Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18]C(=O)C(F)(F)F)=[CH:14][C:13]=2[F:25])[N:4](COCC[Si](C)(C)C)[CH:3]=1.FC(F)(F)C(O)=O.O.[OH-].[Li+]>ClCCl>[Cl:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=2[F:25])[NH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(Cl)c2c(Cc3ccc(NC(=O)C(F)(F)F)cc3F)ccnc21
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Nc1ccc(Cc2ccnc3[nH]cc(Cl)c23)c(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
567 mg (1.13 mmol) of N-{4-[(3-chloro 1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)methyl]-3-fluorophenyl}-2,2,2-trifluoroacetamide are dissolved in 5 ml of dichloromethane. 5 ml (65 mmol) of trifluoroacetic acid are added, and the mixture is stirred at RT for 3 h. The mixture is then concentrated, EA is added and the mixture is washed with sat. sodium carbonate solution. The organic phase is dried over sodium sulfate and concentrated. The residue is taken up in 35 ml of THF, and 15 ml of water and 542 mg (22.7 mmol) of lithium hydroxide are added. The mixture is stirred at RT for 20 h. The mixture is then concentrated under reduced pressure, and the residue is diluted with water. The mixture is extracted with ethyl acetate and the extract is dried over sodium sulfate and concentrated. The residue is purified by chromatography on silica gel (mobile phase dichloromethane:methanol 25:1). This gives crystals.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH3:5][C:6]([C:9]1[CH:10]=[C:11]([O:15][C:16]2[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)([CH3:8])[CH3:7].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:8][C:6]([C:9]1[CH:10]=[C:11]([O:15][C:16]2[CH:17]=[C:18]([CH3:24])[C:19]([N:20]=[C:1]=[S:2])=[CH:21][C:22]=2[CH3:23])[CH:12]=[CH:13][CH:14]=1)([CH3:5])[CH3:7]
Reactant: S=C(Cl)Cl
Reactant: Cc1cc(Oc2cccc(C(C)(C)C)c2)c(C)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(Oc2cccc(C(C)(C)C)c2)c(C)cc1N=C=S
Reaction time: 2 h

Procedure:
Thiophosgene (0.38 ml) is added to a two-phase mixture at room temperature of 4-((3-(1,1-dimethyl-ethyl)phenyl)oxy)-2,5-dimethylaniline (1.35 g) in toluene (6 ml) and sodium bicarbonate (840 mg) in water (6 ml). The reaction mixture obtained is stirred for 2 h and the phases are then separated by settling. The aqueous phase is extracted with toluene and the combined organic phases are then washed with water, dried (magnesium sulphate) and then concentrated to give the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=O)[C:5]([NH:8][C:9](=O)[C:10]([F:13])([F:12])[F:11])=[N:6][CH:7]=1.[H][H]>C(O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]2[N:15]([OH:17])[C:9]([C:10]([F:13])([F:12])[F:11])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C(Nc1ncc(Cl)cc1[N+](=O)[O-])C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: On1c(C(F)(F)F)nc2ncc(Cl)cc21

Procedure:
5-Chloro-3-nitro-2-(trifluoroacetamido)pyridine (2.0 grams) was hydrogenated with two moles of hydrogen in ethanol containing 0.5 gram of 5 percent palladium on carbon. The resulting reaction mixture was filtered and evaporated to separate the desired 6-chloro-1-hydroxy-2-(trifluoromethyl)-1H-imidazo(4,5-b)pyridine compound which, after recrystallization from benzene melted at 268°-70° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:10]([Li])[CH2:11][CH2:12][CH3:13].Br[CH2:16][CH2:17]Br.O>O1CCCC1>[CH:1]1([CH2:13][CH2:12][CH:11]2[C:10]3[C:1](=[CH:2][CH:3]=[CH:16][CH:17]=3)[CH:9]=[CH:8]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: [Li]CCCC
Reactant: BrCCBr
Reactant: C1=Cc2ccccc2C1
Solvent: O
Solvent: C1CCOC1
Product: C1=CC(CCC2C=Cc3ccccc32)c2ccccc21
Temperature: -78 °C
Reaction time: 4 h
Yield: 51.6 %

