Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][N:16]=2)[CH2:13][C:12]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[N:11]1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][N:24]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:23][CH2:22]3)[CH:18]=[CH:17][N:16]=2)[CH2:13][C:12]([C:27]([F:33])([F:32])[C:28]([F:29])([F:30])[F:31])=[N:11]1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cc(N3CCNCC3)ccn2)c(F)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2ccnc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.3 %

Procedure:
1-(2,4-Difluoro-phenyl)-5-[4-(piperazin-1-yl)-pyridin-2-yl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Example 182, triethylamine (42.0 uL, 0.30 mmol) and methanesulfonyl chloride (7.0 uL, 0.09 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 18 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH3:5].[NH:7]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][N:10]=1)[NH2:8].Cl>CCOCC>[CH:1](=[N:8][NH:7][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC=O
Reactant: NNC1=NCCc2ccccc21
Agent: Cl
Solvent: CCOCC
Product: CCCCC=NNC1=NCCc2ccccc21

Procedure:
Valeraldehyde (5.14 g.) was added to a refluxing solution of 1-hydrazino-3,4-dihydroisoquinoline (8 g.) in ether (300 ml.). The mixture was allowed to stand (for 45 min.) at room temperature. Ethereal hydrochloric acid was added. Recrystallization of the resulting solid from ethanol-ether gave 1-(2-pentylidenehydrazino)-3,4-dihydroisoquinoline (I: X=CH3 (CH2)3, X'=Y=Y'=Z=Z'=H) hydrochloride in two crops (11.6 g. and 0.2 g., m.p. 147°-148° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[CH3:9][C:10]1(C)[C:14](C)(C)OB(C(C)=C)O1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.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>[CH2:9]=[C:10]([C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1)[CH3:14]
Reactant: Nc1cncc(Br)c1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)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: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)c1cncc(N)c1
Temperature: 90 °C
Yield: 230.4 %

Procedure:
5-Bromopyridin-3-amine (0.433 g, 2.5 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.630 g, 3.75 mmol), Cs2CO3 (3.10 g, 9.5 mmol) and Pd(PPh3)4 (0.289 g, 0.25 mmol) were suspended in DMF/H2O (3:1, 20 mL). The reaction mixture was degassed with N2 and heated at 90° C. for 16 h. Solvent was removed under reduced pressure. The residue was diluted with H2O (20 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (20 mL), dried, concentrated in vacuo and purified by chromatography to afford 5-(prop-1-en-2-yl)pyridin-3-amine (0.773 g, 230%) as a dark yellow oil. MS (ESI) m/z: 135.0 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=3[N:16]=[C:15]2[C:24](=[O:26])[CH3:25])[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:23][C:21]1[CH:20]=[CH:19][C:18]2[N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:15]([C:24](=[O:26])[CH3:25])=[N:16][C:17]=2[CH:22]=1
Reactant: CC(=O)c1nc2cc(C)ccc2n1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)c1nc2cc(C)ccc2n1C1CCNCC1
Reaction time: 1 h
Yield: 100 %

Procedure:
4-(2-acetyl-5-methyl-benzoimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (107 mg, 0.30 mmol) was dissolved in a mixture of trifluoroacetic acid (2 mL) and CH2Cl2 (2 mL) at rt and stirred for 1 hour. The mixture was concentrated under reduced pressure and the residue was partitioned between dilute aqueous K2CO3 solution (20 mL) and CH2Cl2 (20 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2×15 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 1-(5-methyl-1-piperidin-4-yl-1H-benzoimidazol-2-yl)-ethanone as an oil (77 mg, 0.30 mmol, 100%) that was used without further purification or characterization.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH:10]1([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([NH2:29])=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1COCC1>[CH:10]1([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]4=[N:29][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:25]4[CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: Nc1ncccc1-c1ccc(OC2CCCCC2)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC=C(c3ccc(OC4CCCCC4)cc3)C2=N1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 127 mg) in THF (dry) (5 mL) was added 2-chloroethanesulfonyl chloride (0.200 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-[4-(cyclohexyloxy)phenyl]pyridin-2-amine (170 mg) in THF (dry) (5 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen overnight. The mixture was quenched with water at 0° C. carefully. Water was added to form precipitates which were washed with water and hexane, collected and dried in vacuo to give the title compound (148 mg) as a white powder. A part of this product was crystallized from MeCN-THF/IPE to give a colorless crystal.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[OH-].[K+:26]>O>[C:1]([O-:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[K+:26]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]
Temperature: 85 °C

