Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[F:12].CCN(C(C)C)C(C)C.[CH3:22][C@H:23]1[CH2:28][NH:27][CH2:26][CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CN(C=O)C>[F:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[CH2:2][N:27]1[CH2:26][CH2:25][N:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@@H:23]([CH3:22])[CH2:28]1
Reactant: O=[N+]([O-])c1ccc(CBr)c(F)c1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(Cc2ccc([N+](=O)[O-])cc2F)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A mixture of 2-fluoro-4-nitrotoluene (1.55 g, 10 mmol), N-bromosuccinimide (1.96 g, 11 mmol) and benzoyl peroxide (0.121 g, 0.5 mmol) in CCl4 (60 mL) was irradiated with a 500 W lamp overnight. The reaction mixture was filtered, concentrated and eluted through a silica column with EtOAc/pentane to give a crude product mixture (2.34 g) which was used in step 2. Step 2: A mixture of crude 4-(bromomethyl)-3-fluoro-1-nitrobenzene (2.11 g) from step 1, Hunig's base (1.9 mL, 10.913 mmol) and 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (2 g, 10 mmol) in DMF (15 mL) was stirred at room temperature for 40 minutes. The reaction mixture was concentrated, re-dissolved in DCM and washed with water (×2) and brine, then dried and concentrated. The crude product was purified by column chromatography. Elution with EtOAc/pentane yielded the title compound as a yellow gum which crystallised on standing (2.11 g). δH (CDCl3, 400 MHz) 8.03 (1H, dd), 7.91 (1H, dd), 7.70 (1H, m), 4.22 (1H, br.s), 3.84 (1H, d), 3.61 (2H, m), 3.12 (1H, td), 2.74 (1H, m), 2.57 (1H, m), 2.27 (1H, dd), 2.11 (1H, m), 1.46 (9H, s), 1.25 (3H, d). MS (ES): MH+ 354.1. Description 66
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([OH:10])=[CH:8][C:7]([Br:11])=[CH:6][N:5]=1.Br[C:13]([CH3:20])([CH3:19])[C:14](OCC)=[O:15].O>CN(C)C=O>[Br:11][C:7]1[CH:6]=[N:5][C:4]2[NH:3][C:14](=[O:15])[C:13]([CH3:20])([CH3:19])[O:10][C:9]=2[CH:8]=1
Reactant: Nc1ncc(Br)cc1O
Reactant: CCOC(=O)C(C)(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)Oc2cc(Br)cnc2NC1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 20.6 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 0.68 g) in N,N-dimethylformamide (15 mL) was added dropwise a solution of 2-amino-5-bromopyridin-3-ol (3.22 g) in N,N-dimethylformamide (25 mL) at room temperature over a period of 10 minutes, and the mixture was stirred at room temperature for 20 minutes. To the mixture was added dropwise ethyl α-bromoisobutyrate (3.32 g) over a period of 20 minutes, and the reaction mixture was stirred at room temperature for 1 hour and at 80° C. for 2 hours. After cooling, to the reaction mixture was added cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively water and brine, dried over magnesium sulfate and concentrated in vacuo by a half volume. The precipitates were collected by filtration to give 7-bromo-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (0.90 g) was obtained as a powder.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[O-:12][CH2:13][CH3:14].[Na+].O.[CH2:17](O)C>>[CH2:13]([O:12][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:17])=[O:9])=[N:6][CH:7]=1)[CH3:14]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: CC[O-]
Reactant: CCO
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cnc(OCC)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of methyl 5-chloropyrazine-2-carboxylate (0.50 g) in ethanol (10 mL) was cooled to 0° C., and sodium ethoxide (21% w/w solution in ethanol, 1 mL) was added over 10 mins. After allowing to warm to RT and stir for 2 h, water (100 mL) was added and the mixture extracted with EtOAc (2×150 mL). The combined organic portions were dried over MgSO4 and evaporated to afford the title compound. (0.65 g, purity approx. 85%) 1H NMR (400 MHz, CDCl3) δ ppm 1.45 (t, J=7.1 Hz, 3H), 1.46 (t, J=7.1 Hz, 3H), 4.48 (q, J=7.1 Hz, 2H), 4.49 (q, J=7.1 Hz, 2H), 8.28 (d, J=1.3 Hz, 1H), 8.88 (d, J=1.3 Hz, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9](Cl)=[O:10])=[CH:7][C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:4]=1.[NH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.N1CCCCC1>C(Cl)Cl.[Cl-].[Na+].O>[N:26]1([NH:25][C:9]([C:8]2[C:3]([O:2][CH3:1])=[N:4][C:5]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[C:6]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:7]=2)=[O:10])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COc1nc(-c2ccc(Cl)cc2)c(-c2ccccc2)cc1C(=O)Cl
Reactant: NN1CCCCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCNCC1
Product: COc1nc(-c2ccc(Cl)cc2)c(-c2ccccc2)cc1C(=O)NN1CCCCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 2-(methoxy)-6-(4-chlorophenyl)-5-(phenyl)pyridine-3-carbonyl chloride (0.08 mmol) from Step B in methylene chloride (1 mL) was added to a solution-of 1-aminopiperidine (containing a few percent of piperidine as an impurity) (0.017 mL, 0.16 mmol) and TEA (0.022 mL, 0.16 mmol) in methylene chloride (0.5 mL). The reaction was stirred at rt for 20 h and was then diluted with brine and extracted twice with methylene chloride. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give a mixture of the crude products. These were separated by preparative TLC (5% methanol in methylene chloride) to give N-(piperidin-1-yl)-2-(methoxy)-6-(4-chlorophenyl)-5-(phenyl)pyridine-3-carboxamide as the lower eluting product. HPLC/MS: 422 (M+1); Rt=3.8 min;
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=2)[O:4][C:3]=1[C:26](=[O:31])[C:27]([OH:30])([CH3:29])[CH3:28].[C:32]([O:35][CH2:36][C:37](Cl)=[O:38])(=[O:34])[CH3:33].C(#N)C>C(OCC)(=O)C>[C:32]([O:35][CH2:36][C:37]([NH:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3)[CH:9]=2)[O:4][C:3]=1[C:26](=[O:31])[C:27]([OH:30])([CH3:28])[CH3:29])=[O:38])(=[O:34])[CH3:33]
Reactant: CC(C)(O)C(=O)c1oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc2c1N
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)OCC(=O)Nc1c(C(=O)C(C)(C)O)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 25 °C

