Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[C:25]([C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32])([CH3:28])([CH3:27])[CH3:26].CC1C(C)=CC=CC=1C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1OC)=O>>[C:25]([C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:32])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1ccccc1C(=O)Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: COc1cc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)ccc1NC(=O)c1cccc(C)c1C
Product: CC(C)(C)c1ccccc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 44.1 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, (3), and 2-tert-butylbenzoyl chloride (0.143 mmol), the title compound (20 mg, yield 44%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: C(N1CCC([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:17]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[N:16]=[CH:15]2)CC1)C1C=CC=CC=1.[CH:32]([OH:34])=O.CO>[Pd]>[CH:32]([N:22]1[CH2:23][CH2:24][CH2:19][CH2:20][CH:21]1[C:15]1[NH:14][C:18]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[C:17]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[N:16]=1)=[O:34]
Reactant: O=CO
Reactant: Fc1ccc(-c2ncn(C3CCN(Cc4ccccc4)CC3)c2-c2ccncc2)cc1
Agent: [Pd]
Solvent: CO
Product: O=CN1CCCCC1c1nc(-c2ccc(F)cc2)c(-c2ccncc2)[nH]1
Temperature: 25 °C

Procedure:
1-(1-Benzylpiperidin-4-yl)-4(4-fluorophenyl)-5-(4-pyridyl)imidazole (100 mg; prepared in Example 40) was dissolved in 10% formic acid/methanol under argon and palladium black (100 mg) mixed in 10% formic acid/methanol was added. The reaction was stirred under argon at room temperature for sixteen hours. The reaction mixture was evaporated and the residue mixed in H2O/ethyl acetate and the pH taken to 10. The layers were separated and the aqueous phase extracted with ethyl acetate.
Reaction SMILES: [CH2:1]([C:3]([CH2:9][CH3:10])=[C:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1)[CH3:2].[CH3:11][Li].O>CCOCC>[CH2:1]([C:3]([C:4]1[CH2:8][CH:7]=[CH:6][CH:5]=1)([CH3:11])[CH2:9][CH3:10])[CH3:2]
Reactant: [Li]C
Reactant: CCC(CC)=C1C=CC=C1
Solvent: CCOCC
Solvent: O
Product: CCC(C)(CC)C1=CC=CC1
Temperature: 25 °C
Yield: 61 %

Procedure:
To a solution of 8.00 g (59.6 mmol) of 6,6-diethylfulvene in 35 ml of ether, 60.0 ml (68.4 mmol) of an ether solution of methyllithium was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for one night. Then, 30 ml of water was added. The separated organic phase was washed with water and a saturated saline solution, then dried over magnesium sulfate and filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a liquid. The liquid was subjected to vacuum distillation (92° C./40 mmHg) to obtain 5.50 g (36.6 mmol) of a light yellow liquid (yield: 61%). The analyzed values are given below.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[C:22]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)#[N:23].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[C:22]([C:24]1[CH:29]=[C:28]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)[CH:3]=2)[CH:27]=[CH:26][CH:25]=1)#[N:23]
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Br)c2)CC1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(-c3cccc(C#N)c3)c2)CC1
Temperature: 130 °C
Yield: 85.4 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[(3-bromophenyl)methylidene]-1-piperidinecarboxylate (2.07 g, 5.88 mmol) in p-dioxane (30 mL) and H2O (10 mL) was added (3-cyanophenyl)boronic acid (1.036 g, 7.05 mmol), Pd(PPh3) (0.272 g, 0.235 mmol), and K2CO3 (2.436 g, 17.63 mmol) and then the reaction was heated in a microwave at 130° C. for 15 minutes. The organic layer of the reaction mixture was separated, concentrated and purified by Combiflash chromatograph to afford 1.88 g (85%) of the title compound. LC-MS m/z 749 (2M+H)+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][O:12][C:13]([CH2:15][CH2:16][N:17]([CH2:25][CH2:26][CH3:27])[CH:18]([CH2:23][CH3:24])[C:19](OC)=O)=[O:14].[O:28]1CCCC1>C1(C)C=CC=CC=1>[C:13]([C@@H:15]1[CH2:16][N:17]([CH2:25][CH2:26][CH3:27])[C@@H:18]([CH3:19])[CH2:23][C:24]1=[O:28])([O:12][CH3:11])=[O:14]
Reactant: CCCN(CCC(=O)OC)C(CC)C(=O)OC
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCN1C[C@@H](C(=O)OC)C(=O)C[C@@H]1C
Temperature: -20 °C

