Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([CH2:13][N:14]2[CH:18]=[CH:17][N:16]=[C:15]2[C:19]([C:21]2[C:22]3[CH2:23][CH2:24][CH2:25][CH2:26][C:27]=3[CH:28]=[CH:29][CH:30]=2)=[O:20])[CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH3:38][S:39]([O:12][CH2:11][CH2:10][C@@H:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[C:19]([C:21]1[C:22]2[CH2:23][CH2:24][CH2:25][CH2:26][C:27]=2[CH:28]=[CH:29][CH:30]=1)=[O:20])(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1cccc2c1CCCC2)c1nccn1C[C@@H](CCO)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC[C@H](Cn1ccnc1C(=O)c1cccc2c1CCCC2)c1ccc(Cl)c(Cl)c1
Reaction time: 4 h
Yield: 102.5 %

Procedure:
3(S)-(3,4-Dichlorophenyl)-4-[2-(1,2,3,4-tetrahydro-5-naphthoyl)imidazol-1-yl]butan-1-ol (0.68 g) (see Preparation 103) and triethylamine (0.22 g) were dissolved in dichloromethane (15 ml), the solution cooled in an ice-bath and methanesulphonyl chloride (0.22 g) added. The mixture was stirred for 4 hours before removal of the solvent under reduced pressure to give a residue which was partitioned between ethyl acetate and water. The organic phase was separated and washed with saturated aqueous sodium hydrogen carbonate solution before being dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure to give 1-methanesulphonyloxy-3(S)-(3,4-dichlorophenyl)-4-[2-(1,2,3,4-tetrahydro-5-naphthoyl)imidazol-1-yl]butane (0.82 g) as an oil.
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C(C)([O-])C.[K+].O1CCCC1.[CH:18]([C@@H:20]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:21][C@H:22]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=1)[CH:23]([CH3:25])[CH3:24])=[O:19]>CS(C)=O>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][C@H:22]([CH:23]([CH3:24])[CH3:25])[CH2:21][C@H:20]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[C@@H:18]2[CH2:7][O:19]2)=[CH:28][C:29]=1[O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40]
Reactant: COCCCOc1cc(C[C@@H](C[C@@H](C=O)NC(=O)OC(C)(C)C)C(C)C)ccc1OC
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H]2CO2)C(C)C)ccc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3.87 g of trimethylsulphoxonium iodide and 1.98 g of potassium tert-butoxide are stirred under high vacuum overnight, admixed with 24 ml of tetrahydrofuran and subsequently cooled to 0° C. A solution of 4.00 g of tert-butyl {1(S)-formyl-3(S)-[4-methoxy-3-(3-methoxypropoxy)benzyl]4-methylpentyl}carbamate [CAS 172900-83-3] in 24 ml of dimethyl sulphoxide is added dropwise. After 2 hours, the reaction mixture is partitioned between water and tert-butyl methyl ether and the aqueous phase is extracted once more with tert-butyl methyl ether (2×). The combined organic phases are washed successively with water (3×) and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue first by means of flash chromatography (SiO2 60F) and then by means of crystallization (hexane) as white crystals. Rf=0.43 (1:1 EtOAc-heptane); Rt=21.90 (gradient II); m.p. 59-65° C.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:27]COC)([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[CH2:31][CH2:32][CH3:33])[CH2:7][CH2:6]1)=[O:4].[O:34]1[C:38]2[CH:39]=[CH:40][C:41]([C:43]3([CH3:50])[NH:47][C:46](=[O:48])[NH:45][C:44]3=[O:49])=[CH:42][C:37]=2[CH2:36][CH2:35]1>>[O:34]1[C:38]2[CH:39]=[CH:40][C:41]([C:43]3([CH3:50])[NH:47][C:46](=[O:48])[N:45]([CH2:2][C:3]([N:5]4[CH2:11][CH2:10][CH2:9][N:8]([C:12]5[CH:17]=[CH:16][C:15]([C:18]([OH:27])([C:19]([F:22])([F:20])[F:21])[C:23]([F:26])([F:24])[F:25])=[CH:14][C:13]=5[CH2:31][CH2:32][CH3:33])[CH2:7][CH2:6]4)=[O:4])[C:44]3=[O:49])=[CH:42][C:37]=2[CH2:36][CH2:35]1
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1N1CCCN(C(=O)CBr)CC1
Reactant: CC1(c2ccc3c(c2)CCO3)NC(=O)NC1=O
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCCN(C(=O)CN2C(=O)NC(C)(c3ccc4c(c3)CCO4)C2=O)CC1