Procedure:
The product of Step B (0.120 g; 0.253 mmol) and acetoxyacetyl chloride (0.11 mL; 1.01 mmol) were added to 2 mL of acetonitrile and stirred at room temperature. After 50 minutes the reaction mixture was diluted with ethyl acetate and washed two times with aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate then concentrated. The residue was triturated in 10 mL of methanol. The solid product was collected and rinsed two times with methanol then dried in vacuo. HPLC/MS 576.8 (M+2); Rt=4.32 min.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH2:9][OH:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[C:12]1[N:17]=[CH:16][C:15]([B:18]([OH:20])[OH:19])=[CH:14][N:13]=1.C(N(CC)CC)C>C(O)C>[OH:10][CH2:9][C:3]1([CH3:2])[CH2:8][CH2:7][N:6]([C:12]2[N:17]=[CH:16][C:15]([B:18]([OH:20])[OH:19])=[CH:14][N:13]=2)[CH2:5][CH2:4]1
Reactant: CC1(CO)CCNCC1
Reactant: OB(O)c1cnc(Cl)nc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1(CO)CCN(c2ncc(B(O)O)cn2)CC1
Temperature: 25 °C

Procedure:
(4-Methylpiperidin-4-yl)methanol hydrochloride (2.09 g, 12.63 mmol), (2-chloropyrimidin-5-yl)boronic acid (2 g, 12.63 mmol) and triethylamine (1.8 mL, 12.630 mmol) in ethanol (15 mL) was stirred at 80° C. overnight. The reaction mixture was cooled to r.t. and concentrated in vacuo to give the title compound as an orange semi-solid. This material was used without any further purification. HPLC-MS: MH+ m/z 252.2, RT 0.34 minutes.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH2:12][CH2:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH2:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(C2=CCCc3cncn32)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C2CCCc3cncn32)cc1

