Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4](=[O:21])[CH2:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[C:10]([NH:18][CH3:19])[C:9]=2[CH3:20])=[O:7])[CH2:3][CH2:2]1.CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>C(Cl)Cl>[CH:1]1([C:4](=[O:21])[C:5](=[CH:24][N:25]([CH3:27])[CH3:26])[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[C:10]([NH:18][CH3:19])[C:9]=2[CH3:20])=[O:7])[CH2:3][CH2:2]1
Reactant: CNc1c(S(C)(=O)=O)ccc(C(=O)CC(=O)C2CC2)c1C
Reactant: COC(OC)N(C)C
Solvent: ClCCl
Product: CNc1c(S(C)(=O)=O)ccc(C(=O)C(=CN(C)C)C(=O)C2CC2)c1C
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of 1.58 g (5.1 mmol) of 1-cyclopropyl-3-(3-methylamino-2-methyl-4-methylsulfonylphenyl)propane-1,3-dione and 2.0 ml (15.3 mmol) of N,N-dimethyl formamide dimethyl acetal was stirred for 3 h at RT. The mixture was treated with 10 ml of CH2Cl2, stirred for 2 h at an oil-bath temperature of 50° C., left to stand overnight, stirred for 1 d at an oil-bath temperature of 50° C., and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel. This gave 0.85 g of product in 93% purity.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30](=[O:39])[NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH2:38])([CH3:28])([CH3:27])[CH3:26].[OH:40][CH2:41][C:42]1[CH:50]=[CH:49][C:45]([C:46](O)=[O:47])=[CH:44][CH:43]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[C:25]([O:29][C:30]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH:38][C:41](=[O:40])[C:42]1[CH:50]=[CH:49][C:45]([CH2:46][OH:47])=[CH:44][CH:43]=1)=[O:39])([CH3:28])([CH3:26])[CH3:27]
Reactant: O=C(O)c1ccc(CO)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(CO)cc1

Procedure:
HATU (17 g, 45 mmol) was added to a solution of 2-aminophenylcarbamic acid t-butyl ester (Reference Compound No. 1-1, 8.3 g, 40 mmol), 4-hydroxymethylbenzoic acid (6.2 g, 41 mmol) and N,N-diisopropylethylamine (21 mL, 120 mmol) in anhydrous DMF (200 mL), and then the mixture was stirred at room temperature for 16 hours. Water (500 mL) was added thereto, the whole was extracted with ethyl acetate (500 mL) twice, and then the organic layer was washed with brine (500 mL) twice. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to give 1.7 g of the title reference compound as a pale yellow solid. (Yield 42%)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[C:12]([O-])([O-])=O.[K+].[K+].BrC[CH2:20][CH2:21][C:22]([O-:24])=[O:23]>C(#N)C.O>[CH3:12][O:24][C:22](=[O:23])[CH2:21][CH2:20][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=2)[NH:8][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: O=C([O-])CCCBr
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)CCc1c[nH]c2ccc(C#N)cc12
Yield: 99.5 %

