Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[CH3:7][C:8]1C=CC(S(O)(=O)=O)=C[CH:13]=1.C>CC(C)=O>[C:8](=[C:2]([CH:3]([CH2:5][OH:6])[OH:4])[OH:1])([CH3:13])[CH3:7]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCC(O)CO
Solvent: CC(C)=O
Product: CC(C)=C(O)C(O)CO
Reaction time: 24 h

Procedure:
Freshly distilled glycerol (10 g, 0. 11 mole) was shaken until dissolved with 65 mL of dry acetone containing 1 g of TsOH. After 24 hr. the solution was neutralized first with PbCO3 and afterwards with Ag2CO3, warmed with charcoal, and shaken with a large excess of CaCI2 overnight. The supernatant liquid was then filtered. The solvent was removed by rotary evaporation, and the product fractionated under diminished pressure, giving 9.5 g of the main fraction (b.p. 105-106° C./25 mm) Y=65.4%. NMR: 1H: δ (ppm) 4.14-4.16 (m,1H, CH), 3.65-4.0 (qxd, 2H, CH2),3.57 (m, 2H, CH2OH), 2.05 (sb. 1H,OH), 1.40, 1.33 (CH3); 13C: δ (ppm) 109.4 (COO), 76.1 (CH), 65.7 (CH2O), 62.8 (CH2OH), 26.6, 25.2 (CH3).
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29]1(O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[CH3:20][CH:19]([CH3:21])[C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@H:2]([O:1][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:12]=1)=[O:22]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Reactant: Oc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3ccccc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 23.7 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), phenol (4.70 mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) in THF (1.0 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (2.7 mg, 23.6% yield) as a thick oil: 1H NMR δ 7.46 (s, 2H), 7.40–7.30 (m, 4H), 7.25 (m, 3H), 7.20 (m, 2H), 6.97 (apparent d, 1H, J=7.4 Hz) 6.89 (apparent tt, 1H, J=0.8, 7.6 Hz), 6.84 (apparent dt, 1H, J=0.8, 8.0 Hz), 5.20 (apparent dd, 1H, J=4.4, 8.5 Hz), 3.35 (m, 2H), 2.91 (m, 2H), 2.60 (m, 2H), 2.30–2.10 (m, 6H), 1.90 (m, 2H), 1.25 (d, 6H, J=7.9 Hz); ESMS m/e: 457.4 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9](=[O:16])[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:17]O>>[CH3:17][O:14][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][C:9]([C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=1)=[O:16]
Reactant: CO
Reactant: O=C(O)CCCC(=O)c1ccc(O)c(O)c1
Product: COC(=O)CCCC(=O)c1ccc(O)c(O)c1

Procedure:
A solution of 5.6g of 5-(3,4-dihydroxyphenyl)-5-oxopentanoic acid in 300 ml of methanol is stirred together with 15g of Amberlyst 15 for 16 hours at room temperature. The reaction mixture is filtered on diatomaceous earth, concentrated by evaporation and the residue is chromatographed on silica gel with hexane/ethyl acetate (20-60%). 3.7 g of 5-(3,4-dihydroxyphenyl)-5-oxo-pentanoic acid methyl ester of melting point 104°-106° C. is obtained.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][C@H:16]1[NH:21][C@@H:20]([CH3:22])[CH2:19][N:18]([C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=2)[CH2:17]1.C(O)(=O)C>CO>[CH3:22][C@H:20]1[N:21]([CH3:1])[C@@H:16]([CH3:15])[CH2:17][N:18]([C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=2)[CH2:19]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCOC(=O)c1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(N2C[C@@H](C)N(C)[C@@H](C)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.9 %

