Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]([CH3:22])[CH:3]=[C:4]([C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([F:20])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].NC(C(N)=O)[C:25]([NH2:27])=[O:26]>CC(O)=O>[NH2:27][C:25]([C:22]1[NH:2][CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([F:20])[CH:12]=1)=[O:26]
Reactant: NC(=O)C(N)C(N)=O
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Solvent: CC(=O)O
Product: CCOC(=O)c1c[nH]c(C(N)=O)c1-c1ccc([N+](=O)[O-])c(F)c1
Temperature: 80 °C
Yield: 68.7 %

Procedure:
A 50 mL round bottomed flask was charged with of ethyl 3-(dimethylamino)-2-(3-fluoro-4-nitrobenzoyl)acrylate (51.74 g, 166.75 mmol) and 2-aminomalonamide (23.4 mg, 200 mmol) and AcOH (1 L). The reaction mixture was heated to 80° C. over night. The starting material appeared consumed by TLC. The AcOH was removed under reduced pressure and TFA (300 mL) was added. The mixture was heated over night at 60° C. The reaction was cooled to room temperature and the TFA was removed under reduced pressure. The orange oil was treated with saturated aqueous NaHCO3 (1 L), then solid NaHCO3 was added until the solution was neutral. The solids were filtered and placed in a 1 L erlenmeyer flask. The solids were washed with H2O (3×1 L) and the water was decanted off through the filter. On the last washing the solids were poured onto the filter and allowed to air dry. The solids were once again removed from the filter and washed with Et2O (4×500 mL). The Et2O was decanted off through the filter and on the final washing the solids were transferred to the filter. An addition portion of Et2O (200 mL) was used to wash the flask and the filter cake. The desired product was dried in a vacuum oven at 40° C. to provide a light tan solid (36.8 g, 114.5 mmol, 69% yield). 1H-NMR (DMSO-d6) δ 12.28 (br s, 1H), 8.07 (app t, J=8.4 Hz, 1H), 7.57 (s, 1H), 7.46 (dd, J=12.6, 1.6 Hz, 1H), 7.28 (dd, J=8.4, 1.6 Hz, 1H), 7.25 (br s, 1H), 6.72 (br s, 1H), 4.01 (q, J=7.2 Hz, 2H), 1.07 (t, J=7.2 Hz, 3H); LCMS*RT=4.45 min; MS {M−H]−=320.1.
Reaction SMILES: [SH:1][CH2:2][CH2:3]O.[O-]CC.[Na+].Br[CH:10]([CH:17]=[O:18])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C>[O:18]1[CH2:3][CH2:2][S:1][C:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:17]1
Reactant: CCOC(=O)CC(Br)C=O
Reactant: OCCS
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC1=COCCS1
Temperature: 25 °C
Reaction time: 15 h
Yield: 18.3 %

Procedure:
A solution of 2-mercaptoethanol (38.2 g.) in anhydrous ethanol (146 cc.) is added, at about 10° C. and over the course of one hour, to a solution of sodium ethoxide in ethanol [prepared by reacting sodium (11.2 g.) with anhydrous ethanol (350 cc.)]. After heating the reaction mixture to a temperature of 45°-f 50° C., ethyl 3-bromo-3-formylpropionate (102.8 g.) is added over the course of 20 minutes. The reaction mixture is stirred for 15 hours at a temperature of about 25° C. After filtration, the solvent is evaporated at about 50° C. under reduced pressure (20 mm.Hg). The residue is dissolved in anhydrous toluene (500 cc.); the solution is filtered and toluene-p-sulphonic acid monohydrate (1.5 g.) is then added. The reaction mixture is heated under reflux until complete dehydration has taken place (the water formed being removed in a Dean-Stark apparatus) and then the solvent is evaporated at about 50° C. under reduced pressure (20 mm.Hg). The residue is taken up in diethyl ether (700 cc.); some insoluble matter appears and is removed by filtration through "Supercel". The ether solution is washed three times with water (total 600 cc.), then dried over sodium sulphate, treated with decolourizing charcoal and filtered. The solution is concentrated to dryness under reduced pressure (20 mm.Hg); a residue (65 g.) is obtained and is chromatographed on alumina (600 g.). Elution is effected using a mixture (2.6 liters) of ethyl acetate and cyclohexane (1-19 by volume). After concentration to dryness under reduced pressure (20 mm.Hg), ethyl (5,6-dihydro-1,4-oxathiin-3-yl )acetate (16.8 g.) is obtained in the form of an oil.