Procedure:
To a stirred solution of 162 mL of 0.5M potassium bistrimethylsilylamide in toluene and 600 mL of anhydrous tetrahydrofuran cooled to -78° C. under nitrogen atmosphere was added dropwise a solution of 7.5 g of (±)-methyl 2-(2-methoxycarbonylethyl(1-propyl)amino)butyrate in 50 mL of dry (tetrahydrofuran over 20 min, keeping the internal temperature under -70° C. The mixture was allowed to warm to -20° C. for 2 h, then quenched with 100 mL of saturated aqueous sodium bicarbonate and extracted into 3×200 mL portions of ethyl acetate. The combined extracts were dried over MgSO4 and concentrated under reduced pressure. There was obtained 6.6 g of predominantly (±)-trans-5-carbomethoxy-2-methyl-4-oxo-1-propyl piperidine as an oil: TLC (EtOAc); 1H NMR (400 MHz, CDCl3) 3.76 (s, 3H), 3.2 (m, 1H), 2.9 (m, 1H), 2.62-2.0 (complex m, 6H), 1.5 (m, 2H), 1.25 (d, 3H), 0.5 (dd, 3H).
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.ClC1C(Cl)=NC2C(=CC=CC=2)N=1.S([O:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][CH3:39])=[CH:34][CH:33]=1)(O)(=O)=O>>[CH3:39][N:38]([C:35]1[CH:36]=[CH:37][C:32]([OH:31])=[CH:33][CH:34]=1)[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]=1
Reactant: CNc1ccc(OS(=O)(=O)O)cc1
Reactant: Clc1cc2nc(Cl)c(Cl)nc2cc1Cl
Agent: Clc1nc2ccccc2nc1Cl
Product: CN(c1ccc(O)cc1)c1nc2cc(Cl)c(Cl)cc2nc1Cl

Procedure:
2,3,6,7-Tetrachloroquinoxaline (mp 176° C.; prepared following essentially the same procedure as that referred to in Example 3 Part (a) for the preparation of 2,3-dichloroquinoxaline) was reacted with 4-(N-methylamino)phenol sulfate, following essentially the same procedure as that described in Example 1 Part (a), to give 4-[N-methyl-N-(3,6,7-trichloro-2-quinoxalinyl)amino]phenol.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36]([O:40][C:41](=[O:47])[NH:42][CH:43]([CH3:46])[CH2:44]O)([CH3:39])([CH3:38])[CH3:37].[CH2:48]([O:50][C:51]([C:53]1[NH:54][N:55]=[C:56]([CH2:58][O:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH:57]=1)=[O:52])[CH3:49]>C1COCC1>[CH2:48]([O:50][C:51]([C:53]1[N:54]([CH2:44][CH:43]([NH:42][C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:47])[CH3:46])[N:55]=[C:56]([CH2:58][O:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH:57]=1)=[O:52])[CH3:49]
Reactant: CCOC(=O)c1cc(COc2ccccc2)n[nH]1
Reactant: CC(CO)NC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(COc2ccccc2)nn1CC(C)NC(=O)OC(C)(C)C
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 227.1 %

