Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][C:16](=[O:18])[N:15]([CH3:19])[C:14]([CH3:20])=[C:13]1[C:21]([O:23]C)=O.[NH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][N:30]=[C:29]2[Cl:35].C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[Cl:35][C:29]1[C:28]2[C:32](=[CH:33][CH:34]=[C:26]([NH:25][C:21]([C:13]3[CH:12]([C:3]4[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=4[F:1])[CH2:17][C:16](=[O:18])[N:15]([CH3:19])[C:14]=3[CH3:20])=[O:23])[CH:27]=2)[NH:31][N:30]=1
Reactant: COC(=O)C1=C(C)N(C)C(=O)CC1c1ccc(C(F)(F)F)cc1F
Reactant: Nc1ccc2[nH]nc(Cl)c2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Cl)c3c2)C(c2ccc(C(F)(F)F)cc2F)CC(=O)N1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 6.9 %

Procedure:
The product of Example 45, Step 1 (150 mg, 0.453 mmol, 1.00 equiv), 5-amino-3-chloroindazole (76 mg, 0.453 mmol, 1.0 equiv), and EDC (104 mg, 0.543 mmol, 1.20 equiv) were suspended in 1.0 mL DMF. Et3N (0.076 mL, 0.543 mmol, 1.2 equiv) was added and the solution was stirred at room temperature for 18 hrs. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by flash chromatography (0-80% EtOAc in Hexanes) and further purified by reverse-phase HPLC (30-80% CH3CN/H2O—NH4OH to pH 10 over 27 minutes, retention time 13.98 min) to provide 15 mg (7%) of the title compound as a white solid. MS (ES+) m/e 481 [M+H]+
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(OC(C)C)(C)C>O1CCCC1>[C:25]1([NH:31][C:32]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 80.2 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (1.00 g, 4.06 mmol) and triethylamine (0.565 ml, 4.06 mmol) in tetrahydrofuran (20 ml) was added, under ice-cooling, phenyl isocyanate (0.529 ml, 4.87 mmol), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added diisopropyl ether (40 ml), and the solid was separated by filtration. The resulting solid was recrystallized from a mixed solvent of hexane and ethyl acetate to give 1.19 g (80.4%) of the desired product as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:9][Si:10]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13].C(N)CN>>[C:2]1([NH:1][CH2:9][Si:10]([O:11][CH2:12][CH3:13])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CCO[Si](CCl)(OCC)OCC
Solvent: NCCN
Product: CCO[Si](CNc1ccccc1)(OCC)OCC
Temperature: 70 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
In a 1000 ml four-necked flask having a reflux condenser, KPG stirrer and thermometer, 602 g of dry aniline (pKb 9.4) were heated to 120° C. and 200 g of (chloromethyl)triethoxysilane were added in the course of 180 min with stirring and stirring was effected for a further 60 min. Thereafter, the temperature was reduced to 105° C. and 109 g of ethylenediamine (pKb 4.07) were added to the mixture in the course of 10 min with stirring, phase separation occurring. At constant temperature, stirring was effected for a further 30 min, cooling to 70° C. being effected and the heavier ethylenediamine hydrochloride phase then being separated off. 27 g of anhydrous Lupasol G20 (BASF AG) are then added to the upper phase and distilled as described in Example 4. 200 g of N-phenylaminomethyltriethoxysilane (73.2% yield) having a purity of 94.9% are obtained. The chloride value was 8 ppm.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])([CH3:4])Cl.[CH3:6][C:7]1[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=1>C[Si](N[Si](C)(C)C)(C)C>[CH3:1][Si:2]([C:12]1[NH:11][C:10](=[O:13])[N:9]([Si:2]([CH3:5])([CH3:4])[CH3:1])[C:8](=[O:14])[C:7]=1[CH3:6])([CH3:5])[CH3:4]
Reactant: C[Si](C)(C)Cl
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: Cc1c([Si](C)(C)C)[nH]c(=O)n([Si](C)(C)C)c1=O