Procedure:
To a tank (34) containing 1000 ml of pure water kept at 30° C., the foregoing nucleus particles were continuously introduced. Into a tank (35) containing 244.3 g of behenic acid and 4750 g of pure water with stirring at 85° C., 432.7 ml of 5N aqueous KOH solution was added in 5 min. and reacted further for 60 min. to obtain a potassium behenate solution. Finally, water was added to make the total amount to 6000 ml. To a tank (36), 1050 ml of aqueous solution containing 110.3 g of silver nitrate was added and maintained at 10° C. Further, 600 ml of an aqueous solution containing 43 g of light-sensitive silver halide emulsion A was prepared in a tank (37) and maintained at 30° C. The foregoing potassium behenate solution, aqueous silver nitrate solution and silver halide solution were added by triple jet addition at flow rates of 150 ml/min. 30 ml/min and 15 ml/min, respectively to undergo particle growth.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]1[C:12]2[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[O:22])[C:13]=2[N:14]=[CH:15][N:16]=1)[CH3:2].[C:30](Cl)(=[O:33])[CH2:31][CH3:32]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]1[C:12]2[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH:24]3[CH2:25][CH2:26][N:27]([C:30](=[O:33])[CH2:31][CH3:32])[CH2:28][CH2:29]3)=[O:22])[C:13]=2[N:14]=[CH:15][N:16]=1)[CH3:2]
Reactant: CCC(=O)Cl
Reactant: CCOc1ccc(F)cc1-c1ncnc2c(C(=O)NC3CCNCC3)c(C)[nH]c12
Product: CCOc1ccc(F)cc1-c1ncnc2c(C(=O)NC3CCN(C(=O)CC)CC3)c(C)[nH]c12

Procedure:
Starting from 4-(2-ethoxy-5-fluorophenyl)-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (example D.f17) and commercially propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][O:6][C:7]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:8][CH2:9][NH:10][CH2:11][CH:12]1[CH2:14][CH2:13]1)C.[H][H].[ClH:32]>C(O)C.[Pd]>[ClH:32].[CH:12]1([CH2:11][N:10]2[CH2:9][CH2:8][C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:6][CH2:5][CH2:4]2)[CH2:14][CH2:13]1
Reactant: CCOC(COC(CCNCC1CC1)(c1ccccc1)c1ccccc1)OCC
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1ccc(C2(c3ccccc3)CCN(CC3CC3)CCO2)cc1

Procedure:
The solution of 6.0 g of 2-(3-cyclopropylmethylamino-1,1-diphenylpropoxy)-acetaldehyde diethyl acetal in 60 ml of 95% ethanol and 10 ml of 6N hydrochloric acid is stirred at 20-45° for 3 hours, cooled and 0.5 g of 10% palladium on charcoal are added. The mixture is hydrogenated at 2.7 atm. and 40° until the hydrogen uptake ceases. It is filtered, the filtrate neutralized with aqueous sodium hydroxide and evaporated. The resudue is partitioned between water and methylene chloride, the organic phase separated, dried and evaporated. The residue is taken up in the minimum amount of acetone, the solution acidified with hydrogen chloride and diluted with diethyl ether, to yield the 4-cyclopropylmethyl-7,7-diphenyl-hexahydro-1,4-oxazepine hydrochloride melting at 268°-270°; it is identical with compound No. 11 of Example 2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.[O-:13][CH2:14]C.[Na+]>CO>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([O:13][CH3:14])[N:3]=1
Reactant: CC[O-]
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(OC)nc(Cl)n1
Reaction time: 16 h
Yield: 24 %

Procedure:
Methyl 2,6-dichloropyrimidine-4-carboxylate (10 g) (M. Winn et. al., J.Med.Chem. 36 (18), (1993), 2676-2688) in methanol (100 ml) was treated with sodium ethoxide (3 g) and left for 16 hours. Methanol was evaporated and the residue partitioned between dichloromethane and saturated aqueous NaHCO3. The organic was washed with brine, dried and evaporated to give the title compound (24%). NMR δ(CDCl3) 4.00(3H, s), 4.07(3H, s), 7.37(1H, s). (b) Sodium 2-chloro-6-methoxypyrimidine-4-carboxylate
Reaction SMILES: Br[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[O:13])[C:5](=[O:14])[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[NH3:19]>>[OH:13][C:6]12[NH:19][CH:2]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=31)[C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[C:5]2=[O:14]
Reactant: N
Reactant: O=C1C(=O)c2ccccc2C(Br)c2ccccc21
Product: O=C1c2ccccc2C2NC1(O)c1ccccc12
Temperature: -40 °C
Reaction time: 1 h

