Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:40]=[C:39](I)[CH:38]=[CH:37][C:22]=1[C:23]([NH:25][C@H:26]([C:33]([O:35][CH3:36])=[O:34])[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:24].[C:42]([NH:48][C:49]1[N:50]=[C:51]([OH:61])[C:52]2[CH:58]=[C:57]([C:59]#[CH:60])[CH:56]=[N:55][C:53]=2[N:54]=1)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44].C(N(CC)CC)C>C(#N)C.[Pd](Cl)Cl.[Cu](I)I>[F:20][C:21]1[CH:40]=[C:39]([C:60]#[C:59][C:57]2[CH:56]=[N:55][C:53]3[N:54]=[C:49]([NH:48][C:42](=[O:47])[C:43]([CH3:46])([CH3:44])[CH3:45])[N:50]=[C:51]([OH:61])[C:52]=3[CH:58]=2)[CH:38]=[CH:37][C:22]=1[C:23]([NH:25][C@H:26]([C:33]([O:35][CH3:36])=[O:34])[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:24]
Reactant: COC(=O)CC[C@H](NC(=O)c1ccc(I)cc1F)C(=O)OC
Reactant: C#Cc1cnc2nc(NC(=O)C(C)(C)C)nc(O)c2c1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)CC[C@H](NC(=O)c1ccc(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)cc1F)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
A mixture of 0.44 g (2.56 mmol) of palladium chloride and 1.34 g (5.12 mmol) of triphenylphosphine in 200 mL of acetonitrile is stirred under nitrogen at room temperature for 30 minutes. To this mixture is added an additional 150 mL of acetonitrile, 22.09 g (52.2 mmol) of dimethyl N-(2-fluoro-4-iodobenzoyl)-L-glutamate, 13.830 g (51.2 mmol) of 2-pivaloylamino-4-hydroxy-6-ethynylpyrido[2,3-d]pyrimidine, 0.0244 g (1.28 mmol) of copper iodide, and 15 mL (107.5 mmol) of triethylamine. The reaction mixture is then heated at reflux for 3 hours and then cooled to room temperature, the solvent is then removed in vacuo and the crude solid chromatographed on silica gel with 1:19 methanol:methylene chloride to give 18.1 g (62.5%) of dimethyl N-(2-fluoro-4-[2-(2-pivaloylamino-4-hydroxypyrido[2,3-d]-pyrimidin-6-yl)ethynyl]-benzoyl)-L-glutamate as a white solid m.p. 204°-207° C. (dec); Rf =0.60 (1:19 methanol: chloroform), Mass (FD)=565; IR (KBr, cm-1)=813, 1151, 1201, 1270, 1375, 1444, 1481, 1490, 1527, 1548, 1598, 1623, 1649, 1670, 1741, 1753; UV (EtOH) λmax =325 (epsilon=41100), 266 (epsilon=14600), 210 (epsilon=35700).
Reaction SMILES: [CH2:1]1[O:11][C:10]2[C:3](=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[O:2]1.[OH-:12].[K+]>CCO.O.[N+]([O-])([O-])=O.[Ag+]>[CH2:1]1[O:11][C:10]2[C:3](=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]([OH:12])=[O:6])[O:2]1
Reactant: O=Cc1cccc2c1OCO2
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc2c1OCO2
Reaction time: 2 h

Procedure:
To a solution of 0.85 g (5.66 mmol) of 2,3-methylenedioxybenzaldehyde (Aldrich) in EtOH at 0° C. was added a solution of 2.12 g (12.45 mmol) of AgNO3 in 7.5 mL of H2O. To this was then added a solution of 1.74 g (31.4 mmol) of KOH in 12 mL of H2O. After 2 h, the reaction mixture was filtered and the filter was washed with EtOH. The filtrate was concentrated and the pH was adjusted to pH=2 to 3 with 6N HCl. The title compound precipitated out and was isolated by filtration to give the title compound. 1H NMR (CDCl3) δ6.16 (s, 2H), 6.92 (t, 1H, J=8 Hz), 7.04 (d, 1H, J=8 Hz), 7.48 (d, 1H, J=8 Hz);
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][NH2:9])=O.CCN(CC)CC.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1.C[CH2:40][O:41][C:42]([CH3:44])=[O:43]>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:26][C:44]([C:42]([O:41][CH3:40])=[O:43])=[N:9][N:8]=1
Reactant: NNC(=O)c1cccs1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1nnc(-c2cccs2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
