Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.Cl.[Cl:28][C:29]1[N:34]=[CH:33][C:32]([C:35]2[NH:39][C:38]([C@@H:40]3[CH2:44][CH2:43][CH2:42][NH:41]3)=[N:37][CH:36]=2)=[CH:31][N:30]=1.[N:45]1[CH:50]=[CH:49][CH:48]=[C:47]([CH2:51][C:52](O)=[O:53])[CH:46]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:28][C:29]1[N:34]=[CH:33][C:32]([C:35]2[NH:39][C:38]([C@@H:40]3[CH2:44][CH2:43][CH2:42][N:41]3[C:52](=[O:53])[CH2:51][C:47]3[CH:46]=[N:45][CH:50]=[CH:49][CH:48]=3)=[N:37][CH:36]=2)=[CH:31][N:30]=1
Reactant: O=C(O)Cc1cccnc1
Reactant: Clc1ncc(-c2cnc([C@@H]3CCCN3)[nH]2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1cccnc1)N1CCC[C@H]1c1ncc(-c2cnc(Cl)nc2)[nH]1
Yield: 24.8 %

Procedure:
HATU (0.60 g, 1.57 mmol) was added in one portion to a stirred solution of intermediate (S)-2-chloro-5-(2-(pyrrolidin-2-yl)-1H-imidazol-5-yl)pyrimidine trihydrochloride (0.46 g, 1.43 mmol, theoretical amount), 2-(pyridin-3-yl)acetic acid (0.25 g, 1.43 mmol) and DIEA (1.0 mL, 5.72 mmol) in anhydrous DMF (10 mL) at ambient temperature. The mixture was stirred at room temperature for 2 h before the DMF was removed in vacuo. The residue was taken up in CH2Cl2 and subjected to Biotage™ flash chromatography on silica gel (40M column, preequilibration with 0% B for 600 mL followed by step gradient elution with 0% B to 0% B for 150 mL followed by 0% B to 15% B for 1500 mL followed by 15% B to 25% B for 999 mL where B=MeOH and A=CH2Cl2). There was isolated the title compound (0.131 g, 25%, 2 steps) as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH3:18][O:19][CH2:20][CH2:21][NH2:22]>C(O)C>[CH3:18][O:19][CH2:20][CH2:21][NH:22][C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Reactant: COCCN
Solvent: CCO
Product: COCCNc1c([N+](=O)[O-])cc(C(=O)O)cc1S(N)(=O)=O
Temperature: 60 °C

Procedure:
A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (4.2 g), 2-methoxyethylamine (5.6 g), and 50% ethanol (10 ml) was heated to 60°C for 1 hour. The ethanol was distilled off under reduced pressure, and the resulting 4-(2-methoxyethylamino)-3-nitro-5-sulphamyl-benzoic acid was precipitated by addition of 4N hydrochloric acid until pH 2. After recrystallization from water, the melting point was 192°-194°C. The compound crystallized with 1 molecule of water of crystallization.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:4]([N+:12]([O-])=O)[CH:3]=1.[Cl-].[NH4+].O>CO.[Zn]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:4]([NH2:12])[CH:3]=1
Reactant: CS(=O)(=O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(Br)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
A light brown suspension of 4-bromo-1-methanesulfonyl-2-nitro-benzene (8.65 g, 30.9 mmol) in methanol (300 mL, not completely dissolved in methanol even at hot condition) was treated sequentially with ammonium chloride (24.8 g, 463.5 mmol), zinc dust (20.2 g, 309 mmol), and water (100 mL). Initially, the reaction was exothermic, and the brown color disappeared. The reaction mixture was stirred for 1 h at 25° C. The reaction mixture was then filtered, and the residue was washed with methanol (50 mL) and ethyl acetate (100 mL). The filtrate was concentrated in vacuo, and the organic compound was extracted into ethyl acetate (3×100 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 8/1 to 6/1 to 4/1 hexanes/ethyl acetate) afforded 5-bromo-2-methanesulfonyl-phenylamine (5.7 g, 74%) as-a white solid: mp 107-109° C.; EI-HRMS m/e calcd for C7H8BrNO2S (M+) 248.9459, found 248.9451.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([S:10](Cl)(=[O:12])=[O:11])[C:7]([O:14][CH3:15])=[CH:6][C:5]=1[O:16][CH2:17][CH3:18].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([S:10]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)(=[O:12])=[O:11])[C:7]([O:14][CH3:15])=[CH:6][C:5]=1[O:16][CH2:17][CH3:18]
Reactant: C1CCNC1
Reactant: CCOc1cc(OC)c(S(=O)(=O)Cl)cc1C(=O)OC
Product: CCOc1cc(OC)c(S(=O)(=O)N2CCCC2)cc1C(=O)OC