Procedure:
To a stirred solution of 5-cyanoindole (1.0 g, 7.0 mmol), K2CO3 (0.966 g, 7.0 mmol) in acetonitrile was added 3-bromomethylpropionate (1.17 g, 7.0 mmol). The mixture was stirred at reflux for 18 h under a nitrogen atmosphere, cooled, diluted with H2O, extracted with ethyl acetate, dried with Na2SO4, filtered and concentrated in vacuo to afford 1.59 g of product. 1H NMR (CD3OD) δ ppm 2.85 (t, 2H, J=6.6 Hz), 3.61 (s, 3H), 4.58 (t, 2H, J=6.6 Hz), 6.61 (s, 1H), 7.42, (m, 3H), 7.62 (d, 1H, J=8.4 Hz), 7.99 (s, 1H).
Reaction SMILES: [Na].[CH3:2][C:3]([SH:6])([CH3:5])[CH3:4].[H-].[Na+].ClC(C)[C:11]([C:13]1[CH:14]=C(CC(O)=O)C(OC)=C[CH:18]=1)=O>C1COCC1.O>[C:3]([S:6][C:13]([CH3:14])([CH3:18])[CH3:11])([CH3:5])([CH3:4])[CH3:2]
Reactant: CC(C)(C)S
Reactant: COc1ccc(C(=O)C(C)Cl)cc1CC(=O)O
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)SC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a 50 mL round bottom flask containing 0.9 grams (8.82 mmole) of the sodium salt of 2-methyl-2-propanethiol was added 0.25 grams of sodium hydride (11.3 mmole) and the resulting mixture placed under vacuum and then under a nitrogen atmosphere. To the mixture was then added 15 mL of anhydrous tetrahydrofuran and the mixture cooled to 0° C. To the cooled mixture was added 1.5 grams (5.84 mmole) of 9 dissolved in 15 mL of anhydrous THF over a period of 10 minutes. After addition, the reaction mixture was allowed to stir, at room temperature and under a nitrogen atmosphere for 18 hours. After 18 hours the volatile components of the reaction mixture were removed under reduced pressure to give a brown solid. The brown solid was dissolved in 80 mL of H2O and aqueous washed with 100 mL of diethyl ether. The aqueous layer was then acidified with 1 mL of concentrated HCl (pH=1) and then extracted (2×100 mL) with diethyl ether and organic layers combined, dried over MgSO4, filtered and volatile components removed under reduced pressure to give 1.75 grams of the t-butyl thioether product which was used without any further purification.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:36][C:37]1[N:38]=[C:39]([CH3:42])[S:40][CH:41]=1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[N:38]=[C:39]([CH3:42])[S:40][CH:41]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2csc(C)n2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 4-(chloromethyl)-2-methyl-1,3-thiazole hydrochloride (0.63 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow solid (0.94 g, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([O:16]C)[CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:18]([CH3:33])[C:19]([C:25]1[CH:26]=[CH:27][C:28](=[O:32])[N:29]([CH3:31])[CH:30]=1)([OH:24])[C:20]([F:23])([F:22])[F:21].B(Br)(Br)Br>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([OH:16])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:18]([CH3:33])[C:19]([C:25]1[CH:26]=[CH:27][C:28](=[O:32])[N:29]([CH3:31])[CH:30]=1)([OH:24])[C:20]([F:23])([F:21])[F:22]
Reactant: COc1cc(Oc2ccc(C(C)C(O)(c3ccc(=O)n(C)c3)C(F)(F)F)c(Cl)c2)ccc1F
Agent: BrB(Br)Br
Product: CC(c1ccc(Oc2ccc(F)c(O)c2)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F

Procedure:
In analogy to Example 147, step 5, 5-{2-[2-chloro-4-(4-fluoro-3-methoxy-phenoxy)-phenyl]-1-hydroxy-1-trifluoromethyl-propyl}-1-methyl-1H-pyridin-2-one was reacted with BBr3 to give the title compound as an off-white solid. MS (m/e)=472.2 [M+H+].
Reaction SMILES: C(OC([N:11]1[CH2:19][C@@:18]2([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:13]([CH2:14][CH2:15][O:16][CH2:17]2)[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[C:24]([O:23][C:21]([NH:20][C@:18]12[CH2:19][NH:11][CH2:12][C@H:13]1[CH2:14][CH2:15][O:16][CH2:17]2)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N[C@@]12COCC[C@@H]1CN(C(=O)OCc1ccccc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@]12CNC[C@H]1CCOC2
Yield: 98.7 %

Procedure:
[(1S,6R)-1-tert-Butoxycarbonylamino-3-oxa-8-azabicyclo[4,3,0]nonan-8-yl]carboxylic acid benzyl ester (401 mg, 1.07 mmol) was dissolved in methanol (20 mL). 10% palladium-carbon (50% wet) (200 mg) was added, and the mixture was stirred in a hydrogen atmosphere for 2.5 hours. The catalyst was removed by filtration, and then the filtrate was concentrated under reduced pressure. A 1N sodium hydroxide solution was added, followed by extraction with chloroform. After drying over anhydrous sodium sulfate and filtration, the solvent was evaporated under reduced pressure to give 256 mg of the title compound as a colorless solid.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[Cl:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][CH3:22])=[O:14].C(=O)(O)[O-].[Na+]>ClCCl.O>[Cl:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]([CH3:22])[CH:1]=[O:3])=[O:14]
Reactant: CNc1ccccc1C(=O)CCl
Reactant: O=CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CN(C=O)c1ccccc1C(=O)CCl
Reaction time: 3 h