Procedure:
2-Bromo-1-(4-{4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl]-2-propylphenyl}-1,4-diazepan-1-yl)ethanone and 5-(2,3-dihydrobenzofuran-5-yl)-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Examples 14-1 and 15-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[C:13]([CH3:20])=[C:14]([NH2:19])[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:22])[CH3:21])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C(OCC)(=O)C.CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[C:13]([CH3:20])=[C:14]([NH:19][C:29](=[O:30])[C:28]4[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[CH:26][CH:27]=4)[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:22])[CH3:21])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(F)cc1)C(C)(C)O2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(F)cc2)C(C)(C)O3)cc1
Yield: 79 %

Procedure:
By using 3-(4-fluorophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-methoxybenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 79%. Melting point: 191-194° C. (Ethyl acetate-hexane).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].CO.[CH3:8][C:9]([CH2:11][CH3:12])=O>[Pd].O>[CH:9]([NH:1][CH2:2][C:3]([OH:5])=[O:4])([CH2:11][CH3:12])[CH3:8]
Reactant: NCC(=O)O
Reactant: CCC(C)=O
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CCC(C)NCC(=O)O

Procedure:
338 g of glycine (4.5 mols), 1.5 liters of methanol, 15 g of 10% Pd on C, wet with water, and 500 g of methylethylketone (6.93 mols) are charged into the autoclave.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([CH3:16])[CH:10]=2)=[O:6].[C:17](Cl)(=[O:19])[CH3:18].O>CN(C)C=O>[CH3:3][O:4][C:5]([C:7]1[N:8]([C:17](=[O:19])[CH3:18])[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([CH3:16])[CH:10]=2)=[O:6]
Reactant: COC(=O)c1cc2ccc(C)cc2[nH]1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2ccc(C)cc2n1C(C)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.5 %

Procedure:
Sodium hydride (4.70 g. of 50% dispersion in mineral oil) was added portionwise with stirring to a stirred solution of 6-methylindole-2-carboxylic acid methyl ester (18.0 g.) in dry N,N-dimethylformamide (100 ml.) and the mixture was stirred at room temperature for 1.5 hours. Acetyl chloride (8.0 g.) was then added dropwise with stirring and cooling and the resulting mixture was stirred at room temperature for 5 hours and then poured into water. The mixture was extracted several times with ethyl acetate and the combined extracts were washed with water and dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with chloroform first gave mineral oil followed by pure product. Evaporation of the product-containing fractions gave a solid which are crystallized from methanol to give 1-acetyl-6-methylindole-2-carboxylic acid methyl ester (14.4 g.), m.p. 51°-53° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CN=C1.O>CN(C)C=O>[Si:9]([O:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccncc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
Pyridin-4-ylmethanol (2.2 g, 20 mmol) was dissolved in N,N-dimethylformamide, and tert-butyldimethylsilyl chloride (3.3 g, 22 mmol) and imidazole (2.0 g, 30 mmol were added thereto. The mixture was stirred at a room temperature overnight. After the completion of the reaction was confirmed by HPLC, water was added to the mixture, and the extraction with diethyl ether was performed 3 times. The combined organic layer was washed with a saturated saline solution and dried over magnesium sulfate, and the solvent was distilled off. Thus the title compound (4.5 g, 100%) was obtained as an oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]([O:11][CH2:12][CH3:13])=[C:6]([O:8][CH2:9][CH3:10])[CH:7]=1.C([O-])(=O)C.[Na+].[Br:20]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[C:5]([O:11][CH2:12][CH3:13])=[C:4]([F:14])[C:3]=1[Br:20]
Reactant: CCOc1cc(Br)cc(F)c1OCC
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOc1cc(Br)c(Br)c(F)c1OCC
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 101.4 %

