Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][P:3]([O:7]/[C:8](/[C:11]1[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[C:13]([Cl:19])[CH:12]=1)=[CH:9]\[Cl:10])([O:5][CH3:6])=[O:4].[CH2:20]([OH:25])[CH2:21][CH:22]([OH:24])[CH3:23]>>[CH2:20]([OH:25])[CH2:21][C@H:22]([OH:24])[CH3:23].[CH3:6][O:5][P:3]([O:7]/[C:8](/[C:11]1[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[C:13]([Cl:19])[CH:12]=1)=[CH:9]\[Cl:10])([O:2][CH3:1])=[O:4]
Reactant: CC(O)CCO
Agent: COP(=O)(OC)O/C(=C\Cl)c1cc(Cl)c(Cl)cc1Cl
Product: C[C@@H](O)CCO

Procedure:
The microorganisms usable in the present invention include those belonging to the genera Rhodococcus, Gordona and Streptomyces and capable of acting on an enantiomorphic mixture of 1,3-butanediol so as to leave (R)-1,3-butanediol as such and those belonging to the genera Rhodococcus and Gordona and capable of acting on an enantiomorphic mixture of 1,3-butanediol so as to leave (S)-1,3-butanediol as such.
Reaction SMILES: C[O-:2].[Na+].Cl.[Cl:5][C:6]1[C:16]([Cl:17])=[C:15]([C:18](=O)[CH2:19][CH2:20]N(C)C)[CH:14]=[CH:13][C:7]=1[O:8][CH2:9][C:10]([OH:12])=[O:11].C(O[C:28](=O)[CH:29](C)[C:30]([CH3:32])=O)C>C(O)C>[Cl:5][C:6]1[C:16]([Cl:17])=[C:15]([C:18]2[CH2:32][CH2:30][CH:29]([CH3:28])[C:20](=[O:2])[CH:19]=2)[CH:14]=[CH:13][C:7]=1[O:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: C[O-]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: CN(C)CCC(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC1CCC(c2ccc(OCC(=O)O)c(Cl)c2Cl)=CC1=O

Procedure:
To a stirred solution of sodium methoxide (3.5 g, 0.065 mole) in ethanol (100 ml) and ethyl-2-methylacetoacetate (6.6 ml) was added [2,3-dichloro-4-(3-dimethylamino-1-oxopropyl)phenoxy]acetic acid hydrochloride (7.4 g, 0.021 mole). The reaction mixture was heated at reflux for 3 hours then the solvent was distilled at reduced pressure, treated with 100 ml of 2% sodium hydroxide, heated on a steam bath for 11/2 hours, then acidified, extracted with ether, washed with water, dried over magnesium sulfate and evaporated at reduced pressure. The residue was triturated with 100 ml of hot toluene, filtered, and dried to give 0.9 of [2,3-dichloro-4-(4-methyl-3-oxo-1-cyclohexen-1-yl)phenoxy]acetic acid which melted at 183°-185° C. after recrystallization from 30 ml of toluene.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[NH:15][N:14]=[N:13][C:12]=1[C:16](=[O:18])[NH2:17].O>N1C=CC=CC=1>[C:1]([NH:10][C:11]1[NH:15][N:14]=[N:13][C:12]=1[C:16](=[O:18])[NH2:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(=O)c1nn[nH]c1N
Solvent: c1ccncc1
Solvent: O
Product: NC(=O)c1nn[nH]c1NC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
Benzoyl chloride (28 ml.) was added dropwise, under anhydrous conditions, to an ice-cooled, stirred suspension of 5-amino-4-carbamoyl-1H-1,2,3-triazole (15.24 g.) in anhydrous pyridine (240 ml.), and the reaction mixture was then stirred at room temperature for 40 hours. The mixture was poured into cold water (1,200 ml.), and the solid filtered off and washed well with water. The crude solid was heated in a large volume of boiling ethanol, and the insoluble material filtered off while still hot, to give 5-benzamido-4-carbamoyl-1H-1,2,3-triazole (20.4 g.), m.p. 301° C. (with decomposition).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:17]([CH3:20])([O-:19])=[O:18].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:15]=[CH:20]/[N+:17]([O-:19])=[O:18])=[CH:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)nc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(OCc2ccccc2)nc1
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 95.8 %