Reaction SMILES: [Mg].II.[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[O:13]1[CH2:19][C:18](=[O:20])[CH2:17][O:16][CH2:15][CH2:14]1>C1COCC1>[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:18]2([OH:20])[CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:19]2)=[CH:8][CH:7]=1
Reactant: O=C1COCCOC1
Reactant: COc1ccc(Br)cc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(C2(O)COCCOC2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Magnesium (1.27 g, 0.053 mol), dried in an oven for 1 hr at 75° C., was stirred with THF (125 mL) in a 500 mL three-necked flask at reflux. A crystal of iodine was added followed by a solution of 4-methoxybromobenzene in THF (50 mL), added dropwise over 15 min. After the addition of 10 mL of the solution the reaction initiated. After complete addition of the solution, the reaction mixture was heated at reflux for 2 hrs. The resulting grey solution was cooled to 0° C. and a solution of 1,4-dioxepan-6-one (prepared as described in U.S. Pat. No. 4,410,354) (5.08 g, 0.044 mol) in THF (25 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight then evaporated. The residue was acidified to pH=1 with 1N HCl and extracted with ether (2×250 mL). The ether extracts were washed with water, dried (MgSO4), filtered and concentrated to give a sticky brown solid (9.45 g). This was purified by column chromatography on silica gel eluting with ethyl acetate-hexanes. The relevant fractions were concentrated to give the desired product (6.21 g, 63%).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[O:11][CH2:12][CH2:13][C:14]3([CH2:16][CH2:15]3)[C:6]=12.Cl.O>CO>[C:14]12([C:6]3[C:5]([OH:4])=[CH:10][CH:9]=[CH:8][C:7]=3[O:11][CH2:12][CH2:13]1)[CH2:16][CH2:15]2
Reactant: COCOc1cccc2c1C1(CCO2)CC1
Agent: Cl
Solvent: CO
Solvent: O
Product: Oc1cccc2c1C1(CCO2)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
5-{[(methyloxy)methyl]oxy}-2,3-dihydrospiro[chromene-4,1′-cyclopropane] (Intermediate 220, 145 mg, 0.658 mmol) was dissolved in MeOH (6.0 mL) and a 2N aqueous solution of HCl (0.494 mL, 0.99 mmol) was added and the reaction mixture was stirred at 50° C. overnight. After addition of water, MeOH was removed under vacuum and the aqueous phase was extracted with ethyl acetate (three times). Combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using cyclohexane to cyclohexane/ethyl acetate 9:1 as eluents affording the title compound (64 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[O:14][CH3:15].[CH2:16]([Sn](CCCC)(CCCC)C=C)[CH2:17]CC>ClCCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH:16]=[CH2:17])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[O:14][CH3:15]
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1OC
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: C=Cc1nc(C(=O)OC)c(OC)c(N)c1F
Yield: 97.1 %

Procedure:
A mixture of methyl 4-amino-6-chloro-5-fluoro-3-methoxypicolinate (405 mg, 1.73 mmol), tributyl(vinyl)stannane (1.097 g, 3.46 mmol), and PdCl2(PPh3)2 (181 mg, 0.26 mmol) in 1,2-dichloroethane (3.5 mL) was heated at 120° C. in a Biotage microwave for 30 min Column chromatography (0-40% EtOAc/hexanes) of the crude reaction mixture provided the title compound as a yellow oil (0.38 g, 97%): 1H NMR (400 MHz, CDCl3) δ 6.88 (ddd, J=17.5, 11.1, 1.4 Hz, 1H), 6.33 (dd, J=17.5, 1.6 Hz, 1H), 5.57 (ddd, J=11.1, 1.6, 0.7 Hz, 1H), 4.47 (s, 2H), 3.97 (s, 3H), 3.91 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −143.2; ESIMS m/z 227 ([M+H]+).
