(C)O
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc(O)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A 1 1 three-necked round-bottomed flask equipped with a condenser connected to a gas inlet, a glass rod air driven stirrer and a thermometer was charged with 63.8 g, (306 mmol) of (±)-3-(4'-hydroxybenzoyl)-3-methylpropanoic acid from Example H and 2-propanol (400 ml) at 40° C. The solution was placed under an atmosphere of nitrogen and heated to 65° C. Then hydrazine monohydrate (45 ml, 2.2 mol) was added dropwise over 10 min. The reaction mixture was heated to 80-81° C. (reflux), stirred for 1 hour then slowly cooled to 3° C. over 1 hour with gentle stirring. The formed precipitate was collected by suction filtration, triturated in a 1 L beaker with deionized water (300 ml) at 23° C. for 2 hrs and collected by suction filtration. The solids were dried to constant weight in an air oven (90° C.) to provide 51.9 g (83.5%) of pure (±)-4,5-dihydro-6-(4'-hydroxyphenyl)-5-methyl-3(2H)-pyridazinone, m.p. 268°-273° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([N+]([O-])=O)[CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[CH3:26][O:27][NH2:28]>>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:5][N:4]=2)=[CH:14][C:15]=1[CH2:26][O:27][NH2:28])([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Reactant: CON
Agent: Cl
Product: NOCc1cc(Oc2ncc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
Following the procedure of Example 29, 4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)-1,2-dinitrobenzene and methoxyamine hydrochloride are reacted together to give N-[2-nitro-5-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenyl]methoxyamine (XV; R'=H). ##STR29##
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32]([OH:34])=O)[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][C@@H:36]1[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38][CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:30])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32]([NH:35][C@@H:36]4[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])[CH2:38][CH2:37]4)=[O:34])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c14) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow foam.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Na].C1C=CC=CC=1.S(O[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:29][CH:28]=1)(C1C=CC(C)=CC=1)(=O)=O>O>[CH2:34]([O:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH2:25][O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:32][CH:31]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(OCc3ccccc3)cc2)cc1
Reactant: OC1CCCC1
Agent: [Na]
Solvent: c1ccccc1
Solvent: O
Product: c1ccc(COc2ccc(CCOC3CCCC3)cc2)cc1
Temperature: 80 °C

Procedure:
24.11 g of cyclopentanol and then 1.63 g of sodium are introduced into a 250 ml round-bottomed flask. The mixture is heated at 110°-120° C. until the sodium has disappeared. The mixture is then cooled and 80 cc of benzene are added. 26.77 g of 2-(4-benzyloxyphenyl)ethanol tosylate are then introduced in portions. The mixture is heated at 80° C. for 3 hours. The benzene is driven off, the residue is taken up in water and the solution is extracted with ethyl acetate. This gives an oil.
Reaction SMILES: Cl.CCOC(C)=O.[CH2:8]([O:11][CH2:12][CH2:13][N:14]([CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH3:27])C(=O)OC(C)(C)C)[CH2:9][CH3:10]>>[CH2:25]([O:24][CH2:23][CH2:22][NH:14][CH2:13][CH2:12][O:11][CH2:8][CH2:9][CH3:10])[CH2:26][CH3:27]
Reactant: CCCOCCN(CCOCCC)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCOCCNCCOCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a solution of HCl in EtOAc (15 mL, 30 mmol, 2 M) was added tert-butyl bis(2-propoxyethyl)carbamate (1.78 g, 6.15 mmol). The reaction mixture was stirred at rt overnight, then concentrated in vacuo to give the title compound as colorless oil (1.16 g, 100%).