Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]3[CH:16]=[C:15]4[C@:17]5([CH2:30][C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=6)[CH2:29][CH2:28][C:23]6(OCC[O:24]6)[CH2:22][C@H:18]5[CH2:19][CH2:20][CH2:21][C:14]4=[CH:13][C:12]=23)=[CH:4][CH:3]=1.Cl.C([O-])(O)=O.[Na+].CCOC(C)=O>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[N:10][N:11]3[CH:16]=[C:15]4[C:17]5([CH2:30][C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=6)[CH2:29][CH2:28][C:23](=[O:24])[CH2:22][CH:18]5[CH2:19][CH2:20][CH2:21][C:14]4=[CH:13][C:12]=23)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2nnn3cc4c(cc23)CCC[C@@H]2CC3(CC[C@@]42Cc2ccccn2)OCCO3)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C1CCC2(Cc3ccccn3)c3cn4nnc(-c5ccc(F)cc5)c4cc3CCCC2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
rac-(4aR,13bS)-9-(4-Fluorophenyl)-13 b-(pyridin-2-ylmethyl)-1,2,4,4a,5,6,7,13 b-octahydrospiro[benzo[3,4]cyclohepta[1,2-d][1,2,3]triazolo[1,5-a]pyridine-3,2′-[1,3]dioxolane] (156, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (0.230 g, 0.475 mmol) in acetone (3 mL) was treated with 6 N hydrochloric acid (0.060 mL, 0.322 mmol) then stirred at rt for about 3 h. Sat. aq. NaHCO3 (˜5 mL) and EtOAc (15 mL) were added to the mixture then the layers were separated. The organic layer was washed with brine (˜5 mL) then dried over MgSO4, filtered and concentrated in vacuo to yield rac (4aR,13bS)-9-(4-fluorophenyl)-13b-(pyridin-2-ylmethyl)-4,4a,5,6,7,13b-hexahydro-1H-benzo[3,4]cyclohepta[1,2-d][1,2,3]triazolo[1,5-a]pyridin-3(2H)-one (157, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (0.142 g, 68%); LC/MS, method 3, Rt=2.30 min, MS m/z 441 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 8.36-8.27 (m, 1H), 8.12 (s, 1H), 8.11-8.03 (m, 2H), 7.48-7.30 (m, 3H), 7.08-6.98 (m, 1H), 6.64 (d, J=7.8 Hz, 1H), 3.85-3.73 (m, 1H), 3.55-3.42 (m, 2H), 2.75-2.64 (m, 1H), 2.42-2.23 (m, 3H), 2.20-2.02 (m, 5H), 1.79-1.68 (m, 1H), 1.49-1.36 (m, 1H), 1.29-1.21 (m, 1H).
Reaction SMILES: OCCCCCCCCN[C:11]([C:13]1[CH:14]=[C:15]([S:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([CH3:32])[CH:31]=2)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]3[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)=[O:12].[Si:45]([O:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][O:59][CH:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46]>>[Si:45]([O:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][O:59][CH:60]1[CH2:65][CH2:64][N:63]([C:11]([C:13]2[CH:14]=[C:15]([S:19]([C:22]3[CH:23]=[C:24]4[C:29](=[C:30]([CH3:32])[CH:31]=3)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]4[NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=3)(=[O:20])=[O:21])[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH2:62][CH2:61]1)([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCO)c4)cc23)c1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCOC1CCNCC1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N5CCC(OCCCCCCO[Si](C)(C)C(C)(C)C)CC5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 70, using Intermediate 23 in place of 8-aminooctanol. ES/MS calcd. for C42H57N4O7SSi+ 789.4. Found m/z=789.3 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([NH:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:14])([CH3:11])([CH3:10])[CH3:9].[C:21]([O:27][CH2:28]Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C.C(OCC)(=O)C>[C:8]([O:12][C:13]([NH:15][CH2:16][CH2:17][C:18]([O:20][CH2:28][O:27][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[O:19])=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: CC(C)(C)C(=O)OCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCC(=O)OCOC(=O)C(C)(C)C