Procedure:
To a solution of 5-bromo-1,2-diethoxy-3-fluorobenzene (40.0 g, 0.15 mol) in acetic acid (200 mL), sodium acetate (16.2 g, 0.20 mol) and bromine (31.6 g, 0.20 mol) were added sequentially at room temperature, and the mixture was stirred at 50° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and a saturated aqueous solution of sodium thiosulfate (400 mL) and water (400 mL) were added sequentially. The mixture was extracted once with heptane (800 mL) and three times with heptane (400 mL). The organic layer was washed sequentially with water (400 mL), once with a 2 N aqueous solution of sodium hydroxide (200 mL), once with a 2 N aqueous solution of sodium hydroxide (100 mL), and water (400 mL), then dried over anhydrous magnesium sulfate. The solvent was distilled off from the organic layer under reduced pressure and the residue was filtered. The filtrate was then purified by silica gel column chromatography (hexane, ethyl acetate) to give 52.0 g of the title compound (yield:quant.).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([NH:8][NH2:9])=O.[NH2:10][C:11](=S)[C:12]([O:14][CH2:15][CH3:16])=[O:13].[Cl-].[NH4+]>C(O)C.[Cl-].[Na+].O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9][N:8]=1
Reactant: CCOC(=O)C(N)=S
Reactant: NNC(=O)c1nccs1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1nc(-c2nccs2)n[nH]1
Temperature: 110 °C
Reaction time: 264 h
Yield: 37 %

Procedure:
A suspension of thiazole-2-carbohydrazide (4.2 mmol), ethyl 2-amino-2-thioxoacetate (1 equiv) and ammonium chloride (6 equiv) in ethanol (150 mL) was placed in a sealed tube and this was warmed to 110° C. and stirred at that temperature for 11 days. The reaction solution was cooled to rt and conc. Brine was added and the mixture was adjusted to pH-6 and extracted with EtOAc. The organic phases were dried over Na2SO4, filtered and conc. The crude product was purified using SiO2 chromatography and an appropriate solvent gradient (CH3CN/MeOH/CH2Cl2) to give ethyl 3-(thiazol-2-yl)-1H-1,2,4-triazole-5-carboxylate as an off-white solid (Intermediate-2, 37% yield).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][CH:10]([F:40])[O:11][CH:12]([C:17]1[C:22]2[N:23]3[CH2:29][CH2:28][CH2:27][N:26]([C:30]4[C:31]([CH3:39])=[N:32][C:33]([O:37][CH3:38])=[N:34][C:35]=4[CH3:36])[C:24]3=[N:25][C:21]=2[CH:20]=[CH:19][CH:18]=1)[C:13]([F:16])([F:15])[F:14]>C(#N)C.C(=O)([O-])O.[Na+]>[Br:1][C:20]1[C:21]2[N:25]=[C:24]3[N:26]([C:30]4[C:35]([CH3:36])=[N:34][C:33]([O:37][CH3:38])=[N:32][C:31]=4[CH3:39])[CH2:27][CH2:28][CH2:29][N:23]3[C:22]=2[C:17]([CH:12]([O:11][CH:10]([F:9])[F:40])[C:13]([F:16])([F:15])[F:14])=[CH:18][CH:19]=1
Reactant: COc1nc(C)c(N2CCCn3c2nc2cccc(C(OC(F)F)C(F)(F)F)c23)c(C)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1nc(C)c(N2CCCn3c2nc2c(Br)ccc(C(OC(F)F)C(F)(F)F)c23)c(C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.3 %

Procedure:
N-Bromosuccinimide (190 mg, 1.07 mmol) was added to a stirred solution of 6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (469 mg, 1.02 mmol) in acetonitrile (5.0 mL) at room temperature, and the mixture was stirred at room temperature for 5 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 70-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give a solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as colorless crystals (330 mg, 0.615 mmol, 60%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[CH3:18][S:19]([O:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:6][C:3]=1[CH:4]=[O:5])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: O=Cc1cc(O)ccc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc(OS(C)(=O)=O)c(C=O)c1
Reaction time: 0.5 h