Procedure:
Trimethylchlorosilane (4 ml) was added to a suspension of 5-methyluracil (thymine) (5 g) in hexamethylsilazane (20 ml) followed by refluxing for 5 hours. The resulting ammonium chloride was removed by filtration and the filtrate was evaporated to give bis(trimethylsilyl)-5-methyluracil as oil. To a solution of the oil in dry dichloromethane (10 ml) was added 2-methyl-1,3-dioxolane (15 ml) and then was added dropwise stannic chloride (5 ml). After allowing the mixture to stand at room temperature overnight, it was treated as in Example 10 to give 4.6 g of crystalline 1-[α-(2-hydroxyethoxy)-ethyl]-5-methyluracil.
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]2[CH2:7][CH2:8][C:9]3[CH:15]=[C:14]([CH2:16][CH:17](C(OCC)=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=1)#[N:2].O.[Cl-].[Na+].CS(C)=O>C(Cl)Cl>[C:1]([C:3]1[CH:29]=[CH:28][C:6]2[CH2:7][CH2:8][C:9]3[CH:15]=[C:14]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=1)#[N:2]
Reactant: CCOC(=O)C(Cc1ccc2c(c1)CCc1ccc(C#N)cc1S2)C(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)CCc1ccc2c(c1)CCc1ccc(C#N)cc1S2

Procedure:
A mixture of ethyl 3-(7-cyano-10,11-dihydrodibenzo[b,f]thiepin-2-yl)-2-ethoxycarbonylpropanoate (4.025 g; 4.84 mmole), water (354 mg; 19.7 mmole), sodium chloride (576 mg) and dimethylsulfoxide (100 ml) are heated together under argon in an oil bath at 200°-205° C. for 3 hours. The cool reaction mixture was diluted with methylene chloride and the solution was extracted with water (3×100 ml), then dried (MgSO4) and evaporated to an oil (3.223 g; 97%). The pure title compound was obtained by short path distillation of the crude product (oven temperature 200° C./0.05 Torr).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[F:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:18])[CH:15]=NO)=[CH:9][CH:8]=1>C(OCC)(=O)C>[F:6][C:7]1[CH:12]=[C:11]2[C:10](=[CH:9][CH:8]=1)[NH:13][C:14](=[O:18])[C:15]2=[O:2]
Reactant: O=S(=O)(O)O
Reactant: O=C(C=NO)Nc1ccc(F)cc1
Solvent: CCOC(C)=O
Product: O=C1Nc2ccc(F)cc2C1=O
Temperature: 90 °C

Procedure:
Concentrated sulfuric acid (200 mL) was heated at 50° C., and N-(4-fluorophenyl)-2-hydroxyiminoacetamide was slowly added. The black solution was carefully heated at 90° C. At this temperature, some slight cooling was necessary to keep the temperature at 90° C. When no more heat had developed, the reaction mixture was heated at 90° C. for an additional half hour. The dark-red solution was cooled to room temperature and poured onto 3 L ice water and 1 L ethyl acetate with vigorous stirring. The layers were separated, and the aqueous layer was extracted with ethyl acetate (1×1 L, 1×0.5 L). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to dryness. Yield: 35.3 g (52%) of a dark red solid, 5-fluoro-1H-indole-2,3-dione.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[Br:12][CH2:13][CH2:14]Br>C(O)C>[Br:12][CH2:13][CH2:14][O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: BrCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=Cc1ccc(OCCBr)cc1
Yield: 40.9 %

Procedure:
To a solution of potassium hydroxide (3.70 g, 54.0 mmol) in ethanol (50 ml) is added 4-hydroxybenzaldehyde (6.00 g, 49.1 mmol) and 1,2-dibromoethane (46.15 g, 245.7 mmol). Then the mixture is heated to reflux for 8 hours. After cooled, the reaction mixture is evaporated under vacuum. The residue is dissolved in water and extracted with dichloromethane (3×50 ml). The organic phase is washed with water (3×50 ml), dried over MgSO4 and evaporated to give a crude product, which is crystallized from ethanol to give the title compound (4.60 g, 41%).
Reaction SMILES: CS[C:3]1[S:4][CH2:5][C:6](=[O:8])[N:7]=1.[CH2:9]([N:11]([CH2:16][CH3:17])[CH2:12][CH2:13][NH:14][CH3:15])[CH3:10]>>[CH2:9]([N:11]([CH2:16][CH3:17])[CH2:12][CH2:13][N:14]([CH3:15])[C:3]1[S:4][CH2:5][C:6](=[O:8])[N:7]=1)[CH3:10]
Reactant: CCN(CC)CCNC
Reactant: CSC1=NC(=O)CS1
Product: CCN(CC)CCN(C)C1=NC(=O)CS1