Procedure:
50.8 g of indene (437 mmol) were dissolved under an inert atmosphere in 500 ml of tetrahydrofuran in a 2-necked 2 l flask and cooled to -78° C. 175 ml of n-butyllithium (2.5 M in hexane, 437.5 mmol) were added dropwise slowly (1 hour). The mixture was allowed to warm again to room temperature and was stirred for a further 4 hours. It was cooled to -78° C., and 40.42 g of 1,2-dibromoethane (215 mmol) dissolved in 100 ml of tetrahydrofuran were added dropwise (within 20 minutes). After the end of the addition, the temperature was taken to 50° C., stirring was continued for 12 hours, and the mixture was then allowed to cool to room temperature, and 20 ml of water were added. The organic phase was dried and the residue was extracted with pentane. Evaporation in vacuum gave 28.65 g of product (yield=51.6%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].CN(C)C=O.[C:25](Cl)(=O)[C:26](Cl)=O>C(O)C.ClCCl>[CH2:25]([O:16][C:15]([C:7]1[C:6](=[O:18])[C:5]2[C:10](=[N:11][C:2]([Cl:1])=[C:3]([F:19])[CH:4]=2)[N:9]([CH:12]2[CH2:14][CH2:13]2)[CH:8]=1)=[O:17])[CH3:26]
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 50 %

Procedure:
7-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, (U.S. Pat. No. 4,663,457) (20.0 g, 71 mmol) and dimethylformamide (0.5 mL) were added to dichloromethane (750 mL) to give a tan slurry. Oxalyl chloride (7.4 mL, 85 mmol) was added to this slurry over one minute and the reaction mixture stirred for 90 minutes, then an additional 2.0 mL of oxalyl chloride was added and stirring continued for 60 minutes. To the resulting brown solution was added absolute ethanol (4.3 mL, 78 mmol) and the mixture stirred for 4 hours and then cooled to 0° C. and stored overnight. The reaction was warmed to room temperature and an additional 2 mL of absolute ethanol was added and the stirring continued for 3 hours. The reaction was evaporated to a brown solid. The solid was heated in THF, filtered, and cooled to 0° C. The crystals formed were collected and dried to give the title compound (11.1 g, 50%).
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[C:13]([C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=[CH:11][C:10]=1[OH:23])([CH3:8])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].N1C(C)=CC=CC=1C.Cl[Sn](Cl)(Cl)Cl.[CH2:37]=[O:38].Cl>C1(C)C=CC=CC=1>[CH3:8][C:2]([C:9]1[CH:14]=[C:13]([C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=[C:11]([CH:37]=[O:38])[C:10]=1[OH:23])([CH3:1])[CH2:3][C:4]([CH3:5])([CH3:6])[CH3:7]
Reactant: C=O
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)c(C(C)(C)CC(C)(C)C)c1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)CC(C)(C)c1cc(C=O)c(O)c(C(C)(C)CC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
2,4-bis(1,1,3,3-tetramethylbutyl)phenol (26.2 g, 82.4 mmol, synthesized by the method described in U.S. Pat. No. 3,373,210), toluene (200 ml) and 2,6-lutidine (14.4 g, 135 mmol) was placed in a stirred flask under a blanket of nitrogen and the mixture was cooled to 0° C. SnCl4 (8.57 g, 33 mmol) was then carefully added. The mixture was subsequently stirred at room temperature for 20 minutes, before paraformaldehyde (15.1 g, 502 mmol) was added. The mixture was then stirred at 100° C. for 12 hours. After cooling, hydrochloric acid (1 M, 272 ml) was added. The resulting suspension was filtered through Celite and the solid was washed with 100 ml of ethyl acetate. The organic phase of the filtrate was then separated off, washed twice with 100 ml of NaCl solution, dried over MgSO4 and evaporated at reduced pressure. A slightly yellowish oil was formed as product. According to GC/MS, this crude product contains only about 3% of starting material. Yield: 26.9 g (94%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18].CS(O)(=O)=O.O>O1CCOCC1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:14][C:13]2[CH:15]=[CH:16][C:10]([CH3:9])=[C:11]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Reactant: Clc1ncc(Br)cn1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(Nc2ncc(Br)cn2)cc1[N+](=O)[O-]

