Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O-]CC.[Na+].[CH2:7]([O:9][C:10](=[O:21])[CH:11]([NH:17][C:18](=[O:20])[CH3:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:8].[C:22]1([C:28]2[CH:33]=[CH:32][C:31]([C:34](=[O:37])[CH2:35]Br)=[CH:30][CH:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[CH2:15]([O:14][C:12](=[O:13])[C:11]([NH:17][C:18](=[O:20])[CH3:19])([CH2:35][C:34]([C:31]1[CH:32]=[CH:33][C:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:29][CH:30]=1)=[O:37])[C:10]([O:9][CH2:7][CH3:8])=[O:21])[CH3:16]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: O=C(CBr)c1ccc(-c2ccccc2)cc1
Agent: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CC(=O)c1ccc(-c2ccccc2)cc1)(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (15 mmol) is added to anhydrous ethanol (50 mL). To this resulting sodium ethoxide solution is added 2-acetylaminomalonic acid diethyl ester (15 mmol) in one portion. The resulting mixture is stirred at room temperature for 30 min. A solution of 4′-phenyl-2-bromoacetophenone (10 mmol) in ethanol (10 mL) is then added and the resulting mixture is stirred at room temperature for 12 h. After concentrating under reduced pressure, the residue is dissolved in EtOAc and water. The organic phase is washed with brine and dried over Na2SO4. After removal of the solvent, the crude material is purified by column chromatography using EtOAc/hexane (1/3) giving the desired product as white solid. 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=8.6 Hz, 2H), 7.68 (d, J=8.6 Hz, 2H), 7.61 (d, J=8.5 Hz, 2H), 7.45 (m, 3H), 7.13 (s, 1H), 4.28 (m, 6H), 1.98 (s, 2H), 1.26 (t, J=7.1 Hz, 6H); MS: (ES+): 412.2 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:15])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(O)(=O)C>[C:16]([NH:1][C:2]1[CH:3]=[C:4]([OH:15])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(O)ccc1Oc1ccccc1
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(O)ccc1Oc1ccccc1
Reaction time: 1 h
Yield: 93 %

