Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1>ClCCl.O.CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([NH:33][CH2:32][C:31]2[CH:34]=[CH:35][C:28]([F:27])=[CH:29][CH:30]=2)=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: COc1cc(Br)cc(C)c1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Br)cc(C)c1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a stirred solution of 4-bromo-2-methoxy-6-methyl-benzoic acid (synthesized according to the methods described in sections a) to d) of example 10) (2.0 g, 8.16 mmol) in dichloromethane (50 ml) are added oxalyl chloride (0.84 ml, 9.79 mmol) and dimethylformamide (catalytic amount) at 0° C. The reaction mixture is stirred for 30 min at RT. Excess oxalyl chloride is distilled off under nitrogen. The residue is dissolved in dichloromethane (20 ml), cooled to 0° C. followed by the addition of triethylamine (2.8 ml, 20.4 mmol) and 4-fluorobenzylamine (1.12 ml, 9.79 mmol). The reaction mixture is stirred for 1 h at RT. After completion of the reaction (monitored by TLC) the mixture is diluted with water (50 ml) and extracted with dichloromethane (3×50 ml). The organic layer is washed with water (50 ml), brine (50 ml), dried over anhydrous sodium sulfate and evaporated to get the crude product, which is purified by column chromatography (silica gel, 15% ethyl acetate/hexane) to yield 4-bromo-N-[(4-fluorophenyl)-methyl]-2-methoxy-6-methyl-benzamide (2.70 g, 7.67 mmol, 94%).
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Br:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[F:27]>>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])=[CH:11][CH:12]=2)=[CH:20][C:19]=1[F:27]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(I)cc1
Reactant: OB(O)c1ccc(Br)c(F)c1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(-c2ccc(Br)c(F)c2)cc1
Yield: 73 %

Procedure:
In accordance with Example 4-(2), but using tert-butyl[(4-iodobenzyl)oxy]dimethylsilane instead of tert-butyl[2-(4-iodophenyl)ethoxy]dimethylsilane, and (4-bromo-3-fluorophenyl)boronic acid instead of (4-bromophenyl)boronic acid, the title compound (yield 73%) was afforded as a white solid.
Reaction SMILES: Cl.[F:2][C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1>O1CCOCC1>[F:2][C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(c2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: FC1(c2ccccc2)CCNCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 104.8 %

Procedure:
Hydrochloric acid (4 M in dioxane, 20 mL, 80 mmol) was added to a solution of tert-butyl 4-fluoro-4-phenylpiperidine-1-carboxylate (8.27 g, 29.6 mmol) in dioxane (10 mL). The reaction was stirred at ambient temperature for 4 hours. The reaction was concentrated to an oil. Ether was added, and the resulting solid was sonicated and then stirred vigorously overnight to provide a tan solid. The solid was filtered, rinsed with ether and dried under vacuum at 60° C. for 3 hours to provide 5.56 g (87%) of the titled product. MS (DCI) m/z 180 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:13])[CH2:11][CH3:12])[N:7]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=3)[C:6]=2[CH:21]=1.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1.CCN(C(C)C)C(C)C>CC(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:13][C:23]3[N:31]=[CH:30][N:29]=[C:28]4[C:24]=3[N:25]=[CH:26][N:27]4[CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[CH2:11][CH3:12])[N:7]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=3)[C:6]=2[CH:21]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CC[C@H](N)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Temperature: 90 °C
Yield: 81.5 %

Procedure:
A mixture of (S)-1-[6-fluoro-1-(5-fluoropyridin-3-yl)-1H-benzoimidazol-2-yl]propylamine (70 mg, 0.24 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (57 mg, 0.24 mmol) and DIPEA (84 μL, 0.48 mmol) in IPA (3 mL) was heated for 24 h at 90° C. After cooling to RT, the volatiles were removed in vacuo and the resulting residue purified by column chromatography (Si—PPC, gradient 0-7% MeOH in DCM) to afford the title compound as a pale brown oil (96 mg, 82%). LCMS (Method J): RT=3.03 min, [M+H]+=491.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:12]2[N:13]=[CH:14]C=CC=2N=N1.[Br:25][C:26]1[CH:27]=[CH:28][C:29]([I:35])=[C:30]([CH:34]=1)[C:31](O)=[O:32].CNC.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([I:35])=[C:30]([CH:34]=1)[C:31]([N:13]([CH3:14])[CH3:12])=[O:32]
Reactant: O=C(O)c1cc(Br)ccc1I
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1cc(Br)ccc1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.16 g, 3.06 mmol) was added to a solution of 5-bromo-2-iodo-benzoic acid (1.00 g, 3.06 mmol), dimethyl amine (2 M in THF, 3.06 ml, 3.06 mmol) and di-iso-propyl ethyl amine (1.59 ml, 9.18 mmol) in N,N-Dimethylformamide (12 ml). The reaction was stirred at room temperature overnight. Ethyl acetate was added and the mixture was washed with water, the organic layer was dried over magnesium sulfate and evaporated. The residue was purified by silica gel chromatography to yield 5-bromo-2-iodo-N,N-dimethyl-benzamide as a white solid. (0.96 g, 90%). MS: m/z 328.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:63])[CH:48]([NH:55][C:56]([O:58][C:59](C)(C)C)=[O:57])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:65]OC(NC(C1C=C(C)C=CC=1)C(O)=O)=O>>[CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:32]=[CH:33][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:63])[CH:48]([NH:55][C:56]([O:58][CH3:59])=[O:57])[C:49]6[CH:50]=[C:51]([CH3:65])[CH:52]=[CH:53][CH:54]=6)=[N:40][CH:41]=5)=[CH:35][CH:36]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)O)c1cccc(C)c1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC(C)(C)C)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1cccc(C)c1
Yield: 34 %