Procedure:
5-Bromo-2-chloropyrimidine 4 (50 mmol), 4-methyl-3-nitroaniline (60 mmol) and methylsulphonic acid (15 mmol) are heated at reflux in 1,4-dioxane (100 mL) for 16 h. The mixture is poured into water, filtered and dried under vacuum to give 5-bromo-N-(4-methyl-3-nitrophenyl)pyrimidin-2-amine 27 as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 10.25 (s, 1H), 8.68 (s, 2H), 8.49 (d, J=2.0 Hz, 1H), 7.86 (dd, J=2.4, 8.4 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 2.46 (s, 3H). MS (m/z) (M+1)+: 309.0, 311.0.
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:4]=2[N:3]=1.Cl[CH2:24][C:25]([CH2:27]Cl)=O.C(=O)([O-])[OH:30].[Na+]>O1CCOCC1>[F:21][C:19]([F:22])([F:20])[C:16]1[CH:17]=[CH:18][C:4]2[N:3]3[CH:27]=[C:25]([CH2:24][OH:30])[N:1]=[C:2]3[CH2:8][N:7]=[C:6]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:5]=2[CH:15]=1
Reactant: O=C(CCl)CCl
Reactant: NC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2)=NC1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: OCc1cn2c(n1)CN=C(c1ccccc1)c1cc(C(F)(F)F)ccc1-2
Temperature: 98 °C
Reaction time: 16 h
Yield: 27.2 %

Procedure:
A solution of 10.5 g of 2-amino-7-trifluoromethyl-5-phenyl-3H-1,4-benzodiazepine (K. Meguro, H. Tawada & Y. Kuwada, Yakugaku Zasshi, 1973, 93, 1253-1262) and 4.84 g of 1,3-dichloroacetone in 220 ml of dioxan was treated with 2.72 g of anhydrous sodium hydrogen carbonate and stirred at 98° C. for 16 h. After cooling the inorganic salts were filtered off, the filtrate was treated with 0.75 g of p-toluenesulphonic acid and stirred at 98° C. for 2 h. 60 ml of 1N aqueous sodium hydroxide solution were added to this solution and the mixture was stirred at 80° C. for 3 h. After cooling the mixture was concentrated in a vacuum. The residue was taken up in chloroform and water and the aqueous phase was extracted a further four times with chloroform. The chloroform was evaporated in a vacuum. The residue was recrystallized twice from ethyl acetate. There were obtained 3.15 g of 8-trifluoromethyl-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol of m.p. 193-194° C., which was converted into the hydrochloride of m.p. 252-254° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5]Br.[CH2:11]([O:13][P:14]([O:18]CC)[O:15][CH2:16][CH3:17])[CH3:12]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][P:14](=[O:18])([O:15][CH2:16][CH3:17])[O:13][CH2:11][CH3:12]
Reactant: CCOP(OCC)OCC
Reactant: Fc1cc(F)cc(CBr)c1
Product: CCOP(=O)(Cc1cc(F)cc(F)c1)OCC
Temperature: 135 °C
Reaction time: 8 h

Procedure:
3,5-difluorobenzyl bromide (3.0 mL, 23.2 mmol) was combined with triethylphosphite (9.1 mL, 53.3 mmol) and the mixture heated and stirred at 135° C. overnight. The mixture was put under hi-vacuum and heated to 70° C. for 12 hours. The final product was a clear oil (5.78 g, 94% yield). 1H NMR (400.14 MHz, CDCl3) δ 6.83 (m, 2H), 6.71 (dt, J=9.00, 2.28 Hz), 4.06 (m, 4H), 3.12 (d, J=21.94 Hz, 2H), 1.28 (t, J=7.09 Hz, 6H). 31P {1H} NMR (161.97 MHz, CDCl3): δ 25.22.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1)[CH2:14][CH3:15]
Reactant: CCCBr
Reactant: OCCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1ccc(CCCO)cc1

