Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])C=2OC)[CH2:10][CH2:9]1)=O)(C)C.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].C[CH2:34][O:35]CC>>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[CH3:22][O:21][C:17]1[C:18]([O:35][CH3:34])=[CH:19][CH:20]=[CH:15][C:14]=1[C:11]1([CH:28]=[O:30])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CCOCC
Reactant: COc1cccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1OC
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(C2(C=O)CCNCC2)c1OC
Reaction time: 0.75 h

Procedure:
4-(2,3-Dimethoxybenzoyl)-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (7.75 g, 22.2 mmol) was dissolved in trifluoroacetic acid (50 mL, 650 mmol) and stirred for 45 minutes. The entire solution was poured into ether (900 mL) and allowed to stand overnight. Filtration yielded 4-(2,3-dimethoxyphenyl)-4-piperidinylmethanone trifluoroacetate as fine white needles, m.p. 123° C. Anal. Calcd. for C14H19NO3.CF3CO2H: C, 52.89; H, 5.55; N, 3.86. Found: C, 52.77; H, 5.62; N, 3.82.
Reaction SMILES: [O:1]1[CH:3]2[CH:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:5][CH2:6][CH:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:2]12.C([O-])([O-])=[O:21].[Na+].[Na+].[K+].[Br-]>CC(C)=O>[C:14]1([CH:4]2[CH2:5][CH2:6][CH:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:2]([OH:21])[CH:3]2[OH:1])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C([O-])[O-]
Reactant: c1ccc(C2CCC(c3ccccc3)C3OC23)cc1
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: OC1C(c2ccccc2)CCC(c2ccccc2)C1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1,2-Epoxy-3,6-diphenylcyclohexane (32 mg, 0.13 mmol) was dissolved in acetone (10 mL). HClO4 (6%, 10 mL) was added and the mixture was stirred at room temperature for 24 hours. The reaction solution was neutralized with Na2CO3 and the reaction mixture was reduced to approximately half volume under reduced pressure. Extraction with CH2Cl2 and removal of the solvent yielded crude product (93% yield) as a white solid. Based upon the analyses of NMR spectra of crude and recrystallized product, reaction gave a single product. Recrystallization from hexane/CH2Cl2 gave pure product as a white crystalline solid: mp 134°-135° C.; IR (KBr) 3303, 3086, 3059, 3026, 2935, 2858, 1603, 1495, 1454, 1041, 760, 698 cm-1 ; 1H NMR (200 MHz, CDCl3) δ 7.20-7.60 (m, 10 H), 4.08 (t, J=9.8 Hz, 1 H), 3.95 (dd, J= 9.5, 5.5 Hz, 1 H), 3.56 (m, 1 H), 2.67 (ddd, J=11.7, 9.9, 4.3 Hz, 1 H), 1.65-2.39 (m, 6 H); 13C NMR (50 MHz, CDCl3) δ 142.3, 140.8, 129.7, 128.8, 128.4, 127.8, 126.9, 126.5, 76.8, 74.6, 50.6, 44.7, 29.9, 29.2; MS (EI) m/e (relative intensity) 268 (M+, 61.9), 250 (12.9), 237 (11.5), 219 (7.3), 146 (30.1), 131 (94.9), 117 (55.4), 104 (100.0), 91 (73.6), 77 (15.3); HRMS calcd. for C18H20O2 m/e 268.1463, found m/e 268.1464.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH:7]1([CH2:10][N:11]2[CH2:17][CH:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][CH2:14][CH2:13][C:12]2=[O:24])[CH2:9][CH2:8]1.II.BrBr.[N-:29]=[N+]=[N-].[Na+].[Br-]>ClCCl.CN(C)C=O>[NH2:29][CH:13]1[CH2:14][CH2:15][CH:16]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:17][N:11]([CH2:10][CH:7]2[CH2:9][CH2:8]2)[C:12]1=[O:24]
Reactant: O=C1CCCC(c2ccccc2)CN1CC1CC1
Reactant: [N-]=[N+]=[N-]
Agent: BrBr
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: II
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC1CCC(c2ccccc2)CN(CC2CC2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phosphorus pentachloride (1.99 g, 9.57 mmol) was added to a solution of 1-(cyclopropylmethyl)-6-phenylazepan-2-one (2.33 g, 9.57 mmol) in dichloromethane (55 mL) at 0° C. After 1 h, iodine (0.024 g, 0.096 mmol) and a solution of bromine (0.49 mL, 9.57 mmol) in dichloromethane (5 mL) were added sequentially and the mixture was allowed to warm to ambient temperature. After 18 h, the reaction was quenched with aqueous sodium sulfite. The mixture was extracted with dichloromethane (3×), and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. Sodium azide (5.60 g, 86.2 mmol) was added to a solution of the crude bromide in N,N-dimethylformamide (50 mL) and the mixture heated to 50° C. After 4 h, the reaction was allowed to cool to ambient temperature, concentrated, and diluted with water. The mixture was extracted with ethyl acetate, washed with water (3×) and saturated brine, dried over magnesium sulfate, filtered, and concentrated. 10% palladium on carbon (0.50 g) was added to a solution of the crude azide in ethanol (50 mL). The reaction vessel was evacuated and back-filled with nitrogen (3×), then back-filled with hydrogen (1 atm). After 18 h, the mixture was filtered and concentrated. Purification by silica gel chromatography [100% dichloromethane→95% dichloromethane/(10% ammonium hydroxide/methanol)] gave the racemic amine. MS 259 (M+1).
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:18](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:34][CH2:35][CH3:36])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH2:27]([N:17]([C:18](=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C:15]1[CH:14]=[CH:13][C:12]2[N:8]([CH2:7][C:6]([OH:37])=[O:5])[C:9]([CH2:34][CH2:35][CH3:36])=[N:10][C:11]=2[CH:16]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3cccc(Cl)c3)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3cccc(Cl)c3)ccc2n1CC(=O)O

