Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>CN(C=O)C.C([O-])(O)=O.[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ccc(Cl)cc2)s1
Temperature: 100 °C
Reaction time: 18 h
Yield: 92.7 %

Procedure:
A mixture of ethyl 5-bromothiophene-2-carboxylate (1.0 g, 4.25 mmol), 4-chlorophenylboronic acid (0.998 g, 6.38 mmol), 2.0 M aq NaHCO3 (6.38 ml, 12.76 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.492 g, 0.425 mmol) in DMF (40 ml) under nitrogen was stirred at 100° C. under nitrogen in a sealed tube for 18 hours as described in WO 2007/011284. The reaction was then cooled to RT, diluted with saturated aq NaHCO3 (40 ml) and extracted with EtOAc (40 ml). The EtOAc extracts were dried over Na2SO4 and concentrated. The crude product was purified by ISCO chromatography on a silica gel column (120 g) employing a 10 min gradient ranging from hexane to 30% EtOAc to elute ethyl 5-(4-chlorophenyl)thiophene-2-carboxylate (1.05 g, 3.94 mmol, 93% yield) as a white solid. LC MS at t=2.70 min. (m+H=267) PHENOMENEX® 55 C18 4.6×30 mm column/water-MeOH-TFA 90:10:0.1 to 10:90:0.1 gradient over 2 min at 5 mL/min with 1 min hold at the end of the gradient. 1H NMR (400 MHz, CD3OD) 8 ppm 1.39 (t, J=7.18 Hz, 3H), 4.37 (q, J=7.22 Hz, 2H), 7.43-7.51 (m, 3H), 7.71 (d, J=8.56 Hz, 2H), 7.78 (d, J=4.03 Hz, 1H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1.[I:23][CH2:24]I.[NH4+].[Cl-]>O1CCCC1>[I:23][CH2:24][C:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1
Reactant: ICI
Reactant: CC(C)(C)OC(=O)C1CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)C1(CI)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 14.6 %

Procedure:
To a stirred solution of diisopropylamine (7.7 mL, 0.055 mol) in tetrahydrofuran (80 mL), n-butyl lithium (1.59 M in cyclohexane, 34 mL, 0.055 mol) was added slowly at −70° C. and the mixture was stirred for 20 min at 0° C. The mixture was cooled to −78° C. and tert-butyl cyclopropanecarboxylate (6.5 g, 0.046 mol, Kohlrausch et al., Z. Elektrochem. Angew. Phys. Chem., 1937, 70, 392) in tetrahydrofuran (10 mL) was added dropwise, and the mixture was stirred for 3 h. Then, diiodomethane (4.0 mL, 0.050 mol) in tetrahydrofuran (10 mL) was added dropwise, and the mixture was allowed to warm up to room temperature overnight. Saturated aqueous NH4Cl (80 mL) was added to the solution and it was extracted with diethyl ether (50 mL), washed with brine (20 mL), dried over MgSO4, filtered and concentrated to give brown oil. The oil was chromatographed on a column of silica gel eluting with hexane/diethyl ether (40:1) to give 1.9 g of the title compound as a crude product. The crude product was used without further purification. Rf: 0.3 (hexane/diethyl ether (40:1))
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:34][CH:33]4[CH:28]([CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][CH2:32]4)[CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:34][CH:33]4[CH:28]([CH2:29][NH:30][CH2:31][CH2:32]4)[CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CC4CCN(C(=O)OC(C)(C)C)CC4C3)co2)C2CC2)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CC4CCNCC4C3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AN using tert-butyl 2-{[2-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,3-oxazol-4-yl]carbonyl}octahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate (245 mg, 0.42 mmol), TFA (1 mL) and DCM (3 mL). Following the completion of the reaction the solvent was removed in vacuo, the residue redissolved in DCM (2 mL), absorbed on to 2 g SCX cartridge and washed with DCM (5 mL) and MeOH (5 mL). The title compound was eluted with 7 N NH3 in MeOH (10 mL) and concentrated in vacuo.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=O)[O:22]C4C=CC=CC=4)=[C:16]([CH3:30])[CH:15]=3)[CH:8]=2)=[O:5])[CH2:3][CH2:2]1.[CH:31]([NH:34][C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37]([NH2:45])[CH:36]=1)([CH3:33])[CH3:32].CCN(C(C)C)C(C)C>C1COCC1>[CH:31]([NH:34][C:35]1[CH:36]=[C:37]([NH:45][C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][C:9]3[N:10]=[CH:11][N:12]=[C:7]([NH:6][C:4]([CH:1]4[CH2:2][CH2:3]4)=[O:5])[CH:8]=3)=[CH:15][C:16]=2[CH3:30])=[O:22])[CH:38]=[C:39]([C:41]([F:43])([F:44])[F:42])[CH:40]=1)([CH3:33])[CH3:32]
Reactant: CC(C)Nc1cc(N)cc(C(F)(F)F)c1
Reactant: Cc1cc(Oc2cc(NC(=O)C3CC3)ncn2)ccc1NC(=O)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Oc2cc(NC(=O)C3CC3)ncn2)ccc1NC(=O)Nc1cc(NC(C)C)cc(C(F)(F)F)c1
Yield: 54.2 %

