Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]([F:37])[CH2:13][CH2:14][C:15]1([C:32]([O:34]CC)=[O:33])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][O:23][C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[F:31])[CH2:17][CH2:16]1)=[CH:9][C:8]([O:38][CH3:39])=[CH:7][CH:6]=2.[OH-].[Na+]>O1CCOCC1.CO>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]([F:37])[CH2:13][CH2:14][C:15]1([C:32]([OH:34])=[O:33])[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][O:23][C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[F:31])[CH2:19][CH2:20]1)=[CH:9][C:8]([O:38][CH3:39])=[CH:7][CH:6]=2
Reactant: CCOC(=O)C1(CCC(F)c2c(Cl)cnc3ccc(OC)cc23)CCN(CCOc2cc(F)ccc2F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc2ncc(Cl)c(C(F)CCC3(C(=O)O)CCN(CCOc4cc(F)ccc4F)CC3)c2c1
Temperature: 70 °C
Yield: 28.1 %

Procedure:
A mixture of 0.15 g of ethyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)-fluoropropyl]-1-[2-(2,5-difluorophenoxy)ethyl]piperidine-4-carboxylate in 3 cm3 of dioxane, 3 cm3 of methanol and 1 cm3 of aqueous 5N sodium hydroxide solution was maintained at a temperature in the region of 70° C. for 4 hours. After cooling to about 20° C., the reaction mixture was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue was chromatographed under an atmospheric pressure of 60 kPa, on a Bond Elut of 60 cm3 of silica gel (particle size 70-200μ; mass 25 g), eluting with 60 cm3 of a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume) and then with a dichloromethane/methanol/aqueous ammonia mixture (40/5/2 by volume). The fractions containing the expected product were combined and then concentrated to dryness according to the same conditions as above. 0.04 g of 4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)-fluoropropyl]-1-[2-(2,5-difluorophenoxy)ethyl]piperidine-4-carboxylic acid was obtained in the form of a white solid.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[Cl:7][C:8]1[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=1[O-].C(N(CC)CC)C>C(#N)C>[Cl:7][C:8]1[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:5]#[N:6])[N:12]=1
Reactant: [O-][n+]1ccccc1Cc1ccccc1Cl
Reactant: C[Si](C)(C)C#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1cccc(Cc2ccccc2Cl)n1
Temperature: 25 °C
Yield: 33.5 %

Procedure:
Trimethylsilyl cyanide (36.15 g, 48.6 ml, 0.36 moles) was added dropwise to a solution of 2-(o-chlorobenzyl)-pyridine-N-oxide (32.0 g, 0.15 moles) and triethylamine (22.13 g, 30.5 ml, 0.22 moles) in acetonitrile (100 ml) at 20° C. under a nitrogen atmosphere. After complete addition the reaction mixture was heated under reflux for 48 hours, cooled to room temperature and partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic layer was washed with water and saturated sodium chloride solution and was then dried over anhydrous magnesium sulphate. Removal of the solvent gave an orange brown oil which was purified by column chromatography (silica gel eluted with hexane:ethyl acetate 4:1) to give 2-(o-chlorobenzyl)-6-cyanopyridine (11.5 g, 35%) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])[CH3:3].Cl.[CH2:18](N=C=NCCCN(C)C)[CH3:19].C(O)C>C(OCC)C.CN(C)C1C=CN=CC=1>[CH2:18]([O:15][C:14](=[O:16])[CH2:13][C@H:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)[CH3:19]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CC(=O)O)C1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 95 %

