Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C(NC(C)C)(C)C.[Li].[CH3:21][CH:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:43])(=O)=O)=CC=1>O1CCCC1>[CH3:21][C:22]1([F:43])[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC1CCc2ccccc2C1=O
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC1(F)CCc2ccccc2C1=O
Reaction time: 1.67 h
Yield: 50 %

Procedure:
0.16 milliliter diisopropylamine in 10 milliliters tetrahydrofuran were allowed to stand with 1.15 equivalents butyllithium at -25° C. The resulting solution of lithium diisopropylamine was cooled to -78° C. and 1 equivalent 2-methyl-1-tetralone in 5 milliliters tetrahydrofuran solution was dropped in. The mixture was allowed to stand at -70° C. for 100 minutes. 1.5 equivalents N-fluorobenzenesulfonimide prepared according to Example 1 above in 11 milliliters tetrahydrofuran were mixed rapidly with the mixture at -95° C. The mixture was quenched with 30 milliliters ammonium chloride solution and extracted with dichloromethane. The organic phase was dried with magnesium sulfate, filtered, and evaporated. 2-methyl-2-fluoro-tetralone was obtained in 50% yield.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]=1[O:13][CH3:14])[C:7]([OH:9])=O)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[Br:29][C:30]1[CH:43]=[CH:42][CH:41]=[CH:40][C:31]=1[CH2:32][C:33]1[O:34][C:35]([CH3:39])=[C:36]([CH3:38])[CH:37]=1>CN(C)C=O.C(Cl)Cl>[Br:29][C:30]1[CH:43]=[CH:42][CH:41]=[CH:40][C:31]=1[CH2:32][C:33]1[O:34][C:35]([CH3:39])=[C:36]([CH3:38])[C:37]=1[C:7]([C:6]1[CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]([O:13][CH3:14])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)=[O:9]
Reactant: COc1c(C(C)C)cc(C(=O)O)cc1C(C)C
Reactant: Cc1cc(Cc2ccccc2Br)oc1C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1c(C(C)C)cc(C(=O)c2c(Cc3ccccc3Br)oc(C)c2C)cc1C(C)C
Yield: 49.2 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2 using 3,5-diisopropyl-p-anisic acid (0.983 g, 4.16 mmol, RN-117439-59-5), oxalyl chloride (0.398 mL, 4.56 mmol), N,N-dimethylformamide (2 drops), tin (IV) chloride (0.535 mL, 4.58 mmol) and 2-(2-bromo-benzyl)-4,5-dimethyl-furan (1.10 g, 4.16 mmol) in CH2Cl2. Purification on Biotage KP-Sil eluting with 3% EtOAc/pet. ether gave 0.990 g (49%) of the title compound as a clear oil. 1H NMR (DMSO-d6) δ1.15 (d, 12H), 1.84 (s, 3H), 2.18 (s, 3H), 3.27 (septet, 2H), 3.73 (s, 3H), 3.91 (s, 2H), 7.12-7.16 (m, 2H), 7.29 (t, 1H, 7.44 (s, 2H), 7.50 (d, 1H).
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.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>[CH:11]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=3)[NH:3][C:2]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
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: CCO
Solvent: COCCOC
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3)[nH]c2c1
Temperature: 90 °C
Reaction time: 6 h
Yield: 49 %

