Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[F:10][C:11]1[CH:12]=[C:13]([CH:29]=[CH:30][CH:31]=1)[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1>C1COCC1>[F:10][C:11]1[CH:12]=[C:13]([CH:29]=[CH:30][CH:31]=1)[CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[C:23]3=[N:28][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:24]3[CH:25]=[CH:26][CH:27]=2)=[CH:20][CH:21]=1
Reactant: Nc1ncccc1-c1ccc(OCc2cccc(F)c2)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC=C(c3ccc(OCc4cccc(F)c4)cc3)C2=N1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 136 mg) in THF (dry) (10 mL) was added 2-chloroethanesulfonyl chloride (0.214 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-{4-[(3-fluorobenzyl)oxy]phenyl}pyridin-2-amine (200 mg) in THF (dry) (10 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen overnight. The mixture was quenched with water at 0° C. carefully. Water was added to form precipitates which were washed with water, hexane and collected. The precipitate was sonicated in EtOAc and the insoluble material was collected to give 9-{4-[(3-fluorobenzyl)oxy]phenyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (317.7 mg) as an off-white solid. This was crystallized from MeOH-THF/IPE to give an off-white crystal.
Reaction SMILES: [CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:5](Cl)=[O:6])([CH3:3])[CH3:2].C([NH+](CC)CC)C.CC[O:24]CC>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([CH:4]([CH:1]([CH3:3])[CH3:2])[C:5]([OH:24])=[O:6])=[CH:9][CH:10]=1
Reactant: CC(C)C(C(=O)Cl)c1ccc(Cl)cc1
Reactant: CCOCC
Agent: CC[NH+](CC)CC
Product: CC(C)C(C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution was prepared by admixing 3.0 grams (0.014 mole) of 6-(phenoxy)picolinalcohol, 3.5 grams (0.015 mole) of 2-isopropyl-2-(4-chlorophenyl)acetic acid chloride 10 milliliters of triethylammonium and 100 milliliters of dry ether. The reaction mixture was agitated at room temperature for 1 hour. The resulting reaction product mixture was successively washed with dilute hydrochloric acid, dilute sodium hydroxide, dried over anhydrous magnesium sulfate, filtered through silica gel and concentrated to give 5.3 grams of the desired 4-chloro-α-(1-methylethyl)benzeneacetic acid:(6-phenoxy-2-pyridinyl)methyl ester. The product, a viscous yellow oil, had a refractive index of 1.5664 and the structure of the product was confirmed by NMR. Upon analysis, the product was found to have carbon, hydrogen and nitrogen contents of 68.83, 5.19 and 3.10 percent, respectively, as compared with the theoretical contents of 69.78, 5.60 and 3.54 percent, respectively, as calculated for the above named compounds (Compound No. 2).
Reaction SMILES: OC1C2N=NNC=2C=CC=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:22][C:21]([CH3:23])=[N:20][C:19]=2[C:24]([OH:26])=O)=[CH:14][CH:13]=1.[CH2:27]1[C:29]2([CH2:34][CH2:33][NH:32][CH:31]([CH2:35][NH:36][C:37]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:38]=3[C:39]([O:41][CH3:42])=[O:40])[CH2:30]2)[CH2:28]1>ClCCl>[Cl:47][C:44]1[CH:45]=[CH:46][C:37]([NH:36][CH2:35][CH:31]2[N:32]([C:24]([C:19]3[N:20]=[C:21]([CH3:23])[S:22][C:18]=3[C:15]3[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=3)=[O:26])[CH2:33][CH2:34][C:29]3([CH2:27][CH2:28]3)[CH2:30]2)=[C:38]([CH:43]=1)[C:39]([O:41][CH3:42])=[O:40]
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: COC(=O)c1cc(Cl)ccc1NCC1CC2(CCN1)CC2
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)ccc1NCC1CC2(CCN1C(=O)c1nc(C)sc1-c1ccc(F)cc1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of hydroxybenzotriazole (13 mg, 0.097 mmol) and O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate HCl (23 mg, 0.12 mmol) in anhydrous dichloromethane (2 ml), 5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid (23 mg, 0.097 mmole) was added and the resulting solution was stirred 1 h at room temperature. (±) methyl 2-(6-azaspiro[2.5]octan-5-ylmethylamino)-5-chlorobenzoate (intermediate 10) (20 mg, 0.08 mmol) was added and the resulting mixture was stirred at the same temperature overnight. The mixture was washed with NaHCO3 saturated solution (3×5 ml).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cl-].[Na+].O>[CH2:9]([O:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][CH:6]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(OCc2ccccc2)cn1
Temperature: 40 °C