Procedure:
This compound was prepared using the procedure used to prepare [1-(2-{5-[6-(4-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using Methoxycarbonylamino-m-tolyl-acetic acid (0.046 g, 0.206 mmol) to provide [1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-m-tolyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.039 g, 34%) as a white solid. LCMS-ESI+: calc'd for C48H52N8O6: 836.40 (M+); Found: 837.91 (M+H+).
Reaction SMILES: C(O[C:4]1[C:5](=[O:19])[C:6](=[O:18])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[OH:17])C.[C:20]([NH2:25])([CH2:23][CH3:24])([CH3:22])[CH3:21].ClCl.C(O)C>CCCCCC.C(OCC)(=O)C>[C:20]([NH:25][C:4]1[C:5](=[O:19])[C:6](=[O:18])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[OH:17])([CH2:23][CH3:24])([CH3:22])[CH3:21]
Reactant: CCOc1c(Nc2ccc(C#N)cc2O)c(=O)c1=O
Reactant: CCC(C)(C)N
Agent: ClCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: CCC(C)(C)Nc1c(Nc2ccc(C#N)cc2O)c(=O)c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3-ethoxy-4-(2-hydroxy-4-cyanophenyl)amino-3-cyclobutene-1,2-dione (0.395 g, 0.0015 mol) and tert-amylamine (4 ml, 0.034 mol) in enough CH2 Cl2 to form a solution (a small amount of dry ethanol was required) was stirred at room temperature for two days. During this time, a precipitate forms. TLC (2:1 ethyl acetate:hexane) indicates a loss of starting material. The reaction is evaporated to a solid on a rotary evaporator. The solid is taken up in ethyl acetate and extracted well with 0.25N HCl. The organic layer is washed once with distilled water, dried (Na2SO4), and evaporated to a solid. The solid is collected and washed with diethyl ether to give 3-(tert-amylamino)-4-(2-hydroxy-4-cyanophenyl)amino-3-cyclobutene-1,2-dione, 0.253 g (0.00085 mol, 55%).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:12])[C:4]([CH:6]1CC[C:8](=O)[CH2:7]1)=[O:5].COCCN(S(F)(F)F)CCOC.F[C:27]([F:32])([F:31])[C:28](O)=O>C1(C)C=CC=CC=1.CCOCC>[F:31][C:27]1([F:32])[CH2:8][CH2:7][CH:6]([C:4]([N:3]([O:2][CH3:1])[CH3:12])=[O:5])[CH2:28]1
Reactant: O=C(O)C(F)(F)F
Reactant: CON(C)C(=O)C1CCC(=O)C1
Agent: COCCN(CCOC)S(F)(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CON(C)C(=O)C1CCC(F)(F)C1
Temperature: 40 °C