Procedure:
Dissolve phenyl N-[4-[6-(cyclopropanecarbonylamino)pyrimidin-4-yl]oxy-2-methyl-phenyl]carbamate (343 mg, 1.57 mmol), N1-isopropyl-5-(trifluoromethyl)benzene-1,3-diamine (700 mg, 1.73 mmol) and DIEA (608 mg, 4.72 mmol) in THF (4 mL), heat the reaction at 80° C. for 3 hrs. After the reaction is complete, remove the volatiles under reduced pressure. Purification by chromatography (silica gel, EtOAc:PE=1:1) affords the title compound (450 mg, 83%). MS: (M+1): 529.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18]([NH:20][C@H:21]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)[C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=3[C:32]([O:34]C)=[O:33])[CH2:26][CH2:25]2)=[O:23])=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18]([NH:20][C@H:21]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([Cl:47])=[CH:45][CH:46]=2)[C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=3[C:32]([OH:34])=[O:33])[CH2:26][CH2:25]2)=[O:23])=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2C(=O)O)CC1
Temperature: 60 °C
Yield: 61.8 %

Procedure:
To a 150 mL round-bottomed flask equipped with magnetic stirring was added methyl 2-{4-[(2R)-2-({(3S)-2-[(tert-butyl)oxycarbonyl](3-1,2,3,4-tetrahydroisoquinolyl)}carbonylamino)-3-(4-chlorophenyl)propanoyl]piperazinyl}benzoate (1.6 g, 2.4 mmol) in THF (30 mL). A soln of LiOH (Aldrich) (303 mg, 7.14 mmol) in H2O (ca. 10 mL) was added and the reaction was heated at 60° C. for 12 h. After cooling to RT, the mixture was concentrated in vacuo and diluted with EtOAc (100 mL). A 10% soln of citric acid (25 mL) was added, the organic layer was separated, and the aqueous layer was extracted with EtOAc (2×25 mL). The organic layers were combined, washed with H2O, and brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound as a white solid (960 mg). MS (ESI, pos. ion) m/z: 647 (M+H). Calc'd for C35H39ClN4O6: 646.26.
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=1)[CH3:3].CN(C)C=O.O[NH:23][C:24](=[NH:35])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>C1C=CC=CC=1>[CH2:2]([O:4][C:5](=[O:16])[C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:13]2[O:15][N:23]=[C:24]([CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:35]=2)=[CH:10][CH:11]=1)[CH3:3]
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1
Reactant: COc1ccc(OCC(=N)NO)cc1
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Cc2nc(COc3ccc(OC)cc3)no2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.2 %