Procedure:
20.1 g of 3-amino-4-phenoxyphenol was dissolved in 60 ml of acetic acid. 30 ml of acetic anhydride was added thereto with ice cooling. Stirring was conducted at 20°-25° C. for 1 hour. The mixture was subjected to distillation under reduced pressure to remove the solvent. The resulting crystal was recrystallized from toluene to obtain 22.6 g (yield: 93%) of 3-acetylamino-4-phenoxyphenol having a melting point of 151°-153° C.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:22][C:23]([NH:25][C:26]2[CH:31]=[C:30]([Cl:32])[C:29]([O:33][CH3:34])=[CH:28][C:27]=2[O:35][CH3:36])=[O:24])[C:12]1=[O:37].[CH:38]1([C:42](Cl)=[O:43])[CH2:41][CH2:40][CH2:39]1.O.CCOC(C)=O>C1COCC1.C(N(CC)CC)C>[Cl:32][C:30]1[C:29]([O:33][CH3:34])=[CH:28][C:27]([O:35][CH3:36])=[C:26]([NH:25][C:23]([CH2:22][N:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20](=[O:21])[N:11]([CH2:10][CH2:9][NH:8][C:42]([CH:38]3[CH2:41][CH2:40][CH2:39]3)=[O:43])[C:12]2=[O:37])=[O:24])[CH:31]=1
Reactant: O=C(Cl)C1CCC1
Reactant: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CCN)c(=O)c3ccccc32)cc1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CCNC(=O)C3CCC3)c(=O)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-[3-(2-Amino-ethyl)-2,4-dioxo-3,4-dihydro-2H-quinazolin-1-yl]-N-(5-chloro-2,4-dimethoxy-phenyl)-acetamide trifluoroacetate (75 mg, 0.17 mmol) in THF (1 ml), triethylamine is added (0.06 ml, 0.43 mmol) followed cyclobutane carbonyl chloride (30 mg, 0.26 mmol). The mixture is stirred overnight at RT. Water (3 ml) and then EtOAc is added to the mixture to give a suspension which is filtered to remove the solid. The filtrate is washed with water, dried and evaporated to afford the title compound, [M+H]+ 515
Reaction SMILES: [CH3:1][SiH:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[CH3:13][CH:14]([CH2:17][CH3:18])[CH2:15][OH:16].Cl>N1C=CC=CC=1>[CH3:1][SiH:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:16][CH2:15][CH:14]([CH3:13])[CH2:17][CH3:18])=[O:8])=[CH:5][CH:4]=1
Reactant: CCC(C)CO
Reactant: C[SiH](C)c1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCC(C)COC(=O)c1ccc([SiH](C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
20.0 g (0.101 mol) of 4-dimethylsilylbenzoyl chloride were added dropwise at 10° C.-15° C. to a solution of 8.90 g (0.101 mol) of 2-methylbutan-1-ol in 20 ml of dry pyridine. The reaction solution was stirred for one hour at 25° C., poured onto ice and acidified using HCl. The organic phase was separated off, diluted with toluene and washed by shaking three times with 10% HCl. It was washed with water and dried over sodium sulfate. After the toluene had been stripped off in vacuo on a rotary evaporator, distillation gave 2-methylbutyl 4-dimethylsilylbenzoate; boiling point 86° C.-110° C./0.05 mmHg.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([CH:18]=[C:19]([F:22])[C:20]=1[F:21])[C:5]([C:7](=[CH:13][NH:14][CH:15]1[CH2:17][CH2:16]1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[Cl:1][C:2]1[C:20]([F:21])=[C:19]([F:22])[CH:18]=[C:4]2[C:3]=1[N:14]([CH:15]1[CH2:17][CH2:16]1)[CH:13]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]2=[O:6]
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)c(Cl)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 6 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-cyclopropylaminoacrylate in 40 ml of dry t-butanol is added a slurry of 1.20 g (10.7 mmol) of potassium t-butoxide in 20 ml of dry t-butanol. The reaction mixture is stirred at 6° C. for eight hours, then cooled to room temperature and concentrated. The residue is dissolved in chloroform, washed with water, dried over magnesium sulfate, filtered, and concentrated to give a pale brown solid. The crude product is purified by silica gel chromatography, and eluted with 80:20 chloroform:ethyl acetate to give 1.2 g of the title compound.
Reaction SMILES: C([Mg]Cl)(C)C.[CH:6]1([NH2:9])[CH2:8][CH2:7]1.[F:10][C:11]1[CH:20]=[C:19]([CH3:21])[C:18]([N:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]3([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[OH:38])[CH2:31][CH2:30]3)[C:23]2=[O:39])=[CH:17][C:12]=1[C:13](OC)=[O:14].Cl>C1COCC1.O>[CH:6]1([NH:9][C:13](=[O:14])[C:12]2[CH:17]=[C:18]([N:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]4([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[OH:38])[CH2:31][CH2:30]4)[C:23]3=[O:39])[C:19]([CH3:21])=[CH:20][C:11]=2[F:10])[CH2:8][CH2:7]1
Reactant: NC1CC1
Reactant: COC(=O)c1cc(-n2ccnc(NC3(c4ccccc4O)CC3)c2=O)c(C)cc1F
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(F)c(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3O)CC2)c1=O
Temperature: 25 °C

Procedure:
Isopropylmagnesium chloride (5.19 mL of a 2.0 M solution in THF) was added over 20 min ot a solution of cyclopropylamine (1.830 mL) and methyl 2-fluoro-5-[3-{[1-(2-hydroxyphenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzoate (Example 318f, 1.063 g) in THF (20 mL) stirring at room temperature under nitrogen. The reaction mixture was stirred for 1 h. Water and 2 M HCl were cautiously added and the volatiles removed in vacuo. The residue was basified with saturated aqueous sodium bicarbonate solution and extracted into DCM. The organics were combined, dried (MgSO4) and evaporated to give the subtitle compound (1.189 g).
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH:14]=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:16]([Mg]Br)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOCC>[C:4]([O:3][C:1]([NH:8][CH:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[CH:14]([OH:15])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:2])([CH3:6])([CH3:5])[CH3:7]
Reactant: Br[Mg]CCc1ccccc1
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Solvent: CCOCC
Product: CC(C)CC(NC(=O)OC(C)(C)C)C(O)CCc1ccccc1
Yield: 79.9 %