Procedure:
In an oven-dried 250 mL round bottom flask under nitrogen, ((3R)-1-{[(1,1-dimethylethyl)oxy]carbonyl}-3-pyrrolidinyl)acetic acid (2.181 mmol) dissolved in diethyl ether (5 mL) was treated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.4 mmol), 4-(dimethylamino)pyridine (0.218 mmol), and ethanol (4.8 mmol) at room temperature and the mixture was stirred overnight. The resulting white gummy precipitate was diluted with ether (100 mL) and washed with 1M aq sodium hydrogen sulfate solution (100 mL), saturated aq sodium bicarbonate solution (100 mL), and brine (100 mL). The organic phase was isolated, dried over magnesium sulfate, and concentrated in vacuo to give the title compound as a clear oil (95%). MS(ES)+ m/e 258.1 [M+H]+, 280.0 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[S:10][C:11]=2[C:12]2[N:16](S(N(C)C)(=O)=O)[CH:15]=[N:14][CH:13]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>Br.O.C(Cl)Cl>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CN(C)S(=O)(=O)n1cncc1-c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Clc1ccc(Cc2nc(-c3ccncc3)sc2-c2cnc[nH]2)cc1
Yield: 88.4 %

Procedure:
A solution of 5-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (50 mg, 0.109 mmol) in 48% HBr in water (3.0 mL) was heated to 90° C. for 2.5 hours. The cooled solution was taken up in DCM (20 mL) and saturated sodium bicarbonate (20 mL). The layers were separated and the aqueous extracted with DCM (20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. To this crude material was added the 19 mg of deprotected material obtained in the previous step. The combined material was purified by silica gel chromatography (methanol/DCM=0/100→315/85) to give 34 mg of the title compound as a white solid (27% yield). LC/MS (FA) ES+ 353. 1H NMR (300 MHz, d4-MeOH) δ: 8.63-8.61 (m, 2H), 7.93-7.91 (m, 2H), 7.80 (d, 1H, J=1.1 Hz), 7.30-7.19 (m, 5H), 4.35 (s, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH2:4][CH2:3]1.[CH2:17](Br)[CH:18]1[O:22][CH2:21][CH2:20][CH2:19]1>>[CH2:17]([N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)[CH:18]1[O:22][CH2:21][CH2:20][CH2:19]1
Reactant: BrCC1CCCO1
Reactant: CN1CCC(c2nc3cccnc3[nH]2)CC1
Product: CN1CCC(c2nc3cccnc3n2CC2CCCO2)CC1

Procedure:
Operation is carried out similarly to the above description with the difference that 2-(1-methylpiperidin-4-yl)-3H-imidazo [4,5-b] pyridine is reacted with tetrahydrofurfurylbromide to obtain 3-tetrahydrofurfuryl-2-(1-methylpiperidin-4-yl)-3H-imidazo [4,5-b] pyridine which is isolated as difumarate melting at 154°-156° C. (ethyl alcohol).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.C(N(CC)CC)C.[C:26]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([N:35]3[CH2:36][CH2:37][N:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:33][CH2:34]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: CP(C)(=O)c1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2cc(N3CCN(c4ccccc4)CC3)ncn2)cc1

Procedure:
To a solution of 6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (prepared as in Example 59: 0.12 mmol) in 2 mL of ethanol is added 50 μL of triethylamine and 1-Phenylpiperazine (19 mg, 0.12 mmol). The mixture is microwaved at 120 degrees until formation of the desired compound. The reaction mixture can then be filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][NH:34][CH:35]=2)O1>>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:31]3[CH:32]=[N:33][NH:34][CH:35]=3)=[CH:3][CH:4]=2)[CH2:9][N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[CH:21][CH:20]=1
Reactant: Clc1ccc(C(CN2CCNCC2)c2ccc(Cl)cc2)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: Clc1ccc(C(CN2CCNCC2)c2ccc(-c3cn[nH]c3)cc2)cc1

