Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[C:34]([O:41][CH3:42])[CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:16]4[CH:21]=[CH:20][N:19]=[CH:18][N:17]=4)(=[O:13])=[O:14])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[C:34]([O:41][CH3:42])[CH:33]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Reactant: COc1cc(Cl)ccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(-c4ccc(Cl)cc4OC)nccc3c2)cc1
Temperature: 100 °C
Yield: 91.2 %

Procedure:
A vial was charged with 1-chloro-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (INTERMEDIATE ZZZZ, 310.8 mg, 0.705 mmol), (4-chloro-2-methoxyphenyl)boronic acid (197 mg, 1.057 mmol), potassium carbonate (292 mg, 2.115 mmol), and Pd(PPh3)4 (81 mg, 0.070 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (2643 μl) and water (881 μl) were added. The vial was sealed and heated to 100° C. for 30 min in a Biotage Initiator microwave reactor. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The residue was purified by chromatography on silica gel (40-g Redi-Sep Gold column, 0-40% EtOAc/Heptane) to give 1-(4-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (352 mg, 0.643 mmol, 91% yield) as a cream-colored foam. m/z (ESI) 547.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:9]1[C:14]([F:15])=[CH:13][C:12]([OH:16])=[CH:11][C:10]=1[F:17])[O:6][CH2:7][CH3:8])[CH3:2].O[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:9]1[C:14]([F:15])=[CH:13][C:12]([O:16][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:11][C:10]=1[F:17])[O:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCOC(=O)C(OCC)c1c(F)cc(O)cc1F
Reactant: OCc1ccccn1
Product: CCOC(=O)C(OCC)c1c(F)cc(OCc2ccccn2)cc1F

Procedure:
In analogy to example 22.1 (RS)-(2,6-difluoro-4-hydroxy-phenyl)-ethoxy-acetic acid ethyl ester (example L6) was reacted with 2-(hydroxymethyl)pyridine to give (RS)-[2,6-difluoro-4-(pyridin-2-ylmethoxy)-phenyl]-ethoxy-acetic acid ethyl ester as a yellow semisolid. This material was hydrolysed in analogy to example 101.3 to give (RS)-[2,6-difluoro-4-(pyridin-2-ylmethoxy)-phenyl]-ethoxy-acetic acid. White solid. MS 324.1 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:39]1([C:45]2[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=2)[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[C:3]=1[C:14]([N:42]1[CH2:41][CH2:40][N:39]([C:45]2[CH:46]=[CH:47][C:48]([OH:51])=[CH:49][CH:50]=2)[CH2:44][CH2:43]1)=[O:16]
Reactant: Nc1onc(-c2ccccc2F)c1C(=O)O
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Nc1onc(-c2ccccc2F)c1C(=O)N1CCN(c2ccc(O)cc2)CC1
Yield: 58.7 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 5-amino-3-(2-fluorophenyl)isoxazol-4-carboxylic acid (409 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 4-(piperazine-1-yl)phenol (328 mg, 1.84 mmol), a white solid required compound (412 mg, 1.08 mmol, 59%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][C:11]([NH:13][NH2:14])=[O:12].Cl.[C:16](=N)(OCC)[CH3:17]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][C:11]1[O:12][C:16]([CH3:17])=[N:14][N:13]=1
Reactant: CCOC(C)=N
Reactant: Cc1cccc(C)c1NCC(=O)NN
Agent: Cl
Solvent: c1ccncc1
Product: Cc1nnc(CNc2c(C)cccc2C)o1
Yield: 34.1 %