Procedure:
To a rapidly stirred -78° C. solution of Boc-Leucinal (1.50 g, 6.97 mmol) in anhydrous ether (10 ml) was added a -78° C. solution of phenethyl magnesium bromide (7 mmol) in anhydrous ether (40 ml) dropwise over the course of 15 minutes, and 45 minutes later the mixture was acidified. The oragnic phase was separated, washed with brine (2×10 ml) and dried (Na2SO4). Filtration and evaporation provided an oil (1.79 g) which was chromatographed with 150 g of 40 m SiO2 (7/3, hexane/ether) to give the desired compound (0.17 g). Mass spectrum: M+ =321.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.CC(O)=O.[BH4-].[Na+]>CO>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:1][C@@H:2]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:17][CH:16]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COC(=O)[C@@H](N)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@@H](NCc1ccc(OC)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-methyl 2-amino-2-phenylacetate (1.0 g, 6.06 mmol) in anhydrous MeOH (20 mL) was added 4-methoxy benzaldehyde (0.82 g, 6.06 mmol) and few drops of HOAc. After 30 min, the reaction mixture was cooled to 0° C., NaBH4 (0.69 g, 12.12 mmol) was added and the contents were stirred at ambient temperature. After 2 h, the reaction was quenched with ice cold H2O (10 mL), MeOH was removed under reduced pressure and the organic contents were extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (1×20 mL), dried over Na2SO4, concentrated and (S)-methyl 2-((4-methoxybenzyl)amino)-2-phenylacetate thus obtained was taken directly for step 2. MS: [M+H]+ m/z 286.
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[NH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:20][CH2:21][CH:22]=[CH2:23].N1CCOCC1.Cl>CN(C=O)C.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.CCOC(C)=O>[CH2:23]([N:5]1[C:4]2[N:3]=[C:2]([Cl:1])[NH:10][C:9]=2[C:8](=[O:11])[NH:7][C:6]1=[O:12])[CH2:22][CH:21]=[CH2:20]
Reactant: C=CCCBr
Reactant: O=c1[nH]c(=O)c2[nH]c(Cl)nc2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCN1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCCn1c(=O)[nH]c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 65 h

Procedure:
8-chloro-3,7-dihydro-1H-purine-2,6-dione (100 mg, 0.44 mmol) was stirred with sodium carbonate (52 mg, 0.49 mmol) in dry DMF (3 ml) for 45 min., then 4-bromo-1-butene (66 mg, 0.49 mmol) was added and the mixture was stirred under nitrogen at 40 C for 65 h. After cooling to room temperature, the mixture was thoroughly degassed by evacuating the vessel and refilling with nitrogen several times. Tetrakis(triphenylphosphine)palladium(0) (102 mg, 0.09 mmol) was added, the mixture degassed again and then morpholine (0.385 ml, 4.4 mmol) added and stirring continued for 6.5 h. 2M HCl and EtOAc were added, and the 2-phase system was filtered to remove a yellow precipitated solid. The organic phase of the filtrate was separated and evaporated. The residue was dissolved with warming in THF-MeOH (1:1) and loaded onto an aminopropyl SPE (5 g) which was eluted with THF-MeOH (1:1) followed by MeOH and then 5% AcOH in MeOH-DCM (1:1). The product fraction was further purified by mass-directed autoprep to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[F:19][C:20]([F:32])([F:31])[C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>N1C=CC=CC=1>[F:32][C:20]([F:19])([F:31])[C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:1][C:2]2[S:3][C:4]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:6]=2)(=[O:29])=[O:28])=[CH:25][CH:26]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Nc1nc(-c2ccccc2)c(-c2ccccc2)s1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1nc(-c2ccccc2)c(-c2ccccc2)s1)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Yield: 12 %