Procedure:
To a solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (from Step 3) in DME and EtOH (0.2 M, 3:1, v/v) was added phenyl-boronic acid (1.2 eq.) followed by 2 M aqueous Na2CO3 (8.5 eq,). The mixture was degassed with ultrasound for 30 min, then Pd(PPh3)4 (0.1 eq.) was added and mixture degassed with ultrasound for a further 30 min. The reaction was stirred under nitrogen at 90° C. for 6 h and then cooled to RT. Water was added and the solids filtered off. They were washed with Et2O to give the title compound (49%). The combined mother liquors together with the reaction solvents were washed with water (150 ml) and after phase-cut the organic phase was dried over Na2SO4 and evaporated to dryness. The residual solid was crystallized from boiling CHCl3 to give more title compound (38%, 87% total yield). 1H NMR (400 MHz, DMSO-d6, 300 K) δ 1.21-1.48 (m, 3H), 1.65-1.80 (m, 5H), 1.90-2.05 (m, 2H), 2.79-2.95 (m, 1H), 3.88 (s, 3H), 7.2-7.34 (m, 1H), 7.40-7.50 (m, 1H), 7.51-7.60 (m, 3H), 7.60 (d, J 7.6, 1H), 7.84 (d, J 7.6, 1H), 8.00 (s, 1H); MS (ES+) m/z 334 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]#[N:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([Mg]Br)[CH3:19].O>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2([NH2:16])[CH2:19][CH2:18]2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccnc(C#N)c1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccnc(C2(N)CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (2-cyano-pyridin-4-ylmethyl)-carbamic acid tert-butyl ester (1.2 g, 5.1 mmol) in THF (100 mL) was added ethylmagnesium bromide (3 M, 3.3 mL, 10 mmol) and titanium isopropoxide (2.3 mL, 7.7 mmol). The reaction mixture was stirred at room temperature for 16 h. Water was added (5 mL) and the resulting solids filtered off. The organics were concentrated, then purified by flash chromatography on silica gel using 5-10% MeOH/CH2Cl2 to afford [2-(1-amino-cyclopropyl)-pyridin-4-ylmethyl]-carbamic acid tert-butyl ester as a solid, m/z 264.4 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([C:15](OCC)=[O:16])[C:12]([N+:20]([O-])=O)=[C:11]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])[N:10]=2)=[CH:4][CH:3]=1.ClC1N=C([C:39](OCC)=[O:40])C([N+]([O-])=O)=C(NC2C=CC=CC=2OC)N=1.[NH2:56]C1C=CC(O)=CC=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[N:10]=[C:11]3[C:12]([NH:20][C:39](=[O:40])[N:23]3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[C:13]([C:15]([NH2:56])=[O:16])[N:14]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(Nc2ccc(O)cc2)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Reactant: CCOC(=O)c1nc(Cl)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Reactant: Nc1ccc(O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(Nc3ccc(O)cc3)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
Ethyl 2-(4-hydroxyphenylamino)-6-(2-methoxyphenylamino)-5-nitropyrimidine-4-carboxylate. To a solution of ethyl 2-chloro-6-(2-methoxyphenylamino)-5-nitropyrimidine-4-carboxylate (See Example 30.A) (200 mg, 0.567 mmol) in DMF (3 mL) was added 4-aminophenol (74.3 mg, 0.680 mmol) and N,N-diisopropylethylamine (0.149 mL, 0.851 mmol). The reaction was stirred at room temperature overnight. Solvent was removed under reduced pressure and the resulting residue was purified by chromatography on a normal phase silica gel column (50% ethyl acetate in hexanes). Fractions containing product were combined and the solvent evaporated to provide the title compound (220 mg, 0.517 mmol, 91% yield) as an orange solid. MS (ESI) m/z 426.2 [M+1]+.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>ClCCl>[CH2:21]([O:20][C:18]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 8 h
Yield: 95 %