Procedure:
A solution of 19.3 g (0.1 mol) alpha-(2,6-dimethylphenyl-amino)acethydrazide and 14 g (0.11 mol) ethyl actimidate hydrochloride (Aldrich Chemical Co.) in 150 ml pyridine was heated under reflux for 9 hours. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give an oil. The oil was placed on 400 g silica gel in a chromatography column and eluted the following solvent systems: (1) petroleum ether, (2) petroleum ether/ethyl ether, (3) ethyl ether, and (4) ethyl ether/methanol. The crude product (11.5 g) was eluted from the column with the ethyl ether/methanol solvent system. Crystallization of the crude product from dichloromethane/ethyl ether gave 7.4 g of crystalline product, m.p. 134°-135° C. The product is tabulated in Table I as Compound No. 1-A.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:32])[C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[C:11]([Cl:33])[CH:10]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[Cl:15][C:13]1[CH:14]=[C:9]([OH:8])[CH:10]=[C:11]([Cl:33])[C:12]=1[O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:32])[C:22]1[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=1
Reactant: O=C(NCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl)c1ccc(C(F)(F)F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(NCCCOc1c(Cl)cc(O)cc1Cl)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-Benzyloxy-3,5-dichloro-4-(3-(4-trifluoromethylbenzamido)propyloxy)benzene was dissolved in ethyl acetate, which was put into a reaction vessel, and the air in the vessel was replaced with nitrogen gas. A catalytic amount of 10% palladium on carbon was added, and the nitrogen gas in the vessel was replaced with hydrogen gas, followed by vigorous stirring at room temperature for 24 hours. The hydrogen gas in the vessel was replaced with nitrogen gas, after which the reaction mixture was filtered through cerite and the filtrate was concentrated to give 3,5-dichloro-4-(3-(4-trifluoromethylbenzamido)propyloxy)phenol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]([CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)([CH2:15][C:16]#[C:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:12](O)=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32]>>[OH:32][NH:31][C:12](=[O:13])[C:11]([S:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])([CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH2:15][C:16]#[C:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: NO
Reactant: CCCCCC#CCC(Cc1cccnc1)(C(=O)O)S(=O)(=O)c1ccc(F)cc1
Agent: Cl
Product: CCCCCC#CCC(Cc1cccnc1)(C(=O)NO)S(=O)(=O)c1ccc(F)cc1
Yield: 29 %

Procedure:
2-(4-Fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from 2-(4-fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acid (0.67 g, 1.62 mmol) and hydroxylamine hydrochloride (1.39 g, 20 mmol), 0.22 g of the product was isolated. Yield 29%; white solid; mp 180-182° C.; MS: 433.2 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 0.84 (t, J=6.8 Hz, 3H), 1.20-1.40 (m, 6H), 1.90-2.05 (m, 2H), 2.75 (d, J=19.9 Hz, 1H), 2.94 (d, J=19.9 Hz, 1H), 3.54 (d, J=13.7 Hz, 1H), 3.75 (d, J=13.7 Hz, lH), 7.40-7.60 (m, 2H), 7.70-8.00 (m, 3H), 8.30-8.40 (m, 1H), 8.70-8.80 (m, 2H), 11.1 (brs, 1H); IR (KBr, cm−1): 3154 m, 3105 s, 3067 m, 2957 s, 2933 s, 2873 m, 1690 s, 1631 m.
Reaction SMILES: S=C1[N:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:20])[CH3:19])=[C:13]([O:21][CH3:22])[CH:12]=2)=[O:8])[CH2:5][CH2:4]S1.C(N)[C:24]1[CH:29]=[CH:28]C=[CH:26][CH:25]=1>C1COCC1.C(OCC)C>[C:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][O:9][C:7](=[O:8])[NH:6][CH2:5][C:4]2[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=2)=[CH:12][C:13]=1[O:21][CH3:22])(=[O:20])[CH3:19]
Reactant: NCc1ccccc1
Reactant: COc1cc(COC(=O)N2CCSC2=S)ccc1OC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(COC(=O)NCc2ccccc2)ccc1OC(C)=O
Reaction time: 8 h
Yield: 7 %