Procedure:
1-[2,2-Bis-(4-chloro-phenyl)-ethyl]-piperazine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 to give the title compound. LC/MS: (PS-B3) Rt 2.63 [M+]+ 326.00. 1H NMR (Me-d3-OD) δ 3.55-3.68 (8H, m), 3.74 (1H, t), 4.10-4.17 (2H, m), 7.39 (2H, d), 7.48 (2H, d), 7.54 (2H, d), 7.70 (2H, d), 8.57 (2H, br s).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:19][C:18]3[C:13](=[C:14]([O:45]C)[C:15]([C:22]4[CH:27]=[C:26]([CH:28]5[O:38][C:37]6[C:32](=[C:33]([O:41]C)[CH:34]=[C:35]([O:39]C)[CH:36]=6)[C:30](=[O:31])[CH2:29]5)[CH:25]=[CH:24][C:23]=4[O:43]C)=[C:16]([O:20]C)[CH:17]=3)[C:11](=[O:12])[CH2:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>>[CH:5]1[C:6]([C:9]2[O:19][C:18]3[CH:17]=[C:16]([OH:20])[C:15]([C:22]4[CH:27]=[C:26]([C:28]5[O:38][C:37]6[CH:36]=[C:35]([OH:39])[CH:34]=[C:33]([OH:41])[C:32]=6[C:30](=[O:31])[CH:29]=5)[CH:25]=[CH:24][C:23]=4[OH:43])=[C:14]([OH:45])[C:13]=3[C:11](=[O:12])[CH:10]=2)=[CH:7][CH:8]=[C:3]([OH:2])[CH:4]=1
Reactant: COc1ccc(C2CC(=O)c3c(cc(OC)c(-c4cc(C5CC(=O)c6c(OC)cc(OC)cc6O5)ccc4OC)c3OC)O2)cc1
Agent: BrB(Br)Br
Product: O=c1cc(-c2ccc(O)c(-c3c(O)cc4oc(-c5ccc(O)cc5)cc(=O)c4c3O)c2)oc2cc(O)cc(O)c12
Temperature: 25 °C
Yield: 30 %

Procedure:
To a solution of 10 (75.0 mg, 0.12 mmol) in 10 mL dry CHC3 was added BBr3 (1.0 M in CH2Cl2, 1.45 mL, 1.45 mmol), and the resulting yellow slurry was stirred at reflux overnight. The reaction mixture was cooled to room temperature, quenched by the careful addition of MeOH, and evaporated in vacuo. The resulting orange solid was triturated with MeOH, the solvent again evaporated in vacuo, and the solid was partitioned between EtOAc and 1 M NaOH. The organic layer was discarded, and the aqueous layer was extracted with EtOAc. After cooling to 0° C., the aqueous layer was carefully acidified to pH 3.0 by the dropwise addition of 3 M HCl. The resulting yellow precipitate was collected by vacuum filtration, rinsed with water and air dried (38.7 mg). The crude material was chromatographed through silica gel, eluting with a mixture of toluene/pyridine/formic acid (20:10:1). Appropriate fractions were combined and evaporated to afford 19.4 mg (30.0%) robustaflavone. An analytical sample was obtained via recrystallization from pyridine/H2O (1:1); mp 370-372° C., dec. (lit.1 mp 350-352° C.). Spectral data of synthetic robustaflavone was identical to that recently reported1 for the natural product isolated from Rhus succedanea. Anal. calcd for C30H18O10.1.25 H2O: C, 64.23; H, 3.68. Found: C, 64.17; H, 3.68.
Reaction SMILES: [OH-].[Na+].Cl.Cl.[CH3:5][NH:6][NH:7][CH3:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[S:18])=[CH:12][CH:11]=1>O.C(O)C>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:6]([CH3:5])[NH:7][CH3:8])=[S:18])=[CH:12][CH:11]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: CNNC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CNN(C)C(=S)Nc1ccc(Cl)cc1
Temperature: 50 °C
Yield: 38.9 %