Procedure:
To a solution of N-methoxy-N-methyl-3-oxocyclopentanecarboxamide (2.43 g, 14.19 mmol) in 30 mL toluene under nitrogen was added deoxo-fluor® (7.05 mL, 38.3 mmol) followed by trifluoroacetic acid (0.219 mL, 2.84 mmol). The reaction was sealed and heated to 40° C. overnight. The reaction mixture was cooled, diluted with Et2O, cooled to 0° C. in an ice bath and quenched slowly with 75 mL 2N NaOH with rapid stirring. The aq. Layer was separated and extracted once with Et2O. The combined organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purified by silica gel chromatography (50% EA/hexanes) gave (rac)-3,3-difluoro-N-methoxy-N-methylcyclopentanecarboxamide as a light yellow oil. 1H NMR (400 MHz, CDCl3-d) δ ppm 3.71 (s, 3 H), 3.29-3.43 (m, 1 H), 3.21 (s, 3 H), 2.17-2.54 (m, 3 H), 1.93-2.15 (m, 3 H).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[C:17]=1[NH:25][C:26](=[O:43])[CH2:27][NH:28][CH2:29][C:30]1([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)([CH3:15])[CH3:14].C(N(C(C)C)CC)(C)C.O>ClCCl>[CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[C:17]=1[NH:25][C:26](=[O:43])[CH2:27][N:28]1[CH2:29][C:30]2([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)[N:36]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:2]1=[O:4])([CH3:14])[CH3:15]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNCC1(Nc2ccccc2)CCCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN1CC2(CCCCC2)N(c2ccccc2)C1=O
Temperature: 0 °C
Yield: 79 %

Procedure:
136 mg (0.46 mmol) of triphosgene are added to 10 ml of dichloro-methane. The medium is cooled to 0° C. and a solution of 580 mg (1.37 mmol) of N-(2,6-diisopropylphenyl)-2-[(1-phenylaminocyclohexyl-methyl)amino]acetamide and 260 μl (1.49 mmol) of diisopropylethylamine in 10 ml of dichloromethane are added drop by drop. The mixture is allowed to rise to room temperature and is stirred for one night. The medium is then poured into water and extracted with dichloromethane. The organic phases are collected and washed with water. They are dried over sodium sulfate. The solvents are evaporated. The residue is chromatographed on silica gel (heptane/ethyl acetate 80/20) and 485 mg of N-(2,6-diisopropylphenyl)-2-(2-oxo-1-phenyl-1,3-diazaspiro[4.5]dec-3-yl)acetamide are obtained in the form of a white solid after having been precipitated in dichloromethane and heptane, filtered and dried. M.p. 107-9° C., yield=79%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[N:30]1[CH:34]=[N:33][CH:32]=[N:31]1)[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]([F:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[CH2:25][CH3:26])=[O:6].N1C=CC=CC=1.[C:41](Cl)(=[O:45])[O:42][CH2:43]C>O1CCCC1.O>[CH3:43][O:42][C:41](=[O:45])[NH:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]2[C:13]([CH3:14])=[CH:12][C:11]([C:15]([F:24])([C:20]([F:21])([F:22])[F:23])[C:16]([F:18])([F:19])[F:17])=[CH:10][C:9]=2[CH2:25][CH3:26])[CH:27]=[CH:28][C:29]=1[N:30]1[CH:34]=[N:33][CH:32]=[N:31]1
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(-n2cncn2)c(N)c1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(-n2cncn2)c(NC(=O)OC)c1
Reaction time: 1 h
Yield: 69.4 %

Procedure:
3-Amino-N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methyl-phenyl]-4-(1H-1,2,4-triazol-1-yl)benzamide (0.2 g) and pyridine (0.05 g) were dissolved in tetrahydrofuran (5 ml). To the solution, ethyl chlorocarbonate (0.04 g) was added under ice cooling. After adjusting to room temperature, the mixture was stirred for 1 hr. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, washed with water and dried over magnesium sulfate. After filtering off the drying agent, the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain methyl[5-{[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoro-propan-2-yl)-6-methylphenyl]carbamoyl}-2-(1H-1,2,4-triazol-1-yl)phenyl]carbamate (0.14 g, yield 58%).
Reaction SMILES: [CH2:1]([N:8]([CH2:30][C@H:31]1[CH2:35][O:34]C(C)(C)[O:32]1)[CH2:9][C:10]1[C:14]2[N:15]=[CH:16][N:17]=[C:18]([O:19]C)[C:13]=2[N:12](COCC2C=CC=CC=2)[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl>Cl.CO>[CH2:1]([N:8]([CH2:9][C:10]1[C:14]2[N:15]=[CH:16][N:17]=[C:18]([OH:19])[C:13]=2[NH:12][CH:11]=1)[CH2:30][C@H:31]([OH:32])[CH2:35][OH:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ncnc2c(CN(Cc3ccccc3)C[C@H]3COC(C)(C)O3)cn(COCc3ccccc3)c12
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: OC[C@@H](O)CN(Cc1ccccc1)Cc1c[nH]c2c(O)ncnc12
Yield: 59.4 %