Procedure:
A solution of 1.6 g of 5-p-cyanophenyl-7,8-dihydroimidazo[1,5-a]pyridine in 50 ml of ethyl acetate is hydrogenated at atmospheric pressure with 0.2 g of 5% palladium on charcoal until the theoretical uptake of hydrogen is complete. The catalyst is filtered, and the solvent evaporated to yield the title compound, m.p. 117°-118°.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]([C:15]3[CH:16]=[CH:17][C:18]4[N:22]=[C:21]([CH:23]5[CH2:25][CH2:24]5)[N:20]([CH3:26])[C:19]=4[CH:27]=3)[C:11](=[O:28])[CH:10]=2)[S:5][CH:6]=1.[CH:29]1(B(O)O)[CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+].COCCOC>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.O>[CH:23]1([C:21]2[N:20]([CH3:26])[C:19]3[CH:27]=[C:15]([N:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:4]5[S:5][CH:6]=[C:2]([CH:29]6[CH2:31][CH2:30]6)[N:3]=5)=[CH:10][C:11]4=[O:28])[CH:16]=[CH:17][C:18]=3[N:22]=2)[CH2:25][CH2:24]1
Reactant: OB(O)C1CC1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4nc(Br)cs4)cc3=O)cc21
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: O
Solvent: COCCOC
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4nc(C5CC5)cs4)cc3=O)cc21
Temperature: 150 °C
Yield: 30.8 %

Procedure:
A mixture of 4-((4-bromo-1,3-thiazol-2-yl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (50 mg), cyclopropylboronic acid (10.3 mg), tetrakis(triphenylphosphine)palladium (6.3 mg), potassium carbonate (60.4 mg), DME (1 ml) and water (0.3 ml) was heated at 150° C. for 15 min under microwave irradiation. Additional cyclopropylboronic acid (14.1 mg) was added to the mixture, and the mixture was heated 150° C. for further 15 min under microwave irradiation. The reaction mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH-water to give the title compound (14.1 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Li])C[CH2:11][CH3:12].C(SSCC)C.ClC1C=C(C=CC=1)C(OO)=O.[S:31]([O-])([O-:33])=[O:32].[Na+].[Na+]>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:31]([CH2:11][CH3:12])(=[O:33])=[O:32])=[CH:4][N:3]=1
Reactant: Brc1ccc(Br)nc1
Reactant: O=S([O-])[O-]
Reactant: [Li]CCCC
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: CCOCC
Solvent: CCSSCC
Product: CCS(=O)(=O)c1ccc(Br)nc1
Reaction time: 1 h
Yield: 19 %