Procedure:
A mixture of formic acid (2.3 ml) and acetic anhydride (3.6 ml) was heated at 50 to 60° for 2 hours, cooled to 0 to 5° and dichloromethane (10 ml) added. A solution of 2-chloro-2'-(methylamino)acetophenone (1.6 g) in dichloromethane (25 ml) was added and the solution then stirred at 10°-20° for 3 hours. The solution was cooled to 0 to 5° and water (50 ml) followed by aqueous sodium bicarbonate (1M, 50 ml) was added. The layers were separated and the aqueous layer was extracted with dichloromethane (50 ml). The combined dichloromethane layer and extract were dried over magnesium sulphate and the solvent was removed by distillation to give the novel compound 2'-(2-chloro-acetyl)-N-methylformanilide in the form of an oil.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:9][N:8]([C:10]2[CH:11]=[CH:12][C:13]3[O:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=3[CH:20]=2)[C:7](=[O:21])[CH2:6]1)=[N+]=[N-].O1CCCC1>CO.[Pd]>[NH2:1][CH2:4][C@@H:5]1[CH2:9][N:8]([C:10]2[CH:11]=[CH:12][C:13]3[O:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=3[CH:20]=2)[C:7](=[O:21])[CH2:6]1
Reactant: [N-]=[N+]=NC[C@H]1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: NC[C@H]1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To a solution of 6-[(4S)-4-(azidomethyl)-2-oxopyrrolidin-1-yl]-2H-1,4-benzoxazin-3(4H)-one (430 mg, 1.50 mmol) in methanol (40 ml)/tetrahydrofuran (40 ml) was added 10% palladium on carbon catalyst (53% aqueous, 100 mg) at room temperature and the mixture was stirred at the same temperature for 2 hours under a hydrogen atmosphere. The catalyst was removed by filtration and the residue obtained by concentrating the filtrate was purified by silica gel column chromatography (NH silica gel, dichloromethane/methanol) to yield 336 mg (86%) of the title compound in the form of a light yellow amorphous solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:13][C:14]1[CH:15]=[C:16]([CH2:32][OH:33])[CH:17]=[C:18]([F:31])[C:19]=1[O:20][C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=1>>[F:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:18]([F:31])[C:19]=1[O:20][C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)[CH2:32][O:33][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: OCc1cc(F)c(Oc2ccc(C(F)(F)F)nc2)c(F)c1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Product: CN1CCn2c1cc(OCc1cc(F)c(Oc3ccc(C(F)(F)F)nc3)c(F)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to those described for E1 starting from 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[F:12][C:13]([F:28])([F:27])[C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:12][C:13]([F:27])([F:28])[C:14]1[CH:15]=[C:16]([C:2]2[O:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=2)[CH:17]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:19]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)c1ccc(Br)o1
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: O
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)o1
Yield: 37.6 %

Procedure:
To a solution of ethyl 5-bromofuran-2-carboxylate (100 mg, 0.46 mmol) in benzene (5 mL) were added 3,5-bis(trifluoromethyl)phenylboronic acid (141 mg, 0.55 mmol), 2M Na2CO3 (6860, 1.37 mmol), and catalytic amounts of Pd(PPh3)4 (106 mg, 0.09 mmol). The reaction mixture was refluxed for 6 hrs, diluted with water and extracted with EtOAc. The extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (EtOAc/n-Hex=1:5) to give title compound (61 mg, 38%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:36]=[C:37]([O:39][CH3:40])[CH:38]=1)[CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][O:29][CH2:28][C:27]3[CH:36]=[C:37]([O:39][CH3:40])[CH:38]=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(COCCCCCBr)cc(OC)c1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(COCCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)cc(OC)c1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 5-(3,5-dimethoxybenzyloxy)pentyl bromide are reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-N-((1-(5-(3,5-dimethoxybenzyloxy)pentyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([C:7]1[CH:8]=[C:9]([CH:33]=[CH:34][C:35]=1[OH:36])[C:10]([NH:12][NH:13][C:14]([C:16]1[O:17][CH:18]=[C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:15])=[O:11])#[N:6].C(N(CC)CC)C.ClCCl>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:1]([O:36][C:35]1[CH:34]=[CH:33][C:9]([C:10]([NH:12][NH:13][C:14]([C:16]2[O:17][CH:18]=[C:19]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:15])=[O:11])=[CH:8][C:7]=1[C:5]#[N:6])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: N#Cc1cc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)ccc1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)cc1C#N
Reaction time: 0.5 h

Procedure:
Acetyl chloride (0.080 ml) was added to a mixture of the compound of Example 18 (0.42 g), 4-dimethylaminopyridine (0.013 g), triethylamine (0.17 ml) and dichloromethane (5 ml) at 0° C., and stirred for 0.5 hours at this temperature. The reaction solution was diluted with ethyl acetate, washed with water and dried over MgSO4. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate/hexane, thereby giving 0.26 g of the desired compound. Melting point: 131-133° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=1.[CH2:17]([O:19]CC)C.[Li]CCCC.CN(C=O)C>CCCCCC.O>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[C:4]=1[CH:17]=[O:19]
Reactant: COc1ccc2c(c1)Nc1ccccc1S2
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1C=O)Nc1ccccc1S2
Temperature: 20 °C
Yield: 30 %