Procedure:
Add oxaxyl chloride (1.25 mL, 14 mmol) to 4-carboxymethyl-benzoic acid ethyl ester (365 mg, 1.75 mmol) in benzene (11 mL) and a drop of dimethylformamide at room temperature under argon gas over a 5 minute period. Stir the reaction mixture for 2 hours at room temperature. Concentrate the reaction mixture to an oil. Redissolve the oil in dimethylformamide (10 mL) and N-hydroxy-2-(4-methoxy-phenoxy)-acetamidine (380 mg, 1.9 mmol) is added. Stir the reaction mixture at room temperature for 3 hours. Heat the reaction mixture to 120° C. and stir for 7 hours. After cooling to room temperature, quench the reaction mixture with water and extract with ethyl acetate (3×). Combine the organic layers, wash with brine, dry over sodium sulfate, and concentrate. Purify the residue by flash column chromatography using 20% ethyl acetate/hexane to give the title compound (201 mg, 31%). LC-MS (m/e): 369 (M+1).
Reaction SMILES: [I:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Si](C=[N+]=[N-])(C)(C)[CH3:13]>C1C=CC=CC=1.CO>[I:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1cccc(C(=O)O)c1I
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1cccc(C)c1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of 2-iodo-3-methylbenzoic acid (500 mg, 0.48 mmol) in benzene/MeOH (2 mL, 10:1) was added TMSCHN2 (1 mL, 2N), the reaction mixture was stirred at rt for 30 min and then concentrated. The crude product was purified by flash chromatography (0 to 10% EtOAc/Hexanes, gradient) to afford 500 mg (91%) of Intermediate 299.1.
Reaction SMILES: CN(C)[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[CH2:12][C:11](=O)[CH2:10]2)=CC=1.C1C2(CC(=O)CC(=O)C2)CCC1.C([O-])(=O)C.[NH4+:34]>>[NH2:34][C:11]1[CH2:10][C:9]2([CH2:6][CH2:7][CH2:8][CH2:3]2)[CH2:14][C:13](=[O:15])[CH:12]=1
Reactant: [NH4+]
Reactant: CN(C)c1ccc(C2CC(=O)CC(=O)C2)cc1
Agent: CC(=O)[O-]
Agent: O=C1CC(=O)CC2(CCCC2)C1
Product: NC1=CC(=O)CC2(CCCC2)C1

Procedure:
In analogy to (Baraldi, P. G.; Simoni, D.; Manfredini, S.; Synthesis 1983, (11) 902-903 spiro[4.5]decane-7,9-dione was reacted with ammonium acetate to give the title compound as a colorless solid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[C:10]([OH:17])[C:9]=1[CH2:18][CH2:19][CH3:20].[C-:21]#[N:22].[Na+].[I-].[Na+]>CN(C)C=O>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][C:21]#[N:22])=[C:9]([CH2:18][CH2:19][CH3:20])[C:10]=1[OH:17])(=[O:16])[CH3:15]
Reactant: CCCc1c(OCCOCCBr)ccc(C(C)=O)c1O
Reactant: [C-]#N
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCOCCC#N)ccc(C(C)=O)c1O
Yield: 97.1 %

Procedure:
A solution of 2.60 g of 1-[4-[2-(2-bromoethoxy)ethoxy]-2-hydroxy-3-propylphenyl]ethanone, 0.50 g of sodium cyanide and 1.13 g of sodium iodide in 50 ml of dimethyl formamide was stirred and heated at 80° for 6 hours. The solvent was removed in vacuo, water was added to the residue and the product was extracted with ether. The dried (over magnesium sulfate) extract was concentrated in vacuo to give 2.13 g of impure 3-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]propanenitrile.
Reaction SMILES: [P:1]([O:5]P(O)(O)=O)([OH:4])([OH:3])=[O:2].[C@@H:10]1([N:19]2[C:28]3[N:27]=[CH:26][N:25]=[C:23]([OH:24])[C:22]=3[N:21]=[CH:20]2)[O:18][C@H:15]([CH2:16]O)[C@@H:13]([OH:14])[C@H:11]1[OH:12]>C([O-])(=O)C>[C@@H:10]1([N:19]2[C:28]3[N:27]=[CH:26][N:25]=[C:23]([OH:24])[C:22]=3[N:21]=[CH:20]2)[O:18][C@H:15]([CH2:16][O:5][P:1]([OH:3])([OH:4])=[O:2])[C@@H:13]([OH:14])[C@H:11]1[OH:12]
Reactant: O=P(O)(O)OP(=O)(O)O
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Agent: CC(=O)[O-]
Product: O=P(O)(O)OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 32 h