2-Thiophenecarboxylic acid hydrazide (200 mg, 1.4 mmol) and Et3N (392 μL, 2.8 mmol) were dissolved in CH2Cl2 (7 mL) and treated with methyl oxalyl chloride (130 μL, 1.4 mmol) dropwise at 0° C. The reaction mixture was warmed slowly to room temperature and stirred for 16 h before the solvent was removed in vacuo. The residue was dissolved in toluene (13 mL) and treated with recrystallized Lawesson's reagent (1.14 g, 2.1 mmol), and warmed at 110° C. for 6 h. Upon completion, the reaction mixture was diluted with EtOAc and washed with water, saturated aqueous NaHCO3 and saturated aqueous NaCl. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. Flash chromatography (SiO2, 3×18 cm, 25% EtOAc-hexanes) afforded the title compound (106 mg, 33%) as a yellow solid: 1H NMR (CDCl3, 500 MHz) δ 7.66 (dd, 1H, J=0.9, 3.7 Hz), 7.58 (dd, 1H, J=0.9, 5.1 Hz), 7.16 (dd, 1H, J=3.9, 4.8 Hz), 4.05 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 166.5, 159.2, 158.4, 131.5, 131.2, 131.17, 128.5, 53.9; HRMS-ESI-TOF m/z 226.9943 ([M+H]+, C8H6N2O2S2 requires 226.9943).
Reaction SMILES: CC(CC[OH:13])CCC1C=CC=CC=1.N1C=CC=CC=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.O>CCOCC>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([OH:13])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: CC(CCO)CCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
Phenoxanol (30.00 g, 0.168 mol) and pyridine (130 mL) are combined in a flask fitted with a condenser, internal thermometer, mechanical stirrer and argon inlet. The solution is cooled to -10° C. and to it is added p-toluenesulfonyl chloride (39.28 g, 0.202 mol) in portions via Gooch tubing so as to maintain the reaction temperature between -10°-0° C. After 3 h, water (20 mL) is added in portions so as to keep the temperature of the reaction below 5° C. The reaction mixture is warmed to room temperature and then poured into a separatory funnel containing 275 mL of ether. The layers are separated and the organic layer is washed with 5M H2SO4 (75 mL), saturated CuSO4 solution (75 mL), water (2×75 mL) and saturated NaHCO3 solution (75 mL). After drying over MgSO4, the organic layer is filtered and concentrated to leave a light yellow liquid as phenoxanyl p-toluenesulfonate. Purity of the product is determined by thin layer chromatography and the structure confirmed by 1H and 13C NMR.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:4].[C:16]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(N(CC)CC)C.O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:11][CH2:12][N:13]([S:22]([C:19]3[CH:18]=[CH:17][C:16]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)(=[O:24])=[O:23])[CH2:14][CH2:15]2)=[N:7][CH:6]=1)=[O:4]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1cnc(N2CCNCC2)s1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc(-c4ccccc4)cc3)CC2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.9 %

Procedure:
To a solution of compound 11 (200 mg, 0.886 mmol) in dichloromethane (7.5 mL) were added 4-biphenyl sulfonyl chloride (333 mg, 1.320 mmol) and triethylamine (220 mg, 2.169 mmol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 4 h. Water (10 mL) followed by dichloromethane (10 mL) were added to the reaction mixture and the organic layer was separated, dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel to give the compound 12j as a solid (200 mg, 51.2%). HPLC: 99.88% (Rt=15.46 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:9][CH3:10])=[CH:4][CH:3]=1.[Br:18]Br.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.ClCCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)=[C:9]([Br:18])[CH3:10])=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: CC=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: ClCCCl
Product: CC(Br)=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