Procedure:
6-Chloropyridin-3-ol (6 g, 46 mmol) in N,N-dimethylformamide (50 mL) was treated with benzylbromide (5.5 mL, 46 mmol) and potassium carbonate (12.8 mmol) and the reaction mixture heated to 40° C. for 18 hours. The reaction was cooled to room temperature, poured into brine (200 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with brine (3×100 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 5-benzyloxy-2-chloropyridine. This crude product was dissolved in propionitrile (50 mL) and treated with trimethylsilylbromide (12.36 mL, 92 mmol) and the reaction mixture was heated at 100° C. for 113 hours. The reaction mixture was cooled to room temperature and poured into 2.0 M sodium hydroxide solution to which 50 g of ice had been added. The aqueous phase was extracted with diethyl ether, (3×75 mL). The organic layers were combined and washed with water (2×100 mL) and brine (75 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue (light brown oil) was purified by flash column chromatography on silica gel using 8% ethyl acetate:hexanes as eluent to give 4.72 g of the title compound as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 5.19 (s, 2H), 7.42 (m, 6H), 7.57 (d, J=6 Hz, 1H), 8.19 (d, J=3 Hz, 1H), MS (DCI/NH3) m/e 365 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=3)[C:6]=2[CH:20]=1.[NH2:21][C:22]1[N:27]=[C:26](Cl)[C:25]([C:29]#[N:30])=[CH:24][N:23]=1.CCN(C(C)C)C(C)C>CC(O)C.CO>[NH2:21][C:22]1[N:27]=[C:26]([NH:12][C@H:10]([C:8]2[N:7]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=3)[C:6]3[CH:20]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH3:11])[C:25]([C:29]#[N:30])=[CH:24][N:23]=1
Reactant: N#Cc1cnc(N)nc1Cl
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: C[C@H](Nc1nc(N)ncc1C#N)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Temperature: 25 °C
Yield: 57 %

Procedure:
A mixture of (S)-1-[6-fluoro-1-(5-fluoropyridin-3-yl)-1H-benzoimidazol-2-yl]-ethylamine.2HCl (118 mg, 0.34 mmol), 2-amino-4-chloropyrimidine-5-carbonitrile (40 mg, 0.26 mmol) and DIPEA (222 μL, 1.29 mmol) in IPA (0.75 mL) was heated at 90° C. in a sealed vial for 18 h. After cooling to RT, the reaction mixture was diluted with MeOH and loaded into an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in DCM) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a gradient 5-75%, 0.1% NH4OH in acetonitrile/water) to afford 363 as a white solid (58 mg, 57%). LCMS (Method K): RT 3.10 min [M+H]+ 392.97. 1H NMR (DMSO-d6, 400 MHz): δ 8.66 (1H, d, J=2.64 Hz), 8.62 (1H, s), 8.06 (1H, s), 8.03 (1H, d, J=9.27 Hz), 7.76-7.75 (2H, m), 7.15 (1H, ddd, J=9.85, 8.79, 2.51 Hz), 7.08 (1H, dd, J=8.96, 2.50 Hz), 7.05-6.60 (2H, m), 5.56 (1H, m), 1.55 (3H, d, J=6.75 Hz)
Reaction SMILES: C([BH3-])#N.[Na+].[Cl:5][C:6]1[CH:7]=[C:8]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=2)[CH:12]=[C:11]1[C:20]([O:22][CH3:23])=[O:21].[C:28]([O:32][CH2:33][CH3:34])(=[O:31])[CH:29]=O.C(O)(=O)C>CO>[Cl:5][C:6]1[CH:7]=[C:8]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][CH2:29][C:28]([O:32][CH2:33][CH3:34])=[O:31])=[CH:16][CH:17]=2)[CH:12]=[C:11]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1cc2cc(N)ccc2n1Cc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)CNc1ccc2c(c1)cc(C(=O)OC)n2Cc1ccc(Cl)c(Cl)c1
Reaction time: 0.08 h
Yield: 67 %

