Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][C:10]=1[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:34]1[CH:35]=[C:36]([C:41]([CH3:44])=[CH:42][CH:43]=1)[C:37]([O:39][CH3:40])=[O:38].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC>[C:15]([O:14][C:13]([NH:12][CH2:11][C:10]1[CH:20]=[C:21]([C:34]2[CH:35]=[C:36]([C:41]([CH3:44])=[CH:42][CH:43]=2)[C:37]([O:39][CH3:40])=[O:38])[CH:22]=[CH:23][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:19])([CH3:16])([CH3:17])[CH3:18]
Reactant: COC(=O)c1cc(Br)ccc1C
Reactant: CC(C)(C)OC(=O)NCc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)c1cc(-c2ccc(OCc3ccccc3)c(CNC(=O)OC(C)(C)C)c2)ccc1C

Procedure:
1.01 g of t-butyl N-[2-benzyloxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]carbamate, 593 mg of methyl 3-bromo-6-methylbenzoate, 130 mg of dichloro-bistriphenyl phosphinoferrocene palladium and 1 g of potassium carbonate were dissolved in 15 ml of dimethoxyethane, and the mixture was heated under reflux for 4 hours in a nitrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was evaporated. The residue was purified by silica gel column, to give methyl 3-(3-{[(t-butoxycarbonyl)amino]methyl}-4-benzyloxyphenyl)-6-methylbenzoate in the 4:1 hexane-ethyl acetate fraction. This crude product was dissolved in 100 ml of methanol, then 500 mg of 10% Pd—C was added thereto, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by silica gel column, to give 521 mg of the title compound in the 5:1 hexane-ethyl acetate fraction.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[C:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[O:22]=[C:20]1[NH:19][C:18](=[O:23])[C:17](=[CH:16][C:13]2[CH:12]=[CH:11][C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N:3]([CH2:1][CH3:2])[C:31]([NH:30][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:32])[CH:5]=3)=[CH:15][CH:14]=2)[S:21]1
Reactant: CCNc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Reactant: O=C=Nc1ccccc1
Product: CCN(C(=O)Nc1ccccc1)c1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Yield: 95.2 %

Procedure:
In a manner similar to that of Example 9(a), by reacting 500 mg (1.54 mmol) of 5-(3′-ethylamino-biphenyl-4-ylmethylene)thiazolidine-2,4-dione with 340 μl (3.1 mmol) of phenyl isocyanate, 650 mg (95%) of the expected product are obtained in the form of a yellow solid.
Reaction SMILES: [ClH:1].[NH:2](C(OC(C)(C)C)=O)[C@H:3]([C:11]([N:13]1[CH2:27][CH2:26][CH2:25][C@H:14]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[O:12])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:10])[NH2:9].Cl>C(O)(=O)C.C1COCC1>[NH2:2][C@H:3]([C:11]([N:13]1[CH2:27][CH2:26][CH2:25][C@H:14]1[C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])=[O:12])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:9])[NH2:10].[ClH:1].[ClH:1]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N=C(N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1

Procedure:
Hydrochloric acid (1 M) in acetic acid (380 L) was slowly added at ≦22° C. to a suspension of Boc-Arg-Pro-OBzl.HCl (95.00 kg; Hexagon Labs Inc., USA) in acetic acid (190 L) and THF (19 L). The completion of cleavage (after about 1 hour) was monitored by HPLC.
Reaction SMILES: [C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[H][H]>N1C=CC=CC=1.[Pd]>[CH:1](/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:2]/[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCC#Cc1ccccc1CCC(=O)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccncc1
Product: CCCCCCCCCCC/C=C\c1ccccc1CCC(=O)OC
Yield: 77.5 %