Procedure:
In a manner analogous to the method described in example 33, 5-chlorosulfonyl-2-ethoxy-4-methoxy-benzoic acid methyl ester was reacted with pyrrolidine to give the title compound.
Reaction SMILES: N#N.I[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:13][CH3:14].[S:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.C([O-])(=O)C.[K+]>CN(C=O)C>[CH3:14][O:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[C:19]1[S:15][CH:16]=[N:17][CH:18]=1
Reactant: c1cscn1
Reactant: COc1ccc([N+](=O)[O-])cc1I
Agent: CC(=O)[O-]
Agent: N#N
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1-c1cncs1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
N2 was bubbled through a solution of 2-iodo-4-nitroanisole (2.8 g, 10.0 mmol), thiazole (2.55 g, 30.0 mmol), potassium acetate (1.47 g, 15.0 mmol), and tetrakis(triphenyl phosphine)palladium(0) (0.81 g, 0.70 mmol) in DMF (15 mL) for 10 min. The mixture was then heated to 100° C. and stirred overnight. Solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography (dichloromethane:MeOH=96:4) to afford the title compound. 1H-NMR (CDCl3, 400 MHz): δ=4.08 (s, 3H), 7.09 (d, J=9.2 Hz, 1H), 8.25 (dd, J=2.8, 9.2 Hz, 1H), 8.37 (s, 1H), 8.54 (d, J=3.2 Hz, 1H), 8.88 (s, 1H). MS (ES+): m/z 237.13 [MH+]. HPLC: tR=3.07 min (ZQ2000, polar—5 min).
Reaction SMILES: [CH2:1]([N:5]([CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]1)[C:6](=[O:8])[CH3:7])[CH2:2][CH2:3][CH3:4].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=[O:24].OO>CO>[CH2:1]([N:5]([CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([OH:24])[C:11]([CH3:17])([CH3:18])[CH2:10]1)[C:6](=[O:8])[CH3:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C(C)=O)C1CC(C)(C)NC(C)(C)C1
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: OO
Solvent: CO
Product: CCCCN(C(C)=O)C1CC(C)(C)N(O)C(C)(C)C1
Reaction time: 2 h

Procedure:
To a stirred 50° C. solution of 13.3 g of N-butyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)acetamide, 0.075 g of sodium tungstate-dihydrate and 0.075 g of ethylenediamine-tetraacetic acid in 25 mL of methanol is added 35 mL of 30% aqueous hydrogen peroxide over a three hour period. After the addition is complete, the reaction mixture is stirred another two hours. The reaction mixture is then partitioned between diethyl ether and water. The organic phase is washed with water, 1% aqueous hydrogen chloride and then water. After drying over anhydrous magnesium sulfate and concentrating, the title compound is obtained as a red solid. After crystallization from hexane, the compound melts at 84-85° C.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH:7]1([CH2:10][N:11]2[C:17](=[O:18])[C@@H:16]([NH:19][C:20]([N:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH:32]=[C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[NH:30][C:29]4=[O:39])[CH2:24][CH2:23]3)=[O:21])[CH2:15][NH:14][C@H:13]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:12]2)[CH2:9][CH2:8]1.IC>CC(C)=O>[CH:7]1([CH2:10][N:11]2[C:17](=[O:18])[C@H:16]([NH:19][C:20]([N:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH:32]=[C:31]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[NH:30][C:29]4=[O:39])[CH2:24][CH2:23]3)=[O:21])[CH2:15][N:14]([CH3:1])[C@@H:13]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:12]2)[CH2:9][CH2:8]1
Reactant: O=C(N[C@H]1CN[C@H](c2ccccc2)CN(CC2CC2)C1=O)N1CCC(n2cc(-c3ccccc3)[nH]c2=O)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CN1C[C@@H](NC(=O)N2CCC(n3cc(-c4ccccc4)[nH]c3=O)CC2)C(=O)N(CC2CC2)C[C@@H]1c1ccccc1
Reaction time: 18 h
Yield: 35.1 %