Procedure:
Sodium triacetoxyborohydride (5.30 g, 25.00 mmol) was added to ethyl 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzoate (2.62 g, 10 mmol), and acetic acid (1.145 mL, 20.00 mmol) in methanol (15 mL) at 25° C. The resulting solution was stirred at ambient temperature for 18 h. The reaction mixture was quenched with saturated NaHCO3 (15 mL) to pH7 and the crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford an oil. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford ethyl 4-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)benzoate (1.960 g, 70.9%) as a yellow oil. MS: m/z 277 (MH+).
Reaction SMILES: Cl.[CH3:2][O:3][CH:4]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:5][O:6][C:7]([C:9]1[CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[C:17]2[C:16](=[O:26])[CH2:15][N:14](CC3C=CC=CC=3)[CH2:13][C:12]=2[NH:11][C:10]=1[CH3:34])=[O:8].[H][H]>[Pd].CO>[CH3:2][O:3][CH:4]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:5][O:6][C:7]([C:9]1[CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[C:17]2[C:16](=[O:26])[CH2:15][NH:14][CH2:13][C:12]=2[NH:11][C:10]=1[CH3:34])=[O:8]
Reactant: [H][H]
Reactant: COC(COC(=O)C1=C(C)NC2=C(C(=O)CN(Cc3ccccc3)C2)C1c1cccc(Cl)c1)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(COC(=O)C1=C(C)NC2=C(C(=O)CNC2)C1c1cccc(Cl)c1)c1ccccc1
Reaction time: 4 h
Yield: 35.5 %

Procedure:
A mixture of 15.3 g of 1-benzyl-3-hydroxy-5-oxo-2,3,4,6-tetrahydropyridine hydrate, 10.6 g of 3-chlorobenzaldehyde, 17.7 g of 2-methoxy-2-phenylethyl acetoacetate, 12 g of ammonium acetate and 150 ml of methanol was refluxed for 5 huors. The solvent was removed in vacuo. The residue was dissolved in methylenechloride, extracted with water, then dried over magnesium sulfate. The solution was diluted with diethyl ether to the point of cloudiness, then left at room temperature for 18 hours. The supernatant was decanted and the precipitate was slurried with ethanol and filtered to obtain 12.9 g of the solid, mp. 168°-170° C. dec. The solid was suspended in methanol and saturated with hydrogen chloride. The mixture was cooled in an ice bath, then filtered. The solid was recrystallized from ethanol to obtain 11.1 g of 4-(3-chlorophenyl)-1,4,5,6,7,8-hexahydro-2-methyl-5-oxo-7-(phenylmethyl)-1,7-naphthyridine-3-carboxylic acid 2-methoxy-2-phenylethyl ester hydrochloride, mp. 222°-4° C. dec. The hydrochloride (10.8 g), 1 g of 10% palladium on carbon and 450 ml of methanol were shaken with hydrogen at an initial pressure of 48.5 psig. After 4 hours, the catalyst was separated and the solution was evaporated to dryness The residue was dissolved in methanol, saturated with hydrogen chloride, then evaporated to dryness. The residue was recrystallized from ethanol to obtain 3 g of the title compound as the hydrochloride, monohydrate, mp. 165°-7° C.
Reaction SMILES: N[C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12.[Br:26]CBr.[N+]([O-])(OCCC(C)C)=O>C(OCC)(=O)C>[Br:26][C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N)nc21
Reactant: BrCBr
Agent: CC(C)CCO[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Br)nc21
Temperature: 60 °C
Yield: 98 %