Procedure:
A solution of methyl 3-[2-(1-tridecynyl)phenyl]propanoate (500 mg) in pyridine (20 ml) was hydrogenated at atmospheric pressure over 5% palladium on barium sulphate (20 mg) until 1 equivalent of hydrogen was absorbed. The catalyst was then removed by filtration and the filtrate evaporated to a pale yellow oil. Chromatograpy on silica eluting with 1:1 dichloromethane-petrol (bp 60°-80° C.) gave 390 mg (78%) of the title ester, νmax (film) 2930, 2850, 1740 cm-1, δ(CDCl3), 0.87 (3H, distorted t, terminal CH3), 1.28 (18H, m, alkylene chain), 2.09 (2H, m, allylic CH2), 2.50 (2H, m, ArCH2), 2.90 (2H, m, CH2CO2), 3.65 (3H, s, ester CH3), 5.70 (1H, d.t, Jd 11.5 Hz, Jt 7.5 Hz, C=CH--R), 6.42 (1H, distorted d, Ar CH=C), 7.17 (4H, m, arom).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[C:4]([Br:10])[N:3]=1.ClC1C=CC=C(C(OO)=[O:19])C=1>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:9])=[O:19])[CH:5]=[C:4]([Br:10])[N:3]=1
Reactant: CSc1cc(Br)nc(Br)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1cc(Br)nc(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
To a solution of 0.282 g 2,6-dibromo-4-methylsulfanyl-pyridine (Example 45a) in 5.0 ml dichlormethane was added 0.246 g m-chloroperbenzoic acid at 0° C. and the mixture was then stirred at room temperature for 3 h. The reaction mixture was partitioned between 10% potassium carbonate and ethyl acetate. The phases were separated and the organic phase was washed with brine, dried over sodium sulphate and purified by chromatography on silica gel with ethyl acetate to yield 0.260 g of the title compound as white crystals melting at 98-100° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:22][CH2:23][CH3:24])=[CH:6][C:7]2[NH:13][C:12](=[O:14])[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1)[CH3:2].CI.[CH2:27](I)[CH3:28]>>[CH2:1]([O:3][C:4]1[C:5]([O:22][CH2:23][CH3:24])=[CH:6][C:7]2[N:13]([CH2:27][CH3:28])[C:12](=[O:14])[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1)[CH3:2]
Reactant: CCOc1cc2c(cc1OCC)C(c1ccccc1)=NCC(=O)N2
Reactant: CCI
Solvent: CI
Product: CCOc1cc2c(cc1OCC)N(CC)C(=O)CN=C2c1ccccc1
Yield: 59 %

Procedure:
By replacing 5-(4-bromophenyl)-7,8-dimethoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIaf) in example IIba by 7,8-diethoxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIag), and MeI by ethyl iodide, and proceeding in the same manner, the abovenamed product is obtained. Yield: 59%. M: 99–102° C. 1H-NMR (CDCl3, 300 MHz): d 1.11 (t, 3H, CH3), 1.36 (t, 3H, CH3), 1.53 (t, 3H, CH3), 3.93 (q, 2H, OCH2), 3.97 (AB system, ?d=0.67, JAB=14.0, 2H, —NCH2), 4.17 (q, 2H, OCH2), 4.28 (AB system, ?d=0.96 JAB=10.0, 2H, CH2), 6.68 (s, 1H Ar), 6.84 (s, 1H Ar), 7.38–7.64 (m, 5H Ar).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][N:25]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(OCCCN3CCNCC3)cc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(CCCOc2ccc3c(c2)C(=O)C(c2cccnc2)=C3c2cc(F)cc(F)c2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 73.4 %