Procedure:
{5-[Benzyl-(3-chloro-benzoyl)-amino]-2-propyl-benzoimidazol-1-yl}-acetic acid tert-butyl ester (0.12 mmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ7.89 (m, 1H), 7.71 (m, 1H), 7.52 (m, 1H), 7.45 (m, 1H), 7.21 (m, 6H), 6.91 (m, 1H), 5.11 (s, 2H), 4.91 (s, 2H), 2.65 (t, 2H), 1.71 (m, 2H), 0.92 (t, 3H). MS calculated for C26H24ClN3O3+H: 462, observed: 462.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][O:1][C:2]2[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=2)=[CH:14][CH:13]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=[N+]([O-])c1ccc(O)cn1
Product: O=[N+]([O-])c1ccc(OCc2ccc(Cl)cc2)cn1

Procedure:
The substituted amino-pyridine compounds of formula (I) wherein W is oxygen can be prepared by the reaction of a hydroxy-nitropyridine with a substituted phenalkyl halide to obtain the corresponding substituted nitro-pyridine which is reduced to the desired substituted amino-pyridine of formula (I). For example, the reaction of 5-hydroxy-2-nitropyridine and 4-chlorobenzyl bromide gives 5-(4-chlorobenzyloxy)-2-nitropyridine which is then reduced to 2-amino-5-(4-chlorobenzyloxy)-pyridine of formula I. Alternatively, the compounds of formula I can be prepared by the reaction of a halo-nitropyridine with a substituted phenalkyl alcohol or substituted phenalkyl thiol followed by reduction of the nitro group. For example, the reaction of 2-chloro-5-nitropyridine and 4-bromobenzyl alcohol gives 2-(4-bromobenzyloxy)-5-nitropyridine which is then reduced using, for example, iron powder to give 5-amino-2-(4-bromobenzyloxy)pyridine of formula (I).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].FC1C=CC=C2C=1[C:12]([CH2:21][C:22]([OH:24])=[O:23])=[CH:13][C:14](=[O:20])N2>>[F:1][C:2]1[CH:3]=[C:4]2[C:6]([C:12]([CH2:21][C:22]([OH:24])=[O:23])=[CH:13][C:14](=[O:20])[NH:5]2)=[CH:7][CH:8]=1
Reactant: Nc1cccc(F)c1
Reactant: O=C(O)Cc1cc(=O)[nH]c2cccc(F)c12
Product: O=C(O)Cc1cc(=O)[nH]c2cc(F)ccc12