Procedure:
To a solution of 6-benzyloxy-pyridin-3-carbaldehyde (4.87 g, 22.8 mmol) described in Manufacturing Example 12-1-2 in acetic acid (30 mL) were added nitromethane (6.96 g, 114 mmol) and ammonium acetate (3.51 g, 45.6 mmol) under nitrogen atmosphere at room temperature, which was stirred for 2.5 hours at 110° C. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure to obtain the title compound (5.60 g, 96%) as a crude product.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C@@H:11]([CH2:16][OH:17])[C:12]([O:14][CH3:15])=[O:13])(=[O:9])=[O:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:24](I)[CH3:25]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:24][CH3:25])[C@@H:11]([CH2:16][OH:17])[C:12]([O:14][CH3:15])=[O:13])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](CO)NS(=O)(=O)c1ccc(Cl)s1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN([C@@H](CO)C(=O)OC)S(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
Compound 5 (10 g, 30 mmol) dissolved in DMF (100 ml) was added with K2CO3 (1.1 equiv., 4.56 g) and ethyl iodide (1.1 equiv., 3.16 ml) and the reaction was stirred at rt overnight. The reaction was diluted with ethyl acetate and washed several times with water and finally with Brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by crystallization from ethyl ether and petroleum ether afforded 10 g of a semisolid. Yield=93%. 1HNMR (DMSO, 200 MHz) δ 1.17 (3H, t, J=7 Hz), 3.40 (2H, q), 3.54 (3H, s), 3.80 (2H, t, J=5.8 Hz), 4.50 (1H, t), 5.00 (1H, bt), 7.28 (1H, dd, J=4 Hz, J′=1 Hz), 7.57 (1H, dd, J=4.2 Hz, J′=1 Hz).
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18]([CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])=[CH:19][CH2:20]Br>CN(C)C=O.O>[N+:7]([C:6]1[CH:5]=[CH:4][C:3]([O:10][CH2:20][CH:19]=[C:18]([CH3:17])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])=[CH:2][CH:1]=1)([O-:9])=[O:8]
Reactant: CC(C)=CCCC(C)=CCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCCC(C)=CCOc1ccc([N+](=O)[O-])cc1
Reaction time: 12 h

Procedure:
To a solution of p-nitrophenol (2 g.) in dimethylformamide (10 ml.) is added anhydrous potassium carbonate (2 g.) and 3,7-dimethylocta-2,6-dienyl bromide (3.1 g.). The reaction is kept at 50° for 12 hours, diluted with water and extracted with ether. The ethereal extract is washed with 5% aqueous sodium hydroxide and dried over sodium sulfate. The crude product is purified by distillation to yield 3,7-dimethylocta-2,6-dienyl p-nitrophenyl ether.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:24])[C@@H:10]([CH3:23])[O:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14](Cl)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([CH:41]2[CH2:43][CH2:42]2)(=[N:34][C:35](=[O:40])[C:36]([F:39])([F:38])[F:37])=[O:33])=[CH:28][CH:27]=1.Cl>C(#N)C.O1CCOCC1>[CH2:1]([O:8][C@H:9]([CH3:24])[C@H:10]([O:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([S:32]([CH:41]3[CH2:43][CH2:42]3)(=[N:34][C:35](=[O:40])[C:36]([F:39])([F:37])[F:38])=[O:33])=[CH:30][CH:31]=2)[N:13]=1)[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](OCc1ccccc1)[C@@H](C)Oc1nc(Cl)ncc1C(F)(F)F
Reactant: Nc1ccc(S(=O)(=NC(=O)C(F)(F)F)C2CC2)cc1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: C[C@@H](OCc1ccccc1)[C@@H](C)Oc1nc(Nc2ccc(S(=O)(=NC(=O)C(F)(F)F)C3CC3)cc2)ncc1C(F)(F)F
Temperature: 80 °C
Reaction time: 5 h
Yield: 56 %

Procedure:
4-((1R,2R)-2-benzyloxy-1-methylpropoxy)-2-chloro-5-trifluoromethylpyrimidine and (RS)—S-(4-aminophenyl)-S-cyclopropyl-N-(trifluoroacetyl)sulphoximide in acetonitrile were admixed with a 4N solution of hydrogen chloride in dioxane and stirred for 5 hours at 80° C. After cooling, the mixture was diluted with acetic ester and washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated by evaporation. The resulting residue was purified by means of chromatography (hexane/acetic ester 4:1) (yield: 56%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:18])[CH:5]=[C:6]2[C:11]=1[NH:10][CH:9]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]2=[O:17].[C:19]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([CH3:18])[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:19])[CH:9]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]2=[O:17]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c[nH]c2c(Cl)nc(C)cc2c1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CCOC(=O)c1cn(C)c2c(Cl)nc(C)cc2c1=O
Reaction time: 5 h
Yield: 36.8 %