Procedure:
Sodium cyanoborohydride (0.2 g) was added in a single portion to methyl N-(3,4-dichlorobenzyl)-5-aminoindole-2-carboxylate (0.16 g), ethyl glyoxalate (0.2 ml of 50 wt % solution in toluene) and acetic acid (0.1 ml) in methanol (3 ml). The reaction was stirred for 5 mins then partitioned between ethyl acetate and 2M HCl. Combined organic extracts were dried (MgSO4) and concentrated to give an oil which crystallised upon trituration with i-hexane. Filtration yielded the desired end product as an off-white powder (0.136 g, 67%); NMR δ(CD3SOCD3) 1.18 (t, 3H), 3.79 (s, 3H), 3.82 (d, 2H), 4.08 (q, 2H), 5.72 (s, 2H), 6.60-7.50 (m, 7H); M/z (+) 435 (M+), 133.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH2:27]C#N)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[ClH:32].[C:33](=[O:36])([O-])[OH:34].[Na+]>COCCOCCO.[OH-].[Na+]>[ClH:32].[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH2:27][C:33]([OH:34])=[O:36])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])O
Reactant: CC(C)(C)c1csc(-c2cc3cc(OCc4ccccc4CC#N)ccc3o2)n1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: COCCOCCO
Product: CC(C)(C)c1csc(-c2cc3cc(OCc4ccccc4CC(=O)O)ccc3o2)n1
Temperature: 115 °C

Procedure:
A mixture of 4-tert-butyl-2-[5-(2-cyanomethylphenylmethoxy)benzofuran-2-yl]thiazole (0.5 g) and 40% aqueous potassium hydroxide (10 ml) in diethylene glycol monomethyl ether (10 ml) was heated at 110-120° C. for 1.5 hours. After being cooled, the resulting solution was poured into ice-water, acidified with diluted aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give crude residue. The residue was subjected to column chromatography on silica gel and eluted with a mixture of n-hexane and ethyl acetate (4:1). The fractions containing object compound were combined and concentrated to give an oil. The oil was dissolved in aqueous sodium hydrogen carbonate and washed with ethyl acetate. The ethyl acetate layer was concentrated under reduced pressure to give an oil, which was dissolved in aqueous sodium hydroxide and adjusted to pH 1 with diluted aqueous hydrochloric acid. The resulting precipitates were collected by filtration and washed with water to give 4-tert-butyl-2-[5-(2 -carboxymethylphenylmethoxy)benzofuran-2-yl]thiazole hydrochloride (5.00 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([Cl:23])[CH:15]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].O.Cl>[Fe].C(O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([Cl:23])[CH:15]=2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)c2ccc([N+](=O)[O-])c(Cl)c2)cc1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1ccc(S(=O)(=O)c2ccc(N)c(Cl)c2)cc1
Yield: 1304.3 %

Procedure:
Iron powder (2.5 g) was added to a stirred mixture of 4-(4-acetamidophenyl-sulphonyl)-2-chloro-nitrobenzene (Method 13) (0.67 g), water (2 ml), concentrated hydrochloric acid (0.5 ml) and ethanol (10 ml). The mixture was heated under reflux for 1 hour then evaporated to near dryness and partitioned between ethyl acetate and water. The organic layer was separated the aqueous layer was extracted with ethyl acetate (3×15 ml). The organic extracts were combined and dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-2% methanol/DCM to give the title compound (0.1 8 g) as a solid. NMR: 2.05 (s, 3H), 6.4 (s, 2H), 6.8 (d, 1H), 7.5 (d, 1H), 7.6 (d, 1H), 7.8 (q, 4H), 10.3 (brs, 1H); MS (ESP−): 323.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2].[CH2:40]1[O:48][C:47]2[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][C:42]=2[O:41]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(COC)OC>O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[C:24]([C:45]3[CH:44]=[CH:43][C:42]4[O:41][CH2:40][O:48][C:47]=4[CH:46]=3)[CH:23]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2]
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(OCC)c2)c1CCC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCC)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC
Temperature: 96 °C
Reaction time: 15 h
Yield: 99.7 %