Procedure:
4.6 g (20 mmol) of 2-methoxy-10H-phenothiazine are dissolved, under an argon atmosphere, in a three-necked flask, containing 140 ml anhydrous ethyl ether. 20 ml (50 mmol) of a solution of nBuLi (2.5 M) in hexane is then added dropwise, at 20° C. The reaction mixture is agitated for 3 hours at 20° C. before the dropwise addition of 6.2 ml (80 mmol) of anhydrous DMF. Agitation is maintained for another 15 hours at 20° C. The whole is then poured into 150 ml ice-cooled water and the product is extracted twice using 200 ml of ethyl acetate. The organic solution is washed with 100 ml of salt water, dried over MgSO4, filtered and concentrated under vacuum. The evaporation residue is taken up in diisopropyl ether, filtered and dried to produce a red solid with a yield of 30%. Melting point: 155–160° C.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[S:19][C:18]([CH2:20][C:21]([O:23]CC)=[O:22])=[N:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=O)C.Cl>>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[S:19][C:18]([CH2:20][C:21]([OH:23])=[O:22])=[N:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CCOC(=O)Cc1nnc(NS(=O)(=O)c2ccc(NC(C)=O)cc2)s1
Agent: Cl
Product: Nc1ccc(S(=O)(=O)Nc2nnc(CC(=O)O)s2)cc1
Yield: 82.1 %

Procedure:
Distilled water (3.0 mL) and 10% aqueous NaOH (1.5 mL) were added to compound 118E (300 mg, 0.78 mmol) and the mixture was heated under reflux for 2 h. The pH of the solution was then adjusted to 4.0 by addition of 1.0 M HCl, the resulting precipitate was isolated by filtration, washed with cold water, and dried to give 201 mg (0.64 mmol, 82%) of the product as a solid, mp 209-210° C.; 1H NMR (600 MHz, DMSO-d6) δ 3.59 (s, 2H), 6.52 (d, 2H, J=8.1 Hz), 7.42 (d, 2H, J=8.9 Hz); 13C NMR (75 MHz, DMSO-d6) δ 36.6, 113.3, 127.8, 128.4, 152.4, 153.3, 167.7, 170.4; MS (LCQ, ESI+) Calcd for C10H11N4O4S2 315.0. found 315.0 (M+H)+; HRMS (ESI+, m/z) Calcd for C10H11N4O4S2 315.0222. found 315.0220 (M+H)+.
Reaction SMILES: S[C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[CH:8]([OH:11])([CH3:10])[CH3:9].C1[O:15]C1C.[OH-].[Na+]>O>[OH:15][C:2]1[S:3][C:4]([S:7][CH2:9][CH:8]([OH:11])[CH3:10])=[N:5][N:6]=1
Reactant: CC(C)O
Reactant: Sc1nnc(S)s1
Reactant: CC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(O)CSc1nnc(O)s1

Procedure:
2,5-Dimercapto-1,3,4-thiadiazole (DMTD) (276.21 g, 1.84 mol) and isopropanol (400 ml) were charged to a reaction flask fitted with a reflux condenser. Propylene oxide (22.8 g, 3.84 mol) was added, with stirring, at a rate to maintain reflux. The reaction was stirred for 15 min. and then solvent was stripped under reduced pressure by rotary evaporation. This intermediate product (157.5 g, 0.592 mol), water (100 ml) and sodium hydroxide (23.7 g) were charged to a reaction flask and stirred until homogenous. Unreacted material was extracted with ether (200 ml) and additional water (200 ml). The water layer was acidified and extracted with diethyl ether (200 ml). The ether layer was separated and washed with water (200 ml). The acidified ether extract was dried over magnesium sulfate and filtered. The solvent was removed by rotary evaporation under reduced pressure. A yield of 99.2 g. was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[C:17](=[O:20])([O-])[O-].[K+].[K+].CO[C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([N+:33]([O-:35])=[O:34])[CH:32]=1)[CH2:28]Br>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:28][C:27]3[CH:30]=[C:31]([N+:33]([O-:35])=[O:34])[CH:32]=[CH:25][C:26]=3[O:20][CH3:17])[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: COc1cc(CBr)cc([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1Cn1c(CC(F)(F)F)nc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (387 mg) in DMF (5 mL) was added potassium carbonate powder (596 mg) and 3-methoxy-5-nitro-benzyl bromide (1.06 g). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40% EtOAc/hexanes) to yield the title compound as a peach-colored solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+](N[C:23]1[NH:28][C:27](=[O:29])[C:26]([CH2:30][C:31]2[CH:32]=[N:33][C:34]([CH3:38])=[C:35]([CH3:37])[CH:36]=2)=[CH:25][N:24]=1)([O-])=O>N1C=CC=CC=1>[CH2:6]([N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:23]1[NH:28][C:27](=[O:29])[C:26]([CH2:30][C:31]2[CH:32]=[N:33][C:34]([CH3:38])=[C:35]([CH3:37])[CH:36]=2)=[CH:25][N:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCCCN(Cc1ccccc1)c1ccccn1
Reactant: Cc1cc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cnc1C
Solvent: c1ccncc1
Product: Cc1cc(Cc2cnc(NCCCN(Cc3ccccc3)c3ccccn3)[nH]c2=O)cnc1C