Procedure:
Triethylamine (8.1 mL, 58 mmol) was added to a solution of piperidine-4-carboxylic acid (5 g, 40 mmol) and benzyl chloroformate (7.9 g, 46 mmol) in dichloromethane (100 mL) in an ice-water bath. After being stirred overnight, the solution was washed with concentrated HCl and brine, dried over Na2SO4 and concentrated. Chromatography on silica gel gave the title compound (10 g) as an oil. MS (M+H) 264.2.
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[OH:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[C@H:16]([C:32]([OH:34])=[O:33])[CH2:15]1>C(#N)C>[N+:29]([C:26]1[CH:27]=[CH:28][C:23]([CH2:22][O:21][C:19]([N:17]2[CH2:18][C@H:14]([O:13][Si:2]([CH3:5])([CH3:4])[CH3:3])[CH2:15][C@H:16]2[C:32]([OH:34])=[O:33])=[O:20])=[CH:24][CH:25]=1)([O-:31])=[O:30]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[Si](C)(C)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
608 μl of chlorotrimethylsilane and 670 μl of triethylamine were added, whilst ice-cooling, to a solution of 620 mg of trans-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)-L-proline dissolved in 20 ml of anhydrous acetonitrile, and the resulting mixture was stirred at room temperature for 1hour. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was mixed with an aqueous solution of sodium chloride and then extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and freed from the solvent by distillation under reduced pressure, to afford 648 mg of trans-1-(4-nitrobenzyloxycarbonyl)-4-trimethylsilyloxy-L-proline as a powder. The whole of this product was then dissolved in 14 ml of anhydrous acetonitrile, and 330 mg of N,N'-carbonyldiimidazole were added to the solution. The mixture was then stirred at room temperature for 1 hour. At the end of this time, a solution of 630 mg of 1-[2-(4-nitrobenzyloxycarbonyl)oxyethyl)piperazine in 2 ml of anhydrous acetonitrile was added to the reaction mixture, and the resulting mixture was stirred overnight at room temperature and then at 40° C. for 1 hour. At the ed of this time, 14 ml of 1N aqueous hydrochloric acid were added, and the reaction mixture was stirred at room temperature for 1 hour. It was then made basic by the addition of an aqueous solution of sodium hydrogencarbonate, after which it was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and freed from the solvent by distillation under reduced pressure. The resulting residue was subjected to column chromatography through silica gel using a 9:1 by volume mixture of ethyl acetate and methanol as the eluent. Those fractions containing the title compound were collected and concentrated by evaporation under reduced pressure, to afford 589 mg of the title compound as a powder. The infra-red absorption spectrum and nuclear magnetic resonance spectrum of the product thus obtained were identical with those of the compound prepared as describe din step (a), above.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH:6]([C@H:8]([N:19]=[C:20](C2C=CC=CC=2)C2C=CC=CC=2)[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][C@@H:4]([CH3:33])[O:3]1.Cl.CCN(C(C)C)C(C)C.Cl[C:45](OC)=[O:46].C1C[O:52]CC1>O>[CH3:33][C@@H:4]1[CH2:5][CH:6]([C@H:8]([NH:19][C:20]([O:46][CH3:45])=[O:52])[C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:7][C@@H:2]([CH3:1])[O:3]1
Reactant: C[C@@H]1CC([C@H](N=C(c2ccccc2)c2ccccc2)C(=O)OCc2ccccc2)C[C@@H](C)O1
Reactant: C1CCOC1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)N[C@H](C(=O)OCc1ccccc1)C1C[C@@H](C)O[C@H](C)C1
Reaction time: 2 h

Procedure:
(S)-Benzyl 2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-(diphenylmethyleneamino)acetate (Cap-2, step d.2) (129.6 mg, 0.294 mmol) was dissolved in THF (2 mL) and then treated with 2N HCl (1.0 mL, 2.1 mmol) in water. The reaction was stirred for 2 h and then concentrated under a stream of nitrogen overnight. The crude residue was dissolved in DCM (2 mL) and DIPEA (0.21 mL, 1.2 mmol) and then treated with methyl chloroformate (0.032 mL, 0.41 mmol) and stirred at RT for 4 h. The reaction was diluted with water (˜2.5 mL) and extracted with DCM (4×2 mL). The combined organic phase was concentrated under a stream of nitrogen overnight and the residue was purified with a Biotage® Horizon (4 g SiO2, 10-50% EtOAc/hexanes) to yield (S)-benzyl 2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-(methoxycarbonylamino)acetate (Cap-2, step e) (56 mg) as a colorless glass. LC-MS retention time 3.338 min; m/z 335.99 [M+H]+. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. 1H NMR (400 MHz, D4-MeOH) δ ppm 7.29-7.42 (m, 5H), 5.28 (d, J=12.0 Hz, 1H), 5.09 (d, J=12.0 Hz, 1H), 4.10-4.20 (m, 2H), 3.68-3.78 (m, 1H), 3.65 (s, 3H), 2.22-2.36 (m, 1H), 1.42-1.54 (m, 2H), 1.29-1.38 (m, 1H), 1.17 (d, J=6.8 Hz, 3H), 1.04 (d, J=6.0 Hz, 3H), 0.89-1.00 (m, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:11][CH2:10][C:9](=O)[NH:8]2)[CH:2]=1.[Cl:13]C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>O>[Cl:13][C:9]1[CH2:10][CH2:11][N:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:8]=1
Reactant: Clc1ccccc1
Reactant: O=C1CCN(c2cccnc2)N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: ClC1=NN(c2cccnc2)CC1
Temperature: 80 °C
Yield: 75 %