Procedure:
To a solution of 2,5-dihydroxybenzaldehyde (8.22 g, 59.5 mmol) in 100 mL of dichloromethane at 0° C. was added triethylamine (24.8 mL, 178 mmol), followed by dropwise addition of methanesulfonyl chloride (10.1 mL, 130 mmol). After 30 minutes, the solution was concentrated in vacuo, then partitioned between EtOAc and saturated NaHCO3 solution. The organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The product was isolated as a brown oil which was used without further purification.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:3].Cl.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([CH2:28][NH:29][CH3:30])[CH2:24][CH2:23]1.Cl>O.O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>[F:12][C:11]([F:14])([F:13])[C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2](=[O:3])[N:29]([CH2:28][C@H:25]2[CH2:26][CH2:27][C@H:22]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][Br:16])[CH2:23][CH2:24]2)[CH3:30])=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccc(C(F)(F)F)cc1
Reactant: CNC[C@H]1CC[C@H](CCCCCBr)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C[C@H]1CC[C@H](CCCCCBr)CC1)C(=O)Oc1ccc(C(F)(F)F)cc1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
0.515 ml Diisopropyl-aethylamine, 0.674 g (3.00 mmol) 4-trifluoromethylphenyl chloroformate [Org. Lett. (2000), 2(8), 1049-1051] and 0.828 mg potassium carbonate (dissolved in the minimal amount of water) were added to a suspension of 0.625 g (2.00 mmol) trans-[4-(5-bromo-pentyl)-cyclohexylmethyl]-methyl-amine hydrochloride in 20.0 ml of tetrahydrofuran kept at −10° C. The reaction mixture was then intensively stirred for 1 hour at −10° C. and for 3 hour at room temperature. 0.200 g 4-trifluoromethylphenyl chloroformate were added and stirring at room temperature continued for additional 2 hours. The reaction mixture was subsequently acidified with dilute hydrogen chloride solution. It was then evaporated, poured into 50 ml of an ice/water mixture and extracted 3 times with 50 ml of dichloromethane. The combined dichloromethane phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 1:1 v/v mixture of hexane and dichloromethane as the eluent giving 0.90 g (96.9%) trans-[4-(5-bromo-pentyl)-cyclohexylmethyl]-methyl-carbamic acid 4-trifluoromethyl-phenyl ester as colorless viscous oil, MS: 464 (MH+, 1Br).
Reaction SMILES: [OH-].[NH4+].O.C1(S([O-])(=O)=O)C=CC=CC=1.[NH:14]=[C:15]1[NH2+:19][C:18](=[NH:20])[CH2:17][S:16]1.[NH:21]=[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=N)[NH:23]1>CO>[NH:21]=[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[C:17]2[S:16][C:15](=[NH:14])[NH:19][C:18]2=[NH:20])[NH:23]1
Reactant: N=C1CSC(=N)[NH2+]1
Reactant: N=C1NC(=N)c2ccccc21
Agent: O=S(=O)([O-])c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N=C1NC(=N)C(=C2NC(=N)c3ccccc32)S1

Procedure:
To a stirred solution of 61 parts of 28 percent aqueous ammonium hydroxide solution and 2500 parts of water under at atmosphere of nitrogen there was simultaneously added at ambient temperature during a period of ninety minutes 273 parts of 2,4-diiminothiazolidinium benzenesulfonate and 853 parts of a 17.1 percent by weight methyl alcohol solution of 1,3-diiminoisoindoline. A yellow solid separated during the addition. Stirring was continued at room temperature for approximately sixteen hours after the additions were complete and the thick yellow reaction slurry was then filtered. The product collected on the funnel was washed copiously with distilled water and finely dried at 50° C in vacuo to obtain 233 parts of 1-imino-3-(2,4-diimino-5-thiazolidinylidene)-isoindoline as a yellow solid melting at 252°-263° C (dec.).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[N:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[NH2:21]>CCOC(C)=O.C1CCCCC1>[CH3:28][O:27][C:23]1[CH:22]=[C:20]([NH:21][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[N:3]=2)[CH:19]=[C:18]([O:17][CH3:16])[C:24]=1[O:25][CH3:26]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: Fc1ccccc1Oc1cncc(Cl)n1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: COc1cc(Nc2cncc(Oc3ccccc3F)n2)cc(OC)c1OC
Yield: 71 %

Procedure:
Using Method EE with 2-chloro-6-(2-fluorophenyloxy)-pyrazine (200 mg, 0.89 mmol) and 3,4,5-trimethoxyaniline (196 mg, 1.07 mmol), and purification by column chromatography (AcOEt:cyclohexane, 1:1), the title compound was obtained (234 mg). Yield: 71%. 1H NMR (250 MHz, DMSO-d6) δ 3.42 (s, 6H, [CH3O]3+5), 3.54 (s, 3H, [CH3O]4), 6.69 (s, 2H, Harom2′+6′), 7.24-7.41 (m, 4H, Harom), 7.83 (s, 1H, HPz 5), 7.96 (s, 1H, HPz 3), 9.57 (s, 1H, NH).
Reaction SMILES: Br[CH:2]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[Cl:17][C:18]1[N:23]=[N:22][C:21]([NH2:24])=[CH:20][CH:19]=1>C(O)C>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:2]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:24]=2)[N:23]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: O=C(c1ccccc1)C(Br)c1ccncc1
Solvent: CCO
Product: Clc1ccc2nc(-c3ccccc3)c(-c3ccncc3)n2n1