Procedure:
(S)—N-benzyl-1-(5-(benzyloxymethyl)-4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)methanamine (1.1 g, 2.189 mmol) was heated to 100° C. in HCl (15 ml, 37%) for 3 h. Tlc (CH2Cl2-6M NH3 in MeOH, 9:1) showed reaction over. The solvent was evaporated and the residue dissolved in MeOH, neutralized with Amberlyst A21 resin, filtered and the solvent evaporated. The residue was chromatographed (CH2Cl2-6M NH3 in MeOH, 9:1 then 85:15) to give (S)-3-(benzyl((4-hydroxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)amino)propane-1,2-diol (0.427 g, 1.3 mmol, 59.4% yield) as a colourless solid. [α]D20 12.7 (c 0.715, MeOH). The 1H NMR and 13C NMR were identical to that of compound 3.4. +ESMS Found 329.1618 C17H21N4O3 (M+H) requires 329.1614.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:11](=[O:13])[CH3:12])\[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].O[CH:15]1[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])[CH2:17][CH2:16]1>>[N+:31]([C:28]1[CH:27]=[CH:26][C:25]([CH2:24][O:23][C:21]([C@H:18]2[CH2:19][CH2:20][C@H:15]([O:1]/[N:2]=[C:3](/[C:11](=[O:13])[CH3:12])\[C:4]([O:6][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:5])[CH2:16][CH2:17]2)=[O:22])=[CH:30][CH:29]=1)([O-:33])=[O:32]
Reactant: CC(=O)/C(=N/O)C(=O)OC(C)(C)C
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)C1CCC(O)CC1
Product: CC(=O)/C(=N/O[C@H]1CC[C@H](C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)C(=O)OC(C)(C)C

Procedure:
tert-Butyl (Z)-2-(hydroxyimino)-3-oxobutyrate (7.36 g) was treated with 4-nitrobenzyl 4-hydroxycyclohexanecarboxylate as described in Example 4, Method 3 to give the title compound (5.1 g, 29%) as a gum. νmax (film) 2950, 1740, 1695, and 1525cm-1, δH (CDCl3) 1.53 (9H, s), 1.62 (3H, m), 1.82 (1H, m), 2.14 (4H, m), 2.37 (3H, s), 2.45 (1H, tt, J 3.7 Hz, 10.7 Hz), 4.26 (1H, tt, J 3.8, 9.8 Hz), 5.22 (2H, s), 7.51 (2H, d), and 8.24 (2H, d). δC (CDCl3) 25.2, 26.2, 28.1 (3C), 29.8, 41.6, 64.7, 82.7, 84.0, 123.8 (2C), 128.3 (2C), 143.3, 147.7, 150.7, 160.6, 174.5 and 193.0. [Mass spectrum (ammonia) MNH4+ (466)].
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]=2[C:12]([O:14][CH3:15])=[O:13])[C@H:3]1[OH:24].[CH3:25][C:26]([CH3:28])=O>C1C=CC=CC=1>[CH2:17]([O:16][C:7]1[C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:9]2[C:4](=[CH:5][CH:6]=1)[C@@H:3]([OH:24])[C@H:2]([NH:1][CH:26]([CH3:28])[CH3:25])[CH2:11][CH2:10]2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)=O
Reactant: COC(=O)c1c(OCc2ccccc2)ccc2c1CC[C@@H](N)[C@@H]2O
Solvent: c1ccccc1
Product: COC(=O)c1c(OCc2ccccc2)ccc2c1CC[C@@H](NC(C)C)[C@@H]2O

Procedure:
500 mg. of trans-2-amino-6-benzyloxy-1hydroxy-5-methoxycarbonyl-1,2,3,4-tetrahydronaphthalene is dissolved in a mixture of 3 ml. of acetone and 10 ml. of anhydrous benzene and the solution is heated on reflux for 5 hours. The reaction mixture is concentrated under reduced pressure and 10 ml. of ethanol is added to the residue. After the addition of 100 mg. of sodium borohydride with stirring, the mixture is stirred at room temperature for 5 hours. The reaction mixture is concentrated under reduced pressure, and water and ethyl acetate are added to the residue. The mixture is extracted with ethyl acetate. The organic solvent layers are pooled, washed with water, dried and concentrated under reduced pressure. The residue is recrystallized from ethyl acetate-n-hexane to obtain trans-6-benzyloxy-2isopropylamino-1-hydroxy-5-methoxycarbonyl-1,2,3,4-tetrahydronaphthalene as colorless needles melting at 91°-92° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]([O:11]C)=[O:10])[C:6]([OH:13])=[CH:5][CH:4]=1.CS([C:18]1[N:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[N:19]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.CS(C)=O>[CH3:27][O:26][C:20]1[CH:21]=[C:22]([O:24][CH3:25])[N:23]=[C:18]([O:13][C:6]2[C:7]([C:9]([OH:11])=[O:10])=[N:8][C:3]([NH:2][CH3:1])=[CH:4][CH:5]=2)[N:19]=1
Reactant: CNc1ccc(O)c(C(=O)OC)n1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CNc1ccc(Oc2nc(OC)cc(OC)n2)c(C(=O)O)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84 %