Procedure:
To a 10 mL round-bottomed flask, 6-(3-(piperazin-1-yl)propoxy)-3-(3,5-difluorophenyl)-2-(pyridin-3-yl)-1H-inden-1-one (30 mg, 1.2 eq) obtained in Step 1 of Example 66 and CH2Cl2 (1 mL, 0.05M) were charged. Triethylamine (0.02 mL, 1.5 eq) was added and then the mixture was cooled to 0° C. and treated with a solution of methylsulfonyl chloride (6.2 mg, 0.05 mmol) in CH2Cl2 (1 mL) over 5 min. After being stirred for 3 h, the mixture was diluted with CH2Cl2 and washed with H2O and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH=9:1) and being purified by prep. HPLC (20% H2O/CH3CN) to provide the title compound (19.8 mg, 68%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[Cl:9][CH2:10][C:11](Cl)=[O:12]>ClCCCl>[Cl:9][CH2:10][C:11]([NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[N:7]=1)=[O:12]
Reactant: O=C(Cl)CCl
Reactant: Cc1nccc(N)n1
Solvent: ClCCCl
Product: Cc1nccc(NC(=O)CCl)n1
Temperature: 80 °C
Yield: 7.5 %

Procedure:
2-Methyl-pyrimidin-4-yl amine (545 mg) was suspended in DCE (5 mL) and chloroacetylchloride (0.4 mL) was added dropwise. The reaction was heated in a microwave at 80° C. for 5 mins. The reaction mixture was cooled to give a solid that was filtered, washed with dichloromethane then suspended in dichloromethane and sat. NaHCO3 (aq) was added. The organic phase was collected and the aqueous layer extracted with dichloromethane (×2). The combined organic layer was dried over sodium sulphate and concentrated. The crude product was purified by silica gel chromatography eluting with 0-10% MeOH/dichloromethane to give the sub-titled compound as a yellow solid (70 mg, 7.5%).
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[F:18][C:19]([F:28])([F:27])[C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1.Cl>C(=O)(O)[O-].[Na+]>[N+:15]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])[C:2]=1[O:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([F:18])([F:27])[F:28])[CH:21]=1)[C:6]([OH:8])=[O:7])([O-:17])=[O:16]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1cccc(C(F)(F)F)c1
Temperature: 95 °C
Reaction time: 6 h

Procedure:
A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (7 g), m-trifluoromethylphenol (20 g), and 1N sodium bicarbonate (100 ml) was stirred at 95° C for 6 hours. Then the reaction mixture was acidified by the addition of 4N hydrochloric acid and the excess of trifluoromethylphenol was removed by steam distillation. After cooling, the precipitated 3-nitro-5-sulphamyl-4-(m-trifluoromethylphenoxy)-benzoic acid was collected by suction and recrystallized several times from methanol-water. The melting point of the pure compound was 205°-206° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11]([CH2:15][CH:16]=[CH2:17])[C:12]([OH:14])=O)=[CH:5]2.[CH3:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[C:26]([N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:27])[NH2:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11]([CH2:15][CH:16]=[CH2:17])[C:12]([NH:22][C:21]1[CH:23]=[CH:24][C:25]([C:26]([N:28]3[CH2:29][CH2:30][CH2:31][CH2:32]3)=[O:27])=[C:19]([CH3:18])[CH:20]=1)=[O:14])=[CH:5]2
Reactant: C=CCC(C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(N)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CCC(C(=O)Nc1ccc(C(=O)N2CCCC2)c(C)c1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
Prepared by saponification of ethyl rac.-2-(1-tert-butoxycarbonyl-1H-5-chloroindol-2-yl)pent-4-enoate to rac.-2-(5-chloro-1H-indol-2-yl)pent-4-enoic acid analogously to Example 1f and subsequent amide coupling analogously to Example 1g with 3-methyl-4-(pyrrolidin-1-ylcarbonyl)aniline, TBTU, diisopropylethylamine in tetrahydrofuran. C25H26ClN3O2 (435.96); mass spectrum: (M+H)+=435.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][C@@H:12]([C@@H:20]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:21]([NH:23][N:24]([C:29](=[O:36])[CH2:30][N:31]1[CH:35]=[CH:34][N:33]=[CH:32]1)[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22])[C:13]([O:15]C(C)(C)C)=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:9][CH2:10][CH2:11][C@@H:12]([C@@H:20]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:21]([NH:23][N:24]([C:29](=[O:36])[CH2:30][N:31]1[CH:35]=[CH:34][N:33]=[CH:32]1)[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22])[C:13]([OH:15])=[O:14])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)Cn1ccnc1)[C@H](CCNC(=O)c1ccccc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)Cn1ccnc1)[C@H](CCNC(=O)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.907 g of 2(R)-[3-benzamido-1(S)-(tert-butoxycarbonyl)propyl]-2′-[2-(1H-imidazol-1-yl)acetyl]-2′-isobutyl-4-methylvalerohydrazide in 8 ml of dichloromethane was treated with 6 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 2 hours and then the solvent was evaporated. The residue was dried in vacuo to give 2(R)-[3-benzamido-1(S)-(carboxy)propyl]-2′-[2-(1H-imidazol-1-yl)acetyl]-2′-isobutyl-4-methylvalerohydrazide in the form of a pale orange oil.
Reaction SMILES: [C:1]([CH:6]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])([O:3][CH2:4][CH3:5])=[O:2].C1C(=O)N([Br:29])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([CH:6]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][Br:29])[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)CCC(Oc1ccccc1C)C(=O)OCC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)CCC(Oc1ccccc1CBr)C(=O)OCC
Reaction time: 2 h