Procedure:
The compound is prepared according to the technique described in 1.1. from 3-fluoroaniline. It contains 17% of 5-fluoro-2-oxo-1,2-dihydro-4-quinolineacetic acid. This mixture melts at 224°-225° C.
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:50][O:51][CH3:52])[C:27]([NH:29][CH:30]2[C:48](=[O:49])[N:32]3[C:33]([C:45]([OH:47])=[O:46])=[C:34]([CH2:37][S:38][C:39]4[S:43][C:42]([CH3:44])=[N:41][N:40]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)=O>O.C(N(CC)CC)C>[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:50][O:51][CH3:52])[C:27]([NH:29][CH:30]2[C:48](=[O:49])[N:32]3[C:33]([C:45]([OH:47])=[O:46])=[C:34]([CH2:37][S:38][C:39]4[S:43][C:42]([CH3:44])=[N:41][N:40]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(C)s3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=CO
Solvent: O
Solvent: CCN(CC)CC
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(C)s3)CS[C@H]12)c1csc(N)n1
Temperature: 57 °C
Yield: 28.7 %

Procedure:
A mixture of 1.4 g of the product of Example 1 and 5 ml of 50% aqueous formic acid was heated at 57° C. for 15 minutes and 5 ml of water were added. The mixture was cooled to room temperature and was vacuum filtered. The product was washed with ethanol and ether to obtain 0.687 g of raw product which was dissolved in 7 ml of water and 0.2 ml of triethylamine. The mixture was vacuum filtered and the filter was rinsed. The filtrate was acidified with 0.2 ml of 50% aqueous formic acid and the mixture was stirred and vacuum filtered. The product was washed with alcohol and ether to obtain 0.275 g of 7-[{2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl}amino]-3-[(2-methyl-1,3,4-thiadiazol-5-yl)-thiomethyl]-ceph-3-eme-4-carboxylic acid with a syn configuration.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([P:13]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10][CH:9]1[CH2:26][P:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1C=CC(P(C2C=CC(C)=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([P:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH:9]1[CH2:26][P:27]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(P(C2CCCCC2)C2CCCCC2)CC1CP(c1ccccc1)c1ccccc1
Agent: Cc1ccc(P(c2ccc(C)cc2)c2ccc3ccccc3c2-c2c(P(c3ccc(C)cc3)c3ccc(C)cc3)ccc3ccccc23)cc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Product: CC(C)(C)OC(=O)N1CC(P(c2ccccc2)c2ccccc2)CC1CP(c1ccccc1)c1ccccc1

Procedure:
1-t-butoxycarbonyl-4-dicyclohexylphosphino-2-diphenylphosphinomethylpyrrolidine, and the like. Of these, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and 2,2'-bis[di(4-methylphenyl)phosphino]-1,1'-binaphthyl are preferable.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]([CH2:8][O:9][C@H:10]([CH3:15])[C:11]([F:14])([F:13])[F:12])[CH:7]=1.I[C:26]1[N:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:29]=[C:28]([NH2:37])[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(=O)([O-])O.[Na+]>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:26]2[N:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:29]=[C:28]([NH2:37])[CH:27]=2)[CH:5]=[C:6]([CH2:8][O:9][C@H:10]([CH3:15])[C:11]([F:12])([F:13])[F:14])[CH:7]=1
Reactant: C[C@@H](OCc1cc(Cl)cc(B2OC(C)(C)C(C)(C)O2)c1)C(F)(F)F
Reactant: Nc1cc(I)n(-c2ccccc2)n1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: C[C@@H](OCc1cc(Cl)cc(-c2cc(N)nn2-c2ccccc2)c1)C(F)(F)F
Temperature: 25 °C
Yield: 78 %

Procedure:
Under argon atmosphere, to 2-[3-chloro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (269 mg) were sequentially added a solution of 5-iodo-1-phenyl-1H-pyrazol-3-ylamine (181 mg) prepared according to the same procedures as Preparation 2 in 1,2-dimethoxyethane (2.0 ml), a 2M aqueous solution of sodium carbonate (1.0 ml), tricyclohexylphosphine (36 mg) and palladium (II) acetate (15 mg) at room temperature, and the mixture was stirred at 100° C. for 2 hours. This reaction mixture was cooled to room temperature, a saturated aqueous solution of sodium hydrogen carbonate and ethyl acetate were added thereto, the mixture was filtered through Celite, and subjected to elution with ethyl acetate. The filtrate was extracted with ethyl acetate. The resulting organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (eluent: n-hexane/ethyl acetate=3/7) to give the titled compound (196 mg).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[N:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=2[N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:6]=1
Reactant: C1CNCCN1
Reactant: Brc1ccccc1Oc1cccnc1
Product: c1cncc(Oc2ccccc2N2CCNCC2)c1