Procedure:
To a stirred solution of sodium hydroxide (6.1 g, 0.15 mole) in 40 ml of water and 250 ml of ethanol was added N,N'-dimethylhydrazine dihydrochloride (10 g, 0.076 mole). The reaction mixture was warmed to 50° C., and 4-chlorophenylisothiocyanate (12.8 g, 0.076 mole) was added in small portions. Upon complete addition, the reaction mixture was heated under reflux for two hours and then allowed to cool. The cooled reaction mixture was filtered and the filtrate concentrated under reduced pressure to remove most of the solvent. The concentrate was taken up in 200 ml of toluene. The toluene was removed under reduced pressure. This procedure was repeated with two additional 200 ml portions of toluene to remove the remaining ethanol and water traces by azeotropic distillation. The brown residual oil was recrystallized twice from ethanol to give N-(4-chlorophenyl)-1,2-dimethylhydrazinecarbothioamide (6.8 g, mp 103°-104° C.). The nmr spectrum of the product was consistent with the assigned structure.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[CH2:18]([NH:25][CH:14]1[CH2:15][CH2:16][CH:11]([NH:10][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)[CH2:12][CH2:13]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: c1ccc(CNC2CCC(Nc3ccc4[nH]ncc4c3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.6 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and benzylamine (53 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was added to fractions containing respective compounds, follwed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (14 mg) and a syn-form compound (24 mg).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[CH:30]=[CH:29][C:11]([C:12]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=3)[C:16](CC(O)=O)=[CH:15]2)=[O:13])=[CH:10][CH:9]=1>C(Cl)Cl>[Cl:7][C:8]1[CH:30]=[CH:29][C:11]([C:12]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=3)[C:16]([CH2:1][C:2]([Cl:4])=[O:3])=[CH:15]2)=[O:13])=[CH:10][CH:9]=1
Reactant: COc1ccc2c(c1)c(CC(=O)O)cn2C(=O)c1ccc(Cl)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)c(CC(=O)Cl)cn2C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Oxalyl chloride (30 μL, 0.35 mmol) was added dropwise to a solution of 2-(1-(4-chlorobenzoyl)-5-methoxy-1H-indol-3-yl)acetic acid (100 mg, 0.29 mmol) in 2 mL of dry CH2Cl2 under argon. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated and the crude product was washed with dry hexane (3×1 mL) and dried in vacuo to give the title compound in 95% yield (100 mg). C18H13Cl2NO3, Mr=362.21; 1H NMR (400 MHz, DMSO-d6) d: 3.90 (s, 3H), 4.21 (s, 2H), 6.95 (d, J=2.4 Hz, 1H), 7.04 (dd, J=2.4/9.0 Hz, 1H), 7.29 (s, 1H), 7.52-7.55 (m, 2H), 7.67-7.71 (m, 2H), 8.29 (d, J=9.2 Hz, 1H); LCMS (ESI) tR: 2.72 min (>99%, UV254), m/z: 358.2 [M+1]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)(=O)=O.[I-:18].[Na+].O>CC(C)=O>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[O:14][CH3:15])[CH2:7][CH2:6][I:18]
Reactant: COc1ccc(CCOS(C)(=O)=O)cc1OC
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(CCI)cc1OC
Yield: 92.6 %

Procedure:
To a flask was added 21.2 g (0.078 mole) of 2-(3,4-dimethoxyphenyl)ethyl methanesulfonate and 44.65 g (0.3 mole) of sodium iodide in 420 ml of acetone. The solution was refluxed for 2 hr, poured into water, washed with brine, dried over MgSO4, and evaporated to give 21.1 g of a yellow oil. The oil was recrystallized in MeOH to give 17.1 g of product, mp 43°-46° C.
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].[CH:9]1([C:12](=O)[CH2:13][C:14](=O)[CH3:15])[CH2:11][CH2:10]1>O>[NH2:7][C:6]1[N:8]=[C:12]([CH:9]2[CH2:11][CH2:10]2)[CH:13]=[C:14]([CH3:15])[N:5]=1
Reactant: CC(=O)CC(=O)C1CC1
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: O
Product: Cc1cc(C2CC2)nc(N)n1
Temperature: 95 °C