Procedure:
Di-tert-butyl azodicarboxylate (2.52 g, 10.96 mmol) was added to a stirred solution of triphenylphosphine (2.87 g, 10.96 mmol), rac-2-hydroxy-1-methyl-ethyl-carbamic acid tert-butyl ester (2.13 g, 12.18 mmol) and 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (1.5 g, 6.09 mmol) in THF (45 mL). The mixture was stirred at 120° C. for 20 minutes under microwave irradiation and the solvents evaporated in vacuo. The crude product was purified by open column chromatography (silica; AcOEt in DCM 0/100 to 10/90). The desired fractions were collected and the solvents evaporated in vacuo to yield 2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (5.58 g, 91% yield, 40% pure) as a colorless oil that crystallized upon standing in white crystals.
Reaction SMILES: [NH2:1][C@H:2]([CH2:26][F:27])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]3[CH:17]=[C:18]([CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[N:19]=[C:13]3[CH:12]=2)=[CH:7][CH:6]=1)[OH:4].C(N(CC)CC)C.[F:35][CH:36]([F:42])[C:37](OCC)=[O:38]>CO>[F:35][CH:36]([F:42])[C:37]([NH:1][C@H:2]([CH2:26][F:27])[C@H:3]([OH:4])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]3[CH:17]=[C:18]([CH2:20][NH:21][S:22]([CH3:25])(=[O:23])=[O:24])[N:19]=[C:13]3[CH:12]=2)=[CH:7][CH:6]=1)=[O:38]
Reactant: CS(=O)(=O)NCc1cn2ccc(-c3ccc([C@@H](O)[C@H](N)CF)cc3)cc2n1
Reactant: CCOC(=O)C(F)F
Solvent: CCN(CC)CC
Solvent: CO
Product: CS(=O)(=O)NCc1cn2ccc(-c3ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc3)cc2n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution N-{7-[4-((1R,2S)-2-Amino-3-fluoro-1-hydroxy-propyl)-phenyl]imidazo[1,2-a]pyridin-2-ylmethyl}-methane sulfonamide (88 mg, crude) in methanol (1 mL) is added triethyl amine (0.05 mL, 0.346 mmol) followed by addition of ethyl difluoroacetate (0.02 mL, 0.208 mmol) at 0° C. then stirred at room temperature for 20 h. The reaction mixture is concentrated and purified by flash column chromatography eluting in 2.1% MeOH in CH2Cl2 followed by re-purification by preparative TLC to afford 5 mg and which is re-crystallized in
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([C:11]([OH:13])=O)=[CH:9][C:8]([F:14])=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[N:6]=2)[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:44]([O:51][NH2:52])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(N(CC)CC)C>ClCCl>[CH2:44]([O:51][NH:52][C:11]([C:10]1[C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[N:6][C:7]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[C:8]([F:14])[CH:9]=1)=[O:13])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: NOCc1ccccc1
Reactant: CN1CCN(c2nc(NC3CC3)c(C(=O)O)cc2F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(c2nc(NC3CC3)c(C(=O)NOCc3ccccc3)cc2F)CC1
Yield: 59.8 %

Procedure:
Following the procedure of Example I-2, the reaction of 2-cyclopropylamino-5-fluoro-6-(4-methylpiperazinyl)-3-pyridinecarboxylic acid (Example H-2, 200 mg, 0.67 mmol) and HOBT (99.5 mg, 0.74 mmol) with EDCI (154.6 mg, 0.81 mmol) in dichloromethane (10 mL) followed by adding O-benzylhydroxylamine hydrochloride (0.81 mmol) and triethylamine (0.113 mL, 0.81 mmol) gave a crude oil. Purification of the oil by flash chromatography on a silica gel column with 5% of MeOH in dichloromethane provided 160 mg of the title compound as an oil.
Reaction SMILES: [CH2:1]1[NH:6][C:4](=[O:5])[NH:3][CH:2]1[C:7]([OH:9])=O.[CH:10]1([CH2:13][N:14]2[C:18]3[CH:19]=[CH:20][C:21]([S:23]([CH2:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)(=[O:25])=[O:24])=[CH:22][C:17]=3[N:16]=[C:15]2[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:12][CH2:11]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>ClCCl>[CH:10]1([CH2:13][N:14]2[C:18]3[CH:19]=[CH:20][C:21]([S:23]([CH2:26][CH:27]4[CH2:28][CH2:29][N:30]([C:7]([CH:2]5[CH2:1][NH:6][C:4](=[O:5])[NH:3]5)=[O:9])[CH2:31][CH2:32]4)(=[O:24])=[O:25])=[CH:22][C:17]=3[N:16]=[C:15]2[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:11][CH2:12]1
Reactant: O=C1NCC(C(=O)O)N1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC3CCNCC3)ccc2n1CC1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC3CCN(C(=O)C4CNC(=O)N4)CC3)ccc2n1CC1CC1
Reaction time: 15 h