Reaction time: 0.25 h
Yield: 97.5 %

Procedure:
Triethylamine (32.4 ml) was added to N-tert.-butyloxycarbonyl β-alanine (40 g) in N,N'-dimethylformamide at room temperature under a nitrogen atmosphere in a 1 l round bottom flask. The solution was stirred 15 minutes and chloromethyl pivalate (36.6 g) [M. Rasmussen & N. J. Leonard, J. Amer. Chem. Soc., 89, 5439 (1967)] was added dropwise at 0° C. The solution was stirred at room temperature overnight. The mixture was then diluted with ethyl acetate, filtered, washed with water, then brine, and evaporated to give 70 g crude material which was chromatographed (silica gel) eluting with 15% ethyl acetate-hexane to give 62.5 g of product.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:25])=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:6]([C@H:12]2[CH2:16][CH2:15][C@@H:14]([C:17]([O:19]C)=[O:18])[CH2:13]2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[OH-].[Na+].Cl>CO>[CH3:1][C:2]1[NH:3][C:4]([CH3:25])=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:6]([C@H:12]2[CH2:16][CH2:15][C@@H:14]([C:17]([OH:19])=[O:18])[CH2:13]2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1[C@H]1CC[C@@H](C(=O)OC)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1[C@H]1CC[C@@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the compound of Example 2 91.9 mmol) and 4 mL of 2N NaOH in 4 mL methanol was stirred for 2 hours at room temperature. The clear reaction mixture was neutralized by adding 1 N HCl to produce 1,4-dihydro-2,6-dimethyl-4-[cis-3-(hydroxycarbonyl)cyclopentyl]-3,5-pyridine dicarboxylic acid, dimethyl ester. This compound was obtained as a pale crystalline solid: mp 177-179° C.; 1H NMR (DMSO-d6) δ 11.87 (br. s, 1 H), 8.81 (s, 1 H), 3.85 (d, 1 H, J=6.38 Hz), 3.59 (s, 6 H), 2.5 (m, 1 H), 2.22(s, 6 H), 1.6 (m, 4 H), 1.4 (m, 1 H), 1.2 (m, 2 H); 13C NMR (DMSO-d6) δ 177.2, 168.0, 146.3, 99.5, 50.5, 48.1, 41.9, 34.9, 32.2, 27.3, 27.0, 18.1. Analysis calculated for C17H23NO6. 0.67 H2O: C, 58.44; H, 7.02; N, 4.01. Found: C, 58.44; H, 7.10; N, 3.90. A minor trans-isomer was detected but was not isolated.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:13].[C:14]([N:22]1[CH2:27][CH2:26][CH2:25][C:24]([C:44]2[CH:49]=[CH:48][C:47]([Cl:50])=[C:46]([Cl:51])[CH:45]=2)([CH2:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH:34](C(N3CCCC3)=O)[CH2:33][CH2:32]2)[CH2:23]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.C(#N)C.CCOC(C)=O>[OH2:21].[ClH:50].[ClH:13].[C:14]([N:22]1[CH2:27][CH2:26][CH2:25][C:24]([C:44]2[CH:49]=[CH:48][C:47]([Cl:50])=[C:46]([Cl:51])[CH:45]=2)([CH2:28][CH2:29][CH2:30][N:10]2[CH2:11][CH2:12][CH:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:8][CH2:9]2)[CH2:23]1)(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1.[C:14]([N:22]1[CH2:27][CH2:26][CH2:25][C:24]([CH2:28][CH2:29][CH2:30][N:31]2[CH2:32][CH2:33][CH:34]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:35][CH2:36]2)([C:44]2[CH:49]=[CH:48][C:47]([Cl:50])=[C:46]([Cl:51])[CH:45]=2)[CH2:23]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[ClH:50].[ClH:50]
Reactant: O=C(c1ccccc1)N1CCCC(CCCN2CCC(C(=O)N3CCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1
Reactant: C1CCN(C2CCNCC2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)N1CCCC(CCCN2CCC(N3CCCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1
Temperature: 100 °C

Procedure:
A mixture of 0.55 g of 4-piperidinopiperidine, 1.3 g of the compound obtained in step B of EXAMPLE 1 and 1.14 g of K2CO3 in 10 ml of a DMF/acetonitrile mixture (50/50; v/v) is heated at 100° C. for 3 hours. The reaction mixture is poured into water and extracted with AcOEt, the organic phase is washed twice with water and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using DCM and then a DCM/MeOH mixture (98/2; v/v) as the eluent. The product obtained is dissolved in AcOEt, a stream of HCl gas is bubbled into the solution until the pH is 1, and ether is added until precipitation occurs. This gives 0.53 g of the expected product after filtration and drying, m.p.=265° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH:4]([CH:5]([OH:13])[C:6]([Cl:12])([Cl:11])[C:7]([F:10])([F:9])[F:8])[CH:3]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1)=[O:15].[C:32](OC(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:31])[CH:4]([CH:5]([O:13][C:32](=[O:34])[CH3:33])[C:6]([Cl:11])([Cl:12])[C:7]([F:10])([F:8])[F:9])[CH:3]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1)=[O:15]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)C(C(=O)OCc2cccc(Oc3ccccc3)c2)C1C(O)C(Cl)(Cl)C(F)(F)F
Solvent: c1ccncc1
Product: CC(=O)OC(C1C(C(=O)OCc2cccc(Oc3ccccc3)c2)C1(C)C)C(Cl)(Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
To a solution of 954 mg (2.00 mmol) of (3-phenoxyphenyl)methyl 2,2-dimethyl-3-(1-hydroxy-2,2-dichloro-3,3,3-trifluoropropyl)cyclopropanecarboxylate obtained in Example 4, in 2 ml of pyridine, 2 ml of acetic anhydride was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and purified by column chromatography (silica gel, dichloromethane/hexane =1/1) to obtain 1.02 g of (3-phenoxyphenyl)methyl 2,2-dimethyl-3-(1-acetoxy-2,2-dichloro-3,3,3-trifluoropropyl)cyclopropanecarboxylate as a colorless oily substance.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:18][C@@H:19]1[N:22]([S:23]([O-:26])(=[O:25])=[O:24])[C:21](=[O:27])[C@H:20]1[NH:28]C(OC1C=CC=CC=1)=O.C(N(CC)CC)C.C[Si](C)(C)Cl>ClCCCl>[NH2:28][C@H:20]1[C@H:19]([CH3:18])[N:22]([S:23]([OH:26])(=[O:24])=[O:25])[C:21]1=[O:27]
Reactant: C[C@H]1[C@H](NC(=O)Oc2ccccc2)C(=O)N1S(=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: C[C@H]1[C@H](N)C(=O)N1S(=O)(=O)O
Temperature: 0 °C
Yield: 65.5 %

Procedure:
A solution of 531 mg (0.001 mole) of (3S-trans)-4-methyl-2-oxo-3-(phenyloxycarbonylamino)-1-azetidinesulfonic acid, tetrabutylammonium salt in 10 ml of 1,2-dichloroethane is treated with 278 μl of triethylamine and 250 μl of trimethyl chlorosilane and the solution refluxed for 75 minutes. An aliquot of the reaction mixture shows intense IR absorption of 2270 cm-1 (indicative of the isocyanate group) and almost complete disappearance of the 1745 cm-1 band (for the urethane function) in addition to a strong absorption at 1770 cm-1 (β-lactam). The solution is refluxed for 20 hours (no change in IR), cooled to 0° C., and 2 ml of 88% formic acid is added. After 2.5 hours at room temperature the slurry is filtered to give 118 mg of (3S-trans)-3-amino-4-methyl-2-oxo-1-azetidinesulfonic acid, inner salt.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(CC)CC)C.ClC(OCC)=O.Cl.[CH2:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH:35]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[NH:34]1.Cl>C1COCC1.C(Cl)Cl.C(OCC)(=O)C>[C:1]([NH:11][C@H:12]([C:16]([CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH:35]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[NH:34]1)=[O:18])[CH:13]([CH3:14])[CH3:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CCOC(=O)C1Cc2ccccc2CN1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1Cc2ccccc2C(C(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)N1
Reaction time: 1 h
Yield: 57 %

Procedure:
CBZ-L-Valine (12.6 g, 0.05 mol) and triethylamine (5.06 g 0.05 mol) were dissolved in THF (100 mL) and then cooled to 0°-5° C, with an ice water bath. Ethyl chloroformate (5.44 g, 0.05 mol) in THF (35 mL) was added dropwise at 0°-5° C. Following the addition the mixture was stirred for one hour in the cold. Ethyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride (14.5 g, 0.06 mol) and triethylamine (6.1 g, 0.06 mol) in CH2Cl2 (60 mL) and THF (30 mL) were added at 0° C. The reaction mixture as allowed to sit at room temperature overnight. Evaporation of the solvent yielded a viscous semisolid which was treated with ethyl acetate followed by 1N HCl and the layers were separated. The organic extract was washed with 1N aqueous HCl followed by 5% aqueous Na2CO3 and saturated aqueous NaCl-solution. After drying over MgSO4 , filtration and evaporation under reduced pressure afforded an oil (12.5 g) which was purified over silica gel using hexane: ethyl acetate (8:2) as eluent. Collected 2.9 g of the desired product as a viscous oil.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:31]4[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=4[F:39])=[C:23]([O:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:24]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:31]4[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=4[F:39])=[C:23]([O:25][CH2:26][C:27]([CH3:30])([CH3:28])[CH3:29])[CH:24]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cc(OCc2cnc(-c3cc(OC)ccc3F)c(OCC(C)(C)C)c2)ncn1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(F)c(-c2ncc(COc3cc(C(CC(=O)O)C4CC4)ncn3)cc2OCC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 23.2 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(6-((6-(2-fluoro-5-methoxyphenyl)-5-(neopentyloxy)pyridin-3-yl)methoxy)pyrimidin-4-yl)propanoate (20 mg) in methanol (1.0 mL) was added 2N aqueous sodium hydroxide (91 μL) solution, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was cooled to 0° C. and neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was fractionated by HPLC (C18, mobile phase: water/acetonitrile (10 mM NH4HCO3-containing system)). The obtained fraction was evaporated under reduced pressure to give the title compound (4.4 mg) as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]([N:20]([CH2:43][CH:44]([CH3:46])[CH3:45])[C@H:21]2[CH2:26][C@@H:25]([NH:27][C:28](OCC(Cl)(Cl)Cl)=[O:29])[CH2:24][N:23]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:22]2)=[O:19])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[NH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C)C(=O)C.Cl>[C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]([N:20]([CH2:43][CH:44]([CH3:46])[CH3:45])[C@H:21]2[CH2:26][C@@H:25]([NH:27][C:28]([N:56]3[CH2:61][CH2:60][O:59][CH2:58][CH2:57]3)=[O:29])[CH2:24][N:23]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:22]2)=[O:19])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H]1C[C@@H](NC(=O)OCC(Cl)(Cl)Cl)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H]1C[C@@H](NC(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
tert-Butyl (3S,5R)-3-[({2-tert-butyl-4-[(furan-2-ylmethyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]-5-{[(2,2,2-trichloroethoxy)carbonyl]amino}piperidine-1-carboxylate (98.0 mg) and N,N-diisopropylethylamine (120 μl) were dissolved in N,N-dimethylacetamide (3 ml), morpholine (20 μl) was added, and the mixture was stirred at 80° C. for 1 day. The reaction mixture was diluted with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object compound (12.7 mg).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C.[Cl:19][CH2:20][C:21](C1C=CC(CCC(O)=O)=CC=1)=[O:22]>>[Cl:19][CH2:20][C:21]([C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:3][CH:4]=1)=[O:22]