Procedure:
15 g of guanidine carbonate are added to a mixture of 10 g of 1-cyclopropyl-butane-1,3-dione and 150 g of water, and stirring is maintained at 95° C. for 5 hours. The mixture is then concentrated by evaporation to a volume of 50 ml, and the cooled aqueous concentrate is extracted three times with 100 ml of ethylene chloride each time. The organic phase is dried over magnesium sulfate and concentrated by evaporation. The residue crystallises to thus yield 5 g of the title compound, m.p. 113°-115° C.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:31])[CH2:4][CH2:5][N:6]1[C:12](=[O:13])[C@@H:11]([OH:14])[C@H:10]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[S:9][C:8]2[C:23]3[C:28]([CH:29]=[CH:30][C:7]1=2)=[CH:27][CH:26]=[CH:25][CH:24]=3.[C:32](OC(=O)C)(=[O:34])[CH3:33]>>[C:32]([O:14][C@H:11]1[C@H:10]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[S:9][C:8]2[C:23]3[C:28]([CH:29]=[CH:30][C:7]=2[N:6]([CH2:5][CH2:4][N:3]([CH3:2])[CH3:31])[C:12]1=[O:13])=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCN(C)C)C(=O)[C@H]2O)cc1
Agent: Cl
Product: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCN(C)C)C(=O)[C@H]2OC(C)=O)cc1
Yield: 91 %