Procedure:
2-Bromophenol (355 mg, 2.05 mmol), 3-pyridyl-boronic acid (500 mg, 4.1 mmol), copper acetate (745 mg, 4.1 mmol) and pyridine (3.3 mL, 41 mmol) were added to dichloromethane (41 mL) and stirred for about 48 hours under air. The reaction was diluted with water (50 mL) and the layers separated. The organic layer was washed with 5N NaOH. The organic layer was concentrated, and chromatographed on silica gel (MeOH/dichloromethane) to yield 3-(2-bromo-phenoxy)-pyridine (30 mg, 6%) as a yellow oil. MS found 249.1 M+1. 3-(2-Bromo-phenoxy)-pyridine was coupled to piperazine using the Buchwald chemistry described in preparation 1A to afford the title compound. LRMS (ESI+): 256.1 (M+1)
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.C(NC(C1CCC(O)C1O)=O)C.Cl[C:28]1[CH:33]=[CH:32][NH:31][C:30](=[O:34])[C:29]=1[N+:35]([O-:37])=[O:36].[Cl:38][C:39]1[CH:43]=[CH:42][S:41][C:40]=1[CH2:44][C@@H:45]([CH2:47][CH3:48])[NH2:46]>>[Cl:38][C:39]1[CH:43]=[CH:42][S:41][C:40]=1[CH2:44][C@H:45]([NH:46][C:28]1[CH:33]=[CH:32][N:31]=[C:30]([OH:34])[C:29]=1[N+:35]([O-:37])=[O:36])[CH2:47][CH3:48]
Reactant: O=c1[nH]ccc(Cl)c1[N+](=O)[O-]
Reactant: CC[C@@H](N)Cc1sccc1Cl
Agent: CCNC(=O)C1CCC(O)C1O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC[C@H](Cc1sccc1Cl)Nc1ccnc(O)c1[N+](=O)[O-]

Procedure:
A method for preparing the dihydrochloride salt of [1S-[1a,2b,3b,4a(S*)]]-4-[7-[[1-(3-chloro-2-thienyl) methyl]propyl]amino]-3H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,3-dihydroxycyclopentanecarboxamide comprising the steps of reacting 4-chloro-3-nitropyridin-2(1H)-one with (R)-3-chloro-α-ethyl-2-thiopheneethanamine to form (R)-N-[1-[(3-chloro-2-thienyl)methyl]propyl]-2-hydroxy-3-nitro-4-pyridinamine, followed by replacing the hydroxy moiety of (R)-N-[1-[(3-chloro-2-thienyl)methyl]propyl]-2-hydroxy-3-nitro-4-pyridinamine with a chloro group to form (R)-2-chloro-N-[1-[(3-chloro-2-thienyl)methyl]propyl]-3-nitro-4-pyridinamine, followed by reacting (R)-2-chloro-N-[1-[(3-chloro-2-thienyl)methyl]propyl]-3-nitro-4-pyridinamine wit 2R,3S-isopropylidenedioxy-4R-amino-1S-ethylaminocarbonylcyclopentane to form [3aR-[3aa,4a,6a(R*),6aa]]-6-[[4-[[1-[(3-chloro-2-thienyl)methyl]propyl]amino]-3-nitro-2-pyridinyl]amino, followed by reducing [3aR-[3aa,4a,6a(R*),6aa]]-6-[[4-[[1-[(1-chloro-2-thienyl)methyl]propyl]amino]-3-nitro-2-pyridinyl]amino to [3aR-[3aa,4a,6a(R*),6aa]]-6-[[3-amino-4-[[1-[(3-chloro-2-thienyl)methyl]propyl]amino]-2-pyridinyl]amino]-N-ethyltetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide, followed by hydrolyzing [3aR-[3aa,4a,6a(R*),6aa]]-6-[[3-amino-4-[[1-[(3-chloro-2-thienyl)methyl]propyl]amino]-2-pyridinyl]amino]-N-ethyltetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide, in the presence of hydrochloric acid, said steps being effected in a concatenated manner, without a necessity for interim isolation and purification of intermediate compounds [3aR-[3aa,4a,6a(R*),6aa]]-6-[[3-amino-4-[[1-[(3-chloro-2-thienyl)methyl]propyl]amino]-2-pyridinyl]amino]-N-ethyltetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide, [3aR-[3aa,4a,6a(R*)6aa]]-6-[[4-[[1-[(3-chloro-2-thienyl)methyl]propyl]amino]-3-nitro-2-pyridinyl]amino]-N-ethyltetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide,(R)-2-chloro-N-[1-[(3-chloro-2-thienyl) methyl]propyl]-3-nitro-4-pyridinamine or (R)-N-[1-[(3-chloro-2-thienyl)methyl]propyl]-2-hydroxy-3-nitro-4-pyridinamine.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[O:7].[CH2:23]([CH2:25][NH2:26])[OH:24].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:26][CH2:25][CH2:23][OH:24])=[O:14])=[O:7]
Reactant: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)O)c1
Reactant: NCCO
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)NCCO)c1
Temperature: 25 °C
Yield: 80.1 %