Into a reactor were introduced 2.00 g (8.69 mmol) of the 1,1-bis(4-fluorophenyl)propene and 25 mL of 1,2-dichloroethane under a nitrogen atmosphere. The contents were cooled to −20° C. A mixture of 1.39 g (8.69 mmol) of bromine and 12 mL of 1,2-dichloroethane was added dropwise thereto over 1 hour, and the resultant mixture was stirred at that temperature for 1 hour and then at room temperature for 16 hours. Subsequently, a solution prepared by mixing 0.703 mL (8.69 mmol) of pyridine with 20 mL of toluene was added dropwise thereto over 15 minutes, and this mixture was stirred at 100° C. for 2 hours and then cooled. Saturated aqueous sodium hydrogen carbonate solution was added to the resultant reaction mixture, which was then extracted with toluene. The resultant organic layer was washed with saturated aqueous sodium chloride solution and then dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was recrystallized from ethanol to obtain 1.21 g (45%) of the target compound as white crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:9])[C:3]=1[N+:15]([O-:17])=[O:16].[NH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:22]([NH:24][CH3:25])=[O:23].CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:12][C:11]([CH3:14])([CH3:13])[CH2:10][N:8]([CH3:9])[C:4]1[N:5]=[CH:6][N:7]=[C:2]([NH:18][C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=2[CH3:29])[C:22]([NH:24][CH3:25])=[O:23])[C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: CNC(=O)c1ccc(C)c(N)c1
Reactant: CN(CC(C)(C)C)c1ncnc(Cl)c1[N+](=O)[O-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(C)c(Nc2ncnc(N(C)CC(C)(C)C)c2[N+](=O)[O-])c1
Temperature: 80 °C
Yield: 80.2 %

Procedure:
(6-Chloro-5-nitro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-methyl-amine (1.0 mmol) was dissolved in p-dioxane (2 mL), and 3-amino-4,N-dimethyl-benzamide (0.2 g, 1.2 mmol) and DIEA (0.3 mL) were added. The resulting mixture was heated to 80° C. for overnight. The product (0.31 g, yield 80%) was purified by column silica gel chromatography. MS (m/z): 387 (M+H).
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Mg+2].FC(F)(F)S([O-])(=O)=O.[O:18]1[CH2:20][C@H:19]1[C:21]([O:23][CH3:24])=[O:22].[Si:25]([O:32][CH2:33][C@@H:34]([OH:36])[CH3:35])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>CCOC(C)=O>[Si:25]([O:32][CH2:33][C@@H:34]([O:36][CH2:20][C@H:19]([OH:18])[C:21]([O:23][CH3:24])=[O:22])[CH3:35])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: C[C@H](O)CO[Si](C)(C)C(C)(C)C
Reactant: COC(=O)[C@@H]1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Mg+2]
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](O)CO[C@@H](C)CO[Si](C)(C)C(C)(C)C
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 37.8 %

Procedure:
Magnesium trifluoromethanesulfonate (0.974 g, 3.02 mmol) was added in one portion to (S)-methyl oxirane-2-carboxylate (1.234 g, 12.08 mmol) and (S)-1-(tert-butyldimethylsilyloxy)propan-2-ol (CAS no. 113534-13-7) (2.30 g, 12.08 mmol) in EtOAc (5 mL) cooled to 10° C. The resulting suspension was stirred at 10° C. for 10 minutes and then warmed to 45° C. and stirred for 2 days. The crude product was purified by flash silica chromatography, eluting with 0 to 30% EtOAc in isohexane to afford the product (1.336 g, 37.8%). 1H NMR (400 MHz, DMSO) δ0.00 (s, 6H), 0.83 (s, 9H), 0.98 (d, 3H), 3.34-3.53 (m, 3H), 3.55-3.64 (m, 5H), 4.11 (q, 1H), 5.39 (d, 1H)
Reaction SMILES: CC1(C)O[C:5](=[CH:7][C:8](=[O:13])[C:9]([O:11][CH3:12])=[O:10])[CH2:4][O:3]1.[NH:15]([C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=1)[NH2:16]>C(O)(C)C>[Cl:23][C:22]1[C:17]([N:15]2[C:8]([OH:13])([C:9]([O:11][CH3:12])=[O:10])[CH2:7][C:5]([CH2:4][OH:3])=[N:16]2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: NNc1ncccc1Cl
Reactant: COC(=O)C(=O)C=C1COC(C)(C)O1