Procedure:
Pyrophosphoric acid (15 g/dl) and 8 g/dl of inosine were dissolved in an acetate buffer (pH 4.0). To the solution was added E. coli JM109 strain having introduced therein the above-mentioned mutant and wild-type acid phosphatase genes such that the concentration reached 200 mg/dl in terms of the dry cell weight. The reaction was conducted at 35° C. for 32 hours while maintaining the pH at 4.0, and the amount of 5'-inosinic acid formed over the course of time was measured. Inosinic acid formed was only 5'-inosinic acid, and the formation of 2'-inosinic acid and 3'-inosinic acid as by-products was not observed at all. The results are shown in FIG. 8.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].ClCCCl.[N:16]1([C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=2)[C:24]([O:26][CH3:27])=[O:25])[CH:20]=[CH:19][CH:18]=[CH:17]1>ClC(Cl)C>[C:1]([C:20]1[N:16]([C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=2)[C:24]([O:26][CH3:27])=[O:25])[CH:17]=[CH:18][CH:19]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cccc(-n2cccc2)c1
Reactant: CC(=O)OC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: COC(=O)c1cccc(-n2cccc2C(C)=O)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Acetic anhydride (1.3 ml) was added to a mixture of aluminum chloride (2.7 g) and 1,2-dichloroethane (10 ml) under ice-cooling and the mixture was stirred for 20 minutes at the same temperature. To the mixture was added dropwise a mixture of methyl 3-(pyrrol-1-yl)benzoate (2.0 g) in dichloroethane (3 ml) for 10 minutes at 0° to 5° C., and the mixture was stirred for 3 hours at the same temperature. The reaction mixture was poured into an ice-water and the mixture was extracted with chloroform. The extract was washed with a saturated aqueous sodium bicarbonate solution and water. The organic layer was dried over magnesium sulfate and evaporated in vacuo to give methyl 3-(2-acetylpyrrol-1-yl)benzoate (0.94 g).
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:30][CH3:31])[C:5]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[C:12]2[CH2:16][C@H:17]([NH:19][CH2:20][C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1)[OH:22])[CH3:18])=[O:6])[CH3:3].C(N(CC)CC)C.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:30]([N:4]([CH2:2][CH3:3])[C:5]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[C:12]2[CH2:16][C@H:17]([N:19]1[CH2:20][C@@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[O:22][C:40]1=[O:42])[CH3:18])=[O:6])[CH3:31]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN(CC)C(=O)c1cccc2c(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)c[nH]c12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1cccc2c(C[C@@H](C)N3C[C@@H](c4cccc(Cl)c4)OC3=O)c[nH]c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 247.8 %