Procedure:
A round bottom flask charged with 4-amino-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (134.4 mg, 0.397 mmol) under an atmosphere of nitrogen was treated with dibromomethane (397 μL). Isoamyl nitrate (107 μL, 0.794 mmol) was added and the reaction mixture was heated at 60° C. 3.5 h and cooled to rt. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. 4-Bromo-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (0.156 g, 0.388 mmol, 98% yield) was isolated as a brown glassy solid. The product was used immediately in the next reaction.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1>C(COC)OC.C(OC(=O)C)C>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:34]([C:33]3[CH:36]=[CH:37][C:30]([Cl:29])=[CH:31][CH:32]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[S:15]2(=[O:17])=[O:16])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(NC1CCN(Cc2ccccc2)CC1)c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=S1(=O)c2ccccc2C(c2ccc(Cl)cc2)N1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
To a solution of 19.16 g (58.1 mmol) of N-(1-benzylpiperidin-4-yl)-benzene sulfonamide in 300 mL of dimethoxyethane at 0° C. was added 46.4 mL (116.1 mmol) of a n-butyllithium (2.5 M) slowly via addition funnel. The mixture was stirred using an overhead stirrer for 45 minutes at 0° C., then 9.61 g (63.9 mmol) of p-chlorobenzaldehyde was added in one portion. The mixture was allowed to warm to room temperature, diluted with 1 liter of ethylacetate and washed 2×500 mL of water followed by 500 mL of brine. The organic phase was separated, dried (MgSO4), and concentrated in vacuo. The residue was flash chromatographed over 300 g of silica gel (eluted with ethylacetate:heptane-2:1) to afford 17.3 g of product as an orange paste.
Reaction SMILES: C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)C1C=CC=CC=1.[Cl:23][C:24]1[CH:45]=[CH:44][C:27]([CH2:28][N:29]2[CH2:33][CH2:32][N:31]([C:34]3[S:35][C:36]([C:40](O)=[O:41])=[C:37]([CH3:39])[N:38]=3)[C:30]2=[O:43])=[CH:26][CH:25]=1.[NH2:46][CH2:47][C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1>>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][N:29]2[CH2:33][CH2:32][N:31]([C:34]3[S:35][C:36]([C:40]([NH:46][CH2:47][C:48]4[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=4)=[O:41])=[C:37]([CH3:39])[N:38]=3)[C:30]2=[O:43])=[CH:44][CH:45]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(Cl)cc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(Cl)cc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 32 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-chlorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a white powder in 32% yield: mp 178-179° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 8.48 (s, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.30-7.16 (m, 5H), 6.42 (t, J=5.7 Hz, 1H), 4.56 (d, J=5.7 Hz, 2H), 4.40 (s, 2H), 4.09-3.97 (m, 2H), 3.44-3.39 (m, 2H), 2.57 (s, 3H); 13C NMR (75 MHz, CDCl3) d 162.6, 157.3, 155.4, 153.6, 149.0, 148.5, 135.9, 134.0, 133.9, 129.6, 129.0, 123.7, 117.0, 47.3, 42.0, 41.7, 41.3, 17.2; MS (ES+) m/z 442.3 (M+1), 444.3 (M+1).
Reaction SMILES: [OH-].[K+].[SH:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])=[N:6][N:5]=1.[CH3:20]I>CO>[CH3:20][S:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])=[N:6][N:5]=1
Reactant: NS(=O)(=O)Cc1ccccc1-c1nnc(S)o1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CSc1nnc(-c2ccccc2CS(N)(=O)=O)o1
Temperature: 30 °C
Reaction time: 0.08 h
Yield: 63.4 %

Procedure:
To a solution containing 0.62 g of potassium hydroxide in 50 ml of methanol was added 3 g of the oxadiazole prepared in Example 2. After stirring about five minutes, 2 g of methyl iodide was added. The suspension was refluxed 0.5 hour, cooled to 30° C., an extra 10 g of methyl iodide was added, and the suspension was refluxed an additional two hours, then concentrated in vacuo. After water was added to the residue, the suspension was filtered and the solid was washed with 1×50 ml of water. The suction-dried solid was recrystallized from 2-propanol to give 2 g of the subject compound: m.p. 138°-140° C.
Reaction SMILES: [CH:1]12[CH2:13][CH2:12][CH:8]([CH2:9][NH:10][CH2:11]1)[C:7]1[C:2]2=[CH:3][C:4]([NH:14][C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=3[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:32])=[CH:17][N:16]=2)=[CH:5][CH:6]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[Cl:32][C:18]1[C:19]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:20][C:15]([NH:14][C:4]2[CH:3]=[C:2]3[C:7](=[CH:6][CH:5]=2)[CH:8]2[CH2:12][CH2:13][CH:1]3[CH2:11][N:10]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:9]2)=[N:16][CH:17]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CNC2)ncc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CN(S(C)(=O)=O)C2)ncc1Cl
Reaction time: 0.08 h
Yield: 88.2 %