Solvent: CC(C)O
Product: COC(=O)C1(O)CC(CO)=NN1c1ncccc1Cl
Temperature: 35 °C
Reaction time: 18 h

Procedure:
The mixture of methyl 3-(2,2-dimethyl-1,3-dioxolan-4-ylidene)-2-oxopropanoate (20 g, 0.1 mol) and 2-hydrazino-3-chloropyridine (14.3 g, 0.1 mol) in 40 ml of isopropanol was stirred for 18 hours at 35° C. The precipitate was filtered off and washed with 15 ml of isopropanol. This gave 24.2 g (85%) of the product as a pale yellow solid with a melting point of 113° C.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[Cl:7][C:8]1[C:20]([Cl:21])=[CH:19][C:11]2[N:12]=[C:13](S(O)(=O)=O)[NH:14][C:10]=2[CH:9]=1>P(Cl)(Cl)(Cl)=O>[Cl:2][C:13]1[NH:14][C:10]2[CH:9]=[C:8]([Cl:7])[C:20]([Cl:21])=[CH:19][C:11]=2[N:12]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1nc2cc(Cl)c(Cl)cc2[nH]1
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1nc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
A modified procedure of Balli and Kersting procedure described in Balli, H. et al., Justis Liebigs Am. Chem. 1:647 (1961), was followed. A one liter three neck roundbottom flask was fitted with an over head stirrer and a reflux condenser connected to a gas scrubber. To the flask was added in order, phosphorus oxychloride (80 mL), phosphorus pentachloride (104.0 g, 0.5M) and 5,6-dichlorobenzimidazole-2-sulfonic acid (9) (66.8 g, 0.25M). The resulting mixture was carefully heated until an exothermic reaction occurred. The heat source was removed. When the reaction had subsided, the mixture was carefully heated to reflux. After all gas evolution had ceased (5 hr) the mixture was protected from moisture and allowed to cool to 25° C. The resulting thick slurry was carefully added to cold H2O (2.5 L) containing some ice. Ice was added as needed. The aqueous mixture was allowed to stand for 18 hr at 5° C. while the product precipitated. The pH of the mixture was adjusted to pH 8 with conc. NH4OH then acidified to pH 3 with glacial AcOH. The solid was collected by filtration, washed with H2O, then dried on the filter. The material was dissolved in THF, treated with charcoal, then filtered through Celite. The solvent was removed under reduced pressure. The solid residue was dried at 60° C. under reduced pressure for 18 hr to yield 39.9 g (72%) of 2,5,6-trichlorobenzimidazole (5). MP: 212°-214° C. (eff. then solidifies). See Kawashima, E. et al., Nucleic Acid Chemistry: Improved and New Synthetic Procedures, Methods and Techniques, eds. Townsend, L. B. et al., Wiley Interscience New York, N.Y., Part IV p. 96 (1991). TLC: Rf =0.89 (EtOAc; SiO2). Recrystallization from benzene-hexane raises the melting point to 223°-224° C.
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([CH3:9])[CH:5]=[C:4]([N:10]2[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11]2)[N:3]=1.Cl[S:17]([OH:20])(=[O:19])=[O:18].C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[OH-:8].[NH2:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:11][CH:12]=[CH:13][CH2:14][CH2:15]2)[CH:5]=[C:6]([CH3:9])[N+:7]=1[O:8][S:17]([OH:20])(=[O:19])=[O:18]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1cc(N2CC=CCC2)nc(N)[n+]1[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1cc(N2CC=CCC2)nc(N)[n+]1OS(=O)(=O)O
Product: [OH-]
Reaction time: 8 h

Procedure:
A mixture of 1.00 grams of 2-amino-4-methyl-6-(3,6-dihydro-1-(2H)-pyridinyl) pyrimidine-3-oxide, 1.15 grams of chlorosulfonic acid, and 2.50 grams of di-isopropylethylamine in 25 mls of chloroform is stirred overnight. The mixture is concentrated and the residue is stirred with aqueous sodium bicarbonate, filtered, and washed with ether to give 2-amino-6-methyl-4-(3,6-dihydro-1(2H)-pyridinyl)-1-(sulfooxy)-pyrimidinium hydroxide, inner salt.