Procedure:
To solution of 3-[2-(2,4-dichloro-phenoxy)acetylamino]-benzoic acid (150 mg, 0.44 mmol) and ethanolamine (0.04 ml, 0.66 mmol) in DMF 3.0 mL was added EDC (126.5 mg, 0.66 mmol), HOBt (89.2 mg, 0.66 mmol) and DIPEA (0.11 ml, 0.66 mmol). Reaction mixture was stirred at room temperature, and separated by EtoAC and brine. The organic phase was dried (MgSO4 anh) and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=15:1) to give 3-[2-(2,4-dichloro-phenoxy)-acetylamino]-N-(2-hydroxy-ethyl)-benzamide as a white solid (135 mg, 80% yield).
Reaction SMILES: Cl.[NH2:2][OH:3].[F:4][C:5]([F:18])([F:17])[C:6]([CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:9]#[N:10])=O>CO>[F:4][C:5]([F:18])([F:17])[C:6]1[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([NH2:10])[O:3][N:2]=1
Reactant: NO
Reactant: N#CC(C(=O)C(F)(F)F)c1ccccc1
Agent: Cl
Solvent: CO
Product: Nc1onc(C(F)(F)F)c1-c1ccccc1
Yield: 82.1 %

Procedure:
Methanol (53 ml) and 96% hydroxylamine hydrochloride (2.82 g, 0.0390 mole, 1.3 eq.) were added to -(trifluoroacetyl)phenylacetonitrile (6.96 g, 0.0300 mole) and the mixture was heated under reflux for 68 hours. After methanol was distilled off under reduced pressure and the resulting residue was neutralized with a 8% solution of sodium bicarbonate, the solution was extracted with methylene chloride. After being dried with anhydrous sodium sulfate, it was concentrated and purified by column chromatography on silica gel to give the title compound (5.62 g, 82.1%). The product was recrystallized from benzene-cyclohexane to recover the title compound (4.80 g, 70.1%) as pale yellow needles, m.p. 89°-91° C.
Reaction SMILES: CCCC(OC1C=CC(COCC#CC[N:19]2[C:25]([CH3:27])([CH3:26])[C:23](=[O:24])[N:22]([C:28]3[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[C:30]([C:36]([F:39])([F:38])[F:37])[CH:29]=3)[C:20]2=[O:21])=CC=1C(NCN[C@@H]1[C@H](O)[C@H](C)OC(OC2C3C(=C(O)C4C(=O)C5C=CC=C(OC)C=5C(=O)C=4C=3O)C[C@@](O)(C(CO)=O)C2)C1)=O)=O.FC1C=CC(C#N)=C(C(F)(F)F)C=1.N1CC(=O)NC1=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:26][C:25]1([CH3:27])[NH:19][C:20](=[O:21])[N:22]([C:28]2[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[C:30]([C:36]([F:38])([F:37])[F:39])[CH:29]=2)[C:23]1=[O:24]
Reactant: CCCC(=O)Oc1ccc(COCC#CCN2C(=O)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)cc1C(=O)NCN[C@H]1CC(OC2C[C@](O)(C(=O)CO)Cc3c(O)c4c(c(O)c32)C(=O)c2c(OC)cccc2C4=O)O[C@@H](C)[C@H]1O
Agent: N#Cc1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: O=C1CNC(=O)N1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Temperature: 45 °C
Reaction time: 48 h
Yield: 74 %