Procedure:
2-[(2-Diethylamino-ethyl)-methyl-amino]-thiazol-4-one was prepared from 2-Methylsulfanyl-thiazol-4-one and N,N-Diethyl-N′-methyl-ethane-1,2-diamine following general procedure E.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][CH2:9][CH2:10][CH2:11][CH3:12]>>[C:2]1([C:9]23[CH2:12][CH:11]([CH2:8]2)[CH2:10]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: CCCCC
Product: c1ccc(C23CC(C2)C3)cc1

Procedure:
1.28 ml (0.5 e.g.) of iodobenzene were added to a solution of propellane (10 mmol) generated via Procedure B. The solution was transferred into a borosilicate tube and irradiated 1 hr, after which GC analysis of the solution showed three new major peaks. The reaction mixture was reduced in volume, high vacuum applied (40° C./0.2 mm Hg) to remove starting material and 1-iodobicyclo[1.1.1]pentane. After these products were removed, 1-iodo-3-phenylbicyclo[1.1.1]pentane sublimed out of the mixture (40°-50° C./0.2 mm Hg): 1H NMR 2.06 (s, 6H); EIMS, m/z (relative intensity) 77(24), 127(25), 128(100), 143(91). Resublimation produced an analytical sample having mp. 64°-65° C. Recrystallization from penfane at 0° C. gave a gummy solid. The liquid was diluted with pentane and recrystallization at -78° C., giving 1-phenylbicyclo[1.1.1]pentane: The solid, a mixture of 1-phenyl]2]staffane and 3-iodo-3'-phenyl[2]staffane by GCMS, was recrystallized from benzene.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:9](B(O)O)[CH:10]([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>C1COCC1.[Ag]=O>[Cl:1][C:2]1[C:3]([CH2:9][CH:10]([CH3:12])[CH3:11])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CB(O)O
Reactant: Clc1cccnc1I
Agent: O=[Ag]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Cc1ncccc1Cl
Temperature: 75 °C
Yield: 52.9 %

Procedure:
3-Chloro-2-iodopyridine (1.552 g, 6.482 mmol), isobutylboronic acid (0.725 g, 7.112 mmol), potassium carbonate (2.7 g, 0.0195 mol) and silver oxide (3.8 g, 0.0164 mol) were suspended in THF (25 mL). The mixture was degassed three times and 1,1-Bis(diphenylphosphino)ferrocene-palladium(11)dichloride dichloromethane (1:1) (0.520 g, 0.637 mmol) was added. The reaction mixture was heated at 75° C. under nitrogen for seven hours. The mixture was diluted EtOAc (15 mL) and washed with an aqueous solution of hydrochloric acid (2.0 M, 2×15 mL). The organic layer was discarded and the aqueous layer basified with careful addition of a saturated aqueous solution of sodium hydrogen carbonate (50 mL). The product was extracted with EtOAc (2×15 mL). The organics were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude was purified by silica gel chromatography eluting with 0 to 5% EtOAc in heptane to yield the title compound as a colourless oil (0.582 g, 53% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[C:6]=2[N:7]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[Cl:20])[CH2:13][S:12][C:8]1[C:6]2[N:7]=[C:2]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[N:3]=[C:4]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: C1CNCCN1
Reactant: Clc1nc(N2CCOCC2)c2ncnc(SCc3ccc(Cl)c(Cl)c3)c2n1
Product: Clc1ccc(CSc2ncnc3c(N4CCOCC4)nc(N4CCNCC4)nc23)cc1Cl