Procedure:
To a solution of 2,5-dibromopyridine (2 g, 8.4 mmol) in diethyl ether (50 mL) was added n-butyl lithium (1.6 M in hexanes, 9.24 mmol) dropwise at −78° C. under a nitrogen atmosphere. After the mixture was stirred at this temperature for 1 hour, diethyldisulfide (1.15 mL, 9.24 mmol) was added slowly at −78° C., and the mixture was stirred at this temperature for 1 hour and at 0° C. for an additional 1 hour. The reaction mixture was then quenched with 1 N hydrochloric acid (20 mL). The aqueous layer was separated and extracted with diethyl ether (20 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in dichloromethane (50 mL). To the solution, m-chloroperoxybenzoic acid (4.3 g, 80% purity, 16.8 mmol) was added portion-wise at 0° C. After being stirred at room temperature for 2 hours, the mixture was treated with a saturated aqueous solution of sodium sulfite (20 mL), and stirred for 15 minutes. The organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate (20 mL), then dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (elution with 30% ethyl acetate in petroleum ether) to give 2-bromo-5-ethanesulfonyl-pyridine (400 mg, 19%) as a white solid (reference: Li J. et al., Bioorg. Med. Chem. 13 (2005) 1805-1809).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[N:15]1[CH2:20][C@H:19]([CH3:21])[C@H:18]([C:22]#[N:23])[C@H:17]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:16]1)=O)(C)(C)C.Cl.O1CCOCC1.CCN(C(C)C)C(C)C.C(ON1C(=O)CCC1=O)(OC(C)(C)C)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[N:15]1[CH2:20][C@H:19]([CH3:21])[C@H:18]([C:22]#[N:23])[C@H:17]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:16]1
Reactant: C[C@H]1CN(c2ccncc2NC(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1C#N
Agent: CC(C)(C)OC(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Tert-butyl ((3S,4S,5R)-1-(3-((tert-butoxycarbonyl)amino)pyridin-4-yl)-4-cyano-5-methylpiperidin-3-yl)carbamate (1.0 equiv.) was treated with 4 M HCl in dioxane (30.0 equiv.) at rt for 1 hour. The volatiles were removed in vacuo and the solid was pumped on for 5 minutes on the high vac. To the residue was added CH2Cl2 (0.05 M), DIEA (5.0 equiv.) and Boc-OSu (1.6 equiv.). The solution was left stirring at rt for 1 hr. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and H2O. The organic layer was washed with Na2CO3(sat.), NaCl(sat.), dried over MgSO4, filtered, concentrated to yield tert-butyl (3S,4S,5R)-1-(3-aminopyridin-4-yl)-4-cyano-5-methylpiperidin-3-ylcarbamate in 100% yield. LC/MS (m/z)=332.1 (MH+), Rt=0.59 min.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[C:9]([C:32]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:39])=[N:10][O:11][C:12]=1[C:13]1[CH:14]=[N:15][N:16]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:25]=[CH:26][CH:27]=2)[C:17]=1[C:18]([F:21])([F:20])[F:19])=[O:7])(=O)[CH3:2].C(OC(=O)C)(=O)C>C(O)(=O)C.O>[Cl:39][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([F:38])[C:32]=1[C:9]1[C:8]([C:6]2[O:7][C:1]([CH3:2])=[N:4][N:5]=2)=[C:12]([C:13]2[CH:14]=[N:15][N:16]([C:22]3[CH:23]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:25]=[CH:26][CH:27]=3)[C:17]=2[C:18]([F:20])([F:19])[F:21])[O:11][N:10]=1
Reactant: CC(=O)NNC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccc(NC(C)=O)c2)c1C(F)(F)F
Solvent: O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc(-n2ncc(-c3onc(-c4c(F)cccc4Cl)c3-c3nnc(C)o3)c2C(F)(F)F)c1
Temperature: 140 °C

Procedure:
The intermediate N-(3-(4-(4-(2-acetylhydrazinecarbonyl)-3-(2-chloro-6-fluorophenyl) isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)acetamide (25.0 mg, 0.044 mmol) was dissolved in acetic acid (1.50 mL). Acetic anhydride (104 μL, 1.1 mmol) was added and the reaction mixture was heated in the microwave to 140° C. for 8 h. The reaction mixture was diluted with water (40 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with water (10 mL), dried over Na2SO4 and concentrated in vacuo.
Reaction SMILES: [C:1]1([SH:8])[C:2]([SH:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.Cl[CH2:10][C:11]([C:13](=[N:19][O:20][CH3:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=O>>[S:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[S:8][CH:10]=[C:11]1[C:13](=[N:19][O:20][CH3:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Sc1ccccc1S
Reactant: CCOC(=O)C(=NOC)C(=O)CCl
Product: CCOC(=O)C(=NOC)C1=CSc2ccccc2S1
Yield: 6.8 %

Procedure:
o-Benzenedithiol (7.1 g.) was allowed to react with ethyl 2-chloroacetyl-2-methoxyiminoacetate (11.4 g.) in a similar manner to that of Example A--(i) to give ethyl 2-(1,4-benzodithiin-2-yl)-2-methoxyiminoacetate (syn isomer, 1.0 g.), yellow crystals, mp. 78° to 81° C.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]C)=O.[NH2:19][C:20]1[CH:24]=[C:23]([CH3:25])[O:22][N:21]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[N:4]([CH3:14])[C:3]=1[C:15](=[O:17])[NH:19][C:20]1[CH:24]=[C:23]([CH3:25])[O:22][N:21]=1
Reactant: Cc1cc(N)no1
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: Cc1cc(NC(=O)C2=C(O)c3ccccc3S(=O)(=O)N2C)no1
Temperature: 25 °C