Procedure:
2-[2-(10-Aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-N-methyl-benzamide (30 mg, 0.0667 mmol) was placed in dichloromethane (3 mL) and triethylamine (20.3 mg, 0.201 mmol, 28.2 μL, 3.0 eq) was added followed by methanesulfonyl chloride (8.4 mg, 0.0734 mmol, 5.7 μL, 1.1 eq). The reaction was stirred for 5 minutes and then concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-8% MeOH/CH2Cl2 as the eluting solvent to obtain 2-[5-chloro-2-(10-methanesulfonyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as a yellow foam (31 mg, 88%). LCMS (m/e) 527 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 10.99 (s, 1H), 8.60 (d, 1H, J=7.8 Hz), 8.10 (s, 1H), 7.55-7.40 (m, 3H), 7.30-7.20 (m, 1H), 7.15-7.02 (m, 2H), 6.92 (s, 1H), 6.23 (bs, 1H), 3.87-3.77 (m, 2H), 3.20-3.05 (m, 4H), 3.03 (d, 3H, J=4.9 Hz), 2.47 (s, 3H), 2.20 (d, 2H, J=8.8 Hz), 1.81-1.70 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[C:10](=[O:22])[CH2:11][C:12]1[CH:17]=[C:16]([O:18]C)[CH:15]=[CH:14][C:13]=1OC.N1C(=O)CC[C@H]1C(O)=O.Cl>>[Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:10]1[O:22][C:13]2[CH:14]=[CH:15][C:16]([OH:18])=[CH:17][C:12]=2[CH:11]=1
Reactant: COc1ccc(C(=O)Cc2cc(OC)ccc2OC)c(Br)c1
Agent: Cl
Agent: O=C1CC[C@@H](C(=O)O)N1
Product: Oc1ccc(-c2cc3cc(O)ccc3o2)c(Br)c1
Temperature: 25 °C

Procedure:
Compound 101 (1.25 g, 3.4 mmol) was heated at 200° C. with a large excess of Pyr-HCl and followed by TLC for reaction completion (approx 30 min to 1 h). The reaction mixture was allowed to cool to rt and then partitioned between 2 N HCl aq and EtOAc. The organic layer was washed with saturated NaHCO3 aq, brine, and then dried over MgSO4. After filtering, the reaction mixture was concentrated and chromatographed on silica gel (1:1 EtOAc/hexanes) to yield 0.96 g of the desired pdt: Mp=195° C.; 1H NMR (DMSO-d6) δ 10.33 (br s, 1 H), 9.23 (br s, 1 H), 7.70 (d, 1 H, J=8.6 Hz); 7.37 (d, 1 H, J=8.8 Hz), 7.21 (s, 1 H), 7.16 (d, 1 H, J=2.4 Hz), 6.97 (d, 1 H, J=2.4 Hz), 6.92 (dd, 1 H, J=8.7 Hz, 2.4 Hz), 6.75 (dd, 1 H, J=8.8 Hz, 2.4 Hz); MS 303 (M−H)−.
Reaction SMILES: [Cl:1]C1CCN(C)C1.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCOCC>[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[ClH:1]
Reactant: CN1CCC(Cl)C1
Solvent: NCc1ccccc1
Solvent: CCOCC
Product: Cl