Procedure:
To a solution of 2-imidazolidone-4-carboxylic acid (12 mg, 0.093 mmol) in dichloromethane (1 mL) was added 1-(cyclopropylmethyl)-2-neopentyl-5-(piperidin-4-ylmethylsulfonyl)-1H-benzo[d]imidazole (STEP D of Example 5, 25 mg, 0.062 mmol), triethylamine (13 microL, 0.093 mmol) and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (35 mg, 0.093 mmol) at room temperature, then stirred. After 15 h, 2-imidazolidone-4-carboxylic acid (12 mg, 0.093 mmol) was added to the mixture and stirred at room temperature. After 2 days, the mixture was washed with water (0.5 mL). The organic layer was mounted to a strong cationic exchange column (SCX) which was preconditioning with methanol (4 mL). SCX was washed with methanol (4 mL). Finally SCX was washed with 1 mol/L ammonia in methanol (5 mL), the product was collected a collection tube and concentrated at under reduced pressure by centrifugal concentrator. The residue (25 mg) was purified by prep-LC-MS(“process A”).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.Cl.[CH:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH:13]1[NH2:22])[CH2:19]2.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[CH:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH:13]1[NH:22][C:8](=[O:10])[C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)[CH2:19]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: O=C(O)c1cccc(Br)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
After 6-bromopicolinic acid (500 mg, 2.48 mmol) was suspended in acetonitrile (25 ml), 2-adamantylamine hydrochloride (558 mg, 2.97 mmol), N,N-diisopropylethylamine (1.30 ml, 7.44 mmol), and HBTU (1.13 g, 2.97 mmol) were sequentially added thereto, and then the resulting mixture was stirred at room temperature under nitrogen stream for 3 hours. The resulting reaction liquid was concentrated under reduced pressure, and then the residue thus obtained was subjected to MPLC (30% EtOAc/Hexanes), to obtain 602 mg of white solid (73%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH2:4].[C:10](Cl)(=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12].O>N1C=CC=CC=1>[C:11]([C:10]([NH:4][C:3]1[CH:5]=[C:6]([Cl:9])[CH:7]=[CH:8][C:2]=1[Cl:1])=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cc(Cl)ccc1Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1cc(Cl)ccc1Cl

Procedure:
To a stirred solution of 1 kg of 2,5-dichloroaniline in 2500 ml of pyridine is added 840 ml of pivaloyl chloride and the mixture is refluxed for 4 hours. After cooling, the reaction mixture is poured into water. The solid is filtered, washed with water and air dried to yield N-tert-butylcarbonyl-2,5-dichloroaniline, melting at 74°-76°.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][NH:9][C:10](=[O:14])[O:11][CH2:12][CH3:13].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][NH:9][C:10](=[O:14])[O:11][CH2:12][CH3:13])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)NCCO
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)NCCOS(C)(=O)=O
Reaction time: 16 h