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(3,4-dichlorobenzyl-thio)-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 153°-156° C.) and piperazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][N:12]([CH:22]([O:24][CH2:25][CH3:26])[CH3:23])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.CN(C)CCN(C)C.C([Li])CCC.CN(C)[C:42](=[O:47])[C:43]([F:46])([F:45])[F:44].C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([C:42](=[O:47])[C:43]([F:46])([F:45])[F:44])[N:12]([CH:22]([O:24][CH2:25][CH3:26])[CH3:23])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:7][CH:8]=1
Reactant: CN(C)C(=O)C(F)(F)F
Reactant: CCOC(C)n1cnc(-c2ccc(OC)cc2)c1-c1ccc(OC)cc1
Agent: CN(C)CCN(C)C
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(C)n1c(C(=O)C(F)(F)F)nc(-c2ccc(OC)cc2)c1-c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.2 %

Procedure:
To a stirred solution of 14.12 g (40 mmoles) 4,5-bis(4-methoxyphenyl)-1-(α-ethoxyethyl)imidazole and 4.64 g tetramethylethylenediamine in 100 ml of dry THF under an atmosphere of nitrogen and cooled at -78° was added dropwise 30 ml of 1.6 M n-butyl lithium solution. After stirring for 15 minutes, a solution of 5.7 g (40.1 mmoles) N,N-dimethyltrifluoroacetamide in 30 ml of dry THF was added dropwise. After the addition was complete, the reaction mixture was stirred for 1 hour, with continued cooling, and then 150 ml of a saturated aqueous sodium bicarbonate solution was added dropwise. The mixture was allowed to warm to room temperature. The THF was removed by evaporation under vacuo on a rotary evaporator. The organic components were then extracted with 400 ml of methylene chloride, washed with 100 ml of a saturated solution of sodium bicarbonate, followed by water, and the organic extract was dried over magnesium sulfate. The inorganic salts were removed by filtration, and the solvent was removed by evaporation. The residue was chromatographed on a column of 250 g silica gel, eluting with a solvent mixture consisting of 90 parts toluene and 10 parts ethyl acetate. The chromatographed product thus obtained was crystallized from methyl cyclohexane to give 9 g of 1-[ 4,5-bis(4-methoxyphenyl)-1-(α-ethoxyethyl)-1H-imidazol-2-yl]2,2,2-trifluoro-1-ethanone, m.p. 124°-126°. Infrared and NMR spectra were consistent with the assigned structure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.O>CS(C)=O>[C:1]([O:5][C:6](=[O:13])[NH:7][C:8]([CH3:12])([CH3:11])[CH:9]=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(CO)NC(=O)OC(C)(C)C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C=O)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
(2-Hydroxy-1,1-dimethyl-ethyl)-carbamic acid tert-butyl ester (11.3 g, 0.06 mol) and triethylamine (18.2 g, 0.18 mol) in DMSO (180 mL) at 25° C. was treated with a solution of pyridine-sulfurtrioxide complex (28.6 g, 0.18 mol) in DMSO (150 mL). The resulting mixture was stirred for 0.5 h, poured into H2O (100 mL) and extracted with ether (3×100 mL). The organics were washed with 10% citric acid(aq) (250 mL), saturated NaHCO3 (250 mL) and then with brine (2×250 mL). The organics were dried and concentrated to an off-white solid which was recrystallized from hexanes to afford the desired material (8.0 g, 71%) as white needles: 13C NMR (DMSO-d6, 100 MHz) δ 202.07, 155.58, 78.95, 58.64, 28.42, 21.58.
Reaction SMILES: [CH2:1]([C:3]([C:21]1[CH:34]=[CH:33][C:24]([CH:25]=[C:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[C:23]([CH3:35])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]>CO>[CH2:1]([C:3]([C:21]1[CH:34]=[CH:33][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[C:23]([CH3:35])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:17])([CH3:18])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(c1ccc(C=C2SC(=O)NC2=O)c(C)c1)c1ccc(OCC(O)C(C)(C)C)c(C)c1
Solvent: CO
Product: CCC(CC)(c1ccc(CC2SC(=O)NC2=O)c(C)c1)c1ccc(OCC(O)C(C)(C)C)c(C)c1
Yield: 34 %