Procedure:
To a mixture of 4-[3-[6-(3-bromo-5-ethoxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (155 mg, 0.255 mmol), 3,4-methylenedioxybenzeneboronic acid (85 mg, 0.51 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73 mg, 0.1 mmol), and cesium carbonate (166 mg, 0.51 mmol) was added dimethoxyethane (10 mL) at room temperature under nitrogen atmosphere. The resulting brown reaction mixture was heated to 96° C. and stirred for 15 h at which time the TLC analysis of the reaction mixture indicated the absence of starting material. Then, the reaction mixture was cooled to room temperature and diluted with water (50 mL) and ethyl acetate (50 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL) and the combined organic extracts were washed with water (50 mL) and brine solution (50 mL). The organic layer was dried over anhydrous magnesium sulfate and filtration of the drying agent and removal of the solvent under vacuum gave the colored residue which was purified by using an ISCO 40 column, eluting with 0-25% ethyl acetate in hexanes to obtain 4-[3-[6-(3-benzo[1,3]dioxol-5-yl-5-ethoxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (165 mg, 99%) as a colorless viscous oil: ES(+)-LRMS m/e calcd for C38H48O9 (M+Na)+ 671.3190. found 671.3185.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[O:10][C:6]=2[C:5]([C:12]#[N:13])=[CH:4][CH:3]=1.N(C1C2CCCCC=2C(C#N)=CC=1)=C=O.[OH:29][C@H:30]1[C@@H:37]2[N:33]([C:34](=[O:51])N(C3C4CCCCC=4C(C#N)=CC=3)[C:36]2=[O:38])[CH2:32][CH2:31]1>>[OH:29][C@H:30]1[C@@H:37]2[N:33]([C:34](=[O:51])[N:1]([C:2]3[C:7]4[N:8]=[C:9]([CH3:11])[O:10][C:6]=4[C:5]([C:12]#[N:13])=[CH:4][CH:3]=3)[C:36]2=[O:38])[CH2:32][CH2:31]1
Reactant: Cc1nc2c(N)ccc(C#N)c2o1
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1CCCC2
Agent: N#Cc1ccc(N=C=O)c2c1CCCC2
Product: Cc1nc2c(N3C(=O)[C@@H]4[C@H](O)CCN4C3=O)ccc(C#N)c2o1

Procedure:
The title compound was prepared from 11C by procedures analogous to those described in Example 2 (2E to 2F) to give the product as a white foam. HPLC: 99% pure at 10.55 min (retention time) (CHIRALPAK® OD column 4.6×250 mm; 25% isopropanol in hexane over 30 min, 1 mL/min, monitoring at 220 nm); MS (ES) m/z 313 [M+1]+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1>CO.[Pd]>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[C:9]([NH2:13])[CH:10]=[CH:11][CH:12]=1
Reactant: C[C@H]1CCCN1c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CCCN1c1cccc(N)c1
Reaction time: 16 h
Yield: 106.2 %

Procedure:
A mixture of (S)-2-methyl-1-(3-nitrophenyl)pyrrolidine (1.1 g, 5.34 mmol) and Pd/C (0.2 g) in MeOH (50 mL) was purged with H2 then stirred for 16 hours under H2 atmosphere. Catalyst was removed by filtration and filtrate concentrated to give crude (S)-3-(2-methylpyrrolidin-1-yl)benzenamine (1 g, 100%), used into the next step without further purification. LC-MS: 177 [M+H]+, tR=1.09 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13])[CH3:2].O=S(Cl)Cl.[CH3:19]O>>[CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:19])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13])[CH3:2]
Reactant: CCc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CO
Solvent: O=S(Cl)Cl
Product: CCc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a suspension of 4-ethyl-3-nitrobenzoic acid (5.76 g, 29.53 mmol) in methanol (30 mL) at 0° C., was added SOCl2 (10.54 g, 88.61 mmol) slowly, stirred at this temperature for 1 h, then heated to 50° C. and stirred at this temperature for 3 h. Cooled to room temperature and removed the solvent, the residue was extracted with ethyl acetate, and concentrated to give 6.05 g of the title compound (98%). 1H NMR (400 MHz, CDCl3): δ 1.31 (3H, t, J=7.2 Hz), 2.97 (2H, q, J=7.2 Hz), 3.96 (3H, s), 7.47 (1H, d, J=8.4 Hz), 8.17 (1H, dd, J=1.6, 8.4 Hz), 8.52 (1H, d, J=1.6 Hz).
Reaction SMILES: [C:1]1([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:14][C:15](OCC)=[O:16])[CH2:8][C:9](OCC)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(CCC(C)=O)=O.CC(C[AlH]CC(C)C)C.CO>C1(C)C=CC=CC=1.O>[C:1]1([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:8][CH:9]=[O:10])[CH2:14][CH:15]=[O:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(CC(=O)OCC)(c1ccccc1)c1ccccc1
Agent: CC(=O)CCC(C)=O
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: O=CCC(CC=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a rapidly stirring solution of 14.24 g(0.04 mole) of diethyl 3,3-diphenylglutarate, prepared by the method of H. Ivanov and I. Anghelova, Comptes Rendus Acan. Bul. Sci., 18 (6), 529-32(1965), in 320ml of dry toluene at -78° C. under argon was added 61.12 ml (0.11 mole) of 1.86M DIBAL in toluene solution (Aldrich) over a period of 4 minutes. After 40 minutes, 40 ml of methanol was added over 4 minutes to the -78° C., stirring reaction mixture. After an additional 5 minutes of stirring, 80 ml of water was added over a 5 minute period while keeping the temperature of the reaction at -78° C. The reaction mixture was allowed to warm to room temperature and was stirred an addititional hour. The reaction mixture was filtered and the precipitated salts washed with 300 ml of warmed toluene (100° C.) and then 300 ml of boiling methylene chloride. The organic phase of the filtrate was separated, dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo giving a clear oil. The oil was used in the next step without further purification.
Reaction SMILES: [CH3:1]C(=O)C.C(=O)=O.C[Li].[Cl:10][C:11]1[CH:16]=[C:15]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:14]=[C:13]([Cl:25])[C:12]=1[CH:26]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:27](Cl)=[O:28].[Cl-].[NH4+]>O(CC)CC.O.[Cu]I.O1CCCC1>[Cl:25][C:13]1[CH:14]=[C:15]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:16]=[C:11]([Cl:10])[C:12]=1[CH:26]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:27](=[O:28])[CH3:1]
Reactant: CC(C)=O
Reactant: O=C(Cl)C(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Agent: [Cu]I
Agent: O=C=O
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)C(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Reaction time: 0.5 h
Yield: 18.8 %