Procedure:
10 g of 5-bromo-10,11-dihydro-[5H]-dibenzo (a,d) cycloheptene-10,11-dione was added to 250 ml of ammonia cooled to -40° C and then stirred for 1 hour at -40° C. The ammonia was distilled off and after adding 100 ml of 5 N hydrochloric acid thereto, the mixture was heated at 60°-65° C for 30 minutes. The mixture was cooled, made alkaline with addition of 110 ml of ammonium hydroxide and extracted with methylene chloride. The organic phase was washed with water, dried over magnesium sulfate and distilled to dryness under reduced pressure. The residue was crystallized from ether, vacuum filtered and dried to obtain 7.4 g of 10-hydroxy-10,11-dihydro-5,10-imino-[5H]dibenzo (a,d) cycloheptene-11-one dl melting at 214° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC(OC)OC.[NH2:16][CH2:17][CH2:18][CH2:19][OH:20].[BH4-].[Na+]>CO>[CH2:1]([NH:16][CH2:17][CH2:18][CH2:19][OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: NCCCO
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: OCCCNCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.6 %

Procedure:
To a solution of benzaldehyde (10 g, 94.23 mmol) and trimethylorthoformate (15.5 mL, 141 mmol ) in MeOH (300 mL) was added dropwise 3-amino-1-propanol (7.21 mL, 94.23 mmol) at room temperature. The reaction was allowed to stir at room temperature for 5 hours followed by cooling to 0° C. in an ice bath. Sodium borohydride (3.56 g, 94.23 mmol) was added in two portions and when the bubbling stopped the solvent was evaporated. The resulting residue was partitioned between ethyl acetate (75 mL) and water (75 mL). The aqueous layer was extracted twice with ethyl acetate (75 mL). The ethyl acetate extracts were collected and washed twice with Brine (50 mL), dried over MgSO4, filtered, and concentrated. Drying afforded 14.42 g (93%) of the compound which was used in the next step of synthesis without further purification.
Reaction SMILES: Br[CH:2]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:12]=1[Cl:21])[C:3]1[CH:4]=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.[CH3:22][OH:23]>C1(C)C=CC=CC=1>[CH3:22][O:23][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:12]=1[Cl:21])[C:3]1[CH:4]=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1
Reactant: CO
Reactant: CS(=O)(=O)c1ccc(C(Br)c2cnoc2C2CC2)c(Cl)c1
Solvent: Cc1ccccc1
Product: COC(c1ccc(S(C)(=O)=O)cc1Cl)c1cnoc1C1CC1

Procedure:
A mixture of 4-[bromo-(2-chloro-4-methanesulphonylphenyl)methyl]-5-cyclopropylisoxazole (2.5 g) and methanol (2.0 ml) in toluene was stirred at reflux for 16 hours. The resultant solution was evaporated to dryness and the residue was dissolved in ethyl acetate. This solution was washed with water, dried (MgSO4), and filtered. The filtrate was evaporated to dryness. The residue was purified by chromatography on silica eluted with ethyl acetate and petroleum ether to give 4-[methoxy-(2-chloro-4-methanesulphonylphenyl)methyl]-5-cyclopropylisoxazole (compound 307, 1.40 g) as a colourless oil, NMR: (CDCl3) 1.0(4H,m), 2.1 (1H,m), 3.0(3H,s), 3.3(3H,s), 5.6(1H,s), 7.9(4H,m).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([C:15]([NH2:17])=[O:16])[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]([NH2:17])=[O:16])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: NC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C

Procedure:
10.2 mL benzylchloride was added to 10 g piperidine-4-carboxylic acid amide and 21.6 g potassiumcarbonate in 280 mL DMF at 5° C. The reaction was stirred over night at RT. The solvent was removed and the residue was dissolved in water and dichlormethane. The organic layer was separated and evaporated. The residue was purified by column chromatographie (silica gel, eluent: dichlormethane/methanol 95:5 to 90:10) to give 9.8 g of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH3:14])=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:8][C:4]=2[CH:3]=1.[N+:17]([O-])([OH:19])=[O:18]>C(O)(=O)C>[CH2:12]([O:11][C:9]([C:7]1[O:8][C:4]2[C:3]([N+:17]([O-:19])=[O:18])=[C:2]([OH:1])[CH:16]=[CH:15][C:5]=2[C:6]=1[CH3:14])=[O:10])[CH3:13]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1oc2cc(O)ccc2c1C
Solvent: CC(=O)O
Product: CCOC(=O)c1oc2c([N+](=O)[O-])c(O)ccc2c1C