Procedure:
To the paste-like solid obtained from Step 1 in a 4-neck round bottomed flask (500 mL) was added chlorobenzene (120 mL). Phosphoryl chloride (10.2 mL, 0.110 mol) was added dropwise to the thick mixture over 10 minutes. The temperature of the mixture went from 22° C. to 27° C. The slurry was heated at 80° C. for 1 hour. The mixture was cooled to 25° C., water (120 mL) was added to dissolve the solids, and the temperature rose to 28° C. The two phase mixture was brought to pH˜12 with sodium hydroxide (50% in water, 42.8 g) using an ice-bath cooling to keep the temperature below 40° C. After cooling to 30° C., the mixture was transferred to a separatory funnel. The phases separated rapidly, and the bottom aqueous layer (containing some suspended solids) was removed from the dark organic phase. Attempted re-extraction of the aqueous phase with chlorobenzene (30 mL) resulted in an emulsion with solids present. The mixture was filtered through Celite®, the phases allowed to settle, and the organics added to the above organic phase to give a solution of the title compound as a dark amber liquid containing a small amount of fine solids (319 g, LC internal standard analysis indicated 4.3 wt % (75.4 mmol) 3-chloro-4,5-dihydro-1-(3-pyridinyl)-1H-pyrazole in the solution, for an in-pot yield of 75% starting from 3-hydrazinopyridine).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][CH:15]=[CH:16][C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:9][CH:8]=1.O([Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])S(C(F)(F)F)(=O)=O>CCCCCC.O1CCCC1>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]([Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[CH:15]=[CH:16][C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:11][CH:12]=1
Reactant: Fc1ccc(-c2[nH]ccc2-c2ccncc2)cc1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2ccncc2)c1-c1ccc(F)cc1
Reaction time: 0.17 h
Yield: 100 %

Procedure:
31 ml (47.4 mmol) of a 1.57 N solution of butyllithium in hexane were added to a solution of 11.30 g (47.4 mmol) of 2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole [prepared as described in step 7(i) above] in 300 ml of tetrahydrofuran at −78° C. and the mixture was stirred for 10 minutes. At the end of this time, 13.4 ml (49.8 mmol) of triisopropylsilyl triflate were added to the reaction mixture at the same temperature. After removal of the cooling bath, the mixture was stirred at room temperature for 30 minutes. 200 ml of water and 300 ml of a saturated aqueous solution of sodium hydrogencarbonate were then added to the reaction mixture before extracting with ethyl acetate. The organic extract was washed with water, dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure to give 18.70 g (quantitative yield) of the title compound as a reddish purple oil.
Reaction SMILES: [CH2:1]([N:3]([C:5]([NH2:7])=[O:6])[NH2:4])[CH3:2].[CH3:8][NH:9][C:10](=[O:13])[NH:11][NH2:12].[CH3:14][N:15]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][N:17]=[C:16]1[C:23](=[NH:27])OCC>>[CH3:14][N:15]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][N:17]=[C:16]1[C:23]([NH:4][N:3]([CH2:1][CH3:2])[C:5]([NH2:7])=[O:6])=[NH:27].[CH3:14][N:15]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][N:17]=[C:16]1[C:23]([NH:12][NH:11][C:10]([NH:9][CH3:8])=[O:13])=[NH:27]
Reactant: CCN(N)C(N)=O
Reactant: CNC(=O)NN
Reactant: CCOC(=N)c1ncc([N+](=O)[O-])n1C
Product: CCN(NC(=N)c1ncc([N+](=O)[O-])n1C)C(N)=O
Product: CNC(=O)NNC(=N)c1ncc([N+](=O)[O-])n1C

Procedure:
In a similar manner, 2-ethylsemicarbazide and 4-methylsemicarbazide are reacted with ethyl 1-methyl-5-nitro-2-imidazolecarboximidate to give 1-(1-methyl-5-nitro-2-imidazolecarboximidoyl)-2-ethylsemicarbazide (IIIG) and 1-(1-methyl-5-nitro-2-imidazolecarboximidoyl)-4-methylsemicarbazide (IIIH), respectively.
Reaction SMILES: C([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.I[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].[BrH:35].C(O)(=O)C>C(OCC)C>[BrH:35].[CH2:25]([C:22]1[CH:23]=[N:24][C:19]([N:18]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:5])=[O:27])[S:12][CH:13]=2)=[N:20][CH:21]=1)[CH3:26]
Reactant: CCCCCCI
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(CC)cn1

Procedure:
A compound obtained using 2-[(4-{2-[(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 265-1 and 1-iodohexane as starting materials and by an operation similar to that of Example 326 was dissolved in diethyl ether, and reacted with 30% hydrobromic acid-acetic acid to give the title compound.
Reaction SMILES: [N:1]1([C:5]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[C:13]1([CH:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:20]2[CH2:23][C:22](=O)[CH2:21]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CO>C(O)(=O)C>[N:1]1([C:5]([CH:7]2[CH2:12][CH2:11][N:10]([CH:22]3[CH2:23][N:20]([CH:19]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:21]3)[CH2:9][CH2:8]2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=C(C1CCNCC1)N1CCC1
Solvent: CO
Solvent: CC(=O)O
Product: O=C(C1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1)N1CCC1
Temperature: 120 °C
Yield: 67.4 %