Procedure:
Compound 3-chloro-1-methyl pyrrolidine, 1.33 g (0.0111 mol), and 6.9 ml (6.3 g, 0.063 mol) benzylamine were combined and gently refluxed at 150° for 8 hr. Et2O was added to the cooled reaction and the white solid that formed (benzylamine.HCl) was filtered. The filtrate was distilled at atmospheric pressure to remove Et2O, then at water aspirator vacuum to remove benzylamine (bp 78°-85°) and then at 0.1 mm Hg to yield 1.24 g (52%) colorless liquid, bp 85°-88°. This was dissolved in 150 ml Et2O, treated with 2.3 ml 6N ethanolic HCl, stirred in ice for 1 hr, and filtered. Trituration in hot abs. EtOH followed by filtration yielded 0.55 g white solid, mp 105°-110°. An additional 0.1 g crystallized from the mother liquor, mp 113°-118°. A white solid weighting 0.5 g, mp 90°- 98°, was precipitated from the mother liquor with Et2O. The HCl.salt, mp 113°-118°, analyzed as an hydrate. Analysis calculated for C12H18N2.2HCl.H2O (percent): C, 51.25; H, 7.89; N, 9.96. Found (percent): C, 51.04; H, 7.61; N, 9.78.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>O>[C:10]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)(=[O:12])[CH3:11]
Reactant: O=C(O)C1CCNCC1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)N1CCC(C(=O)O)CC1
Temperature: 55 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
Isonipecotic acid (129.2 g, 1.00 mol) was dissolved in water (390 mL), and acetic anhydride (153.1 g, 1.50 mol) was added dropwise under ice-cooling for about 10 min. (dropwise addition at 15–18° C. for about 10 min.). After stirring at 55±5° C. for 2 hrs., the mixture was allowed to cool to room temperature and stirred under ice-cooling for 1 hr. The precipitated crystals were collected by filtration, washed with cold diisopropyl ether (125 mL×2) and dried under reduced pressure at 40° C. for 8 hrs. to give the title compound (129.1 g, yield 75.4%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9]3=[C:10]([CH2:17][CH2:18][CH2:19][N:8]3[CH:7]=1)[CH:11]=[CH:12][CH:13]=2)=[O:5])[CH3:2].[Br:20]Br>C(O)(=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9]3=[C:10]([CH2:17][CH2:18][CH2:19][N:8]3[CH:7]=1)[CH:11]=[C:12]([Br:20])[CH:13]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2c3c(cccc3c1=O)CCC2
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cn2c3c(cc(Br)cc3c1=O)CCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 134.1 %

Procedure:
To the solution of 1-Oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid ethyl ester (7.5 g, 29 mmol) in glacial acetic acid (120 mL) was added bromine (1.6 ml, 32 mmol). The mixture was stirred over night at room temperature, and new portion of bromine (1.6 mL, 32 mmol) was added. After 24 h, reaction mixture was diluted with 100 mL of H2O and pH was adjusted to 2.9. Precipitate was filtered and dried. The crude product was precipitated from CH2Cl2/Diisoprophylether and dried in vacuum drier yielding 13.07 g of the crude title product.
Reaction SMILES: [CH2:1]([C:8]1([CH2:23][CH2:24]OS(C)(=O)=O)[C:20](=[O:21])[N:11]2[CH2:12][CH:13]=[CH:14][CH:15]([C:16]([O:18][CH3:19])=[O:17])[N:10]2[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:30].[Na+]>>[CH2:1]([C:8]1([CH2:23][CH2:24][I:30])[C:20](=[O:21])[N:11]2[CH2:12][CH:13]=[CH:14][CH:15]([C:16]([O:18][CH3:19])=[O:17])[N:10]2[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1C=CCN2C(=O)C(CCOS(C)(=O)=O)(Cc3ccccc3)C(=O)N12
Reactant: [I-]
Agent: [Na+]
Product: COC(=O)C1C=CCN2C(=O)C(CCI)(Cc3ccccc3)C(=O)N12
Yield: 51.2 %