Reactant: COC(=O)CCCOc1ccccc1
Reactant: O=C(O)CCc1ccc(C(=O)CCl)cc1
Solvent: CC(=O)Cl
Product: COC(=O)CCCOc1ccc(C(=O)CCl)cc1

Procedure:
Methyl 4-phenoxybutyrate was reacted with acetyl chloride in a similar manner to that described above for 3-[4-(chloroacetyl)phenyl]propionic acid, except that the crude product was triturated with petrol to give methyl 4-[4-(chloroacetyl)phenoxy]butyrate as a crystalline solid which was pure by TLC analysis (on silica plates; eluant: 50% ether/50% petrol).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[C@@H:13]([OH:16])[CH2:14][OH:15].C([Sn](=O)CCCC)CCC.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.CCN(CC)CC>C(Cl)Cl>[CH3:37][C:27]1[CH:32]=[CH:31][C:30]([S:33]([O:15][CH2:14][C@@H:13]([C:3]2[C:4]([CH3:12])=[CH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]=2[Cl:1])[OH:16])(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc2ccccc2c(Cl)c1[C@@H](O)CO
Agent: CCCC[Sn](=O)CCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@H](O)c2c(C)cc3ccccc3c2Cl)cc1
Reaction time: 15 h

Procedure:
To a stirred solution of (R)-1-(1-chloro-3-methylnaphthalen-2-yl)ethane-1,2-diol (2.30 g, 9.74 mmol) in CH2Cl2 (97 mL), dibutyltinoxide (48.5 mg, 0.19 mmol), p-toluenesulfonyl chloride (2.08 g, 10.90 mmol), and Et3N (1.60 mL, 11.58 mmol) were added at room temperature). After stirring for 15 h, the reaction mixture was quenched with saturated aqueous NH4Cl, and then diluted with CH2Cl2. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give (R)-2-(1-chloro-3-methylnaphthalen-2-yl)-2-hydroxyethyl 4-methylbenzenesulfonate. 1H-NMR: 400 MHz, (CDCl3) δ 8.18 (d, J=8.8 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.57-7.54 (m, 5H), 5.82 (t, J=5.6 Hz, 1H), 4.44 (dd, J=10.0, 6.8 Hz, 1H), 4.35 (dd, J=10.4, 5.6 Hz, 1H), 2.59 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: OS(O)(=O)=O.[N+:6]([O-:9])(O)=[O:7].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18]>O>[Cl:10][C:11]1[CH:16]=[C:15]([N+:6]([O-:9])=[O:7])[C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18]
Reactant: O=[N+]([O-])O
Reactant: Clc1ccc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Cl

Procedure:
A mixture of 300 ml concentrated H2SO4 (98%) and 150 ml concentrated HNO3 (90%) was prepared in a 2 liter flask equipped with an agitator, thermometer, and dropping funnel. A total of 90.8 gm of 1,2,4-trichlorobenzene (0.5 mol) was added to the acid mixture at 70°-90° C. over a 1 hour period of time. The reaction was maintained at this temperature for 2 to 3 hours or until analysis of the reaction mixture showed the reaction to be complete. Work-up of the product involved addition of 1 liter of cold water to the reaction mass while maintaining a temperature from 55°-65° C. Separation of the organic and aqueous layers gave the desired product, 1,2,4-trichloro-5-nitrobenzene. Crude yield is 95-98% of theory with an isomer purity of 91-95%. Subsequent reactions outlined in Example 1 show this material to be suitable for preparation of TCDD free 2,4,5-TCP and 2,4,5-T.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]([CH:8]([CH2:12][C:13](O)=O)[C:9](O)=O)[CH:7]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C1(C)C(C)=CC=CC=1>[CH2:18]([N:25]1[CH2:13][CH2:12][CH:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:16][CH3:17])[CH2:9]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(Cl)cc1C(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1C
Solvent: O
Product: COc1ccc(Cl)cc1C1CCN(Cc2ccccc2)C1

Procedure:
1.0 g of 2-(5-chloro-2-methoxyphenyl)succinic acid is suspended in 50 ml of xylene, 0.47 ml of benzylamine is added and the mixture refluxed for 8 hours with separation of water. The solvent is evaporated and the residue taken up in ethylacetate and extracted with 2N HCl, followed by 2N NaOH and aqueous NaCl. The organic layer is dried, filtered and the solvent evaporated. The dried residue is purified by flash chromatography using t-butylmethylether/hexane 1/1 providing the amorphous product: MS (EI): M+=329; NMR (DMSO): 2.65 (1H, dd), 3.1 (1H, dd), 3.45 (3H, s), 4.2 (1H, dd), 4.6 (2H, s), 7.0 (1H, d), 7.25-7.4 (7H, m).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([C:11]([CH3:15])([CH3:14])[C:12]#[N:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:27]([O:29][CH3:30])=[O:28]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:27](=[O:28])([O:29][CH3:30])[O:16][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][C:9]=1[C:11]([C:12]#[N:13])([CH3:15])[CH3:14]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C#N)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Oc1ccc(C(C)(C)C)cc1C(C)(C)C#N
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a stirred mixture of compound 15 (126.6 g, 0.564 mol), DMAP (6.0 g) and DIEA (188 g, 1.46 mol) in anhydrous DCM (1500 mL) was added dropwise methyl chloroformate (110 g, 1.17 mol) in anhydrous DCM (300 mL) at 0° C. within 2 hours. After stirring for 12 hours at 0° C., ice-water (1.5 L) was added and the mixture was stirred at 0° C. for 30 minutes. The organic layer was separated and washed with 1 N HCl, water, and brine. The DCM solution was dried over MgSO4 and concentrated in vacuo to give compound 16 as a yellow solid. 1H NMR (DMSO-d6; 400 MHz) δ 7.47 (m), δ 7.39 (d), δ 7.24 (d), δ 3.84 (s), δ 1.71 (s), δ 1.30 (s).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21]3[C:20]4[CH:19]=[CH:18][CH:17]=[N:16][C:15]=4[N:14]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:13](=[O:28])[C:12]=3[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.COC1C=CC(N)=CC=1.NC1C=CC=CC=1>>[C:6]1([N:9]2[C:21]3[C:20]4[CH:19]=[CH:18][CH:17]=[N:16][C:15]=4[N:14]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:13](=[O:28])[C:12]=3[CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=[CH:8][CH:7]=1
Reactant: COc1ccc(N2CCc3c2c2cccnc2n(-c2ccccc2)c3=O)cc1
Solvent: COc1ccc(N)cc1
Solvent: Nc1ccccc1
Product: O=c1c2c(c3cccnc3n1-c1ccccc1)N(c1ccccc1)CC2

Procedure:
This procedure will also produce 1,2,3,5-tetrahydro-1-(4-methoxyphenyl)-5-phenyl-4-H-pyrrolo [3,2-c][1,8]naphthyridin-4-one when 4-methoxyaniline (also known as p-anisidine) is substituted for aniline
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[N:3]=1.[NH2:9][C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([OH:32])=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)=[CH:18][C:17]=2[F:33])=[CH:12][N:11]=1>>[NH2:9][C:10]1[N:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][C:23]=3[O:32][C:2]3[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[N:3]=3)=[CH:18][C:17]=2[F:33])=[CH:14][N:15]=1
Reactant: Nc1nccc(Cl)n1
Reactant: Nc1ncc(-c2ccc(-c3ccc(C(F)(F)F)cc3O)cc2F)cn1
Product: Nc1ncc(-c2ccc(-c3ccc(C(F)(F)F)cc3Oc3ccnc(N)n3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 555 using 4-chloropyrimidin-2-amine and 4′-(2-aminopyrimidin-5-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-ol. MS (ESI): mass calcd. for C21H14F4N6O, 442.12; m/z found, 443.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.51-8.43 (d, J=1.3, 2H), 8.06-7.94 (d, J=5.7, 1H), 7.72-7.69 (m, 1H), 7.69-7.66 (m, 1H), 7.55 (s, 1H), 7.52-7.47 (m, 1H), 7.39-7.31 (m, 2H), 6.31-6.03 (d, J=5.7, 1H).