Procedure:
A mixture of ethyl 4-carbethoxy-4-(2-methylphenoxy)butyrate (0.05 mol) and NBS (0.055 mol) and 150 mg of benzoyl peroxide in 150 mL of CCl4 is refluxed and shined with a sun lamp for 2 hours. Filtration and evaporation of solvent gives 2-(1,3-dicarbethoxypropoxy) benzyl bromide which is used without purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])=[CH:5][CH:4]=1)#[N:2].[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-].[NH4+]>CN(C)C=O.CCOCC>[N:2]1[NH:19][N:20]=[N:21][C:1]=1[C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])=[CH:7][CH:8]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(-c2nn[nH]n2)cc1
Temperature: 110 °C
Yield: 91.2 %

Procedure:
A mixture of tert-butyl [(1S)-1-(4-cyanophenyl)ethyl]carbamate (step 1, 1.11 g, 4.51 mmol), sodium azide (1.75 g, 27.1 mmol) and ammonium chloride (1.15 g, 27.1 mmol) in N,N-dimethylforamide (25 mL) was heated at 110° C. for 24 h. After cooling to room temperature, the mixture was diluted with ether (200 mL) and washed with 1 N hydrochloric acid (100 mL). The organic layer was dried over magnesium sulfate and evaporated. The residue was crystallized from dichloromethane and hexane to give 1.19 g (91%) of the title compounds as white solids: 1H-NMR (DMSO-d6) δ 7.98 (2H, d, J=8.3 Hz), 7.51 (2H, d, J=8.3 Hz), 4.74–4.63 (1H, m), 1.37–1.32 (12H, m); MS (ESI) m/z 290 (M+H)+, 288 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:14]2([C:18](=[O:19])[N:17]([OH:20])[C:16](=[O:21])[CH2:15]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][N+:26]([O-:28])=[O:27]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:14]2([C:18](=[O:19])[N:17]([O:20][CH2:25][N+:26]([O-:28])=[O:27])[C:16](=[O:21])[CH2:15]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CC(=O)N(O)C2=O
Reactant: O=[N+]([O-])CBr
Product: O=C(OCc1ccccc1)N1CCC2(CC1)CC(=O)N(OC[N+](=O)[O-])C2=O

Procedure:
Employing 8-benzyloxycarbonyl-2-hydroxy-2,8-diazaspiro[4,5]decane-1,3-dione (0.64 g) and bromonitromethane (140 μl), reaction was conducted in the same manner as in Example 40 to obtain 0.25 g of a colorless solid, m.p. 137° to 139° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][CH:5]=1.Cl[C:16]([S:18]Cl)=[O:17]>C1(C)C=CC=CC=1>[F:1][C:2]([F:13])([F:14])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]2[O:9][C:16](=[O:17])[S:18][N:10]=2)=[CH:6][CH:5]=1
Reactant: O=C(Cl)SCl
Reactant: NC(=O)c1ccc(OC(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: O=c1oc(-c2ccc(OC(F)(F)F)cc2)ns1
Temperature: 90 °C