Procedure:
To a solution of 3-{(2R)-2-[2-(3-chlorophenyl)-(2R)-2-hydroxy-ethylamino]propyl}-1H-indole-7-carboxylic acid diethylamide.hydrochloride (47 mg, 0.1 mmol) and triethylamine (139 μL, 1 mmol) in tetrahydrofuran (3 mL) is added triphosgene (12 mg, 0.04 mmol), and the mixture is stirred at room temperature for 4 hours. To the mixture is added a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (methanol/chloroform=1/50) to give 3-{(2R)-2-[(5R)-5-(3-chlorophenyl)-2-oxooxazolidin-3-yl]propyl}-1H-indole-7-carboxylic acid diethylamide (45 mg, yield: 100%).
Reaction SMILES: [N:1]1([CH:6]2[CH2:11][CH2:10][CH:9]([NH:12]C(=O)OC(C)(C)C)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[N:1]1([CH:6]2[CH2:11][CH2:10][CH:9]([NH2:12])[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)NC1CCC(N2CCCC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCC(N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
tert-butyl N-(4-pyrrolidin-1-ylcyclohexyl)carbamate (Intermediate 238; 222 mg, 0.83 mmol) was taken up in DCM (1.5 mL) and TFA (1 mL). The reaction mixture was stirred at ambient temperature for 3 hours, poured directly onto an SCX-3 cartridge (2 g), pre-wet with DCM. The cartridge was washed through with DCM (10 mL), followed by methanol (30 mL) and then eluted with 2M ammonia in Methanol (25 mL). Evaporation to dryness of the ammoniacal solution yielded the title compound as an amber coloured oil (103 mg, 74%)
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[C:3]=1[O:15][CH2:16][O:17][CH3:18].[S:19]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20]1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C(OCC)C.C1(P([Pd-4](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:14][O:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3]([O:15][CH2:16][O:17][CH3:18])=[C:2]([C:21]1[CH:22]=[CH:23][S:19][CH:20]=1)[C:11]([CH3:12])=[CH:10]2
Reactant: COCOc1c(Br)c(C)cc2cc(OC)ccc12
Reactant: OB(O)c1ccsc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: COCOc1c(-c2ccsc2)c(C)cc2cc(OC)ccc12
Temperature: 160 °C

Procedure:
2-bromo-6-methoxy-1-(methoxymethoxy)-3-methylnaphthalene (14) (0.35 g, 1.12 mmol), thiophene 3-boronic acid (0.359 g, 2.81 mmol), tetrakis(triphenylphosphino)palladium (0) (0.031 g, 0.027 mmol), 2 M sodium carbonate (4 mL) and ethylene glycol dimethyl ether (4 mL) were added in a sealed tube and heated at 160° C. for 20 min. Reaction mixture was cooled to room temperature then diluted with diethyl ether. The mixture was washed with water followed by brine, dried over Na2SO4, filtered and concentrated. The crude material purified with a gradient of 1% EtOAc to 4% EtOAc in hexanes over 45 min to afford the title compound (199) as oil, 0.347 g, (98%). 1H NMR (400 MHz, d-CDCl3): δ 2.29 (s, 3H), 3.23 (s, 3H), 3.93 (s, 3H), 4.76 (s, 2H), 7.06-7.07 (m, 1H), 7.10-7.15 (m, 2H), 7.25-7.26 (m, 1H), 7.40-7.42 (m, 2H), 8.04 (d, J=9.2 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([OH:23])[CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12]2)=[CH:5][CH:4]=1)#[N:2].CCN(C(C)C)C(C)C.FC(F)(F)S(O[Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])(=O)=O>C(Cl)Cl>[Si:39]([O:23][C@@H:9]([C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)[CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12]1)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40]
Reactant: CCOC(=O)C[C@H]1CCCN(C[C@@H](O)c2ccc(C#N)cc2)C1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C[C@H]1CCCN(C[C@@H](O[Si](C)(C)C(C)(C)C)c2ccc(C#N)cc2)C1
Reaction time: 2 h
Yield: 98 %

Procedure:
To a mixture of (18C)-isomer A, ethyl 2-((R)-1-((S)-2-(4-cyanophenyl)-2-hydroxyethyl)piperidin-3-yl)acetate (6.00 g, 18.96 mmol) and DIPEA (5.96 ml, 34.1 mmol) in DCM (63 mL) was added tert-butyldimethylsilyl trifluoromethane-sulfonate (5.67 ml, 24.65 mmol) slowly. The reaction was monitored with HPLC and the reaction was complete in 2 hours. The reaction mixture (a light brown solution) was quenched with water, the aqueous layer was extracted twice with DCM. The organic phase was combined, dried with Na2SO4, filtered, and concentrated. The crude material was purified with on a silica gel cartridge (330 g silica, 10-30% EtOAc/hexanes gradient) to give ethyl 2-((R)-1-((S)-2-(tert-butyldimethylsilyloxy)-2-(4-cyanophenyl)ethyl)piperidin-3-yl)acetate (8 g, 18.58 mmol, 98% yield).
Reaction SMILES: C(=O)([O-])[O-:2].[Na+].[Na+].[CH3:7][C:8]1([CH3:15])[O:14][CH2:13][CH:12]=[CH:11][CH2:10][O:9]1.C(#N)C1C=CC=CC=1.OO>CO>[CH3:7][C:8]1([CH3:15])[O:14][CH2:13][CH:12]2[CH:11]([O:2]2)[CH2:10][O:9]1
Reactant: CC1(C)OCC=CCO1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: N#Cc1ccccc1
Product: CC1(C)OCC2OC2CO1
Yield: 70 %

