Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1Br)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CCCC)CCCC)CCC.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH2:52]([O:54][C:55](=[O:59])/[CH:56]=[CH:57]/[CH3:58])[CH3:53]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:52]([O:54][C:55](=[O:59])[CH:56]=[C:57]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH3:58])[CH3:53]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1Br
Reactant: C/C=C/C(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)C=C(C)c1ccccc1CNC(=O)OC(C)(C)C
Temperature: 110 °C
Yield: 20 %

Procedure:
N-Boc-2-bromobenzylamine (7.15 g, 25 mmol) was dissolved into tributylamine (12 mL) and degassed under vacuum. Palladium acetate (224 mg, 1 mmol) and tri-o-tolylphosphine (608 mg, 2 mmol) was then added and the mixture degassed under vacuum. Trans-ethylcrotonate (6.25 mL, 50 mmol) was then added and the mixture was degassed with nitrogen. The tube was sealed and the mixture was heated to 110° C. for 48 h. The solution was cooled to room temperature, diluted with diethyl ether (200 mL) and filtered through celite. The solution was washed with 1N HCl (2×50 mL) and brine (50 mL) dried over magnesium sulfate and concentrated to dryness. Flash chromatography (9:1 hexanes/ethyl acetate) gave the title compound as a yellow oil (1.6 g, 20%). 1H NMR 7.22–7.37 (m, 3H), 7.08 (dd, J=7.4, 1.6 Hz, 1H), 5.75 (d, J=1.3 Hz, 1H), 4.29–4.31 (m, 2H), 4.20 (q, J=7.1 Hz, 2H), 2.45 (d, J=1.3 Hz, 3H), 1.44 (s, 9H), 1.30 (t, J=7.1 Hz, 3H).
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][N:6]=1>>[NH:2]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][N:6]=1)[NH2:3]
Reactant: Cc1ccc(Cl)nc1
Reactant: NN
Solvent: O
Product: Cc1ccc(NN)nc1

Procedure:
5.7 ml (5.9 g, 117.6 mmol) of hydrazine hydrate are added to 1.0 g (7.8 mmol) of 2-chloro-5-methylpyridine, and the mixture is stirred at boiling point (bath temperature 150° C.) for 16 h. The reaction mixture is cooled and then concentrated on a rotary evaporator, and the residue is co-evaporated three times with in each case 10 ml of ethylene glycol monoethyl ether. The residue is then taken up in dichloromethane, the precipitate is separated off and the filtrate is concentrated under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O:23][C:24](=O)[CH:25]=[C:26]1[CH2:31][CH:30]([CH2:32][CH3:33])[CH2:29][CH2:28][C:27]1=O)C.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[N:4]1[C:27]2[C:26]([CH2:31][CH:30]([CH2:32][CH3:33])[CH2:29][CH:28]=2)=[CH:25][C:24]1=[O:23]
Reactant: Cc1cccc(Cl)c1N
Reactant: CCOC(=O)C=C1CC(CC)CCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC1CC=C2C(=CC(=O)N2c2c(C)cccc2Cl)C1
Temperature: 22 °C

Procedure:
3.45 g of 2-Chloro-6-methyl-aniline are dissolved in 26 ml of toluene. 0.227 g of p-toluene-sulfonic acid (mono hydrate) are added and the mixture is heated to reflux. A solution of 5.0 g of (5-Ethyl-2-oxo-cyclohexylidene)-acetic acid ethyl ester in 13 ml of toluene is added drop-wise during 75 minutes and the water formed is collected by the means of a water separator. The reaction mixture is heated to reflux for 15 hours, during which time the condensing solvent is frequently removed and replaced by fresh toluene. For work-up, the mixture is cooled to 22° C. and is treated with 70 ml of saturated aqueous sodium bicarbonate solution under rigorous stirring. The layers are separated and the toluene phase is washed with a 5% aqueous solution of citric acid and finally with a 10% solution of sodium chloride in water. The aqueous phases are extracted with 70 ml of toluene and the toluene phases are combined. The solvent is evaporated in vacuo to yield 7.1 g of the crude product as a highly viscous oil. An analytical sample of the crude product can be purified by chromatography on silica gel using toluene/ethyl acetate (9:1) as eluent to yield pure 1-(2-Chloro-6-methyl-phenyl)-5-ethyl-1,4,5,6-tetrahydro-indol-2-one.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)(=O)[CH3:15]>C(Cl)Cl.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH3:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1ccccn1
Reactant: CC(C)(C)OC(=O)NCCCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(NCCCCNC(=O)OC(C)(C)C)c1ccccn1