Procedure:
3.12 g of 2-amino-4,5-diphenylthiazole and 2.44 g of 4-trifluoromethylbenzenesulfonyl chloride were stirred in pyridine at room temperature for 4.5 hours. Then the reaction mixture was poured into ice-water and the crystals thus precipitated were recovered by filtration and recrystallized from isopropyl ether/ethyl acetate to give 0.55 g of 2-(4-trifluoromethylbenzenesulfonyl)amino-4,5-diphenylthiazole. The melting point of this product was from 248° to 249° C.
Reaction SMILES: FC1C=C(CC(N[C@H](C(O)=O)C(C)C)=O)C=C(F)C=1.[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29]([NH:31][C@H:32]([C:37]([O:39]C)=[O:38])[CH2:33][CH2:34][S:35][CH3:36])=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29]([NH:31][C@H:32]([C:37]([OH:39])=[O:38])[CH2:33][CH2:34][S:35][CH3:36])=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)Cc1cc(F)cc(F)c1
Agent: CC(C)[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: CSCC[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Yield: 82.7 %

Procedure:
A method similar to that used for the preparation of (107b) was used except that methyl N-[(3,5-difluorophenyl)acetyl]-L-methioninate (109a) (300 mg) was used instead of methyl N-[(3,5-difluorophenyl)acetyl]-L-valinate to afford the desired product (237 mg). This material was not further characterized but used in the next step.
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:13]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:14][CH:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)C=CC=CC=1.[OH:28][CH2:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.N1C=CC=CC=1>ClC(Cl)C.O1CCCC1>[CH3:20][O:19][C:16]1[C:17]2[N:18]=[C:10]([NH:9][C:8]([N:33]3[CH2:34][CH2:35][CH:30]([CH2:29][OH:28])[CH2:31][CH2:32]3)=[O:27])[S:11][C:12]=2[C:13]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[N:14][CH:15]=1
Reactant: OCC1CCNCC1
Reactant: COc1cnc(N2CCOCC2)c2sc(NC(=O)Oc3ccccc3)nc12
Solvent: C1CCOC1
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)N3CCC(CO)CC3)nc12

Procedure:
From (7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-carbamic acid phenyl ester with 4-(hydroxymethyl)piperidine and pyridine in dichloroethane and tetrahydrofuran. ES-MS m/e (%): 408 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:27][N:28]([CH3:37])[C:29]1[CH:34]=[CH:33][C:32]([NH:35][CH3:36])=[CH:31][CH:30]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:35]([C:32]3[CH:33]=[CH:34][C:29]([N:28]([CH3:27])[CH3:37])=[CH:30][CH:31]=3)[CH3:36])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CNc1ccc(N(C)C)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(N(C)C(=O)Cn2c(-c3ccc(Cl)cc3)nc3cccnc32)cc1
Temperature: 0 °C
Yield: 90.3 %

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole) in dry dimethylformamide (75 ml) was cooled in an ice bath and oxalyl chloride (2.2 g, 0.0172 mole) was added dropwise, with stirring, under nitrogen. The reaction mixture was stirred at room temperature for 3.5 hours and then N,N,N'-trimethyl-1,4-benzenediamine (2.9 g, 0.0193 mole) was added dropwise. The reaction mixture was stirred at room temperature under nitrogen overnight, poured into 400 ml of ice water and made basic with triethylamine (6 ml). The resulting white solid was collected by filtration, dissolved in hot isopropyl alcohol, treated with charcoal, and filtered while hot. Water was added to the cloud point an upon cooling, a solid precipitated. The gray solid was collected by filtration and rinsed with water to yield 6.6 g (92%) of product. A 1.0-g sample was dried under high vacuum to give 0.6 g of title compound, mp 152°-155° C.
Reaction SMILES: Cl.[Br:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:4]=1[CH:19]([NH:21]C(=O)OC(C)(C)C)[CH3:20]>O1CCOCC1.CCOC(C)=O>[Br:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:4]=1[CH:19]([NH2:21])[CH3:20]
Reactant: CC(NC(=O)OC(C)(C)C)c1c(Br)c2ccccc2n1-c1cccc(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(N)c1c(Br)c2ccccc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.9 %