Procedure:
60 g of methanesulfonyl chloride are metered over approximately 30 minutes at 0° to +5° C. to a solution of 66.5 g of ethyl 2-hydroxyethylcarbamate, 43.5 g of pyridine and 1.9 g of 4-dimethylaminopyridine in 150 ml of methylene chloride, with stirring, and the mixture is stirred for 2 more hours at +5° C. and then for 16 hours at room temperature. The reaction mixture is filtered, the residue is washed with a small quantity of ethyl acetate, and the combined filtrates are washed with dilute hydrochloric acid and water. After the mixture has been dried over magnesium sulfate, the solvent mixture is removed completely by distillation in vacuo, which gives ethyl 2-methylsulfonyloxyethylcarbamate, nD20 1.4450.
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:8]=[CH:9][C:10]([C:13](=O)[CH2:14][CH2:15][C:16](=O)[CH:17]([C:25]2[CH:30]=[CH:29][C:28]([S:31][CH3:32])=[CH:27][N:26]=2)[CH2:18][CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[N:11][CH:12]=1)[C:3]([OH:6])([CH3:5])[CH3:4].C([O-])(=O)C.[NH4+:39].[OH-].[Na+]>C(O)(=O)C>[CH3:4][C:3]([OH:6])([CH3:5])[CH:2]([C:7]1[CH:12]=[N:11][C:10]([C:13]2[NH:39][C:16]([CH:17]([C:25]3[CH:30]=[CH:29][C:28]([S:31][CH3:32])=[CH:27][N:26]=3)[CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[OH:1]
Reactant: CSc1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ccc(C(O)C(C)(C)O)cn2)nc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CSc1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(C(O)C(C)(C)O)cn3)[nH]2)nc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 78.6 %

Procedure:
A mixture of 1-[5-(1,2-dihydroxy-2-methylpropyl)pyridin-2-yl]-5-[5-(methylsulfanyl)pyridin-2-yl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (0.49 g), ammonium acetate (0.39 g) and acetic acid (5 mL) was stirred at 80° C. for 3 hr. The reaction mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography, and the title compound (0.37 g, yield 79%) was obtained as a colorless amorphous form from a fraction eluted with ethyl acetate. MS: 468 (MH+).
Reaction SMILES: [N+:1]([CH2:4][C:5]1([CH2:11][CH2:12][NH2:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([O-:3])=[O:2].[C:14](Cl)(=[O:16])[CH3:15].C(N(CC)CC)C>O1CCCC1>[N+:1]([CH2:4][C:5]1([CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([O-:3])=[O:2]
Reactant: NCCC1(C[N+](=O)[O-])CCCCC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCCC1(C[N+](=O)[O-])CCCCC1
Yield: 68.1 %

Procedure:
The amine hydrochloride salt (compound 4, 0.50 g, 2.25 mmol) was reacted with acetyl chloride (0.20 g, 2.55 mmol) and triethylamine (0.45 g, 4.45 mmol) in tetrahydrofuran following the procedure described in Example 1, Step 4. Purification by chromatography on silica eluting with ethyl acetate gave the required product as a crystalline solid (0.35 g, 69%); mp 68–70° C.
Reaction SMILES: [CH2:1]([O:7][CH:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[NH:11][C:10]([CH3:17])([CH3:16])[CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N(CC)CC)C.[C:25]1([C:31](=[O:35])[C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH2:1]([O:7][CH:8]1[CH2:9][C:10]([CH3:16])([CH3:17])[N:11]([C:32](=[O:33])[C:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:35])[C:12]([CH3:15])([CH3:14])[CH2:13]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOC1CC(C)(C)NC(C)(C)C1
Reactant: O=C(Cl)C(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCOC1CC(C)(C)N(C(=O)C(=O)c2ccccc2)C(C)(C)C1
Temperature: -10 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
24.1 g (0.1 mole) of 4-hexyloxy-2,2,6,6-tetramethylpiperidine are dissolved in 100 ml of absolute methylene chloride. To this solution are added 15.2 g (0.15 mole) of absolute triethylamine and the whole solution is cooled to -10° C. At this temperature a solution of 16.8 g (0.1 mole) of phenylglyoxylyl chloride in 100 ml of methylene chloride is slowly added dropwise. When this addition is complete, the reaction mixture is allowed to warm to room temperature and stirred for about 4 hours. Precipitated hydrochloride is removed by filtration and the solution is clarified by filtration over a small amount of silica gel and concentrated by evaporation, affording 28.4 g of 1-(4-hexyloxy-2,2,6,6-tetramethylpiperidino)-2-phenyl-ethane-1,2-dione as a yellow oil (stabiliser 1).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:14]N1C(=O)CCC1=O.O>C(O)(=O)C>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Cl:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(C(=O)O)cc(Cl)cc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
To a solution of 2-amino-3-nitrobenzoic acid (1 g, 5.5 mmol) in acetic acid (5 mL) at room temperature was added N-chlorosuccinimide (0.953 g, 7.14 mmol). The reaction was sealed and heated via microwave for 2 h at 80° C. The resulting mixture was poured into water (ca. 20 mL), cooled to 0° C., and the product collected by filtration. 1H-NMR (2:1 CDCl3/CD3OD, 500 MHz) δ 8.24 (d, J=2.7 Hz, 1H), 8.14 (d, J=2.8 Hz, 1H); 13C NMR (126 MHz, 2:1 CDCl3/CD3OD) δ ppm 167.8, 145.7, 139.6, 132.8, 130.9, 118.5, 116.1. Mass spec.: 215.18 (M−H)−.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[CH3:24][N:25]([C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[S:26]([CH3:29])(=[O:28])=[O:27].[OH-].[Na+]>CN(C=O)C.CO>[CH3:24][N:25]([C:30]1[CH:36]=[CH:35][C:33]([NH:34]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:32][CH:31]=1)[S:26]([CH3:29])(=[O:27])=[O:28]
Reactant: CN(c1ccc(N)cc1)S(C)(=O)=O
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1)S(C)(=O)=O