Procedure:
To a mixture of enantiomer 2 of 5-(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzylidene)-thiazolidine-2,4-dione (example Rupp-7) (0.25 g, 0.50 mmol) and MeOH (10 mL) is added Mg (0.12 g, 5.04 mmol). The solution is heated at a reflux for 4 hours. The solution is filtered thru celite® rinsed with MeOH (2 mL), and the solution concentrated. The residue is purified by ISCO (15%-30% EtOAc gradient) to furnish the title compound (0.084 g, 0.17 mmol, 34%).
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[C:7]([CH3:15])[C:5]=2[N:6]=1.[Cl-:16].[Na+].C1OCCOCCOCCOCCOC1.N(OC(C)(C)C)=O>C(#N)C.[Cu]Cl.O>[Cl:16][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[C:7]([CH3:15])[C:5]=2[N:6]=1
Reactant: [Cl-]
Reactant: COC(=O)c1ccc2sc(N)nc2c1C
Agent: Cl[Cu]
Agent: C1COCCOCCOCCOCCO1
Agent: CC(C)(C)ON=O
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc2sc(Cl)nc2c1C
Yield: 77.3 %

Procedure:
A solution of 5 g (22.5 mmol) of methyl 2-amino-4-methyl-benzothiazole-5-carboxylate in 2 l of acetonitrile was admixed with 10 ml of water, 4.5 g (44.8 mmol) of copper(I) chloride, 6.6 g of sodium chloride (110 mmol) and 2 ml of 15-crown-5. A solution of 3 g (29 mmol) of tert-butyl nitrite was then added dropwise with stirring, the solution was heated at reflux for 15 h, the resulting precipitate was filtered off and the solution was concentrated under reduced pressure. The residue was then extracted three times with in each case 500 ml of ethyl acetate. To this end, the solvent was heated to boiling point and the solution was filtered whilst hot. The extracts were concentrated under reduced pressure. The residue was purified by trituration with n-hexane/diethyl ether. This gave 4.2 g (17.4 mmol, 77% yield) of methyl 2-chloro-4-methylbenzothiazole-5-carboxylate of m.p. 112° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([CH2:15][OH:16])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([CH:15]=[O:16])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(CO)cc2s1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCOC(=O)c1cc2ccc(C=O)cc2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-hydroxymethyl-benzo[b]thiophene-2-carboxylic acid ethyl ester (2.651 g, 11.22 mmol) in 110 mL of CH2Cl2 was added MnO2 (13.50 g). The mixture was allowed to stir at rt for 30 min and then filtered through a pad of Celite. The filtrate was concentrated and dried to give 6-formyl-benzo[b]thiophene-2-carboxylic acid ethyl ester as a pale solid. 1H NMR (CDCl3, 200 MHz) δ 10.09 (s, 1H), 8.34 (s, 1H), 8.07 (s, 1H), 7.97 (d, J=8.0 Hz, 2H), 7.88 (dd, J=8.4, 1.4 Hz, 1H), 4.40 (q, J=7.0 Hz, 2H), 1.41 (t, J=7.0 Hz, 3H). MS (EI): cal'd 235.0 (MH+), exp 235.1 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:16]([CH3:20])[CH:17]=[CH:18][N:19]=2)[C:5]([Cl:21])=[CH:4][N:3]=1.[CH2:22]([N:24]1[CH2:30][CH2:29][C:28]2[CH:31]=[C:32]([NH2:35])[CH:33]=[CH:34][C:27]=2[CH2:26][CH2:25]1)[CH3:23].Cl.O1CCOCC1.C(O)(C(F)(F)F)=O>COCCO>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:16]([CH3:20])[CH:17]=[CH:18][N:19]=2)=[N:7][C:2]([NH:35][C:32]2[CH:33]=[CH:34][C:27]3[CH2:26][CH2:25][N:24]([CH2:22][CH3:23])[CH2:30][CH2:29][C:28]=3[CH:31]=2)=[N:3][CH:4]=1
Reactant: Cn1ccnc1-c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCc2ccc(N)cc2CC1
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4-c4nccn4C)n3)cc2CC1
Temperature: 120 °C
Reaction time: 4 h
Yield: 62.6 %