Procedure:
Using General Procedure B, (4-aminobutyl)-carbamic acid tert-butyl ester and 2-acetylpyridine in CH2Cl2 and NaBH(OAc)3 were reacted to obtain [4-(1-pyridin-2-ylethylamino)-butyl]-carbamic acid tert-butyl ester as a light brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6](OC)=[O:7])=[C:4]([O:13][CH3:14])[CH:3]=1.O.[NH2:16][NH2:17]>C(O)C>[NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([NH:16][NH2:17])=[O:7])=[C:4]([O:13][CH3:14])[CH:3]=1
Reactant: COC(=O)c1cc(Cl)c(N)cc1OC
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1cc(N)c(Cl)cc1C(=O)NN

Procedure:
51.5 g (0.239 mol) of methyl 4-amino-5-chloro-2-methoxybenzoate suspended in 460 ml of ethanol are introduced into a 1 l reactor. 119 g (2.39 mol) of hydrazine hydrate are added, over 15 min, and the mixture is refluxed for 15 h.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7](S)[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:15]>>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[O:15])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cccc(S)c1
Reactant: COc1ccc(C(=O)CBr)cc1
Product: COc1ccc(C(=O)Cc2cccc(OC(C)C)c2)cc1

Procedure:
3-Isopropoxythiophenol and 2-bromo-4′-methoxyacetophenone were converted to the title compound by the procedure of Preparation 1.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:22][O:23][CH3:24])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:25])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[C:33]=1[CH:34]=[O:35]>C1COCC1>[Cl:25][C:5]1[CH:6]=[C:7]([N:8]([CH2:22][O:23][CH3:24])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)(=[O:11])=[O:10])[C:2]([CH:34]([C:33]2[C:36]([O:40][CH3:41])=[CH:37][CH:38]=[CH:39][C:32]=2[F:31])[OH:35])=[N:3][CH:4]=1
Reactant: COc1cccc(F)c1C=O
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(O)c1c(F)cccc1OC)S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N-(2-Bromo-5-chloro-pyridin-3-yl)-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (459 mg, 1.00 mmol) in anhydrous THF (5 mL) at −10° C. was added 2 M isopropylmagnesium chloride in THF (1.1 mL, 2.2 mmol) and stirred at the same temperature for 30 min. 2-Fluoro-6-methoxy-benzaldehyde (308 mg, 2.00 mmol) was subsequently added in one portion, and the reaction mixture was warmed to room temperature and stirred overnight (18 h). It was then quenched with saturated aqueous NH4Cl (10 mL), and extracted with EtOAc (3×75 mL). The combined extracts were washed with aqueous NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using ethyl acetate-hexane to provide N-{5-chloro-2-[(2-fluoro-6-methoxy-phenyl)-hydroxy-methyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide. MS m/z 535.4 (M+H).
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[NH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([NH:20][CH2:21][CH2:22][CH2:23][N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)([CH3:19])[CH3:18])=[CH:13][CH:12]=1>ClCCl>[CH2:1]([NH:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([NH:20][CH2:21][CH2:22][CH2:23][N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)([CH3:19])[CH3:18])=[CH:13][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(NCCCn1ccnc1)c1ccc(CCN)cc1
Reactant: CCCCN=C=O
Solvent: ClCCl
Product: CCCCNC(=O)NCCc1ccc(C(C)(C)NCCCn2ccnc2)cc1