Procedure:
A mixture of 3-(4-hydroxyphenyl)-1-propanol (1.33 g), 1-bromopropane (1.2 ml) and potassium carbonate (2.25 g) and acetone (100 ml) was heated at reflux for 2 days. After concentration under reduced pressure, the residue was mixed with water and was extracted with ethyl acetate. The organic layer was washed with a 1 N aqueous solution of sodium hydroxide and an aqueous saturated solution of sodium chloride, and was dried with magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain 3-(4-propoxyphenyl)-1-propanol (1.61 g) as a colorless oily substance.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[S:44][C:22]3=[CH:23][CH:24]=[C:25]4[C:30]([N:29]=[C:28]([NH:31][C:32]5[CH:37]=[CH:36][CH:35]=[C:34]([N:38]6[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]6)[CH:33]=5)[N:27]=[CH:26]4)=[C:21]3[CH:20]=2)=[O:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.Br.CO>C(Cl)Cl>[N:14]1([C:17]([C:19]2[S:44][C:22]3=[CH:23][CH:24]=[C:25]4[C:30]([N:29]=[C:28]([NH:31][C:32]5[CH:37]=[CH:36][CH:35]=[C:34]([N:38]6[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]6)[CH:33]=5)[N:27]=[CH:26]4)=[C:21]3[CH:20]=2)=[O:18])[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1
Reactant: O=C(OCc1ccccc1)N1CCN(C(=O)c2cc3c(ccc4cnc(Nc5cccc(N6CCCCC6)c5)nc43)s2)CC1
Agent: Br
Solvent: CO
Solvent: ClCCl
Product: O=C(c1cc2c(ccc3cnc(Nc4cccc(N5CCCCC5)c4)nc32)s1)N1CCNCC1
Yield: 60 %