Procedure:
To an appropriate flask equipped for reflux and/or distillation, 900 ml xylene, 40 grams (0.149 moles) methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide and 19.94 grams (0.203 moles) of 3-amino-5-methylisoxazole are added. The mixture is refluxed for 13-18 hours. At 1 hour intervals, about 3-4% of the solvent volume is distilled off. Every 4 to 5 hours fresh xylene is added, equal in amount to that distilled during this period. At the end of the heating period, the reaction is cooled to 25°C., filtered and the cake is washed with xylene. After drying, the crude product weighed 43.8 grams (88%). This material could be recrystallized from about 40-50 volumes of dioxane with an 80-85% recovery of acceptable material. An alternate procedure for the purification of crude product is as follows:
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[C:14]([OH:16])=O)=[O:8])=[CH:3][CH:2]=1.[F:26][C:27]([F:32])([F:31])C(O)=O>>[OH2:8].[F:26][C:27]([F:32])([F:31])[C:14]([CH:13]([NH:17][C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:12][CH2:11][CH2:10][NH:9][C:7](=[O:8])[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[O:16]
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(NCCC[C@H](NC(=O)c1ccccc1)C(=O)O)c1ccccc1
Product: O
Product: O=C(NCCCC(NC(=O)c1ccccc1)C(=O)C(F)(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of the ornithuric acid, as described in Step A, (501.5 g, 1.47 mol) and trifluoroacetic acid (TFAA) (400 ml) was stirred at room temperature for one hour. The resulting solution was evaporated (0.1 Torr) and 1 L of TFAA was added. The solution was stirred for 16 hours and evaporated to dryness (0.01 Torr). Further 1 L of TFAA was added and the solution stirred for 4hours. Reevaporation of the solution to dryness (0.1 Torr) was followed by addition of further 500 ml of TFAA. The solution was stirred for another 16 hours and evaporated to dryness (0.1 Torr). The oily residue was dissolved in 1.6 L of anhydrous THF and freshly dehydrated oxalic acid (440 g) added to the solution over a period of two hours. Stirring of the mixture was continued for 16 hours, when 7.5 L of ethyl acetate was added. The solution was washed with brine, aqueous sodium bicarbonate (4×), and brine, dried over MgSO4 and evaporated to dryness. Yield of the title compound: 522.8 g (90.5%). Rf =0.33 and 0.27 (eluent: ethyl acetate/petroleum ether 1:1), ketone and its hydrate.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][CH2:36][NH:37][C:38](=[O:52])[CH2:39][C:40]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[F:53][C:54]1[CH:59]=[CH:58][C:57]([CH2:60][CH2:61][C:62](O)=[O:63])=[CH:56][CH:55]=1.C(N(CC)CC)C>O1CCCC1.C(OCC)C>[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][CH2:36][NH:37][C:38](=[O:52])[CH2:39][C:40]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:45][CH2:44][N:43]([C:62](=[O:63])[CH2:61][CH2:60][C:57]2[CH:58]=[CH:59][C:54]([F:53])=[CH:55][CH:56]=2)[CH2:42][CH2:41]1
Reactant: O=C(O)CCc1ccc(F)cc1
Reactant: O=C(CC1(c2ccccc2)CCNCC1)NCCc1ccccc1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(CC1(c2ccccc2)CCN(C(=O)CCc2ccc(F)cc2)CC1)NCCc1ccccc1F
Yield: 34 %