Procedure:
A solution of butylisocyanate (0.17 g) in dichloromethane was added to a solution of N-{1-[4-(2-aminoethyl)phenyl]-1-methylethyl}-3-(imidazol-1-yl)propylamine (0.5 g) in dichloromethane (7 ml). The mixture was boiled under reflux for 30 minutes and then the solvent removed under reduced pressure. The residue was purified by flash chromatography on silica using methanol as the mobile phase to give N-butyl-N'-[2-(4-{1-[3-(imidazol-1-yl)propylamino]-1-methylethyl}phenyl)ethyl]urea as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].Br[C:14]1[CH:15]=[C:16]([CH2:20][N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:23]([CH3:34])[CH2:22]2)[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.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>[C:1]([C:3]1[CH:4]=[C:5]([C:18]2[CH:19]=[CH:14][CH:15]=[C:16]([CH2:20][N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:23]([CH3:34])[CH2:22]3)[CH:17]=2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: C[C@H]1CN(Cc2cccc(Br)c2)CCN1C(=O)OC(C)(C)C
Reactant: N#Cc1cc(B(O)O)ccc1F
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: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: C[C@H]1CN(Cc2cccc(-c3ccc(F)c(C#N)c3)c2)CCN1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
To a solution of (3-cyano-4-fluorophenyl)boronic acid (0.983 g, 5.96 mmol) in DME (40 mL) was added 1,1-dimethylethyl (2S)-4-[(3-bromophenyl)methyl]-2-methyl-1-piperazinecarboxylate (2.20 g, 5.96 mmol) followed by Na2CO3 (17 mL, 2M in H2O, 34.0 mmol). The reaction vessel was flushed with Ar, and tetrakis(triphenylphosphine)palladium(0) (2.06 g, 1.78 mmol) was added. The reaction mixture was placed in an oil bath at 78° C. under Ar for overnight. The reaction was diluted with EtOAc (600 mL) and washed with H2O (250 mL). The water layer was extracted with EtOAc (1×100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. Purification of the crude residue by flash chromatography (20% EtOAc/80% hexane) on silica gel gave the title compound (1.77 g, 73.1%). EI-MS m/z 410 (M−H)+.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH:11]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:18].C(=O)([O-])[O-].[K+].[K+]>[Cu].O>[CH3:18][C:12]1[CH:11]=[C:16]([CH:15]=[CH:14][CH:13]=1)[O:17][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: Cc1cccc(O)c1
Reactant: O=C(CCl)c1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cccc(OCC(=O)c2ccccc2)c1
Temperature: 120 °C
Yield: 91.7 %

Procedure:
A mixture of 50 g (0.324 mol) of 2-chloroacetophenone, 104.8 g (0.97 mol) of m-cresol, 45 g (0.326 mol) of potassium carbonate and 1 g of copper is heated at 120° C. for 16 hours. After cooling it is poured into water and extracted twice with methyl tert-butyl ether (MTB ether). The ether phase is washed five times with concentrated sodium hydroxide solution and then twice with water, dried and concentrated. 67.2 g (92% yield) of 2-(3-methylphenoxy)acetophenone remain as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[NH:7][C:8](=[O:11])[CH2:9][O:10][C:5]=2[CH:4]=1.[H-].[Na+].[CH3:16]I.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[N:7]([CH3:16])[C:8](=[O:11])[CH2:9][O:10][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)OCC(=O)N2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OCC(=O)N2C
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 104.1 %

Procedure:
7-Methoxy-4H-benzo[1,4]oxazin-3-one (11.61 g, 0.065 mol) in 100 mL dry DMF was stirred at 0° C. under nitrogen. Sodium hydride (60% , 2.85 g, 0.072 mol) was added in portions over 30 minutes, after which methyl iodide (4.44 mL, 0.071 mol) was added dropwise. The reaction mixture was stirred at 0° C. for 2.5 hours, then poured into 1400 mL water. The resulting aqueous mixture was extracted four times with 400 mL EtOAc, and the combined organic layers were washed with water, then brine, dried (MgSO4), filtered, and evaporated under reduced pressure to provide 13.07 g of 7-Methoxy-4-methyl-4H-benzo[1,4]oxazin-3-one. (M+H)=194.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1>C(OCC)(=O)C>[CH2:7]([O:6][C:4]([CH:3]1[CH2:9][CH2:10][CH2:11][N:1]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[CH2:2]1)=[O:5])[CH3:8]
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)C1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCN(Cc2ccc(OC)cc2)C1
Temperature: 25 °C
Yield: 82.8 %