Procedure:
4-[2-(3-Piperidin-1-yl-phenylamino)-thieno[2,3-h]quinazoline-8-carbonyl]-piperazine-1-carboxylic acid benzyl ester (205 mg, 0.34 mmol) was dissolved in dry DCM (4 mL) and HBr (2 mL, 33wt % solution in AcOH) added. The resultant mixture was stirred at room temperature for 0.5 hours and concentrated under reduced pressure. The yellow gum obtained was partitioned between Et2O and dilute HCl. The aqueous layer was extracted with Et2O (1×10 mL). The aqueous layer was then basified with saturated Na2CO3 and extracted with DCM (3×10 mL). The DCM organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The brown gum obtained was redissolved in DCM, silica (˜5 mL) added and concentrated under reduced pressure. The solid obtained was subjected to column chromatography (10% MeOH in DCM, ˜100 mL silica) to give a bright yellow solid. This solid was triturated with Et2O, filtered and washed with Et2O (3×5 mL) and pentane (3×5 mL) to give a yellow powder (96.4 mg, 60% yield). MS (ES+) 473, (ES−) 472. δH (CDCl3) 1.5-1.9 (6H, m), 2.9-3.1 (4H, m), 3.2-3.3 (4H, m), 3.8-3.9 (4H, m), 6.7 (1H, m), 7.2-7.3 (3H, m), 7.4 (1H, s), 7.6-7.7 (3H, m), 8.2-8.3 (1H, s), 9.1 (1H, s)
Reaction SMILES: [OH:1][CH:2]([CH3:12])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].CCN(CC)CC.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:20][S:21]([O:1][CH:2]([CH3:12])[CH2:3][NH:4][C:5]([O:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:11])(=[O:23])=[O:22]
Reactant: CC(O)CNC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CNC(=O)OC(C)(C)C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To a solution of tert-butyl 2-hydroxypropylcarbamate (14.3 g, 81.7 mmol) and Et3N (35.6 ml, 245.1 mmol) in CH2Cl2 (250 mL) at 0° C. was slowly added a solution of methanesulfonyl chloride (9.5 mL, 122.6 mmol) in CH2Cl2 (250 mL). The mixture was stirred at 0° C. for 2 h, diluted with CH2Cl2 (300 mL) and washed with water, 1 N HCl, 5% NaHCO3 and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure to afford 1-(tert-butoxycarbonylamino)propan-2-yl methanesulfonate (19.5 g, 94%) as a light yellow oil. Mass calculated for C9H19NO5S=253.32. found: [M+H]+=254.2.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[Na].[H][H].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>O1CCCC1>[CH2:12]([N:3]1[C:2]([CH3:1])=[CH:6][C:5]([CH3:7])=[N:4]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: [H][H]
Reactant: Cc1cc(C)[nH]n1
Reactant: CCCCCCCCBr
Agent: [Na]
Solvent: C1CCOC1
Product: CCCCCCCCn1nc(C)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Octyl-3,5-dimethylpyrazole was prepared in the following manner. All manipulations were performed under a nitrogen atmosphere. 3,5-Dimethylpyrazole (5 g) was placed in a 100-mL 3-neck round-bottom flask with a magnetic stir bar and dissolved in 50 mL tetrahydrofuran. A condenser and stoppers were added. Sodium metal (1.2 g) was added in pieces. Hydrogen evolution was evident. Mixture was stirred at room temperature overnight. 1-Bromooctane (9 mL) was then added all at once. The mixture was brought to a gentle reflux for seven hours and then stirred overnight at room temperature. The reaction mixture was filtered through a sintered-glass frit to remove a white precipitate. Solvent was removed under vacuum. Product was distilled under vacuum. The fractions distilling at 65-70° C. were collected and used in subsequent preparations.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[CH3:13][C:14]1[NH:18][C:17]2[CH:19]=[CH:20][C:21]([C:23](O)=[O:24])=[CH:22][C:16]=2[N:15]=1.N>>[ClH:1].[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH:12][C:23]([C:21]3[CH:20]=[CH:19][C:17]4[NH:18][C:14]([CH3:13])=[N:15][C:16]=4[CH:22]=3)=[O:24])[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: Cc1nc2cc(C(=O)O)ccc2[nH]1
Agent: Cl
Agent: N
Product: Cc1nc2cc(C(=O)NC3C4CC5CC3CN(C5)C4)ccc2[nH]1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 2-methyl-1H-benzimidazole-5-carboxylic acid (Acros) according to methods A and C; yield 84 mg, 0.21 mmol (58%): 1H NMR (300 MHz, methanol-d4) δ 1.99 (d, J=13 Hz, 2H), 2.30-2.46 (m, 3H), 2.51 (s, 2H), 2.90 (s, 3H), 3.59 (s, 2H), 3.69 (s, 4H), 4.45 (s, 1H), 7.82 (dd, J=9, 1 Hz, 1H), 8.07 (dd, J=8, 1 Hz, 1H), 8.25 (dd, J=1, 1 Hz, 1H), 8.50 (d, J=5 Hz, 1H); MS (DCI/NH3) m/z 311 (M+H)+; Anal. C18H22N4O2HCl 1.0H2O: C, H,N.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:17]2[C:25]3[C:20](=[C:21]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)([CH2:15][CH3:16])[C:9](O)([CH3:13])[CH2:10][C:11]#[N:12])=[CH:4][CH:3]=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:17]2[C:25]3[C:20](=[C:21]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)([CH2:15][CH3:16])[C:9]([CH3:13])=[CH:10][C:11]#[N:12])=[CH:4][CH:3]=1
Reactant: CCC(c1ccc(Cl)cc1)(n1ccc2c(NS(C)(=O)=O)cccc21)C(C)(O)CC#N
Agent: CN(C)c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C(C)=CC#N)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the product from Step B (200 mg, 0.449 mmol), TFAA (283 mg, 1.35 mmol), triethylamine (136 mg, 1.35 mmol) and DMAP (165 mg, 1.35 mmol) in dichloromethane (20 mL) was stirred at room temperature for 2 h. The solvent was evaporated and the residue was purified by PREP-TLC eluting with PE/EA (3/1, v/v) to give the title compound as a colorless amorphous solid. LC/MS m/z=450.0 [M+Na]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[C:21]([C:22]([OH:24])=O)=[C:20]([C:25]4[CH:30]=[CH:29][C:28]([N:31]5[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]5)=[CH:27][CH:26]=4)[N:19](COCC[Si](C)(C)C)[C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:46][N:47](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.C1COCC1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[C:21]([C:22]([NH:47][CH3:46])=[O:24])=[C:20]([C:25]4[CH:26]=[CH:27][C:28]([N:31]5[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]5)=[CH:29][CH:30]=4)[NH:19][C:16]3=[N:17][CH:18]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(CCc2cnc3c(n2)c(C(=O)O)c(-c2ccc(N4CCN(C)CC4)cc2)n3COCC[Si](C)(C)C)cc(OC)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(N3CCN(C)CC3)cc2)[nH]c2ncc(CCc3cc(OC)cc(OC)c3)nc12
Reaction time: 1 h
Yield: 21.5 %