Procedure:
To a stirred and cooled (-70° C., 2-propanone/CO2 bath) solution of 5.7 parts of copper(I) iodide in 67.5 parts of tetrahydrofuran were added dropwise 37.5 parts of a methyllithium solution 1.6 M in 1,1'-oxybisethane during a period of 15 minutes under nitrogen atmosphere. Upon complete addition, stirring was continued for 30 minutes at this low temperature. A mixture of 4.45 parts of 2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetyl chloride and 22.5 parts of tetrahydrofuran was added dropwise during a period of 30 minutes at -65° C. Upon completion, stirring was continued first for 2 hours at -60° C. and then for 1 hour at -20° C. A saturated ammonium chloride solution in water was added dropwise (exothermic reaction). The precipitate was filtered off and from the filtrate, the organic layer was dried, filtered and evaporated. The residue was purified three times by column chromatography over silica gel: twice using a mixture of trichloromethane and methanol (95:5 and 98:2 by volume) and then a mixture of trichloromethane and ethyl acetate (92.5:7.5 by volume) as eluents. The pure fractions were collected and the eluent was evaporated in vacuo. The residue was stirred in acetonitrile. The product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 0.8 parts (18.8%) of 2-[3,5-dichloro-4-[1-(4-chlorophenyl)-2-oxopropyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione; mp. 208.4° C. (intermediate 42).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:31][C:32]1[C:37]([Cl:38])=[CH:36][C:35]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:34][C:33]=1[Cl:47]>C1COCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH:15]([CH2:31][C:32]1[C:33]([Cl:47])=[CH:34][C:35]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[CH:36][C:37]=1[Cl:38])[CH2:16][CH:17]=[CH2:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: Clc1cc(OCc2ccccc2)cc(Cl)c1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -75 °C
Yield: 86 %

Procedure:
Stir a mixture of (R)-4-benzyl-3-pent-4-enoyl-oxazolidin-2-one (345 g, 1.33 mol) and THF (1.8 L) in a 12 L 3-neck round bottom flask, with internal temperature probe/nitrogen inlet and addition funnel, under a nitrogen atmosphere and cool to −75° C. Transfer 1 M LiHMDS (1.6 L) to the addition funnel and add at a rate such that the internal temperature does not reach above −60° C. After the addition is complete, allow the reaction to stir at −25° C. for 30 min then cool to about −60° C. At this point add solid 2-bromomethyl-1,3-dichloro-5-benzyloxy-benzene portionwise over 5 min. After the addition is complete, transfer the reaction vessel to a −10° C. acetone bath and maintain the internal reaction temperature below 10° C. for 1 hr. Cool the mixture to 0° C. then quench with 2 L aqueous 1N hydrochloric acid. Transfer the mixture to a 22 L separatory funnel and dilute with 2.5 L water and 2 L ether. Separate the layers and extract the aqueous layer with ether. Dry the combined organic phase over anhydrous magnesium sulfate, filter and concentrate to 800 g of a thick oil. Purify by silica gel chromatography using hexanes:ethyl acetate to obtain 597 g, (86%) of a colorless oil.