Procedure:
Combine Ethyl nipecotate (9.9 mL, 63.6 mmol), K2CO3 (13.2 g, 95.4 mmol), and DMF (300 mL) at room temperature under a Nitrogen atmosphere. Heat reaction mixture to 70° C. for 30 minutes then add 4-Methoxybenzyl chloride (9.5 mL, 69.9 mmol). Stir the reaction for 5 hours at 70° C. then cool the reaction mixture to room temperature and stir for an additional 12 hours. Add Ethyl acetate to the reaction mixture and extract with water and then brine. Dry the organic layer over Na2SO4. Concentrate under reduced pressure and flash chromatograph using 3:1 Hexanes:Ethyl acetate to give 14.6 g (82% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 1.2 (3H, t), 1.4-1.6 (2H, m), 1.6-1.7 (1H, m), 1.9-2.1 (2H, m), 2.2 (1H, t), 1.5-1.8 (2H, m), 2.9 (1H, d), 3.5 (2H, q), 3.8 (3H, s), 4.1 (2H, dd), 6.8 (2H, d), 7.2 (2H, d); MS m/z 278 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][OH:29])=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[C:1]([O:5][C:6]([N:7]([CH3:8])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:21][CH:22]=2)=[CH:11][CH:10]=1)=[O:30])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(C=Cc2ccc(OCCOCCO)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)c1ccc(C=Cc2ccc(OCCOCCOS(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.2 %

Procedure:
Compound 9a (36 mg, 0.087 mmol) was dissolved in dichloromethane (5 ml) followed by triethylamine (44 mg, 0.44 mmol). Methanesulfonyl chloride (30 mg, 0.26 mmol) was then added via a syringe. The solution was stirred at room temperature for 4 hours. After standard workup with dichloromethane, the residue was purified by silica gel preparative TLC (2.0% methanol in dichloromethane) to afford 10a (39 mg, 91%): 1H NMR δ 7.43 (d, 4H, J=8.6 Hz), 7.20 (d, 2H, J=8.4 Hz), 6.98 (q, 2H), 6.89 (d, 2H, J=8.6 Hz), 4.41 (m, 2H), 4.16 (m, 2H), 3.87 (m, 4H), 3.27 (s, 3H), 3.05 (s, 3H), 1.46 (s, 9H). Anal. (C25H33NO7S) C. H. N.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:9]([SH:10])=[N:8][N:7]=[N:6]1)(O)=[O:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CC(C)=O>[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:1]([CH2:4][N:5]2[C:9]([SH:10])=[N:8][N:7]=[N:6]2)=[O:2])[CH2:28][CH2:27]1
Reactant: O=C(O)Cn1nnnc1S
Reactant: CN1CCNCC1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CN1CCN(C(=O)Cn2nnnc2S)CC1
Temperature: -15 °C
Reaction time: 0.08 h
Yield: 45.4 %