Procedure:
Compound VII (339 mg, 0.993 mmol) was dissolved in anhydrous THF (5 mL). To the stirred, yellow solution was added at room temperature a solution of benzylamine (160 mg, 163 pt, 1.5×0.993 mmol) in anhydrous THF (5 mL), After being stirred overnight, the reaction solution was diluted with diethyl ether and extracted with 1N HCl, water and saturated NaCl. The organic phase was dried over anhydrous MgSO4, filtered and concentrated. Purification by column chromatography on silica gel eluting with hexanes/ethyl acetate (7:3-1:1, v/v) afforded 23 mg (7%) of 8 as a clear oil: Rf=0.30 (hexanes/ethyl acetate, 1:1, v/v); 1HNMR (CDCl3) δ 7.34-7.25 (m, 5H), 6.99 (d, 3J=8.0 Hz, 1H), 6.96 (s, 1H), 6.92 (d, 3J=8.1 Hz, 1H), 5.09 (s, 2H), 5.04 (bs, 1H, NH), 4.38 (d, 3J=6 Hz, 2H), 3.81 (s, 3H) and 2.29 (s, 3H). While the synthesis proceeded in excellent yield, product isolation was compromised by decomposition during work-up.
Reaction SMILES: [CH:1]([O:4][C@@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:16]C(=O)OCC3C=CC=CC=3)[C:12]2=[O:27])[C@H:7]([CH2:28][S:29]([CH:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])[CH2:6]1)([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:16][C@H:13]1[CH2:14][CH2:15][N:11]([C@H:8]2[CH2:9][CH2:10][C@@H:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH2:6][C@H:7]2[CH2:28][S:29]([CH:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])[C:12]1=[O:27]
Reactant: CC(C)O[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)O[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Reaction time: 8 h

Procedure:
A sample of benzyl (S)-1-((1S,2R,4R)-4-isopropoxy-2-(isopropylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate A (faster ismer, 0.41 g) and Pd/C (0.08 g) were taken in MeOH (20 mL) and stirred at rt under 50 psi hydrogen pressure. After stirring overnight, the reaction mixture was filtered through Celite using EtOAc. Upon concentration and drying in vacuo, (S)-3-amino-1-((1S,2R,4R)-4-isopropoxy-2-(isopropylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one was obtained as a clear viscous oil.
Reaction SMILES: CC(CC([C:7]1[C:12](O)=[CH:11][C:10]([OH:14])=[C:9]([CH2:15][CH:16]=[C:17](C)C)[C:8]=1[O-])=O)C.[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12>>[CH2:15]([C:9]1[CH:8]=[CH:7][CH:12]=[CH:11][C:10]=1[O:14][CH2:9][CH:10]([OH:14])[CH2:11][N:25]1[C:21](=[O:31])[C:22]2=[CH:30][CH:29]=[CH:28][CH:27]=[C:23]2[C:24]1=[O:26])[CH:16]=[CH2:17]
Reactant: CC(C)=CCc1c(O)cc(O)c(C(=O)CC(C)C)c1[O-]
Reactant: O=C1NC(=O)c2ccccc21
Product: C=CCc1ccccc1OCC(O)CN1C(=O)c2ccccc2C1=O

Procedure:
The title compound was prepared from compound X (R=2-allylphenyl) and phthalimide by the general procedure described above for the 1-naphthyl derivative (Compound XII).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]([CH:12]=[O:13])=[CH:11][C:4]=2[NH:3]1.CI.[C:16](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:16][N:3]1[C:2](=[O:1])[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]([CH:12]=[O:13])=[CH:11][C:4]1=2
Reactant: O=Cc1ccc2c(c1)NC(=O)CO2
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)COc2ccc(C=O)cc21
Yield: 85.3 %