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[C:8]([N:17]2[CH2:21][CH2:20][O:19][C:18]2=[O:22])[C:7]([CH3:23])=[C:6]([Cl:24])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:31].[Na+]>CO.C(#N)C>[NH2:31][CH:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[C:8]([N:17]2[CH2:21][CH2:20][O:19][C:18]2=[O:22])[C:7]([CH3:23])=[C:6]([Cl:24])[CH:5]=1)[CH3:2]
Reactant: CC(=O)c1cc(Cl)c(C)c(N2CCOC2=O)c1-c1cccc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1N1CCOC1=O
Temperature: 65 °C

Procedure:
A mixture of 3-(6-acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl)-1,3-oxazolidin-2-one (14 mg, 0.040 mmol) and ammonium acetate (31 mg, 0.40 mmol) and sodium cyanoborohydride (5 mg, 0.08 mmol) in methanol (0.1 mL) and acetonitrile (0.1 mL) was heated at 65° C. overnight in a sealed tube. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step (10 mg, 70%). LCMS calculated for C18H16ClFNO2 (M−NH2)+: m/z=332.1. found: 332.1.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:32](OCC)[O:33]CC)=[C:5]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:9].Cl.C(=O)(O)[O-].[Na+]>CC(C)=O>[CH3:1][C:2]1[NH:3][C:4]([CH:32]=[O:33])=[C:5]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:9]
Reactant: CCOC(=O)C1=C(C(OCC)OCC)NC(C)=C(C(=O)OCCN(CC)CC)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C=O)NC(C)=C(C(=O)OCCN(CC)CC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
To a mixture of a brown oil (2.46 g) of 2-(N,N-diethylamino)ethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate in acetone (24.6 ml) was added 6 N hydrochloric acid (2.46 ml) and this mixture was stirred for two hours at room temperature. The reaction mixture was adjusted to pH 7 with an aqueous solution of sodium bicarbonate and the acetone was distilled off. The residue was extracted with ethyl acetate, and the extract was washed with water, dried, and concentrated to give an oil (1.81 g) of 2-(N,N-diethylamino)ethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:23])[CH2:19][N:20]([CH3:22])[CH3:21])[CH:14]=[CH:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:46]=[CH:45][CH:44]=[C:43]3[C:39]=2[CH:40]=[N:41][NH:42]3)O1>>[NH:42]1[C:43]2[C:39](=[C:38]([C:2]3[N:3]=[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:5]4[S:10][C:9]([C:11]5[CH:12]=[C:13]([NH:17][C:18](=[O:23])[CH2:19][N:20]([CH3:22])[CH3:21])[CH:14]=[CH:15][CH:16]=5)=[CH:8][C:6]=4[N:7]=3)[CH:46]=[CH:45][CH:44]=2)[CH:40]=[N:41]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CN(C)CC(=O)Nc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Product: CN(C)CC(=O)Nc1cccc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1

Procedure:
55 mg of 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzenamine was reacted with N,N-dimethylglycine via General Procedure I to give N-(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-(dimethylamino)acetamide. 70 mg of the crude N-(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-(dimethylamino)acetamide was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A. The product was purified by reverse phase HPLC to yield 3 mg of 152. MS (Q1) 514 (M)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:19])=[C:4]([C:8]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[Br:1][C:2]1[C:3]([CH3:19])=[C:4]([C:8]([NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[CH:9][CH:10]=1)[C:5]([O:7][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:6]
Reactant: BrCc1ccccc1
Reactant: Cc1c(Br)ccc(NC(=O)OC(C)(C)C)c1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Br)ccc(NC(=O)OC(C)(C)C)c1C(=O)OCc1ccccc1
Reaction time: 5 h

Procedure:
A mixture of Example 104B (10 g, 30.3 mmol), potassium carbonate (6.3 g, 45.4 mmol), and DMF (300 mL) was treated with benzyl bromide (3.6 mL, 30.3 mmol), stirred for 5 hours, concentrated, and partitioned between water (1 L) and ethyl acetate (1 L). The organic layer was washed with water (2×1 L) and brine, dried (Na2SO4), filtered, and concentrated to provide the desired product. MS (ESI(+)) m/e 420, 422 (M+H)+, 437, 439 (M+NH4)+, 442, 444 (M+Na)+; (ESI(−)) m/e 418, 420 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 9.04 (s, 1H), 7.65 (d, 1H), 7.45 (m, 2H), 7.37 (m, 3H), 7.22 (d, 1H), 5.28 (s, 2H), 2.30 (s, 3H), 1.42 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.CN(C)C1C=CC=CC=1.[C:21](Cl)(=[O:25])[CH2:22][CH2:23][CH3:24]>C(OCC)(=O)C>[C:21]([NH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1)(=[O:25])[CH2:22][CH2:23][CH3:24]
Reactant: CCCC(=O)Cl
Reactant: Cc1ccnc(N)c1[N+](=O)[O-]
Solvent: CN(C)c1ccccc1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1nccc(C)c1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 2-amino-4-methyl-3nitropyridine (5.0 g) and N,N-dimethylaniline (8.5 ml) was heated at 100° C. under nitrogen atmosphere. To the solution was added butyryl chloride (3.5 ml) and the mixture was stirred at 100° C. for 5 hours. After being cooled to room temperature, ethyl acetate was added to the reaction mixture. The organic layer was separated and washed successively with water and brine. The solution was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was washed with n-hexane to give 2-butyrylamino-4-methyl-3-nitropyridine (7.0 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:43])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([CH3:42])=[CH:39][C:40]=2[CH3:41])[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:41][C:40]1[CH:39]=[C:38]([CH3:42])[N:37]=[CH:36][C:35]=1[C:31]1[CH:30]=[C:29]([C:27]2[CH2:26][C:25](=[O:43])[NH:24][C:9]3[CH:10]=[C:11]([C:20]([F:22])([F:21])[F:23])[C:12]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:13][C:8]=3[N:7]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: Cc1cc(C)c(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)c(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from [2-{3-[3-(4,6-dimethyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M233) (378 mg, 0.604 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (269 mg, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2[C:16](=[O:20])[N:17]([CH3:19])[NH:18][C:11]1=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:40][CH2:41][CH2:42][CH:43](O)[CH2:44][CH2:45][CH3:46].CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2=[C:16]([O:20][CH:43]([CH2:44][CH2:45][CH3:46])[CH2:42][CH2:41][CH3:40])[N:17]([CH3:19])[N:18]=[C:11]12
Reactant: CCCC(O)CCC
Reactant: Cc1cc(C)c(N2CCCc3c2[nH]n(C)c3=O)c(Cl)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(CCC)Oc1c2c(nn1C)N(c1c(C)cc(C)cc1Cl)CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.4 %

Procedure:
A mixture of 200 mg of 7-(2-chloro-4,6-dimethylphenyl)-2-methyl-1,2,4,5,6,7-hexahydropyrazolo[3,4-b]pyridin-3-one (Example 1, step 5) and 337 mg of triphenylphosphine in 15 mL of dry tetrahydrofuran was treated with 124 mg of 4-heptanol and 224 mg of diethylazodicarboxylate. The mixture was placed under an atmosphere of nitrogen and stirred at room temperature for 16 h. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel using 15% ethyl acetate/hexane as solvent giving 84 mg of 7-(2-chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbutoxy)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine as a colorless oil, ms m/z 390 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][N:11](C(OC(C)(C)C)=O)[C:12]([NH:21]C(OC(C)(C)C)=O)=[N:13]C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.Cl>O1CCOCC1>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]([NH2:21])=[NH:13])[CH2:6][CH2:7]1