Procedure:
A suspension of ethyl 6-hydroxy-3-methyl-benzofuran-2-carboxylate (220 mg, 1 mmole) in acetic acid (10 ml) was treated dropwise and with stirring with 0.2N nitric acid in acetic acid (5 ml). Solution occurred and then a yellow precipitate was formed. The solid was collected and washed with 50% aqueous acetic acid to give 98 mg of ethyl-6-hydroxy-7-nitro-3-methylbenzofuran-2-carboxylate, m.p. 186°-187.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[O:10][CH3:11].C([Li])CCC.CON(C)[C:20]([C:22]1[C:23]([NH2:31])=[N:24][C:25]([S:28][CH2:29][CH3:30])=[N:26][CH:27]=1)=[O:21]>CCCCC.O1CCCC1.O1CCCC1>[NH2:31][C:23]1[C:22]([C:20]([C:2]2[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=2[O:10][CH3:11])=[O:21])=[CH:27][N:26]=[C:25]([S:28][CH2:29][CH3:30])[N:24]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: COc1cc(F)c(F)cc1Br
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCSc1ncc(C(=O)c2cc(F)c(F)cc2OC)c(N)n1
Temperature: -72 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-bromo4,5-difluoro-anisole (1.95 g, 8.75 mmol, Astatech) in a mixture of pentane/tetrahydrofuran (5 mL/17 mL) was cooled to −72° C. and treated with n-butyl lithium (2.5 M in hexane, 3.6 mL, 9.0 mmol). After stirring for 10 minutes, a solution of 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide (0.78 g, 3.21 mmol, Example 1) in tetrahydrofuran (3 mL) was added. The temperature was slowly raised to −35° C. for ˜2 hours. The reaction was quenched at −35° C. with 5% aqueous ammonium chloride solution and the mixture was diluted with ethyl acetate/hexane (100 mL). The organic phase was separated, washed with 1:1 water/saturated aqueous sodium chloride solution and dried (Na2SO4). The residue after solvent removal was purified by HPLC chromatography (Waters Prep 500 eluting with 35% ethyl acetate/hexane) to give, in approximately 1:1 ratio, the two positional isomers (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone identical to material prepared in Example 102, and (4-Amino-2-ethylsulfanyl-pyrimidin-5-yl)-(4,5-difluoro-2-methoxy-phenyl)-methanone as a white solid after evaporation. HRMS, observed: 326.0772; Calcd for M+: 326.0770.
Reaction SMILES: Cl[C:2](/[CH:4]=[C:5](/[C:7]1[CH:8]=[CH:9][C:10]([O:17][CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13])\[CH3:6])=[O:3].[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>C1COCC1>[CH2:26]([N:28]([CH2:29][CH3:30])[C:2](/[CH:4]=[C:5](/[C:7]1[CH:8]=[CH:9][C:10]([O:17][CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13])\[CH3:6])=[O:3])[CH3:27]
Reactant: CCNCC
Reactant: COC(=O)c1cc(/C(C)=C/C(=O)Cl)ccc1OC(C)c1ccccc1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)/C=C(\C)c1ccc(OC(C)c2ccccc2)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl (E)-5-(2-chlorocarbonyl-1-methylvinyl)-2-(1-phenylethoxy)-benzoate (1.0 g, 2.79 mmol)in THF (50 mL) is added diethylamine (1.16 mL, 11.8 mmol), and the mixture is stirred at room temperature for 3 hours, after which time THF is removed in vacuo, and the residue is lssoved in CH2Cl2 (75 mL) and then washed with 1 N HCl (2×100 mL) and brine (1×50 mL), and dried over MgSO4. Chromatography (silica, 2:1 hexane/EtOAc) yields methyl (E)-5-(2-diethylcarbamoyl-1-methylvinyl)-2-(1-phenylethoxy)-benzoate.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([CH2:12][C:13]#[N:14])=[C:9]([CH3:11])[O:10][C:6]=2[C:5]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]2=[O:27])=[C:4]([F:28])[CH:3]=1.[OH2:29]>S(=O)(=O)(O)O>[C:13]([CH2:12][C:8]1[C:7]2[C:2]([Cl:1])=[CH:3][C:4]([F:28])=[C:5]([N:15]3[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]3=[O:27])[C:6]=2[O:10][C:9]=1[CH3:11])(=[O:29])[NH2:14]
Reactant: O
Reactant: Cc1oc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c2c1CC#N
Agent: O=S(=O)(O)O
Product: Cc1oc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c2c1CC(N)=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
0.50 g (1.2 mmol) of 3-(4-chloro-3-cyanomethyl-6-fluoro-2-methylbenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil was dissolved in 30 ml of 50% sulfuric acid, followed by stirring at 60° C. for 2 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.39 g (yield: 75%) of the desired product as white crystals. Melting point: 127-129° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:18]4[CH2:19][C:20]5[S:21][C:22]([C:25]6[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=6)=[CH:23][C:24]=5[C:17]=4[N:16](COCC[Si](C)(C)C)[N:15]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[ClH:39]>CO>[ClH:39].[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[C:18]4[CH2:19][C:20]5[S:21][C:22]([C:25]6[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=6)=[CH:23][C:24]=5[C:17]=4[NH:16][N:15]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc(-c3nn(COCC[Si](C)(C)C)c4c3Cc3sc(-c5cccnc5)cc3-4)cc2)CC1
Agent: Cl
Solvent: CO
Product: CN1CCN(c2ccc(-c3n[nH]c4c3Cc3sc(-c5cccnc5)cc3-4)cc2)CC1
Temperature: 100 °C
Yield: 55 %