Reaction SMILES: O.[NH2:2][C:3]1[N:8]=[C:7]([CH:9]2[CH2:11][CH2:10]2)[N:6]=[C:5]([C:12]([OH:14])=[O:13])[C:4]=1[Cl:15].S(Cl)(Cl)=O.[OH-].[Na+].Cl.[CH3:23]O>>[NH2:2][C:3]1[N:8]=[C:7]([CH:9]2[CH2:11][CH2:10]2)[N:6]=[C:5]([C:12]([O:14][CH3:23])=[O:13])[C:4]=1[Cl:15]
Reactant: Nc1nc(C2CC2)nc(C(=O)O)c1Cl
Reactant: CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)c1nc(C2CC2)nc(N)c1Cl
Temperature: 60 °C
Yield: 80 %

Procedure:
A 1-L flask equipped with a nitrogen bubbler connected to a trap and caustic-containing scrubber, an addition funnel, reflux condenser and thermocouple, was charged with 6-amino-5-chloro-2-cyclopropyl-4-pyrimidinecarboxylic acid monohydrate (144 g, 0.62 mol) and methanol (500 mL). Thionyl chloride (185 g, 115 mL, 1.58 mol) was added over about 30 minutes with cooling, and then the reaction mixture was heated at 60° C. for 12 h. The resulting mixture was concentrated at 40-45° C./6 kPa to remove excess methanol (about 300 mL), and the reaction mixture was diluted with water (580 mL). Phenolphthalein (5 mg) was added, and 50% aqueous NaOH (80 g, 1.0 mol) was added dropwise with cooling at 10-25° C. to bring the pH to about 9 as indicated by appearance of pink color. Then just enough 1 N aqueous hydrochloric acid was added to extinguish the pink color. The resulting slurry was cooled to 5° C. and filtered. The filtered wet cake was washed with water and dried to constant weight at 50° C./6 kPa to give 123 g (80% yield) of the title compound with 98% purity by HPLC analysis as a solid melting at 147-148° C.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]([OH:8])=[O:7])([O-:3])=[O:2].S(Cl)(Cl)=O.[CH2:13](O)[CH3:14]>C(Cl)(Cl)Cl>[N+:1]([CH2:4][CH2:5][C:6]([O:8][CH2:13][CH3:14])=[O:7])([O-:3])=[O:2]
Reactant: CCO
Reactant: O=C(O)CC[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CC[N+](=O)[O-]

Procedure:
A suspension of 116 g (0.97 mole) β-nitropropanoic acid (CAS number 504-88-1) in chloroform (1 l) is stirred and treated with 127.5 g (1.07 mole) thionyl chloride. A rapid evolution of gas takes place and the mixture is stirred one hour at room temperature. Ethanol (50 g, 1.07 mole) is added dropwise followed by rapid gas evolution. The mixture is stirred 72 hours, concentrated and distilled to yield ethyl β-nitropropanoate, bp 95°-105° C. at 15 mm. A solution of 182 g (1.84 mole) ethyl acrylate [CAS number 140-88-5] in t-butanol (150 ml) and 10 ml of Triton B is treated at 40° C. with 135.5 g (0.92 mole) of ethyl β-nitropropanoate. Additional portions of Triton B (2 ml×3) and ethyl acrylate (25 g×3) are added over a five-hour period. The mixture is cooled and poured into a solution of 100 ml of concentrated hydrochloric acid in water (1 l). The diethyl-γ-nitro-γ-carboethoxymethylpimelate is extracted using dichloromethane (4×500 ml). The combined extracts are dried over anhydrous magnesium sulfate, filtered, and concentrated to yield an oil. The oil (160 g) is dissolved in ethanol (1.5 l) and treated with hydrogen in the presence of 7 g 20% Pd/C. The mixture is filtered through filter aid and concentrated to yield a mixture of 5-carboethoxyethyl-5carboethoxymethyl-2-pyrrolidinone (major product), 5-carboethoxymethyl-5-carboxyethyl-2-pyrrolidinone, and 5-carboethoxyethyl-5-carboxymethyl-2-pyrrolidinone as an oil. The oil dissolved in 1 l of 50% ethanol is titrated with a solution of 50% sodium hydroxide with stirring at reflux accompanied by removal of ethanol. The hydrolyzed mixture is neutralized with concentrated hydrochloric acid to yield 5-carboxyethyl-5-carboxymethyl-2-pyrrolidinone in water. The water is removed at reduced pressure and the resulting solid is added to acetic anhydride (1 kg) with stirring. The mixture is heated at 100° C. for 16 hours. The mixture is filtered through filter aid and concentrated at reduced pressure to yield tetrahydro-3,5-dioxo-1H-pyrrolizine-7a(5H)acetic acid anhydride with acetic acid as an oil. The oil is dissolved in a minimum amount of acetonitrile, an equivalent amount of water is added, and the mixture is stirred 16 hours. The mixture is concentrated at reduced pressure to yield a solid. The solid is recrystallized from acetonitrile to yield tetrahydro-3,5 -dioxo-1H-pyrrolizine-7a(5H)-acetic acid with a melting point of 177°-180° C.