Procedure:
To a solution of 4-trifluoromethoxybenzamide (0.50 g, 2.43 mmol) in toluene (10 ml) was added chlorocarbonylsulfenyl chloride (0.50 ml, 6.09 mmol). The resulting reaction mixture was refluxed at 90° C. for 2 h. After the completion of the reaction (TLC monitoring), the mixture was concentrated, added diethyl ether and washed twice with water, twice with 5% NaHCO3, again with water, and was dried (Na2SO4), concentrated under vacuum to give the product (crude yield 0.74 g) that was carried forward to the next step without further purification. MS ES+ (264.18).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:19]1([CH2:22][NH2:23])[CH2:21][CH2:20]1.Cl.CN(C)CCCN=C=NCC>ClCCl>[C:1]([O:5][C:6]([NH:8][NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:12]([C:13](=[O:15])[NH:23][CH2:22][CH:19]2[CH2:21][CH2:20]2)[CH:11]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCC1CC1
Reactant: CC(C)(C)OC(=O)NNc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNc1cccc(C(=O)NCC2CC2)c1
Temperature: 25 °C
Yield: 64.2 %

Procedure:
The 4.40 g of unpurified 3-(2-tert-butoxycarbonylhydrazino)benzoic acid was dissolved in 80 ml of dichloromethane. To this mixture, 1.78 g of cyclopropylmethylamine and 3.45 g of 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloric acid salt were added and the resulting mixture was heated to reflux for 2 hours. After leaving the reaction mixture to cool to room temperature, the mixture was sequentially washed with 50 ml of water, 50 ml of 1N hydrochloric acid and then 50 ml of aqueous saturated sodium hydrogen carbonate solution, dried and concentrated to obtain 3.42 g of crude crystals. The crude crystals were recrystallized twice from ethyl acetate-hexane to obtain 1.29 g (yield 40%, three steps) of the captioned compound.
Reaction SMILES: [OH-].[Na+].O.[NH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6]1.C(Cl)(=O)OCC.[C:21](=S)=[S:22]>>[N:4]([CH:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6]1)=[C:21]=[S:22]
Reactant: CCOC(=O)N1CCC(N)C1
Reactant: S=C=S
Agent: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)N1CCC(N=C=S)C1
Reaction time: 3 h
Yield: 100 %

Procedure:
a-4) A mixture of 8.6 parts of sodium hydroxide and 120 parts of water was stirred at a temperature below 10° C. and there were added successively 17 parts of carbon disulfide and 35 parts of ethyl 3-amino-1-pyrrolidinecarboxylate. Stirring was continued for 3 hours. Then there were added dropwise 23.5 parts of ethyl carbonochloridate. Upon completion, stirring was continued for 2 hours at 60° C. The reaction mixture was extracted with methylbenzene. The extract was dried, filtered and evaporated, yielding 55 parts (100%) of ethyl 3-isothiocyanato-1-pyrrolidinecarboxylate as a residue (interm. 6).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([OH:31])[CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Br:32][C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1>>[Br:32][C:33]1[CH:38]=[CH:37][C:36]([O:31][CH:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[CH2:1][CH2:2][CH2:3]3)[CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=3)[CH2:17][CH2:18]2)=[CH:35][CH:34]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc4c(c3)CCC4)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(Br)cc3)c3ccc4c(c3)CCC4)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(2,3-dihydro-1H-inden-5-yl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-bromophenol:
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:10]([C:13]1[CH:14]=[N:15][C:16]([N:19]2[CH2:24][CH2:23][CH2:22][C@H:21]([NH:25][C@@H:26]3[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]3[NH2:32])[CH2:20]2)=[N:17][CH:18]=1)([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:14]=[N:15][C:16]([N:19]2[CH2:24][CH2:23][CH2:22][C@H:21]([NH:25][C@@H:26]3[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]3[NH:32][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])[CH2:20]2)=[N:17][CH:18]=1)([O-:12])=[O:11]
Reactant: N[C@@H]1CCCC[C@H]1N[C@H]1CCCN(c2ncc([N+](=O)[O-])cn2)C1
Reactant: O=C=Nc1ccccc1
Product: O=C(Nc1ccccc1)N[C@@H]1CCCC[C@H]1N[C@H]1CCCN(c2ncc([N+](=O)[O-])cn2)C1
Yield: 51.7 %