Procedure:
(Cogan, P. S.; Koch, T. H. Rational Design and Synthesis of Androgen Receptor-Targeted Nonsteroidal Anti-Androgen Ligands for the Tumor-Specific Delivery of a Doxorubicin-Formaldehyde Conjugate. J. Med. Chem. 2003, 46, 5258-5270) 4-Fluoro-2-(trifluoromethyl)benzonitrile (4.02 g, 21.3 mmol) was added to Hydantoin (13.6 g, 106.3 mmol) and Potassium Carbonate (4.40 g, 31.9 mmol) in 60 mL DMF and stirred at 45° C. under argon for 48 hours. Reaction mixture was then diluted in ethyl acetate and washed three times with water. Organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Column chromatography (eluent 30:1 DCM/Methanol) gave 1 as a white solid (4.62 g, 74%). 1H NMR (400 MHz, (CD3)2—CO) δ 1.54 (6H, s), 7.80 (1H, s), 8.13 (1H, dd, J=1.8 Hz, J=8.4 Hz), 8.20 (1H, d, J=8.4 Hz), 8.26 (1H, d, J=1.8 Hz)
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:16](=[O:18])[CH3:17])[CH:3]1[OH:19])=[N:10][O:11][N:12]=3.N1C=CC=CC=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(OCC)(=O)C>[CH3:1][C:2]1([CH3:20])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:16](=[O:18])[CH3:17])[CH:3]1[O:19][C:27](=[O:29])[CH3:28])=[N:10][O:11][N:12]=3
Reactant: CC(=O)NC1c2cc3nonc3cc2OC(C)(C)C1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)NC1c2cc3nonc3cc2OC(C)(C)C1OC(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 26 %

Procedure:
A mixture of 100 mg (0.36 m mol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-acetylamino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole, 2 ml of pyridine and 34 μl (0.36 m mol) of acetic anhydride was stirred at the room temperature for 24 hours. After the completion of the reaction, the mixture was diluted with ethyl acetate, washed with water and saturated anhydrous NaCl solution and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was recrystallized from chloroform to obtain 58 mg (yield: 26%) of the intended compound.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9])(=[O:3])[CH3:2].Br[C:11]1[CH:12]=[CH:13][C:14]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=3[CH3:32])[CH2:21][CH2:20]2)=[O:18])=[N:15][CH:16]=1>>[C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:11]2[CH:16]=[N:15][C:14]([C:17]([N:19]3[CH2:20][CH2:21][N:22]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=4[CH3:32])[CH2:23][CH2:24]3)=[O:18])=[CH:13][CH:12]=2)[C:5]1=[O:9])(=[O:3])[CH3:2]
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ccc(C)cc4C)CC3)nc2)C1=O
Yield: 36.8 %

Procedure:
Using 1-acetyl-2-imidazolidinone (128 mg) and (5-bromopyridin-2-yl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (374 mg) described in Preparation Example 137 and by the reaction and treatment in the same manner as in Example 1, the title compound (155 mg) was obtained.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10](=[O:21])[C:11]1[CH:16]=[CH:15][C:14]([I:17])=[C:13]([N+:18]([O-])=O)[CH:12]=1)[CH2:2]2.O.O.[Sn](Cl)Cl>CN(C=O)C>[NH2:18][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[I:17])[C:10]([NH:9][CH:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1)=[O:21]
Reactant: O=C(NC1CN2CCC1CC2)c1ccc(I)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(C(=O)NC2CN3CCC2CC3)ccc1I
Yield: 98.1 %

Procedure:
A solution of 100 mg (0.25 mmol) of N-(1-azabicyclo[2.2.2]oct-3-yl)-4-iodo-3-nitrobenzamide and 281 mg (1.25 mmol) of tin(II) chloride dihydrate in 5 ml of DMF was stirred at room temperature for 6 h. The solvent was distilled off in a rotary evaporator, the residue was taken up in 10 ml of dichloromethane, and 10 ml of aqueous 1 M sodium hydroxide solution were added. The organic phase was dried over sodium sulfate, and the solvent was distilled off in a rotary evaporator. 91 mg (98%) of the desired title compound were obtained.