Procedure:
To a suspension of sodium carbonate (37 g, 0.35 mole) in a mixture of the dioxepin (II) (158.7 g, 1.26 mole), benzonitrile (127.9 g, 1.26 mole) and methanol (150 ml), was added 30% aqueous hydrogen peroxide (42.2 g, 1.24 mole) during 30 min at such a rate that the temperature stayed below 80°. The mixture was kept at 80° with an oil bath for 2 hr, by which time 99% of the hydrogen peroxide added had reacted. The mixture was decanted and, then, subjected to fractional distillation first at 60 mm, then at 20 mm and finally at 6 mm. The fraction boiling at 75°-85° at 6 mm was refractionated at 6 mm to obtain the product (III) as a colorless liquid. (125.5 g) (70% yield). b.p. 82°-87°/6 mm.
Reaction SMILES: [NH:1]([C:3](=[O:15])[C:4]([N:6]([CH3:14])[CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=[O:5])[NH2:2].[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[S:25])=[CH:19][CH:18]=1>CCO>[F:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:2][NH:1][C:3](=[O:15])[C:4]([N:6]([CH3:14])[CH2:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)=[O:5])=[S:25])=[CH:19][CH:18]=1
Reactant: CN(Cc1ccncc1)C(=O)C(=O)NN
Reactant: Fc1ccc(N=C=S)cc1
Solvent: CCO
Product: CN(Cc1ccncc1)C(=O)C(=O)NNC(=S)Nc1ccc(F)cc1
Temperature: 25 °C

Procedure:
A mixture of 2-hydrazinyl-N-methyl-2-oxo-N-(pyridin-4-ylmethyl)acetamide (78) (0.96 g, 4.61 mmol) and 4-fluorophenyl isothiocyanate (0.71 g, 4.16 mmol) in EtOH was refluxed for 2 h. The reaction was cooled down to room temperature and concentrated in vacuo to afford 2-(2-((4-fluorophenyl)carbamothioyl)hydrazinyl)-N-methyl-2-oxo-N-(pyridin-4-ylmethyl)acetamide (79) as yellow crystals was obtained in a quantitative yield.
Reaction SMILES: [C:1]1(N)[NH:8][C:6](=[O:7])[NH:5][C:3](=[O:4])[N:2]=1.C1(N)NC(N)=NC(=[O:13])N=1>>[NH:8]1[C:1](=[O:13])[NH:2][C:3](=[O:4])[NH:5][C:6]1=[O:7]
Reactant: Nc1nc(=O)[nH]c(=O)[nH]1
Reactant: Nc1nc(=O)nc(N)[nH]1
Product: O=c1[nH]c(=O)[nH]c(=O)[nH]1
Yield: 6 %

Procedure:
The procedure of Example 10 was repeated with a 1-liter glass reactor and a nitrogen purge prior to the urea addition. After a two-hour stirring period, the crude cyanuric acid in the cooled slurry showed no sign of hydration at which time the slurry was vacuum filtered. The filter cake was then washed with water at which time the cyanuric acid hydrated. The hardened hydrated product was crushed and dried in an oven to produce a 93% yield of anhydrous cyanuric acid having an assay of 99+% purity and an ammelide content of 0.39% and an ammeline content of only 0.02%. Analysis of the filtrate showed an additional 6% yield of cyanuric acid.