Procedure:
Hydrogen chloride (4.0 M) in 1,4-dioxane (1.2 mL, 4.8 mmol) was added to a solution of tert-butyl {1-[3-bromo-1-(3-fluorophenyl)-1H-indol-2-yl]ethyl}carbamate (0.15 g, 0.35 mmol) in 1,4-dioxane (2.0 mL) The reaction was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with saturated NaHCO3 solution, dried over MgSO4 and concentrated to give the crude product (0.12 g). LCMS calculated for C16H12BrFN (M-NH2)+: m/z=316.0. Found: 316.0.
Reaction SMILES: [I:1][C:2]1[C:3]([O:16][CH3:17])=[C:4]2[C:8](=[C:9]([O:12][CH3:13])[C:10]=1[I:11])[C:7](=[NH:14])[NH:6][C:5]2=N.[ClH:18].[CH2:19]([N:21]([CH2:28][CH3:29])[C:22]1[S:23][CH2:24][C:25](=[NH:27])[N:26]=1)[CH3:20].Cl.N1(C2SCC(=N)N=2)CCCCC1>>[ClH:18].[NH:14]=[C:7]1[C:8]2[C:4](=[C:3]([O:16][CH3:17])[C:2]([I:1])=[C:10]([I:11])[C:9]=2[O:12][CH3:13])[C:5](=[C:24]2[S:23][C:22]([N:21]([CH2:28][CH3:29])[CH2:19][CH3:20])=[N:26][C:25]2=[NH:27])[NH:6]1
Reactant: CCN(CC)C1=NC(=N)CS1
Reactant: COc1c(I)c(I)c(OC)c2c1C(=N)NC2=N
Agent: Cl
Agent: N=C1CSC(N2CCCCC2)=N1
Product: CCN(CC)C1=NC(=N)C(=C2NC(=N)c3c(OC)c(I)c(I)c(OC)c32)S1

Procedure:
Following the procedure described in Example 9, part B above but using equivalent amounts of 5,6-diiodo-4,7-dimethoxy-1,3-diiminoisoindoline and 2-diethylamino-4-imino-2-thiazoline hydrochloride in place of 1,3-diiminoisoindoline and 2-piperidino-4-imino-2-thiazoline hydrochloride respectively, there is obtained as the product 1-imino-5,6-diiodo-4,7-dimethoxy-3-(2-diethylamino-4-imino-2-thiazolin-5-ylidene)isoindoline hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10](Cl)(=O)=O.[Na+].[I-].FCC(O[C:21](=O)[CH2:22]F)=O>CC(C)=O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10][S:10][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:21]=1[CH3:22]
Reactant: O=C(CF)OC(=O)CF
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1cc(C)c(SSc2c(C)cc(C)cc2C)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,4,6-trimethylphenylsulfonyl chloride (500 mg, 2.3 mmol) was dissolved in acetone (60 mL), and then NaI (3.4 g, 23 mmol) and fluoroacetic anhydride (1.45 mL, 6.9 mmol) were added and the mixture was stirred at room temperature for one hour. The reaction solution was concentrated, water was added, extraction was performed with ether and the organic layer was further washed with aqueous sodium thiosulfate, water and saturated saline. After drying over magnesium sulfate and vacuum concentration, the residue was purified with a silica gel column (hexane) to obtain 2,4,6-trimethylphenyldisulfide as a light yellow crystalline compound (231 mg, 0.76 mmol, 67% yield). The NMR and mass spectral data for the obtained compound were as follows:
Reaction SMILES: [N+](=C)=[N-].N(N[C:7](N)=O)=O.[OH-].[K+].[S:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[C:17]1[C:18](=[O:26])[CH2:19][C:20]([CH3:25])([CH3:24])[CH2:21][C:22]=1[OH:23]>C(O)(=O)C.CCOCC>[S:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[C:17]1[C:22](=[O:23])[CH2:21][C:20]([CH3:24])([CH3:25])[CH2:19][C:18]=1[O:26][CH3:7]
Reactant: CC1(C)CC(=O)C(C2CCCS2)=C(O)C1
Reactant: NC(=O)NN=O
Agent: C=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC1=C(C2CCCS2)C(=O)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To 500 parts by volume of an ether solution of diazomethane prepared using 47 parts of N-nitroso urea and 140 parts by volume of a 40% aqueous solution of potassium hydroxide in a conventional manner, 17.7 parts of 2-(2-tetrahydrothienyl)-3-hydroxy-5,5-dimethyl-2-cyclohexen-1-one was added little by little over a period of 20 minutes. After stirring for 15 hours at room temperature, the unreacted diazomethane was decomposed by the addition of 5 parts of acetic acid and washed with 1 N aqueous sodium hydroxide solution and then with a saturated aqueous sodium chloride solution followed by drying. After removing ether by distillation, the residue was passed through a column containing a silica gel using a solvent mixture of chloroform and benzene (1:3) as a spreading agent. Upon recrystallization of the raw product from a solvent mixture of benzene and n-hexane, 2-(2-tetrahydrothienyl)-3-methoxy-5,5-dimethyl-2-cyclohexen-1-one was obtained in the form of colorless scale-like crystals. The melting point was 111° to 112° C. The yield was 5.7 parts.
Reaction SMILES: [C:1]([C:3]1[CH:14]=[C:13]([NH:15][C:16]([CH:18]2[CH2:21][CH2:20][CH2:19]2)=[O:17])[CH:12]=[CH:11][C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8]Cl)#[N:2].[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>C(O)C>[C:1]([C:3]1[CH:14]=[C:13]([NH:15][C:16]([CH:18]2[CH2:21][CH2:20][CH2:19]2)=[O:17])[CH:12]=[CH:11][C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8][NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])#[N:2]
Reactant: N#Cc1cc(NC(=O)C2CCC2)ccc1OCC(O)CCl
Reactant: CC(C)(C)N
Solvent: CCO
Product: CC(C)(C)NCC(O)COc1ccc(NC(=O)C2CCC2)cc1C#N