Procedure:
Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.311 g, 0.704 mmol) was added to a solution of N-[2-(2-fluoro-phenyl)-ethyl]-2-(4-phenyl-piperidin-4-yl)-acetamide (0.200 g, 0.587 mmol), 3-(4-Fluoro-phenyl)-propionic acid (0.118 g, 0.704 mmol) and triethylamine (0.245 mL, 1.76 mmol) in tetrahydrofuran (5 mL). After 1 hour the mixture was diluted with ethyl ether (20 mL) and washed with saturated aqueous sodium bicarbonate (20 mL) followed by water (2×10 mL). The organic layer was collected, concentrated under reduced pressure and crude product purified by column chromatography on silica gel to give 0.098 g (34 %) of N-[2-(2-fluoro-phenyl)-ethyl]-2-{1-[3-(4-fluoro-phenyl)-propionyl]-4-phenyl-piperidin-4-yl}-acetamide. LRMS m/z 491.1 (M+H)+.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=1.N1C=CC=CC=1>ClCCl>[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])=[C:17]([C:22]([F:23])([F:24])[F:25])[CH:16]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(F)cc1C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(O)c1ccc(S(=O)(=O)Nc2ccc(F)cc2C(F)(F)F)cc1
Temperature: -5 °C
Reaction time: 12 h

Procedure:
2.21 g (10 mmol) of 4-chlorosulfonylbenzoic acid is suspended under exclusion of moisture in 30 ml of dichloromethane, the suspension is cooled to -5° C. and, at this temperature, a solution of 1.79 g (10 mmol) of 4-fluoro-2-(trifluoromethyl)aniline and 1 ml of pyridine in 20 ml of dichloromethane is added dropwise thereto. After this dropwise addition has been completed, the mixture is allowed to warm up to room temperature and is agitated for another 12 hours. The thus-produced precipitate is suctioned off and extracted with ether. This ether extract and the filtrate are evaporated together, and the residue is dissolved in dichloroethane. The solution is extracted three times with respectively 10 ml of saturated sodium bicarbonate solution. The combined aqueous extracts are acidified with 2N hydrochloric acid and the thus-precipitated product is removed by filtration. The filter residue is dried under vacuum at 50° C., thus obtaining 3.3 g (9.08 mmol)=90.84% of theory.
Reaction SMILES: N[C@@H:2]([CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[C:3]([OH:5])=O.[CH:13]1([NH:20][C:21]([NH2:23])=[S:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([NH:20][C:21]2[S:22][CH:2]([CH2:6][C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)[C:3](=[O:5])[N:23]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: N[C@@H](Cc1cccnc1)C(=O)O
Reactant: NC(=S)NC1CCCCCC1
Product: O=C1N=C(NC2CCCCCC2)SC1Cc1cccnc1

Procedure:
Synthesis was performed from (2S)-2-amino-3-pyridin-3-ylpropanoic acid and N-cycloheptylthiourea according to Method E and C.
Reaction SMILES: [CH2:1]1[CH2:6][NH:5][CH2:4][C:3]2[C:7](=[O:15])[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:2]1=2.C(N(CC)CC)C.Cl.Cl[CH2:25][CH2:26][N:27]1[CH2:34][CH:33]2[CH2:35][CH:29]([CH2:30][CH2:31][CH2:32]2)[CH2:28]1>>[CH:33]12[CH2:35][CH:29]([CH2:30][CH2:31][CH2:32]1)[CH2:28][N:27]([CH2:26][CH2:25][N:5]1[CH2:6][CH2:1][C:2]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[O:8][C:7](=[O:15])[C:3]=3[CH2:4]1)[CH2:34]2
Reactant: ClCCN1CC2CCCC(C2)C1
Reactant: O=c1oc2ccccc2c2c1CNCC2
Agent: Cl
Solvent: CCN(CC)CC
Product: O=c1oc2ccccc2c2c1CN(CCN1CC3CCCC(C3)C1)CC2
Reaction time: 72 h
Yield: 35.5 %

Procedure:
Prepared by the method described for Example 13 from 1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridin-5-one (0.8 g, 0.004 moles), triethylamine (1.3 ml, 0.009 moles), and 3-(2-chloroethyl)-3-azabicyclo[3.3.1]nonane hydrochloride (1.0 g, 0.0045 moles). The reflux time is 72 hours. The crude product is triturated in 10% aqueous potassium carbonate, filtered off, rinsed with water, and dried to give the product (0.5 g), mp 129°-130° C.