Procedure:
A mixture of 1.1 g of (±)-trans-5-[2-(dimethylamino)ethyl]-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)naphtho[1,2-b]-1,4-thiazepin-4(5H)-one hydrochloride and 20 mL acetic anhydride was heated at 100° for 17 hours. The excess reagent was removed under reduced pressure and the residue was partitioned between ethyl acetate and dilute sodium hydroxide. The ethyl acetate solution was washed with brine and dried (magnesium sulfate). Removal of the solvent gave 1.0 g (91%) of (±)-trans-3-(acetyloxy)-2,3-dihydro-2-(4-methoxyphenyl)-5-[2-(dimethylamino)ethyl]naphtho[1,2-b]-1,4-thiazepin-4(5H)-one. A sample was crystallized from ether--pet. ether, mp 122°-123°.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:15][CH:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=3)[C:4]=2[C:5]([N:8]=CN(C)C)=[N:6][CH:7]=1.[CH3:37][N:38]([CH3:48])[C:39]1[CH:44]=[CH:43][C:42]([N:45]=[C:46]=[O:47])=[CH:41][CH:40]=1>>[NH2:8][C:5]1[C:4]2[C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=3)=[CH:14][S:15][C:3]=2[C:2]([NH:1][C:46]([NH:45][C:42]2[CH:43]=[CH:44][C:39]([N:38]([CH3:48])[CH3:37])=[CH:40][CH:41]=2)=[O:47])=[CH:7][N:6]=1
Reactant: COc1cc(-c2csc3c(N)cnc(N=CN(C)C)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CN(C)c1ccc(N=C=O)cc1
Product: COc1cc(-c2csc3c(NC(=O)Nc4ccc(N(C)C)cc4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using N-[4-(7-amino-4-{[(dimethylamino)methylene]amino}thieno[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-indole-2-carboxamide and 4-(dimethylamino)phenyl isocyanate using General Procedure N followed by General Procedure M. 1H NMR (DMSO-d6, 400 MHz) δ 9.52 (s, 1H), 8.48 (s, 1H), 8.11 (s, 1H), 7.99 (d, 1H), 7.95 (s, 1H), 7.71 (d, 1H), 7.59 (d, 1H), 7.55 (s, 1H), 7.35 (s, 1H), 7.29 (m, 3H), 7.21 (m, 1H), 7.15 (t, 1H), 7.08 (d, 1H), 6.70 (d, 2H), 5.39 (br, 2H), 4.04 (s, 3H), 3.92 (s, 3H), 2.83 (s, 6H); MS: (MH)+ 606.
Reaction SMILES: [Br-:1].[Br-:2].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[C:34]([C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44](=[O:46])[CH3:45])=[CH:39][C:38]=1[O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)(=[O:36])[CH3:35]>C1COCC1>[CH2:48]([O:47][C:38]1[CH:39]=[C:40]([NH:43][C:44](=[O:46])[CH3:45])[CH:41]=[CH:42][C:37]=1[C:34](=[O:36])[CH:35]([Br:2])[Br:1])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: CC(=O)Nc1ccc(C(C)=O)c(OCc2ccccc2)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(=O)C(Br)Br)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
Phenyltrimethylammonium tribromide (102 mg, 0.272 mmol) was added to a solution of N-(4-acetyl-3-benzyloxy-phenyl)-acetamide (35 mg, 0.124 mmol) in THF (3.5 mL), and stirred at room temperature for 2 hours. The mixture was partitioned between water (25 mL) and EtOAc (25 mL), the layers separated and the organic layer dried (MgSO4). The solvents were removed in vacuo to give crude N-[3-benzyloxy-4-(2,2-dibromo-acetyl)-phenyl]-acetamide (54 mg, 100%) as a pale brown solid; δH (CDCl3) 7.92 (1H, br s), 7.85 (1H, d, J=8.5 Hz), 7.55 (1H, br s), 7.50-7.35 (5H, m), 7.09 (1H, s), 6.78 (1H, dd, J=8.5, 1.9 Hz), 5.20 (2H, s), 2.21 (3H, s); LCMS retention time 2.65 min, M+H+ 440.1/442.1/444.1. The mixture was used crude in the next step.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl>C(O)C>[CH2:31]([NH:30][C:26]1[N:25]=[C:24]([C:21]2[N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][CH:11]4[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]4)[C:16]3=[N:23][CH:22]=2)[CH:29]=[CH:28][N:27]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2nccn3c(-c4ccnc(NCc5ccccc5)n4)cnc23)CC1
Agent: Cl
Solvent: CCO
Product: NC1CCC(Nc2nccn3c(-c4ccnc(NCc5ccccc5)n4)cnc23)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of crude {4-[3-(2-benzylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (400 mg, 0.182 mmol) in ethanol (5 mL) was added concentrated hydrochloric acid (5 mL) slowly. The reaction mixture was stirred at room temperature for 15 hours. The solvent was removed under reduced pressure and then the solid was purified by prep-HPLC. Several drops of concentrated HCl were added to the fractions with product. After sonicating for several minutes, solution was concentrated under reduced pressure to afford N-[3-(2-benzylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-cyclohexane-1,4-diamine; hydrochloride. (Yield 33 mg, 28.9%). 1H NMR (300 MHz, CD3OD): δ 8.73 (s, 1H), 8.45 (brs, 2H), 7.61-7.32 (m, 7H), 4.91 (brs, 2H), 4.11 (brs, 1H), 3.25 (brs, 1H), 2.23 (brs, 4H), 1.77-1.75 (m, 4H). LC-MS: [M+H]+ 415.
Reaction SMILES: [C:1]1(=[O:31])[N:5]([CH2:6][CH2:7][C:8]#[C:9][C:10]2[C:11](=[O:25])[NH:12][C:13](=[O:24])[N:14]([CH:23]=2)[C@@H:15]2[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[CH2:16]2)[C:4](=[O:26])[C:3]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:2]12>CCO.[Ni]>[C:4]1(=[O:26])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[C:11](=[O:25])[NH:12][C:13](=[O:24])[N:14]([CH:23]=2)[C@@H:15]2[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[CH2:16]2)[C:1](=[O:31])[C:2]2=[CH:30][CH:29]=[CH:28][CH:27]=[C:3]12
Reactant: O=C1c2ccccc2C(=O)N1CCC#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: [Ni]
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CCCCc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reaction time: 48 h
Yield: 97 %

Procedure:
1.00 Gram of 5-(4-Phthalimidobut-1-yn-1-yl)-2'-deoxyuridine was dissolved in 95% EtOH and about 3 g of neutral Raney nickel was added. After 48 hours, the catalyst was removed by cautious filtration and the filtrate was evaporated to a solid which was recrystallized from methanol-water to give 960 mg (97%) of the title compound.