Procedure:
Potassium carbonate (5.8 mg, 0.040 mmol) was added to a solution of N-[(3R,6S)-1-(cyclopropylmethyl)-7-oxo-3-phenyl-1,4-diazepan-6-yl]-4-(2-oxo-4-phenyl-2,3-dihydro-1H-imidazol-1-yl)piperidine-1-carboxamide (11.0 mg, 0.021 mmol) and iodomethane (3 □L, 0.040 mmol) in acetone (0.5 mL). After 18 h, the mixture was concentrated. Purification by silica gel chromatography (1% methanol/dichloromethane→5% methanol/dichloromethane) gave the title compound (4 mg). MS 543.3 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)[CH:10]([NH2:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O-])([O-])=O.[K+].[K+].ClC(OCC)=O.B>C1COCC1.O>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)[CH:10]([NH:21][CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(F)c1
Reactant: O=C([O-])[O-]
Agent: B
Agent: CCOC(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CNC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(F)c1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 70.6 %

Procedure:
To a solution of (3RS,4SR)-1-benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-ylamine (0.46 g, 1.51 mmol) in THF (5 ml) was added a solution of K2CO3 (0.419 g, 3.0 mmol) in H2O (2 ml). After 10 minutes, ethyl chloroformate (0.3 ml, 3.0 mmol) was added and stirring was continued at RT for an additional 4 h. The intermediate carbamate was then extracted with Et2O, dried over Na2SO4 and concentrated under vacuo to give viscous oil. The oil was taken up in THF (10 ml) and a solution of borane in THF (1M) was added (6.0 ml). The reaction mixture was then heated at 65° C. over night, cooled to RT and carefully quenched with conc. HCl (5 ml). The mixture was then heated at 80° C. for 2 h, cooled to RT, concentrated under vacuo, diluted with Et2O (10 ml) and neutralized with an aqueous solution of NaHCO3. The organic phases were dried over Na2SO4 and the product purified by flash chromatography (SiO2, CH2Cl2/MeOH 9:1) to afford 0.34 g (70%) of the title compound as a colorless oil. ES-MS m/e: 319.1 (M+H+).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].O=[C:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.CCCCCC>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH2:1]=[C:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOCC
Product: C=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Yield: 94.2 %

Procedure:
To a suspension of methyltriphenylphosphonium bromide (36.3 g, 101.6 mmol, 1.35 equiv) in ether (dry, 300 mL) was added potassium t-butoxide (11 g, 98 mmol, 1.3 equiv) in one portion at 0° C. under nitrogen balloon. The mixture was then stirred at reflux for 2 hrs. The hot reaction mixture was cooled to 0° C. with an external ice-bath and then a solution of tert-butyl 4-oxopiperidine-1-carboxylate (15 g, 75.3 mmol, 1.0 equiv) in ether (60 mL) was added dropwise. The mixture was allowed to warm to room temperature and stirred at room temperature for 1 h. The mixture was then stirred at reflux overnight (16 h). The mixture was cooled to room temperature and hexane (300 mL) was added. The mixture was stirred for 10 min, filtered and eluted with Hexane/EtOAc (100/100 mL). The combined organic solution was concentrated to give the residue which was purified by CombiFlash (100 g silica gel column, EtOAc/Hex=0-30%) to afford 14 g (yield 94%) of tert-butyl 4-methylenepiperidine-1-carboxylate as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([F:17])[CH:11]=2)[N:3]=1.[CH:18]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[OH-].[Na+].O>CC(C)=O>[Cl:8][C:6]1[N:7]=[C:2]([NH:25][CH:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([F:17])[CH:11]=2)[N:5]=1
Reactant: Cc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1F
Reactant: NC1CCCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1F