Procedure:
2-[N-(3-aminopropyl)-N-benzylamino]pyridine (1 g) and 2-nitroamino-5-(5,6-dimethylpyrid-3-ylmethyl)pyrimid-4-one (0.94 g) were heated together under reflux in pyridine (5 ml) for 20 hrs. After stripping the resulting solid was recrystallized from ethanol/water to give 2-[3-(N-benzyl-N-pyrid-2-ylamino)propylamino]-5-(5,6-dimethylpyrid-3-ylmethyl)pyrimid-4-one 0.75 H2O, 0.61 g (38%) m.p. 95°-99° C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.CC(O)(C#C)C.[S:31]1[CH:35]=[CH:34][N:33]=[C:32]1[C:36]([OH:40])([C:38]#[CH:39])[CH3:37]>>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:39]#[C:38][C:36]([C:32]4[S:31][CH:35]=[CH:34][N:33]=4)([OH:40])[CH3:37])[CH:10]=3)[C:6]([CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:7]2)[CH:16]=[CH:15][N:14]=1
Reactant: C#CC(C)(O)c1nccs1
Reactant: Nc1nccc(-n2nc(CN3CCOCC3)c3ccc(Br)cc32)n1
Agent: C#CC(C)(C)O
Product: CC(O)(C#Cc1ccc2c(CN3CCOCC3)nn(-c3ccnc(N)n3)c2c1)c1nccs1
Reaction time: 1.5 h

Procedure:
The title compound was prepared by the procedure described in Example 6-c by substituting 4-{6-bromo-3-[(dimethylamino)methyl]-1H-indazol-1-yl}pyrimidin-2-amine with 4-[6-bromo-3-(morpholin-4-ylmethyl)-1H-indazol-1-yl]pyrimidin-2-amine and 2-methyl-but-3-yn-2-ol with 2-(1,3-thiazol-2-yl)but-3-yn-2-ol. The reaction was carried out at 60° C. for 1.5 hr. Title compound was obtained: 1H NMR (500 MHz, DMSO) δ 1.93 (3H, s), 2.45 (4H, br. s.), 3.55-3.57 (4H, m), 3.88 (2H, s), 6.98 (2H, br. s.), 7.05 (1H, d, J=5.52 Hz), 7.12 (1H, s), 7.35 (1H, dd, J=8.35, 1.26 Hz), 7.68 (1H, d, J=3.31 Hz), 7.78 (1H, d, J=3.31 Hz), 8.01 (1H, d, J=8.35 Hz), 8.27 (1H, d, J=5.52 Hz), 8.87 (1H, s); LC-MS: m/z=+462.1 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH:6]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[CH2:7][CH3:8])[CH2:3][OH:4].[N:16]#[C:17]Br>>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([CH:6]([CH2:7][CH3:8])[CH2:5][C@H:2]2[CH2:3][O:4][C:17]([NH2:16])=[N:1]2)=[CH:14][CH:13]=1
Reactant: N#CBr
Reactant: CCC(C[C@H](N)CO)c1ccc(Cl)cc1
Product: CCC(C[C@H]1COC(N)=N1)c1ccc(Cl)cc1

Procedure:
In analogy to example 1b (S)-2-amino-4-(4-chloro-phenyl)-hexan-1-ol was reacted with cyanogen bromide to give (S)-4-[2-(4-chloro-phenyl)-butyl]-4,5-dihydro-oxazol-2-ylamine (mainly one epimer). Colourless oil. MS (ISP): 255.2 ([{37Cl}M+H]+), 253.2 ([{35Cl}M+H]+).