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-[2-(1-methyl-1H-imidazol-2-yl)-phenyl]-amine. A solution of crude 2-(1-Methyl-1H-imidazol-2-yl)-phenylamine (220 mg, 1.27 mmol) in DMF (8 mL) was treated with 2,4,5-trichloropyrimidine (233 mg, 1.27 mmol) and potassium carbonate (526 mg, 3.81 mmol). The mixture was then heated to 80° C. and was allowed to stir overnight. The reaction mixture was then cooled and DMF was removed en vacuo. The residue was taken up in ethyl acetate (20 mL) and was poured over saturated NH4Cl (20 mL). The organics were then extracted with ethyl acetate (3×20 mL). Combined extracts were dried over sodium sulfate, filtered and reduced. The product was then isolated and purified by flash column chromatography (0% ethyl acetate/hexane-75% ethyl acetate hexane) to afford 140 mg of (2,5-Dichloro-pyrimidin-4-yl)-[2-(1-methyl-1H-imidazol-2-yl)-phenyl]-amine as an off white solid. 216d) A solution of (2,5-Dichloro-pyrimidin-4-yl)-[2-(1-methyl-1H-imidazol-2-yl)-phenyl]-amine (47 mg, 0.15 mmol) in 2-methoxyethanol (3 mL) was treated with 3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (28 mg, 0.15 mmol) and 4N HCl/Dioxane (0.074 mL, 0.29 mmol). The reaction mixture was heated to 120° C. and was allowed to stir for approximately 4 hours. The reaction mixture was then reduced en vacuo and the product was purified and isolated by prep HPLC to afford 44.5 mg of 5-Chloro-N*2*-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-N*4*-[2-(1-methyl-1H-imidazol-2-yl)-phenyl]-pyrimidine-2,4-diamine as the TFA salt. The product was isolated as a foam, LC/MS (ESI)=474.42 (M+H). 1H NMR (400 MHz, CDCl3) δ 7.89 (t, 1H, J=7.58 Hz), 7.74 (m, 2H), 7.66 (d, 1H), 7.45 (d, 1H, J=7.83 Hz), 7.39 (s, 1H), 7.08 (s, 1H), 6.97 (m, 2H), 6.81 (d, 1H, J=8.08 Hz), 3.72 (m, 2H), 3.49 (m, 2H), 3.33 (m, 2H), 3.21 (s, 3H), 2.87 (m, 2H), 2.67 (m, 2H), 1.40 (t, 3H, J=7.07 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([O:20][CH3:21])=[C:13]([O:22][CH3:23])[CH:12]=2)=O)=[CH:5][CH:4]=1.Cl.[F:25][C:26]1[CH:27]=[C:28]([CH:33]([NH2:35])[CH3:34])[CH:29]=[C:30]([F:32])[CH:31]=1.C(N(CC)CC)C.C([BH3-])#N.[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C>[F:25][C:26]1[CH:27]=[C:28]([CH:33]([NH:35][CH:9]([C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([O:20][CH3:21])=[C:13]([O:22][CH3:23])[CH:12]=2)[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH3:34])[CH:29]=[C:30]([F:32])[CH:31]=1
Reactant: CC(N)c1cc(F)cc(F)c1
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)c([N+](=O)[O-])c2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: COc1ccc(C(NC(C)c2cc(F)cc(F)c2)c2cc(OC)c(OC)c([N+](=O)[O-])c2)cc1
Yield: 91.4 %

Procedure:
Following a similar procedure to that described in Example (1a), 750 mg of 3,4-dimethoxy-5-nitrophenyl 4-methoxyphenyl ketone, 915 mg of 1-(3,5-difluorophenyl)ethylamine hydrochloride, 1.98 ml of triethylamine, 0.31 ml of titanium tetrachloride, 660 mg of sodium cyanoborohydride and 0.20 ml of acetic acid were reacted, to obtain 990 mg of the title compound as a yellow oil.