Reaction SMILES: BrC1C=C([O:8]C)C=CC=1.C([Li])(CC)C.[CH2:15]([N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[CH2:19][CH2:18]1)[CH3:16]>O1CCCC1.CCCCCC>[CH2:15]([N:17]1[CH2:22][CH2:21][C:20]([OH:8])([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[CH2:19][CH2:18]1)[CH3:16]
Reactant: COc1cccc(Br)c1
Reactant: CCN1CCC(c2cccc(OC)c2)CC1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCN1CCC(O)(c2cccc(OC)c2)CC1
Temperature: -50 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
To a stirred solution of 3-bromoanisole (12.83 g, 0.069 mol) in dry tetrahydrofuran (70 ml) at -50° C. under an atmosphere of nitrogen was added sec-butyllithium (1.3M in hexanes, 68.5 ml, 0.089 mol) dropwise, ensuring that the temperature in the reaction vessel did not rise above -50° C. After complete addition of the sec-butyllithium, a white precipitate formed, and the reaction was stirred for 1 hour at -50° C. N-Ethyl-4-(3-methoxyphenyl)piperidine (10.5 ml, 0.079 mol) in dry tetrahydrofuran (50 ml) was added dropwise at a rate to maintain the reaction temperature below -40° C., resulting in an orange solution. The reaction mixture was allowed to warm to -20° C. over 1.5 hours, and then to room temperature over a further 1 hour. After this time, the reaction mixture was quenched by the addition of saturated brine (21 ml) and water (30 ml). The quenched reaction was stirred for a further 30 minutes, and then the two phases separated, and the organic phase retained. The aqueous phase was extracted with dichloromethane (3×75 ml), and the two organics combined and washed with hydrochloric acid (1N, 2×50 ml). The aqueous layer was separated, basified with ammonium hydroxide to pH 10, and extracted with dichloromethane (3×40 ml). The dichloromethane extracts were concentrated to yield a thick oil, which was triturated in cold hexane until a solid was obtained. This crude solid was stirred in hot hexane, allowed to cool, and filtered to yield N-ethyl-4-hydroxy-4-(3-methoxyphenyl)piperidine (5.5 g, 33.7%) as a white solid. m.p.=86.7-91.1° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH2:22]Cl)=[CH:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH:24]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH2:22][N:24]3[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(S(=O)(=O)n2cc(CCl)c3ccccc32)cc1
Reactant: C1CNCCNC1
Product: CC(C)c1ccc(S(=O)(=O)n2cc(CN3CCCNCC3)c3ccccc32)cc1

Procedure:
Using essentially the same procedure as described in example 127, 1-(4-isopropylbenzenesulfonyl)-3-chloromethyl-1H-indole was reacted with homopiperazine to obtain the above derivative.
Reaction SMILES: [CH3:1][C:2]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[C:9]([Cl:16])[CH:8]=1)=[O:5].S(Cl)([Cl:24])=O>>[CH3:1][C:2]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:24])=[O:12])=[C:9]([Cl:16])[CH:8]=1)=[O:5]
Reactant: Cc1c(F)cccc1C(=O)Nc1ccc(C(=O)O)c(Cl)c1
Reactant: O=S(Cl)Cl
Product: Cc1c(F)cccc1C(=O)Nc1ccc(C(=O)Cl)c(Cl)c1

Procedure:
A mixture of 1.85 g of 4-[(2-methyl-3-fluorobenzoyl)amino]-2-chlorobenzoic acid in 30 ml of thionyl chloride under argon is heated at reflux for 1 hour. The thionyl chloride is evaporated in vauco to a residue which is stirred with hexane and collected to give 1.94 g of 4-[(2-methyl-3-fluorobenzoyl)amino]-2-chlorobenzoyl chloride which is dissolved in 25 ml of methylene chloride and 0.49 g of N,N-diisopropylethylamine added, followed by 0.65 g of 6,11-dihydro-5H-dibenz[b,e]azepine. The reactants are stirred at room temperature for 18 hours and washed with water, saturated NaHCO3, dried (Na2SO4) and passed through a short pad of hydrous magnesium silicate to give 1.19 g of the desired product as a glass.