Procedure:
Ethyl 8-chloro-6-methyl-4-oxo-1,4-dihydro[1,7]naphthyridine-3-carboxylate (Preparation 43, 1.86 g) is dissolved in DMF (20 mL) and K2CO3 (2.4 g) is added followed by iodomethane (1.28 g) at room temperature. The mixture is stirred for 5 hours and then added to water (120 mL). The solid is washed with additional water, collected and dried under high vacuum to obtain 0.72 g (37%) of the title compound as a pale green powder. Physical characteristics: MS (ESI+) m/z 281 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:10]=[C:11]([C@:15]23[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][C@H:20]2[CH2:19][S:18][C:17]([NH:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:16]3)[CH:12]=[CH:13][CH:14]=1>ClCCl>[NH3:8].[NH2:8][C:9]1[CH:10]=[C:11]([C@:15]23[CH2:23][NH:22][CH2:21][C@H:20]2[CH2:19][S:18][C:17]([NH:31][C:32](=[O:39])[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[N:16]3)[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cccc(N)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N
Product: Nc1cccc([C@]23CNC[C@H]2CSC(NC(=O)c2ccccc2)=N3)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 159.8 %

Procedure:
Trifluoroacetic acid (25 mL) is added to a solution of tert-butyl (4aR,7aS)-7a-(3-aminophenyl)-2-benzamido-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate (4 g, 8.84 mmol) in dichloromethane (100 mL) and the mixture is stirred at room temperature under nitrogen for 4 hours. The solvent is removed in vacuo and the crude product is purified with an SCX column using 3:1 dichloromethane:methanol and then 2:1 dichloromethane:7 N ammonia in methanol to give the title compound (2.49 g, 80%). ES/MS (m/e): 353 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH3:21]>CC(C)=O>[CH2:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[CH:6][CH:7]=1)[CH3:21]
Reactant: Oc1ccc(-c2nccs2)cc1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc(-c2nccs2)cc1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
To a mixture of 2-(4-hydroxyphenyl)thiazole (21.27 g, 0.12 mol) and K2CO3 (82.93 g, 0.60 mol) in acetone (1000 mL) was added bromoethane (39.24 g, 0.36 mol) with stirring at rt. The reaction mixture was heated at 60° C. for 11 h, then cooled to rt, filtered and concentrated in vacuo to give the title compound as a white solid (24.54 g, 100%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[N:22]3[C:17]([C:18]([NH2:23])=[N:19][CH:20]=[N:21]3)=[C:16]([C:24]3[CH:25]=[CH:26][C:27]4[C:31]([CH:32]=3)=[N:30][N:29]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:28]=4)[CH:15]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:33]([N:29]1[CH:28]=[C:27]2[C:31]([CH:32]=[C:24]([C:16]3[CH:15]=[C:14]([CH2:13][CH:10]4[CH2:11][CH2:12][NH:8][CH2:9]4)[N:22]4[C:17]=3[C:18]([NH2:23])=[N:19][CH:20]=[N:21]4)[CH:25]=[CH:26]2)=[N:30]1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnn2c(CC3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reaction time: 18 h
Yield: 31.1 %

Procedure:
The product from Step 4 (0.10 g, 0.19 mmol) was dissolved in dichloromethane (3 mL) and TFA (0.14 mL, 1.95 mmol) was added. The mixture was stirred for 18 hours and concentrated. The residue was purified by preparative HPLC using 10-90% gradient of acetonitrile/water to provide 25 mg (31%) of the title compound. 1H-NMR (CD3OD-d4) 8.30-8.35 (m, 1H), 7.85-7.80 (m, 2 H), 7.67-7.64 (m, 1H), 7.40-7.22 (m, 5 H), 7.24 (dd, 1 H), 6.64 (s, 1 H), 5.67 (s, 2 H), 3.17-2.94 (m, 3 H), 2.77-2.68 (m, 2 H), 2.08-1.98 (m, 1 H), 1.70-1.59 (m, 1 H); LC-MS [M+H]+=424.2, RT=2.03 min.
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([CH3:10])[S:8][CH:9]=1)[CH2:3][NH2:4].[C:11]([CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](=O)[CH3:25])=[CH:19][CH:18]=1)([O:13][CH3:14])=[O:12]>>[C:11]([CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH:24]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[N:6]=[C:7]([CH3:10])[S:8][CH:9]=2)[CH3:25])=[CH:21][CH:22]=1)([O:13][CH3:14])=[O:12]
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Reactant: Cc1nc(C(O)CN)cs1
Product: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(C)n2)cc1