Procedure:
A mixture of 13 g (36.5 mmol) of 2-bromo-1-phenyl-2-pyrid-4-ylethanone (CAS No.: 741633-76-1) and 18.9 g (146 mmol) of 6-chloropyridazin-3-ylamine in 200 mL of ethanol is maintained at 90° C. for 5 hours 30 minutes. After cooling, the solvent is evaporated off under reduced pressure, the medium is taken up in 50 mL of water and the product is extracted with ethyl acetate. The organic phases are dried over magnesium sulfate and then concentrated under reduced pressure.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:19]>ClCCl>[N+:27]([C:24]1[CH:23]=[CH:22][C:21]([O:20][C:18](=[O:19])[NH:10][C:8]2[O:7][N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=2)=[CH:26][CH:25]=1)([O-:29])=[O:28]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)c1cc(N)on1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.4 %

Procedure:
A solution of 3-tert-butyl-isoxazol-5-ylamine (2.50 g, 17.83 mmol) in dichloromethane was treated with pyridine (2 mL, 26.7 mmol) followed by p-nitrophenyl chloroformate (3.77 g, 18.73 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with 1N HCl, filtered, and concentrated under reduced pressure. The residue was triturated with ether and collected by filtration to afford 2.2 g of product (41% yield).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([F:13])([F:12])[F:11])=[C:2]=[O:3].[CH3:14][C:15]([CH3:18])([O-:17])[CH3:16].[K+]>C1COCC1>[F:11][C:10]([F:12])([F:13])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH:1][C:2](=[O:3])[O:17][C:15]([CH3:18])([CH3:16])[CH3:14]
Reactant: O=C=Nc1ccccc1C(F)(F)F
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
To a solution of 1-isocyanato-2-(trifluoromethyl)benzene (4.0 g, 21.4 mmol) in 50 mL of THF at 0° C. was added potassium tert-butoxide (32.0 mL of a 1M solution in THF, 32 mmol) dropwise. The reaction was allowed to stir for 3 h with warming to ambient temperature and then was quenched with 10 mL of water. The mixture was diluted with ethyl acetate and the organics were washed sequentially with 1N HCl, sat'd. aq. NaHCO3 and brine, dried (MgSO4) and concentrated. The residue was taken up in chloroform, filtered through a pad of silica gel and concentrated to afford 2.9 g (52%) of the title compound which was sufficiently pure to be used without further purification. 1H NMR (CDCl3): δ 8.13 (d, 1H, J=8.2 Hz), 7.56 (d, 1H, J=7.7 Hz), 7.52 (t, 1H, J=8.0 Hz), 7.14 (t, 1H, J=7.7 Hz), 6.80 (broad s, 1H), 1.53 (s, 9H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:33]=[CH:34][C:35]=1[OH:36])[O:7][CH2:8][CH2:9][N:10](CC1C=CC=CC=1)[CH2:11][CH:12]([OH:25])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][OH:24])=[CH:17][CH:16]=1)(=[O:3])[NH2:2].[H][H]>CO.[Pd]>[C:1]([C:4]1[CH:5]=[C:6]([CH:33]=[CH:34][C:35]=1[OH:36])[O:7][CH2:8][CH2:9][NH:10][CH2:11][CH:12]([OH:25])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][OH:24])=[CH:17][CH:16]=1)(=[O:3])[NH2:2]
Reactant: [H][H]
Reactant: NC(=O)c1cc(OCCN(Cc2ccccc2)CC(O)COc2ccc(OCCO)cc2)ccc1O
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1cc(OCCNCC(O)COc2ccc(OCCO)cc2)ccc1O

Procedure:
A solution of 23 g of crude 1-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)ethyl]-benzylamino]-3-[4-(2-hydroxyethoxy)phenoxy]-2-propanol in 500 ml of methanol is hydrogenated, under normal conditions, with the addition of 2 g of 5% palladium on carbon catalyst, until hydrogen absorption has ceased. The catalyst is then removed by filtration and the filtrate is concentrated by evaporation under reduced pressure. The crystalline residue is stirred in a mixture of 50 ml of methanol and ether. The crystals so obtained are isolated by filtration and dried in vacuo, affording 1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-[4-(2-hydroxyethoxy)phenoxy]-2-propanol with a melting point of 150°-151° C. Reaction with the equivalent amount of hydrogen chloride, as solution in methanol, affords the hydrochloride with a melting point of 205°-206° C.