Procedure:
1-((1R,2R)-2-((S)-1-(5-Nitropyrimidin-2-yl)piperidin-3-ylamino)cyclohexyl)-3-phenylurea (17.5 mg, 0.031 mmol, 51.5% yield) was synthesized as described in General Procedure F using phenyl isocyanate (7.15 mg, 0.060 mmol) and (1R,2R)—N1-((S)-1-(5-nitropyrimidin-2-yl)piperidin-3-yl)cyclohexane-1,2-diamine (32.9 mg, 0.060 mmol). Anal. Calcd. for C22H29N7O3 m/z 439.5, found: 440.4 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 10.25 (br. s., 1H), 8.90 (d, J=6.60 Hz, 1H), 8.78-8.59 (m, 2H), 7.23-7.123 (m, 4H), 6.98 (t, J=6.87 Hz, 1H), 6.56 (br. s., 1H), 4.27 (d, J=12.09 Hz, 1H), 4.12-3.92 (m, 2H), 3.88-3.73 (m, 1H), 3.64 (br. s., 1H), 3.21 (br. s., 1H), 3.02-2.77 (m, 3H), 2.20-2.00 (m, 2H), 1.92 (ddd, J=7.01, 3.44, 3.30 Hz, 1H), 1.80 (d, J=10.99 Hz, 2H), 1.63 (d, J=14.29 Hz, 3H), 1.35-1.11 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11](=[O:16])[CH:10]=[N:9]2)=[C:4]([F:17])[CH:3]=1.Cl[CH2:19][C:20]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:21]=1[O:22][CH:23]([CH3:28])[C:24]([O:26][CH3:27])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:15][N:12]1[C:11](=[O:16])[CH:10]=[N:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:19][C:20]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:21]=3[O:22][CH:23]([CH3:28])[C:24]([O:26][CH3:27])=[O:25])=[CH:3][C:4]=2[F:17])[C:13]1=[O:14]
Reactant: COC(=O)C(C)Oc1cc(C)ccc1CCl
Reactant: Cn1c(=O)cnn(-c2ccc(O)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cc(C)ccc1COc1ccc(-n2ncc(=O)n(C)c2=O)c(F)c1
Yield: 78.9 %

Procedure:
By the method of Example 1, Step K, 0.47 g (0.002 mole) of 2-(4-hydroxy-2-fluorophenyl)-4-methyl-1,2,4-triazine-3,5-dione and 0.73 g (0.003 mole) of methyl 2 -(2-chloromethyl-5-methylphenoxy)propionate were reacted in the presence of 0.41 g (0.003 mole) of anhydrous potassium carbonate in 30 mL of N,N-dimethylformamide, yielding 0.70 g of methyl 2-[2-[4-(4-methyl-1,2,4-triazine-3,5-dion-2-yl)-3-fluorophenoxymethyl]-5-methylphenoxy]propionate as a syrup. The IR and NMR spectra were consistent with the proposed structure. NMR: 1.60 (d, 3H, JHH =8.0 Hz); 2.30 (s, 3H); 3.40 (s, 3H); 3.78 (s, 3H); 4.84 (q, 1H, JHH =8.0 Hz); 5.18 (dd, 2H, JHH =10 Hz); 6.58 (s, 1H); 6.8-7.3 (m, 5H); 7.54 (s, 1H).