Procedure:
Prepared analogously to Example 1 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-(N-methyl-N-methylsulphonyl-amino)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][CH:16]=[C:17]([CH2:19]Cl)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][CH:16]=[C:17]([CH2:19][O:31][C:28]3[CH:27]=[CH:26][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:30][CH:29]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(CCl)cs2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(COc3ccc(S(C)(=O)=O)cc3)cs2)CC1

Procedure:
A mixture of 4-(4-Chloromethyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (700 m g, 2.20 mmol), 4-methanesulfonyl-phenol (417 mg, 1.1 eq.) and K2CO3 (609 mg, 2 eq.) in acetone (30 mL) was heated to reflux overnight. After cooling, the solid was filtered off through a pad of celite. The filtrate was concentrated in vacuo. The crude product was purified on silica gel (EtOAc:hexanes=1:1) to afford the desired product as an off-white solid. 1H NMR (CDCl3): δ 7.87 (2H, d, J=8.8 Hz), 7.12 (2H, d, J=8.8 Hz), 6.59 (1H, s), 5.05 (2H, s), 3.56 (4H, m), 3.48 (4H, m), 3.04 (3H, s), 1.49 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:11]([CH2:15][C:16](=O)[CH3:17])[C:12]([CH3:14])=O.C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH3:17][C:16]1[N:1]([C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=2)[C:5]([OH:7])=[O:6])[C:12]([CH3:14])=[CH:11][CH:15]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1cccc(C(=O)O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C)n1-c1cccc(C(=O)O)c1
Yield: 89.7 %

Procedure:
In a reaction vessel equipped with a Dean-Stark trap was placed 13.7 grams (0.10 mole) of 3-aminobenzoic acid, 11.4 grams (0.10 mole) of acetonylacetone, 0.10 gram of p-toluenesulfonic acid and 150 ml of toluene. The stirred reaction mixture was heated under reflux for 15.5 hours during which time the theoretical amount of by-product water was collected in the Dean-Stark trap. The reaction mixture was cooled and placed in a separatory funnel where it was washed with two portions of 50 ml each of aqueous 2N sodium hydroxide. The combined base washes were backwashed with 50 ml of toluene then acidified with aqueous 2 N hydrochloric acid. A solid precipitate was collected by filtration and recrystallized from heptane to give 19.3 grams of 3-(2,5-dimethylpyrrol-1-yl)benzoic acid; mp 148°-150° C.