Procedure:
To a stirred solution of crude 2-[2-(3,5-dimethoxyphenyl)ethyl]-6-[4-(4-methylpiperazin-1-yl)phenyl]-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (20 mg, 31.6 μmol) in N,N-dimethylformamide (2 mL), HATU (12.0 mg, 31.6 μmol), 2.0 M methylamine in THF (15.8 μL, 31.6 μmol) and N,N-diisopropylethylamine (11.0 μL, 63.3 mmol) were added sequentially at ambient temperature. After 1 hour, the reaction was quenched with saturated aqueous NH4Cl, extracted with methylene chloride. The combined organic layers were dried over MgSO4, concentrated. The residue was dissolved in methylene chloride (1 mL) and trifluoroacetic acid (1 mL) was added at ambient temperature. After 2 hours, the volatiles were removed under vacuum and the residue was dissolved in methanol (1 mL), followed by the addition of ethylenediamine (0.1 mL). After another 1 hour, the reaction mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) to give the desired product (3.5 mg) as its TFA salt. LCMS calculated for C29H35N6O3 (M+H)+: m/z=515.3. Found: 515.2.
Reaction SMILES: [Cl:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[S:7][CH2:8][C:9]([OH:11])=[O:10].[CH3:12]O>>[Cl:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[S:7][CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: CO
Reactant: O=C(O)CS[C@@H]1CCC[C@H]1Cl
Product: COC(=O)CSC1CCCC1Cl
Temperature: 5 °C

Procedure:
trans-[(2-Chlorocyclopentyl)thio]acetic acid was dissolved in methanol (35 ml) and the solution was cooled to 5° C. with an ice bath. Hydrogen chloride gas was bubbled into the solution for 15 minutes. The methanol was removed with a gentle flush of nitrogen gas. The residue was dissolved in diethyl ether (50 ml) and washed twice with 50 ml of 15% sodium hydroxide, dried over anhydrous magnesium sulfate, filtered and concentrated to give the product as an oil. The structure was supported by NMR.
Reaction SMILES: I.[C:2]1([N:8]2[C:12]([NH:13][C:14](=[NH:17])SC)=[CH:11][C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24](N)[CH2:25][NH2:26]>>[C:2]1([N:8]2[C:12]([NH:13][C:14]3[NH:26][CH2:25][CH2:24][N:17]=3)=[CH:11][C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSC(=N)Nc1cc(-c2ccccc2)nn1-c1ccccc1
Reactant: NCCN
Agent: I
Product: c1ccc(-c2cc(NC3=NCCN3)n(-c3ccccc3)n2)cc1

Procedure:
N(1,3-Diphenyl-5-pyrazolyl)-S-methyl isothiourea hydroiodide (43.6 g.) and ethylene diamine (12.0 g.) were reacted as described in Example VI to give 26.0 g. of the product, mp 228°-230° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH3:10])=[N:6][CH:7]=1.C(O[CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>>[CH2:9]([O:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:3][CH:4]=1)[CH3:10]
Reactant: CCOc1ccc(N)cn1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1ccc(OCC)nc1)C(=O)OCC

Procedure:
5-Amino-2-ethoxypyridine (9.25 g) and diethyl ethoxymethylenemalonate (14.5 g) was heated at 95° C. for 1 hour. On cooling in ice the oil solidified. The solid was ground up in petroleum ether (b.p. 60°-80° C.) and filtered to give diethyl 2-(6-ethoxy-3-pyridylaminomethylene)malonate, m.p. 68°-71° C.