Procedure:
3-Oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde (0.5 g, 2.82 mmol), methyl iodide (0.6 g, 4.23 mmol) and cesium carbonate (1.37 g, 4.23 mmol) were dissolved in dry dimethylformamide (2 mL). The reaction mixture was irradiated by microwave at 100° C. for 30 minutes. The solvent was removed and the residue was washed with water and extracted with dichloromethane. Purification by silica chromatography (ISCO) produced 4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde (0.46 g, 85%). 1H NMR (400 MHz, DMSO-d6): δ 9.95 (s, 1H), 7.62 (s, 1H), 7.59 (d, 1H), 7.20 (d, 1H), 4.80 (s, 2H), 3.34 (s, 3H); MS (ESI) m/z: Calculated for C10H9NO3: 191.1. found: 192.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([C:7]#[N:8])=O.C(=O)(O)O.[NH2:17][NH:18][C:19]([NH2:21])=[NH:20].[OH-].[K+]>>[NH2:20][C:19]1[N:18]=[N:17][C:5]([C:4]2[CH:9]=[CH:10][CH:11]=[C:2]([Cl:1])[C:3]=2[Cl:12])=[C:7]([NH2:8])[N:21]=1
Reactant: N#CC(=O)c1cccc(Cl)c1Cl
Reactant: N=C(N)NN
Agent: O=C(O)O
Agent: [K+]
Agent: [OH-]
Product: Nc1nnc(-c2cccc(Cl)c2Cl)c(N)n1

Procedure:
There is disclosed an improved process for the preparation of 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine which process comprises the step of reacting 2,3-dichlorobenzoylchloride with cuprous cyanide in presence of acetonitrile and a cosolvent to produce dichlorobenzoyl cyanide, said dichlorobenzoyl cyanide is reacted with aminoguanidine bicarbonate to produce an intermediate product, which is cyclized in presence of aqueous potassium hydroxide to produce 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[C:18](OC(=O)C)(=O)C.OS(O)(=O)=O.CC(C)=O>O>[CH3:10][C:9]1([CH3:18])[O:8][C:6](=[O:7])[CH:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4](=[O:3])[O:17]1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)OC(=O)C(c2ccccc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 11.8 g (50 mmol) of phenylmalonic acid diethyl ester in 23 ml. of acetic anhydride there are added 0.5 ml. of concentrated H2SO4 and 20 ml. of acetone. The mixture is stirred at 25° C for 8 hours, water (250 ml.) is then added thereto and the mixture is stirred for 30 minutes. The obtained precipitate is washed with 250 ml. of water up to pH 6.5, dried under reduced pressure and dissolved in 100 ml. of chloroform. The organic solution is dried over anhydrous sodium sulfate, most of the solvent is evaporated under reduced pressure and 100 ml. of petroleum ether (50°-70° C) is added thereto. The suspension is stirred for 30 minutes and filtered. The precipitate is washed with 20 ml. of petroleum ether (50°-70° C) and dried over P2O5 under reduced pressure to yield 2.2-dimethyl-5-phenyl-1.3-dioxane-4.6-dione with the same characteristics as the compound described by P. J. Scheuer in J.A.C.S. 80, 4933-38 (1958).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:30]=[C:29]([Cl:31])[C:28]([NH2:32])=[C:27]([Cl:33])[CH:26]=1>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:22]([CH3:21])[CH2:23][CH2:24][C:25]3[CH:26]=[C:27]([Cl:33])[C:28]([NH2:32])=[C:29]([Cl:31])[CH:30]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNCCc1cc(Cl)c(N)c(Cl)c1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1cc(Cl)c(N)c(Cl)c1)CC2