Procedure:
To 156a (1.0010 g, 3.7 mmol) dissolved in acetone (20 mL) was added a solution of N-cycloheptylamine (0.5 mL, 3.7 mmol) in acetone (5 mL) followed by addition of 2.5 N NaOH (1.5 mL, 3.7 mmol) and water (4 mL). The reaction mixture was allowed to stir at reflux for 3 hours under nitrogen. The reaction mixture was extracted 3 times with dichloromethane; the combined organic layers were washed with brine, and dried over potassium carbonate. After filtering, the sample was concentrated, and the resulting solid was dried overnight under vacuum. Flash column chromatography (SiO2, 70:30 hexanes:ethyl acetate) yielded a white solid (156b, 1.144 g, 88%), mp 149° C.; HPLC: Inertsil ODS-3V C18, 30:70 [KH2PO4 (0.01M, pH 3.2): CH3CN], 264 nm, Rt 28.9 min, 90.4% purity; MS (TOF MS ES+): m/z 427 (40.2), 351 (32.2), 350 (M+H, 100).
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].Cl.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH:3]([CH2:4][N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])=[O:2]
Reactant: COC(CN(C(=O)C1CCCCC1)c1ccccn1)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=CCN(C(=O)C1CCCCC1)c1ccccn1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 76.4 %

Procedure:
A mixture of 1.46 g of N-[(2,2-dimethoxy)ethyl]-N-(2-pyridyl)cyclohexanecarboxamide, 0.05 g of 1,4-hydroquinone, and 25 ml of 2N HCl was stirred at 80° C. for 20 min under nitrogen stream. Afterwards, it was cooled at 0° C., diluted with 50 ml of methylene chloride, and alkalinized to pH=10 with 20% aqueous Na2CO3. The aqueous layer was extracted twice with methylene chloride and the combined organic layers were dried (sodium sulfate) and evaporated to dryness in vacuo affording 0.94 g of the title compound, used without further purification in the next reaction step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[S:30](Cl)(=[O:32])=[O:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:30]([C:23]2[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:22]=2[O:21][CH3:20])(=[O:32])=[O:31])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Product: COc1ccc(S(=O)(=O)Nc2cnc(Oc3cnc4ccccc4c3)c(Cl)c2)c(OC)c1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and 2,4-dimethoxybenzene-1-sulfonyl chloride.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Br:18])=[CH:15][N:16]=2)[C:11](=[O:19])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>CO>[Br:18][C:14]1[CH:13]=[C:12]2[C:17](=[N:16][CH:15]=1)[NH:8][CH2:9][CH2:10][C:11]2=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)c2cc(Br)cnc21
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C1CCNc2ncc(Br)cc21
Reaction time: 16 h
Yield: 88.5 %

Procedure:
6-Bromo-4-oxo-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (628 mg, 1.92 mmol) is dissolved into 3 mL of MeOH and 3 mL of 4 M HCl/1,4-dioxane is added. The mixture is stirred for 16 h and concentrated to dryness. The residue is dissolved into 10 mL CH2Cl2 and 10 mL of H2O and neutralized with saturated aqueous Na2CO3 solution. The aqueous layer is extracted with 2×20 mL of CH2Cl2. The organic phase is dried with MgSO4, filtered and concentrated to give 386 mg of 6-bromo-2,3-dihydro-1H-[1,8]naphthyridin-4-one
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-])=O)=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.C1C(N)=CC=[C:13]([OH:18])[CH:12]=1>>[C:13]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([OH:10])=[CH:2][CH:1]=1)(=[O:18])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Nc1ccc(O)cc1
Product: CC(=O)Nc1ccc(O)cc1