Procedure:
Prepared analogously to Example 13 by reaction of 2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine with 1-(4-carbomethoxymethoxyphenyl)propan-2-one followed by purification of the base on a silica gel column using ethyl acetate/methanol =9:1 as eluant.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:19]3=[O:29])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH2:30]([N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1)[CH3:31].C([O-])([O-])=O.[K+].[K+]>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.O1CCOCC1.O>[CH2:30]([N:32]1[CH:36]=[C:35]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]([N:18]4[CH2:22][CH2:21][N:20]([CH:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)[C:19]4=[O:29])=[O:17])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[CH:34]=[N:33]1)[CH3:31]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(Nc1ccc(Oc2ccnc(Cl)c2)cn1)N1CCN(C2CCOCC2)C1=O
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCn1cc(-c2cc(Oc3ccc(NC(=O)N4CCN(C5CCOCC5)C4=O)nc3)ccn2)cn1
Temperature: 80 °C
Yield: 71.7 %

Procedure:
A mixture of Example C1 (0.15 g, 0.40 mmol), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.088 g, 0.40 mmol), and K2CO3 (0.2 g, 1.44 mmol) in 4:1 dioxane/water (5 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.040 g, 0.036 mmol), sparged again with Ar and heated at 80° C. overnight. The mixture was cooled to RT, treated with brine, extracted with EtOAc (2×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The material was treated with Et2O, allowed to stand at RT and the resulting solid collected via filtration to afford N-(5-((2-(1-ethyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (137 mg, 80%). 1H NMR (400 MHz, DMSO-d6): δ 10.96 (s, 1 H), 8.37 (d, J=5.7 Hz, 1 H), 8.30 (s, 1 H), 8.23 (d, J=2.9 Hz, 1 H), 8.07 (d, J=9.0 Hz, 1 H), 7.97 (s, 1 H), 7.71 (dd, J=9.0, 2.9 Hz, 1 H), 7.24 (d, J=2.4 Hz, 1 H), 6.69 (dd, J=5.7, 2.4 Hz, 1 H), 4.13 (q, J=7.3 Hz, 2 H), 3.86 (m, 5 H), 3.40 (m, 4 H), 1.71 (m, 2 H), 1.59 (m, 2 H), 1.37 (t, J=7.3 Hz, 3 H); MS (ESI) m/z: 478.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[C:24]([N+:32]([O-:34])=[O:33])[CH:23]=1.CCCCCC.CCOC(C)=O>C(Cl)Cl>[NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:28]([C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][C:24]=2[N+:32]([O-:34])=[O:33])(=[O:29])=[O:30])[C:3]1=[O:12]
Reactant: NC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1ccc(S(=O)(=O)N2C(=O)C(N)(c3ccccc3Cl)c3cc(Cl)ccc32)c([N+](=O)[O-])c1
Yield: 81.1 %

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 1 from 2 g of 3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one and 1.71 g of 4-methoxy-2-nitrobenzenesulfonyl chloride. Chromatography on silica using a DCM/hexane mixture (80/20; v/v) and then DCM as the eluent gives 2.8 g of the expected product after crystallization from a DCM/iso ether mixture. M.p.=192°-195° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.O.[C:10]1([CH3:19])[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:3][C:4](=[O:5])[NH:6][C:7]1=[N:8][C:17]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)=[O:18]
Reactant: CN1CC(=O)N=C1N
Reactant: Cc1ccc(N=C=O)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)N=C2NC(=O)CN2C)cc1
Reaction time: 3.5 h

Procedure:
To a stirring suspension of creatinine (11.88 g, 0.105 mole) in 100 ml dry DMF, p-tolylisocyanate (13.31 g- 0.100 mole) is added dropwise over a period of about 15 minutes with cooling. After stirring for 3.5 hrs., the mixture is poured into about 500 ml iced-water to give white crystals of product which are filtered off and washed with water. Recrystallization of the product from acetone-methanol and then from THF-methanol affords the product, 1-(1-methyl-4-oxo-2-imidazolidinylidene)-3-p-tolyl urea. The crystalline particles are reduced to finer size by adding a solution of the thus-obtained product in minimal DMF to about 1.1 liters of vigorously stirring water, filtering off and drying the resultant fine crystals in vacuo for 24 hours; m.p. 198°-200° C. dec.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][C:3]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[SH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.O>CN(C)C=O>[F:15][C:10]1[C:9]([C:3]2[CH:4]=[C:5]([CH:7]=[O:8])[S:6][C:2]=2[S:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Sc1ccccn1
Reactant: O=Cc1cc(-c2cccnc2F)c(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(-c2cccnc2F)c(Sc2ccccn2)s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.6 %