Procedure:
7.5 gm (0.024 mol) of 1-(2-cyano-4-cyclobutylcarbonylamino-phenoxy)-3-chloro-propan-2-ol were dissolved in 80 ml of ethanol, and the solution was mixed with 8.7 gm (0.12 mol) of tert. butylamine, and the mixture was refluxed for four hours. The solvent was distilled off in vacuo, the residue was extracted by shaking with dilute hydrochloric acid with the addition of ether, and the organic phase was separated. The aqueous phase was washed with ether and made alkaline with NH4OH. The base which precipitated was extracted with ethyl acetate, and the organic phase was dried over MgSO4. The ethyl acetate was distilled off, and the crystalline residue was recrystallized twice from acetonitrile.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([Cl:30])=[N:6][C:7]2[N:8]([N:27]=[CH:28][CH:29]=2)[C:9]=1[N:10]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][CH:19]=1)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:2]=[CH2:3].CSC.B.[OH-:35].[Na+].OO>O1CCCC1>[C:13]([O:12][C:11](=[O:17])[N:10]([C:9]1[N:8]2[N:27]=[CH:28][CH:29]=[C:7]2[N:6]=[C:5]([Cl:30])[C:4]=1[CH2:1][CH2:2][CH2:3][OH:35])[C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH3:26])=[CH:22][CH:23]=1)([CH3:15])([CH3:14])[CH3:16]
Reactant: C=CCc1c(Cl)nc2ccnn2c1N(C(=O)OC(C)(C)C)c1ccc(OCC)cc1
Reactant: [OH-]
Agent: B
Agent: OO
Agent: [Na+]
Solvent: CSC
Solvent: C1CCOC1
Product: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CCCO)c(Cl)nc3ccnn23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
To a tetrahydrofuran (23 mL) solution containing tert-butyl (6-allyl-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(4-ethoxyphenyl)carbamate (3.0 g, 7.0 mmol), borane-dimethyl sulfide complex (2 mol/L tetrahydrofuran solution, 5.6 mL, 23 mmol) was added over 30 min with ice-cooling. This mixture was stirred at room temperature for 2 hr and then again cooled on ice. Here, 1 mol/L aqueous sodium hydroxide (11.2 mL, 11.2 mmol) was added over 20 min, and hydrogen peroxide (30% aqueous solution, 0.81 mL, 8.4 mmol) was added. The resultant mixture was stirred for 1 hr. After the reaction, the reaction mixture was extracted with ethyl acetate. The combined ethyl acetate layer was washed with brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off and the residue was purified with column chromatography (20% ethyl acetate-hexane) to obtain the title compound (2.02 g, yield 65%).