Procedure:
This compound was prepared analogous to Example 5(b) from 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloro-propane and N-methyl-N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-amine.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14])=[O:7].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1ccccc1F
Product: CCC(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3F)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-(2-fluorophenyl)-1-pentanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 411.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].Cl[CH2:10][O:11][CH2:12][CH2:13][CH2:14][Br:15]>CCOCC>[CH2:10]([O:11][CH2:12][CH2:13][CH2:14][Br:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCOCCCBr
Reactant: Brc1ccccc1
Agent: [Mg]
Solvent: CCOCC
Product: BrCCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
To the Grignard reagent prepared from bromobenzene (46.3 g., 0.294 mole) and magnesium (7.15 g., 0.294 mole) in ether (150 ml.) is added, dropwise over one hour at 0°, a solution of 3-chloromethoxy-1-bromopropane (55.0 g., 0.294 mole) in ether (50 ml.). The resulting solution is stirred at 25° for 16 hours, then heated at reflux for 1/4 hour, cooled to 0° and cautiously treated with ice water (200 ml.) with vigorous stirring. After separating the phases, the aqueous layer is extracted with ether (200 ml.). The combined organic extract is washed with water, 5% potassium carbonate, water and saturated brine, dried over sodium sulfate and evaporated in vacuo leaving a pale yellow oil (64.4 g., 96%) which is distilled to provide the title compound as a colorless liquid (92% recovery), b.p. 140°-141°/14 mm.; pmr (CDCl3)δ2.12 (2H,p), 3.51 (2H,t), 3.60 (2H,t), 4.50 (2H,t) and 7.31 (5H,s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15](=[O:17])[CH3:16])=[C:13]([OH:18])[C:12]([O:19][C:20]2[C:28]([CH3:29])=[CH:27][C:26]([N+:30]([O-:32])=[O:31])=[C:25]3[C:21]=2[CH2:22][CH2:23][CH2:24]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](=O)([O-])[O-].[Cs+].[Cs+].CI>O1CCCC1>[CH2:1]([O:8][C:9]1[C:14]([C:15](=[O:17])[CH3:16])=[C:13]([O:18][CH3:33])[C:12]([O:19][C:20]2[C:28]([CH3:29])=[CH:27][C:26]([N+:30]([O-:32])=[O:31])=[C:25]3[C:21]=2[CH2:22][CH2:23][CH2:24]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1c(OCc2ccccc2)ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)c1O
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1c(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)ccc(OCc2ccccc2)c1C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To a solution of 1-[6-benzyloxy-2-hydroxy-3-(5-methyl-7-nitroindan-4-yloxy)phenyl]ethanone (10.0 g) in tetrahydrofuran (15 mL) was added cesium carbonate (7.53 g) under ice-cooling, and then was added dropwise methyl iodide (2.88 mL). After stirring at room temperature overnight, the reaction mixture was evaporated under reduced pressure to dryness. Adding ethyl acetate (30 mL), the mixture was stirred for 30 min. The insoluble material was removed by filtration. The filtrate was evaporated under reduced pressure to dryness to give the title compound (10.2 g).
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:15][NH:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]>ClCCl>[CH3:21][O:20][C:18](=[O:19])[CH2:17][N:16]([CH3:15])[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: CNCC(=O)OC
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Solvent: ClCCl
Product: COC(=O)CN(C)c1ncc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 99.5 %

Procedure:
Methyl 6-chloro-5-nitronicotinate (2.0 g, 9.23 mmol) was added to methyl 2-(methylamino)acetate (1.9 g, 18.47 mmol) neat while stirring at room temperature. The viscous yellow reaction was heated to 90° C. for one hour and then allowed to cool back to room temperature. The reaction was diluted with dichloromethane (20 mL) and purified using flash column chromatography (220 g SiO2, 20-30% gradient, ethyl acetate in hexanes) to yield 2.60 g (99% yield) of the title compound as a yellow oil. [M+H] calc'd for C11H13N3O6, 284; found, 284.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=[O:5].[C:9](O)([CH3:12])([CH3:11])[CH3:10].C1CCN2C(=NCCC2)CC1.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:9]([O:5][C:4](=[O:6])[C:3]([CH3:8])([CH3:7])[CH2:2][Cl:1])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(CCl)C(=O)O
Reactant: CC(C)(C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)CCl
Temperature: 40 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
prepared as follows: To a solution of 3-chloro-2,2-dimethylpropionic acid (5.00 g; 36.6 mmol) in DMF (25 mL) was added N,N′-carbonyldiimidazole (5.94 g; 36.6 mmol) and the resulting mixture was stirred for 1 hour at 40° C. Subsequently, tert-butyl alcohol (7.1 mL; 73 mmol) and DBU (5.5 mL; 36.6 mmol) were added and the mixture stirred overnight at 40° C. After cooling to RT, 5% aqueous NaHCO3 solution (50 mL) was added to the mixture and stirred for another 15 minutes. The reaction mixture was extracted with EtOAc. The organic layer was dried (Na2SO4), concentrated in vacuo and purified by column chromatography (SiO2, Et2O:hexanes 1:1) to afford 3-chloro-2,2-dimethyl-propionic acid tert-butyl ester (3.34 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2([CH2:14][CH3:15])[CH2:12][CH3:13].C(N(CC)CC)C.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:12]([C:5]1([CH2:14][CH3:15])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])[CH:3]=2)[S:8][CH2:7][CH2:6]1)[CH3:13]
Reactant: CCC1(CC)CCSc2ccc(Br)cc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCC1(CC)CCSc2ccc(C#C[Si](C)(C)C)cc21
Temperature: 0 °C