Procedure:
10.5 mg (0.0576 mmol) of methyl 6-methylamino-3-hydroxypicolinate, 11.6 mg (0.0532 mmol) of 2-methylsulfonyl-4,6-dimethoxypyrimidine, 8.8 mg (0.637 mmol) of potassium carbonate and 0.5 ml of dry dimethylsulfoxide were mixed. The mixture was stirred at room temperature for 5 hours, and then a 10% potassium hydroxide aqueous solution (corresponding to 90 mg, 0.160 mmol) was added thereto. The mixture was reacted at room temperature for one hour, and then 2.0 ml of water was added to the reaction mixture. Further, 1.0 ml of a 10% citric acid aqueous solution was added thereto, and the mixture was left to stand, whereby crystals precipitated. After being thoroughly precipitated, the crystals were filtered under suction and washed with water. The crystals were dried to obtain 3-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-methylaminopicolinic acid.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[N+](C1C=CC([O:32][C:33](=O)[C@H:34]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=CC=1)([O-])=O.O>CN(C)C=O>[F:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:33](=[O:32])[CH:34]([NH:35][C:36](=[O:37])[O:38][C:39]([CH3:40])([CH3:41])[CH3:42])[CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)N1CCN(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
To a solution of 1-(4-fluorophenyl)piperazine dihydrochloride (2.53 g, 10 mmol) in N,N-dimethylformamide (40 ml) were added triethylamine (2.8 ml, 20 mmol) and N-tert-butoxycarbonylphenylalanine p-nitrophenyl ester (2.65 g, 10 mmol) in the order mentioned, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into cold water and extracted with ethyl acetate. The extract was washed with 1 w/v % aqueous ammonia, saturated brine, 0.1N hydrochloric acid, saturated brine, saturated aqueous sodium hydrogencarbonate solution, and saturated brine in the order mentioned, and the organic layer was dried over anhydrous magnesium sulfate and further concentrated under reduced pressure. The residue was purified by silica gel column chromatography using chloroform-methanol (50:1, v/v) to give 1,1-dimethylethyl 2-(4-(4-fluorophenyl)-1-piperazinyl)-2-oxo-1-(phenylmethyl)ethylcarbamate (2.7 g, 92.2%) as colorless oil.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[O:14][CH2:13][CH2:12][O:11]2)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+]>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:10]2([CH:7]3[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]3)[O:14][CH2:13][CH2:12][O:11]2)=[CH:16][CH:17]=1
Reactant: CC(=O)N1CCC(C2(c3ccc(F)cc3)OCCO2)CC1
Agent: [Na+]
Agent: [OH-]
Product: Fc1ccc(C2(C3CCNCC3)OCCO2)cc1
Yield: 82 %

Procedure:
A mixture of 5 parts of 1-acetyl-4-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]piperidine and 100 parts of sodium hydroxide solution 10% is stirred and refluxed overnight. The reaction mixture is cooled and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The solid residue is stirred in 2,2'-oxybispropane. The product is filtered off and dried in vacuo at 40° C, yielding 3.5 parts (82%) of 4-[2(4-fluorophenyl)-1,3-dioxolan-2-yl]-piperidine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=O)[NH:11][N:10]=2)[CH:2]=1.P(Cl)(Cl)([Cl:22])=O.Cl>C(#N)C.O1CCOCC1>[Cl:22][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([CH2:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:10][N:11]=1
Reactant: O=c1[nH]nc(CCc2cccnc2)c2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: Clc1nnc(CCc2cccnc2)c2ccccc12
Temperature: 60 °C
Reaction time: 3.5 h

Procedure:
Under exclusion of air, 2.4 g (9.55 mmol) 4-[2-(pyridin-3-yl)ethyl]phthalazin-1(2H)-one in 36 ml acetonitrile is mixed with 2.18 ml (23.8 mmol) phosphoryl chloride and 4.75 ml 4 N HCl in dioxane and stirred for 3.5 h at 60° C. After cooling to RT, the product is filtered off as hydrochloride and washed with CH3CN. The crystals are dissolved in about 10 ml H2O, mixed with 15 ml H2O and 1.5 ml sat. NH3 solution and extracted immediately 3 times with EtOAc. Drying (Na2SO4) of the organic phases and evaporation yield the title compound; FAB-MS (M+H)+=270.