Procedure:
A suspension of 5-bromo-4-(2-fluoropyridin-3-yl)thiophene-2-carbaldehyde (297 mg), potassium carbonate (171 mg) and 2-mercaptopyridine (129 mg) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 2 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound as a pale-yellow solid (yield 281 mg, yield 85%).
Reaction SMILES: [C:1]([O-:5])(=O)[CH2:2][OH:3].C=C.[Na+].[N+:9]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1Cl)([O-:11])=[O:10].O>C(O)CO>[N+:9]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[O:3][CH2:2][CH2:1][OH:5])([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=C([O-])CO
Agent: C=C
Agent: [Na+]
Solvent: O
Solvent: OCCO
Product: O=[N+]([O-])c1ccc(OCCO)c([N+](=O)[O-])c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
200 ml of ethylene glycol and 40 ml of a 14.4% strength mono-sodium ethylene glycolate solution were introduced initially under nitrogen and were heated to 65° C. in a 2 l reaction vessel fitted with a stirrer. Over the course of 5 h, 162 g of molten 2,4-dinitrochlorbenzene and a further 480 ml of a 14.4% strength mono-sodium ethylene glycolate solution in ethylene glycol were simultaneously metered in. The mixture was then stirred for one hour at 65° C., and then 600 ml of water were added. The precipitate which formed was filtered off and washed with 1000 ml of water and dried, giving 161.3 g of 2-(2′,4′-dinitrophenoxy)-ethanol in a purity of 97%. Hence, a yield of 92.2% is achieved based on 2,4-dinitrochloro-benzene.
Reaction SMILES: C(O)(=O)C.O=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:33]1[CH2:38][CH2:37][CH:36]([OH:39])[CH2:35][CH2:34]1.C(N(CC)CC)C>ClCCl>[NH3:9].[OH:39][CH:36]1[CH2:37][CH2:38][N:33]([CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:34][CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: OC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(O)CC2)CC1
Product: N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Acetic acid (3.25 ml, 41.3 mmol) followed by tert-butyl 4-oxo-1-piperidinecarboxylate (1 g, 5.0 mmol) and sodium triacetoxyborohydride (2.11 g, 10 mmol) were added to a solution of 4-piperidinol (757 mg, 7.5 mmol) and triethylamine (5.5 ml, 37.5 mmol) in dichloromethane (50 ml), and the reaction stirred at room temperature for 18 hours. The reaction was washed with sodium bicarbonate solution, dried (MgSO4) and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (95:5:0.5 to 93:7:0.5) to give the title compound as a clear gum, 700 mg.
Reaction SMILES: [C:1](=[C:4]1[NH:8][C:7](=O)[NH:6][C:5]1=[O:10])([CH3:3])[CH3:2].CC(C)=O.N1CC(=O)NC1=[S:17]>N1CCCCC1>[C:1](=[C:4]1[NH:8][C:7](=[S:17])[NH:6][C:5]1=[O:10])([CH3:3])[CH3:2]
Reactant: O=C1CNC(=S)N1
Reactant: CC(C)=C1NC(=O)NC1=O
Solvent: C1CCNCC1
Solvent: CC(C)=O
Product: CC(C)=C1NC(=S)NC1=O

Procedure:
Doyle et al, J. Chem. Soc. 1955, 2265-73 (Chemical Abstracts 1956, 50, 8602g at 8603b) teach the preparation of 5-iso-propylidenehydantoin via the reaction of acetone with 2-thiohydantoin in piperdine to yield 5-iso-propylidene-2-thiohydantoin which is then desulfurized with chloroacetic acid to yield 5-iso-propylidenehydantoin.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH:3]([CH:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)[O:4][Si](C)(C)C.[ClH:24].CCOCC>C(Cl)Cl.CO>[ClH:24].[F:23][C:2]([F:1])([F:22])[CH:3]([CH:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1)[OH:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(O[Si](C)(C)C)C(F)(F)F)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: OC(C1CCNCC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
To a solution of tert-butyl 4-(2,2,2-trifluoro-1-(trimethylsilyloxy)ethyl)piperidine-1-carboxylate (1.6 g, 4.50 mmol) in DCM (9 mL) and MeOH (1 mL) was added 2 M HCl in ether (11.25 mL, 22.51 mmol). The reaction was stirred at RT for 16 hours. The precipitate that formed was collected by vacuum filtration, washed with diethyl ether, and dried in vacuo to generate 2,2,2-trifluoro-1-(piperidin-4-yl)ethanol hydrochloride as a white powder (0.83 g, 84% yield).