Procedure:
A mixture of 1.96 g (6.90 mmol) of 6-bromo-4,4-diethylthiochroman (Compound 25), 0.11 g (0.59 mmol) of copper (I) iodide and 4.36 g (4.31 mmol) of triethylamine was degassed with argon for 15 minutes at -78° C. To the suspension was added 6.95 g (71 mmol) of (trimethylsilyl)acetylene then 0.41 g (58 mmol) of bis(triphenylphosphine)palladium (II) chloride. The solution was degassed with argon for an additional 5 minutes and the resulting mixture was allowed to warm to 0° C. The tube was sealed and the mixture heated to 55° C. for 15 hours.
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=[O:3].[C:7]([N:11]1C(=O)C(O)=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:12]1(=[O:25])=[O:24])([CH3:10])([CH3:9])[CH3:8].CN(C=O)C>C(Cl)Cl>[C:7]([N:11]1[C:2](=[O:3])[C:1]([Cl:6])=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:12]1(=[O:25])=[O:24])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)N1C(=O)C(O)=C(c2ccccc2)S1(=O)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Temperature: 50 °C
Yield: 480.1 %

Procedure:
Oxalyl chloride (3.39 g, 2.71 mmol) was added dropwise to a solution of 2-tert-butyl-4-hydroxy-5-phenylisothiazol-3(2H)-one 1,1-dioxide (5 g, 17.77 mol) and DMF (15 mL) in DCM (220 mL) at 0° C. The reaction mixture was heated at 50° C. for 4 h, concentrated and the residue was diluted with EtOAc and washed with water, then brine and evaporated. The residue was purified by silica gel column chromatography, using a 98:2 mixture of petroleum ether and EtOAc as eluant. The product containing fractions were evaporated, the residue was triturated in petroleum ether and the solvent was decanted to give the title compound (3.9 g, 74%) as a solid; 1H NMR (500 MHz, CDCl3): δ 7.97-7.92 (m, 2H), 7.61-7.51 (m, 3H), 1.75 (s, 9H); 13C NMR (125 MHz, CDCl3): δ 156.5, 142.8, 132.3, 129.3, 128.8, 123.4, 63.0, 27.7.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]#[N:10])[CH3:2].[NH2:11][OH:12]>CCO>[CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9](=[N:11][OH:12])[NH2:10])[CH3:2]
Reactant: CCOCCOCCC#N
Reactant: NO
Solvent: CCO
Product: CCOCCOCCC(N)=NO
Yield: 97.3 %

Procedure:
A solution of 3-(2-ethoxyethoxy)propanenitrile (1 g, 7 mmol) and NH2OH (50% in water, 0.64 cm3, 10.5 mmol) in EtOH (10 cm3) were heated to reflux for 24 hours, after which the solvent and excess hydroxylamine were removed by rotary evaporator. The residue was freeze-dried and kept in high vacuum line for several hours to give 3(2-ethoxyethoxy)N′-hydroxypropanimidamide (1.2 g, 97.6%) as a colourless oil.