Procedure:
To a mixture of 4-(azetidin-1-ylcarbonyl)piperidine (0.34 g, 2.0 mmol) and 1-(diphenylmethyl)azetidin-3-one (see Bioorg. Med. Chem. Lett.; 13; 2003; 2191-2194, 0.37 g, 1.6 mmol), methanol (5 mL) and acetic acid (0.1 mL) was added (polystyrylmethyl)trimethylammonium cyanoborohydride (4.1 mmol/g, 0.61 g). The reaction mixture was heated for 10 min at 120° C. using microwave single node heating and then filtered through a phase separator. The solvent was removed by evaporation and the product was purified by chromatography on silica gel (methanol-methylene chloride, 5:95). There was obtained 0.42 g (70%) of 4-(azetidin-1-ylcarbonyl)-1-[1-(diphenylmethyl)azetidin-3-yl]piperidine as a colorless foam. 1H NMR (500 MHz, CDCl3): 1.6-1.7 (m, 2H), 1.7-1.8 (m, 4H), 2.0-2.1 (m, 1H), 2.2 (qn, 2H), 2.7-2.8 (m, 2H), 2.8-3.0 (m, 3H), 3.4 (t, 2H), 4.0 (t, 2H), 4.1 (t, 2H), 4.4 (s, 1H), 7.1-7.2 (t, 2H), 7.2-7.3 (t, 4H), 7.4 (d, 4H); LCMS: m/z 390 (M+1)+.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([N:10]=[C:11]([S-])[S-:12])(=[O:9])=[O:8].[K+].[K+].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[C:14]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[S:7]([N:10]=[C:11]=[S:12])(=[O:9])=[O:8])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=S(=O)(N=C([S-])[S-])c1ccccc1-c1ccccc1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=S(=O)(N=C=S)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.6 %

Procedure:
77 g of potassium N-(2-biphenylylsulfonyl)carbonimidodithioate were suspended in 100 ml of toluene, and 37 ml of thionyl chloride were added dropwise at 0° to 10° C. over the course of 1 hour. After the addition, the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure and distilled under reduces pressure to give 30 g of 2-phenylbenzenesulfonyl isothiocyanate represented by the following formula: ##STR27##
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:17]=2)[N:12]([CH2:26][C:27](O)=[O:28])[N:11]=1.CCN(CC)CC.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[CH3:52][N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1>C(Cl)Cl>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:17]=2)[N:12]([CH2:26][C:27]([N:56]2[CH2:57][CH2:58][N:53]([CH3:52])[CH2:54][CH2:55]2)=[O:28])[N:11]=1
Reactant: CN1CCNCC1
Reactant: Cc1cccc(C)c1Nc1nn(CC(=O)O)c2cc(Nc3ccccc3)ccc12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(C)c1Nc1nn(CC(=O)N2CCN(C)CC2)c2cc(Nc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 100 mg (0.26 mmol) of 2-(3-(2,6-dimethylphenylamino)-6-(phenylamino)-1H-indazol-1-yl)acetic acid 69 (Example 34) in DCM (10 mL) at room temperature was treated with Et3N (43 μL, 1.2 eq) followed with Bop-Cl (73 mg, 1.1 eq) and 1-methylpiperazine (35 μL, 1.2 eq). The mixture was stirred at room temperature for 3 hours before it was quenched with water (5 mL). The organic layer was separated and washed with water, brine, dried over sodium sulfate and filtered. The filtrate was concentrated and purified by column chromatography on silica gel (eluens: DCM:MeOH:NH4OH, 20:1:0.2) to give the title compound 70. 1H-NMR (CDCl3) δ 2.28 (s, 6H), 2.32 (s, 3H), 2.35-2.45 (m, 4H), 3.59-3.69 (m, 4H), 4.98 (s, 2H), 5.91 (s, 1H), 7.04 (t, J=7.3 Hz, 1H), 7.08-7.16 (m, 3H), 7.19 (s, 1H), 7.32 (t, J=8.4 Hz, 2H), 7.47 (s, 1H), 7.58 (d, J=7.7 Hz, 2H). Mass Spectrum (ESI) m/e=471 (M+1).