Procedure:
This example shows the stepwise reduction of p-nitrophenol and acetylation of p-aminophenol to produce the N-acetyl-p-aminophenol according to this invention: 90 grams of p-nitrophenol was added to 243 ml of water containing 1.25 grams charcoal and 0.31 grams catalyst (50% catalyst 50% water) of 5% palladium-on-charcoal. The system was heated to 95°-98° C. and hydrogen pressure of 70 psig. After 1 hour hydrogenation, the batch was cooled to 48° C. (pH 5.8) and 35 grams acetic anhydride was added. The reduction was continued at 95°-98° C. and 70 psig until hydrogen uptake ceased. The batch was cooled to 40° C. (pH 5.0) and 35 grams of acetic anhydride was added with heating to 95° C. The batch was filtered to recover catalyst. The N-acetyl-p-aminophenol was crystallized to yield a white crystalline product. Quality of the APAP was good giving only a slight pink caustic test and the product yield was 81.2 %.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N1C=CC=CC=1.[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>ClCCl.CN(C)C1C=CN=CC=1>[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:1](=[O:10])[CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:21][CH:20]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Nc1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(C=Cc1ccccc1)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
In a round-bottomed flask, a solution of the crude cinnamoyl chloride (25.2 g) in dichloromethane (50 ml) was added to a stirring mixture of pyridine (14.4 g, 182 mmol) and 4-dimethylaminopyridine (1.44 g, 11.8 mmol) in dichloromethane (100 ml) at 0° C. and stirred for 15 minutes before a solution of 4-fluoroaniline (13.2 g, 118.79 mmol) in dichloromethane (50 ml) was added over 20 min. After being stirred for 3 h at room temperature, the mixture was quenched with water (500 ml) and extracted with dichloromethane (3×150 ml). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to give a residue. The crude material was purified by silica gel chromatography using 1-5% ethyl acetate in petroleum to elute. The product-containing fractions were combined to afford N-(4-fluorophenyl)cinnamamide as a light yellow solid (17.8 g, 61%); (ES, m/z): [M+H]+ 242; 1H NMR (300 MHz, CDCl3): δ 10.28 (s, 1H), 7.70-7.75 (m, 5H), 7.39-7.65 (m, 3H), 7.15 (t, J=9.0 Hz, 2H), 6.79 (d, J=15.6 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[CH:5]=[N:6]O>C(#N)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]#[N:6]
Reactant: ON=Cc1cc(F)cc(Br)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: N#Cc1cc(F)cc(Br)c1
Reaction time: 5 h
Yield: 89.3 %

Procedure:
The above oxime (3.76 g, 17.24 mmol) and copper(II)acetate (370 mg) were dissolved in acetonitrile (100 cm3) under nitrogen and heated under reflux. After 5 h, the mixture was evaporated, the residue taken into EtOAc, washed with sulfuric acid (1N), water, brine, dried (MgSO4) and evaporated to give 3-fluoro-5-bromobenzonitrile (3.08 g, 15.39 mmol, 89%) which was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:25]([OH:35])=[CH:24][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])[CH3:2].[OH-].[Na+]>C(O)C.Cl>[CH2:1]([C:3]1[CH:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:25]([OH:35])=[CH:24][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH3:2]
Reactant: CCOC(=O)CCc1ccccc1OCCCCOc1cc(O)c(-c2ccc(F)cc2)cc1CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc(-c2ccc(F)cc2)c(O)cc1OCCCCOc1ccccc1CCC(=O)O
Reaction time: 16 h
Yield: 72 %