Procedure:
To a solution of 1-carboxymethyl-1H-tetrazole-5-thiol (3.2 g) in dry acetone (60 ml) was added triethyl amine (4.2 g). After the addition of a solution of pivaloyl chloride (4.8 g) in dry acetone (10 ml) with stirring at -15° C. over a period of 5 minutes, the mixture was stirred for one hour and 15 minutes at the same temperature. A solution of 1-methylpiperazine (4.0 g) in dry acetone (10 ml) was dropwise added over a period of 5 minutes and the resulting mixture was stirred at -15° C. for 40 minutes and under ice-cooling for a further 2.5 hours. After the evaporation of the reaction mixture under reduced pressure, water was added to the residue, 4N aqueous solution of sodium hydroxide was added until the crystals were dissolved. The resulting solution was evaporated under reduced pressure and the residue was crystallized from water to give 1-(4-methyl-1-piperazinyl)carbonylmethyl-1H-tetrazole-5-thiol (2.2 g). mp>250° C.
Reaction SMILES: [OH-].[K+].CO.[CH3:5][O:6][C@:7]1([C:19]2[S:20][C:21]([C:24]3[CH:29]=[C:28]([NH:30][C:31]4[N:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][N:32]=4)[CH:27]=[C:26]([CH3:41])[CH:25]=3)=[CH:22][N:23]=2)[CH2:12][CH2:11][C@H:10]([C:13]([O:15]C)=[O:14])[C:9]([CH3:18])([CH3:17])[CH2:8]1>>[CH3:5][O:6][C@:7]1([C:19]2[S:20][C:21]([C:24]3[CH:29]=[C:28]([NH:30][C:31]4[N:36]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:34]=[CH:33][N:32]=4)[CH:27]=[C:26]([CH3:41])[CH:25]=3)=[CH:22][N:23]=2)[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=[O:14])[C:9]([CH3:18])([CH3:17])[CH2:8]1
Reactant: COC(=O)[C@H]1CC[C@](OC)(c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CO[C@]1(c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC[C@H](C(=O)O)C(C)(C)C1
Temperature: 65 °C
Yield: 79.3 %

Procedure:
Potassium hydroxide in methanol (3.0 mL, 3.0 mmol) was added to the product of Step 2 (150 mg, 0.23 mmol) and the reaction mixture heated to 65° C. for 110 h. The reaction mixture was cooled and then quenched with HCl (2N in H2O). The mixture was filtered and washed with ˜20 mL of water to obtain an off-white solid. The solid was dried under reduced pressure at 40° C. in a vacuum oven for 1.5 h to provide the title compound (95 mg, 79%) as a yellow solid. ESI: [M+H]+ m/z 521. 1H NMR (500 MHz, DMSO-d6) δ 12.15-11.94 (m, 1H), 10.26 (s, 1H), 8.83 (d, J=4.9, 1H), 8.00 (s, 1H), 7.96 (s, 1H), 7.45 (s, 1H), 7.28 (d, J=4.9, 1H), 7.16 (s, 1H), 3.07 (s, 3H), 2.31 (s, 3H), 2.22-2.09 (m, 2H), 1.99-1.80 (m, 3H), 1.72 (d, J=14.5, 1H), 1.62 (s, 11.1), 1.07 (s, 3H), 1.01 (s, 3H). rhSYK activity=+++
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:27])[C:11]([NH:14][C:15](=[O:26])[CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:17][CH2:18][CH3:19])([CH3:13])[CH3:12].[C:28](=O)([O-])[O-].[K+].[K+].C=O.O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:27])[C:11]([N:14]1[C:15](=[O:26])[CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:17]([CH2:18][CH3:19])[CH2:28]1)([CH3:12])[CH3:13]
Reactant: O=C([O-])[O-]
Reactant: CCNC(C(=O)NC(C)(C)C(=O)Nc1cc(Cl)ccc1Cl)c1ccccc1
Agent: C=O
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCN1CN(C(C)(C)C(=O)Nc2cc(Cl)ccc2Cl)C(=O)C1c1ccccc1
Yield: 43.2 %