Procedure:
6-[4-(4-Methyl-piperazin-1-yl)-phenyl]-2-pyridin-3-yl-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.45 g, 0.8 mmol) was dissolved in MeOH and treated with concentrated HCl (0.25 mL, 8 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding 6-[4-(4-Methyl-piperazin-1-yl)-phenyl]-2-pyridin-3-yl-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene hydrochloride (0.2 g, 0.44 mmol) as yellow solid in 55% yield.
Reaction SMILES: [OH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[N+:11]([O-])([OH:13])=[O:12]>>[OH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:4]=2[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1nc2ccccc2[nH]1
Product: O=[N+]([O-])c1ccc2[nH]c(O)nc2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
According to the procedure of A. T. James, et al., J. Chem. Soc., 1515, (1950), to cooled (0° C.), stirred nitric acid (300 mL) was added all at once 2-hydroxy-1H-benzimidazole. After 1 minute a yellow precipitate had formed. The cooling bath was removed and stirring was continued for 10 minutes. The mixture was poured onto ice, and the off-white solid was collected by filtration and dried under vacuum at 60° C. to give 25.1 g (94%) of product m.p. >300° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH2:11])=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C>[CH2:1]([NH:8][C:9]1[S:10][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)NCc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1csc(NCc2ccccc2)n1

Procedure:
The reaction described in Preparation 42 was repeated, but using 5.02 g of benzylthiourea, 5.87 g of ethyl bromopyruvate and 50 ml of ethanol, giving the title compound as pale yellow needles.
Reaction SMILES: C(OC([N:11]1[C@@H:15]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:14]([CH:23]([OH:32])[CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]2)[O:13]C1(C)C)=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C@@H:15]([CH2:16][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)[CH:14]([OH:13])[CH:23]([OH:32])[CH2:24][N:25]1[CH2:26][CH2:27][CH:28]([CH3:31])[CH2:29][CH2:30]1
Reactant: CC1CCN(CC(O)C2OC(C)(C)N(C(=O)OCc3ccccc3)[C@H]2CC2CCCCC2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC1CCN(CC(O)C(O)[C@@H](N)CC2CCCCC2)CC1
Yield: 101.8 %

Procedure:
70 mg of (4S,5RS)-3-benzyloxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-5-[(1RS)-1-hydroxy-2-(4-methylpiperidino)ethyl]oxazolidine was dissolved in 1.5 ml of ethanol, and palladium black was added thereto. The mixture was treated in the same manner as in Example 17 to obtain 45 mg of (2RS,3RS,4S)-4-amino-5-cyclohexyl-1-(4-methylpiperidino)-2,3-pentanediol as colorless oily substance.