Procedure:
A solution of 375 mg of ethyl 3-(2-(4-(2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy)butyloxy)phenyl)propionate in 25 ml of ethanol was mixed with 5 ml of 5.0N sodium hydroxide and stirred 16 hours. The mixture was diluted with 1.0N hydrochloric acid and extracted with 3:1 dichloromethane/isopropanol. The organic phase was washed with saturated sodium chloride, dried over sodium sulfate, and evaporated in vacuo providing the desired title product in 72% yield. NMR.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Br:10])[C:7]([OH:11])=[C:6]([Br:12])[CH:5]=1)=[O:3].[Br:13][CH2:14][CH2:15][CH2:16]Br>C(#N)C>[Br:13][CH2:14][CH2:15][CH2:16][O:11][C:7]1[C:6]([Br:12])=[CH:5][C:4]([C:2](=[O:3])[CH3:1])=[CH:9][C:8]=1[Br:10]
Reactant: CC(=O)c1cc(Br)c(O)c(Br)c1
Reactant: BrCCCBr
Solvent: CC#N
Product: CC(=O)c1cc(Br)c(OCCCBr)c(Br)c1

Procedure:
A stirred mixture of 3,5-dibromo-4-hydroxyacetophenone (3.0 g, 10.1 mmol), K2CO2 (2.9 g, 20.3mmol), 1,3-dibromopropane (4.0 g, 19.8 mmol) in acetonitrile (100 ml) was heated at reflux for 5 hours. The solvent was removed. The crude product was extracted into dichloromethane (150 ml) and the insoluble inorganics were filtered off. The solution was concentrated to dryness again. Purification was carried out by flash chromatography on silica gel (45 g, SiO2; eluted with 1:1 hexane:dichloromethane). The material thus obtained (2.9 g) was recrystallized twice from isopropyl ether to give analytically pure 1-[4-(3-bromopropoxy)-3,5-dibromophenyl]ethanone, m.p.=87°-88° C.
Reaction SMILES: [CH2:1]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]1=[O:22])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])(=O)C.[Na+].Cl.[NH2:29][OH:30]>CCO.O>[CH2:1]([N:9]1[CH2:14][CH2:13][C:12](=[N:29][OH:30])[CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]1=[O:22])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1CCN(CCc2ccccc2)C(=O)C1c1ccccc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1C(c2ccccc2)C(=NO)CCN1CCc1ccccc1
Temperature: 0 °C
Yield: 59.6 %

Procedure:
Phenethyl-3-phenyl-piperidine-2,4-dione (781 mg), sodium acetate (1.15 g) and hydroxylamine hydrochloride (925 mg) were suspended in EtOH/water 1:1 (25 ml) and the mixture was refluxed for 4 hours. The mixture was then poured into ice/water/1N NaOH and extracted with ethyl acetate. The organic layer was washed with brine, dried and evaporated to give the crude product that was purified by flash chromatography (DCM/MeOH/NH4OH 98:2:0.25) to give the compound as a white foam (489 mg). MS (ESI): 309.4 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:7][C:8]=1[Cl:9])#[N:2].[C:14]([N:16]=[C:17]([NH2:19])[NH2:18])#[N:15].[OH-].[K+]>COCCOCCOC.O>[NH2:15][C:14]1[N:16]=[C:17]([NH2:19])[N:18]=[C:1]([C:3]2[C:8]([Cl:9])=[CH:7][CH:6]=[C:5]([C:10]([F:13])([F:11])[F:12])[CH:4]=2)[N:2]=1
Reactant: N#CN=C(N)N
Reactant: N#Cc1cc(C(F)(F)F)ccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: COCCOCCOC
Solvent: O
Product: Nc1nc(N)nc(-c2cc(C(F)(F)F)ccc2Cl)n1

Procedure:
4.0 g of 3-cyano-4-chlorobenzotrifluoride (90°-102° C./29 mm Hg), 2.0 g of dicyanodiamide and 1.0 g of caustic potash are refluxed in 10 ml of diglyme for 3 hours. After cooling, the mixture is diluted with water and the separated crystals are recrystallized from methanol. Melting point: 210°-212° C.; yield: 3.8 g.