Procedure:
To a solution of N-(2,5-dichlorophenyl)-2-(α-ethylaminophenylacetylamino)isobutyramide (0.9 g) in ethanol (15 mL) were added potassium carbonate (0.5 g) and paraformaldehyde (0.5 g), and the mixture was heated at reflux for 4 hours. After the reaction solution was added to water, the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the resulting crude product was purified by thin-layer chromatography (silica gel, diethyl ether/n-hexane=1/1) to give 0.4 g of the title compound.
Reaction SMILES: Cl.[CH2:2]([C:4]([S:30]([CH3:33])(=[O:32])=[O:31])([CH2:15][CH2:16][N:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][C:18]1=[O:29])[C:5]([NH:7][O:8]C1CCCCO1)=[O:6])[CH3:3]>ClCCl.CO>[CH2:2]([C:4]([S:30]([CH3:33])(=[O:32])=[O:31])([CH2:15][CH2:16][N:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][C:18]1=[O:29])[C:5]([NH:7][OH:8])=[O:6])[CH3:3]
Reactant: CCC(CCn1ccc(-c2ccccc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCC(CCn1ccc(-c2ccccc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 2 h
Yield: 26.4 %

Procedure:
A solution of hydrochloric acid (0.5 mL, 4.0 M in 1,4-dioxane) was added dropwise to a solution of 2-ethyl-2-(methylsulfonyl)-4-(2-oxo-4-phenylpyridin-1(2H)-yl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (45 mg, 0.1 mmol) in dichloromethane (0.5 mL) and methanol (0.1 mL) at 0° C. After 2 h, the reaction was concentrated under reduced pressure. The resulting residue was triturated with diethyl ether, filtered, washed with heptane, and dried under reduced pressure to provide an off-white solid (10 mg, 27%). MS (LCMS) m/z 379.5 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 0.97 (t, J=7.5 Hz, 3H), 1.86-1.95 (m, 1H), 2.31-2.45 (m, 3H), 3.29 (s, 3H), 3.99-4.08 (m 1H), 4.53-4.63 (m, 1H), 6.69 (br d, J=5.6 Hz, 1H), 6.99 (br s, 1H), 7.44-7.49 (m, 4H), 7.55-7.60 (m, 2H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]21[CH2:14][CH2:13][C:12](=NO)[CH2:11][CH2:10]2.C(OC(=O)C)(=[O:19])C>N1C=CC=CC=1>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]21[CH2:14][CH2:13][C:12](=[O:19])[CH2:11][CH2:10]2
Reactant: ON=C1CCC2(CC1)Cc1ccccc1C2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: O=C1CCC2(CC1)Cc1ccccc1C2
Reaction time: 6 h
Yield: 88 %

Procedure:
A solution of 3.1 g. spiro(cyclohexane-1,2'-indan)-4-one oxime [12] (prepared in Example 24B) and 6 ml. of acetic anhydride in 25 ml. of pyridine is allowed to stand at room temperature for about 6 hours. The reaction mixture is then poured into ice: water and the solid collected on a filter. The solid is recrystallized from Skellysolve B to give 2.94 g. (88% yield) of spiro(cyclohexane-1,2'-indan)-4-one, oxime acetate [13] having a melting point of 91° to 94° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]1[CH2:9][O:8]1.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]2[NH:22][C:21](=[O:23])[N:20]([CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]3)[C:19]=2[CH:31]=1>CC(O)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]2[NH:22][C:21](=[O:23])[N:20]([CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][N:27]([CH2:9][CH:7]([OH:8])[CH2:6][O:5][C:4]4[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=4[O:2][CH3:1])[CH2:26]3)[C:19]=2[CH:31]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2n1CC1CCCNC1
Reactant: COc1ccccc1OCC1CO1
Solvent: CC(C)O
Product: COc1ccccc1OCC(O)CN1CCCC(Cn2c(=O)[nH]c3ccc(Cl)cc32)C1
Yield: 28 %

Procedure:
A mixture of 4 parts of [(2-methoxyphenoxy)methyl]oxirane, 5.3 parts of 6-chloro-1,3-dihydro-1-(3-piperidinylmethyl)-2H-benzimidazol-2-one and 120 parts of 2-propanol is stirred and refluxed for 5 hours. The reaction mixture is cooled and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone and 2,2'-oxybispropane. The product is filtered off and crystallized from 4-methyl-2-pentanone, yielding 2.5 parts (28%) of 6-chloro-1,3-dihydro-1-{1-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-3-piperidinylmethyl}-2H-benzimidazol-2-one; mp. 167° C.