Procedure:
In a manner analogous to that described in Example 7(E), from 5.9 g of methyl 2-benzyl-2,3,5,8-tetrahydro-2-(2-methanesulfonyloxyethyl)-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate and 4.2 g of sodium iodide there were obtained 3.25 g (51%) of methyl 2-benzyl-2,3,5,8-tetrahydro-2-(2-iodoethyl)-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate in the form of a white solid having a melting point of 90°-92° C. (from diethyl ether).
Reaction SMILES: [NH2:1][CH:2]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][O:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>ClCCl>[Cl:24][CH2:25][C:26]([NH:1][CH:2]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][O:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2)=[O:27]
Reactant: NC1c2ccccc2OCc2ncccc21
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)NC1c2ccccc2OCc2ncccc21
Reaction time: 2 h
Yield: 90 %

Procedure:
In this example, 1.9 g of 5-amino-5,11-dihydro[1]benzoxepino[3,4-b]pyridine prepared in a similar manner to that in Example 24 and 0.9 g of triethylamine were dissolved in 30 ml of dichloromethane. A solution of 1.0 g of chloroacetyl chloride in 5 ml of dichloromethane was added dropwise thereto under ice cooling. The mixture was stirred under ice cooling for 2 hours, and concentrated under reduced pressure to distill away about two thirds of the dichloromethane. Then, 40 ml of diisopropyl ether and 10 ml of water were added thereto, and the mixture was stirred and filtered. Drying the residue gave 2.3 g of 5-(chloroacetyl)amino-5,11-dihydro[1]benzoxepino[3,4-b]pyridine as crude crystals.
Reaction SMILES: [Na+].[CH2:2]([N:9]1[C:21]2[CH2:20][CH2:19][CH2:18][CH:17]([C:22](=[O:24])[NH2:23])[C:16]=2[C:15]2[C:10]1=[CH:11][C:12]([O:30][CH3:31])=[CH:13][C:14]=2[O:25][CH2:26][C:27]([O-])=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[N:33](C)C=O.[H-].[Na+].BrCC#N>C(OCC)(=O)C.O1CCCC1>[CH2:2]([N:9]1[C:21]2[CH2:20][CH2:19][CH2:18][CH:17]([C:22]([NH2:23])=[O:24])[C:16]=2[C:15]2[C:10]1=[CH:11][C:12]([O:30][CH3:31])=[CH:13][C:14]=2[O:25][CH2:26][C:27]#[N:33])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C)C=O
Reactant: COc1cc(OCC(=O)[O-])c2c3c(n(Cc4ccccc4)c2c1)CCCC3C(N)=O
Agent: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(OCC#N)c2c3c(n(Cc4ccccc4)c2c1)CCCC3C(N)=O

Procedure:
A solution of 1.47 gram (4.19 mmol) of the product from Example 3, Part A in 146 ml. of dimethylformamide and 31 ml. tetrahydrofuran was treated with 210 mg. of sodium hydride (60% in mineral oil; 5.24 mmol) for 10 minutes and then with 0.39 ml. (0.66 mmol) of bromoacetonitrile for 3.5 hours. The mixture was diluted with ethyl acetate, washed with water, washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a gradient of 0 to 4% methanol in methylene chloride to give the titled product, 1.34 gram, 82%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:7]=1[Cl:13])[CH3:2].[Br:15][C:16]1[CH:17]=[CH:18][C:19](F)=[C:20]([CH:23]=1)[CH:21]=[O:22].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[C:10]([O:12][C:19]2[CH:18]=[CH:17][C:16]([Br:15])=[CH:23][C:20]=2[CH:21]=[O:22])[CH:9]=[CH:8][C:7]=1[Cl:13])[CH3:2]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CCOC(=O)Cc1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cc(Oc2ccc(Br)cc2C=O)ccc1Cl
Temperature: 110 °C
Yield: 32.8 %

Procedure:
(2-Chloro-5-hydroxy-phenyl)-acetic acid ethyl ester (0.5 g, 2.3 mmol), 5-bromo-2-fluorobenzaldehyde (0.33 mL, 2.8 mmol), and potassium carbonate (0.5 g, 3.5 mmol) were combined in 1,4-dioxane (30 mL) and heated to 110° C. for 3 days. After work-up, the crude material was purified by silica gel chromatography (0-20% EtOAc in hexanes) to give the desired product (0.3 g).