Reactant: CN1CCC(CCCN(C(=O)OC(C)(C)C)C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCC(CCCNC(=N)N)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a 200 mL round bottom flask were added N-[3-(1-methylpiperidin-4-yl)-propyl]-N,N′,N″-tri-Boc-guanidine prepared as in Example 27 above (3.20 g, 0.0064 mol) and 1,4-dioxane (anhydrous, 50 mL). To the resultant stirred solution was added 4.0 M HCl in 1,4-dioxanes (6.42 mL, 0.026 mol) drop wise over 2.0 min. The resultant mixture was then warmed to 75° C., aged for 3 h then cooled to 0° C. A precipitate was formed. The bulk solvent was decanted and the solids were dried under vacuum for 12 h to yield N-[3-(N-methyl-4-piperidinyl)-1-propyl]guanidine, as its corresponding HCl salt.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].C(N(C(C)C)CC)(C)C.[Cl:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26]>ClCCl>[Cl:21][CH2:22][CH2:23][CH2:24][C:25]([NH:4][C:3]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:2]=1[F:1])=[O:26]
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: O=C(Cl)CCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCCCl)Nc1cc([N+](=O)[O-])ccc1F
Reaction time: 2 h

Procedure:
2-Fluoro-5-nitroaniline (500 mg, 3.2 mmol) and diisopropylethylamine (1.1 ml, 6.4 mmol) were stirred in dry dichloromethane (10 ml) under nitrogen. 4-Chlorobutyryl chloride was added drop-wise over 1 minute and the reaction was stirred for a further 2 hrs. The reaction mixture was partitioned between water (50 ml) and dichloromethane (50 ml). The organics were collected, dried (magnesium sulphate), concentrated in vacuo and the residue purified by flash column chromatography (SiO2) eluting with dichloromethane to give 537 mg of 4-chloro-N-(2-fluoro-5-nitro-phenyl)-butyramide as a white solid. This material was re-dissolved in dry tetrahydrofuran and cooled over an ice-bath. Sodium hydride (83 mg, 2 mmol) was added and the reaction was stirred at room temperature for 3 hr. The reaction mixture was concentrated in vacuo and the residue was dissolved in dichloromethane (50 ml). The organics were washed with water (50 ml), dried (magnesium sulphate) and concentrated in vacuo to give 430 mg of crude 1-(2-fluoro-5-nitro-phenyl)-pyrrolidin-2-one as a yellow solid. This material was suspended in diethyl ether (20 ml) and ethanol (2 ml). A solution of tin (II) chloride dihydrate in concentrated HCl (20 ml) was added drop-wise over 5 minutes and the reaction stirred at room temperature for 3 hrs. The reaction mixture was neutralised to pH 7 by addition of 2M sodium hydroxide (aq) and the resulting solution was extracted with dichloromethane (2×100 ml). The organic extracts were combined, dried (magnesium sulphate) and concentrated in vacuo to afford crude 1-(5-amino-2-fluoro-phenyl)-pyrrolidin-2-one (424 mg, 68%) as a yellow solid. HPLC retention time 3.3 min. Mass spectrum (ES+) m/z 195 (M+H).
Reaction SMILES: C(O[C:4](=[O:14])[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.Cl.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[NH:22])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]2[N:23]=[C:4]([OH:14])[CH:5]=[C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:22]=2)=[CH:19][CH:18]=1
Reactant: N=C(N)c1ccc(Cl)cc1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: Cl
Product: Oc1cc(-c2ccccc2)nc(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was prepared from 3-oxo-3-phenyl-propionic acid ethyl ester and 4-chloro-benzamidine hydrochloride according to general procedure 1. 1H NMR (DMSO-d6, 400 MHz) δ 6.97 (s, 1H), 7.50-7.58 (m, 3H), 7.16 (d, J=8.5 Hz, 2H), 8.10-8.20 (m, 2 H), 8.30 (d, J=8.5 Hz, 2H), 12.50 (br s, 1H); MS: m/z (ESI) 283 (M+H).
Reaction SMILES: [CH2:1]([C:3]([OH:19])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Cl)[N:28]=1>CC(CC(C)C)=O>[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][O:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])([OH:19])[CH2:1][CH3:2])=[CH:9][CH:8]=2)[N:28]=1
Reactant: Cc1cccc(CCl)n1
Reactant: CCC(O)(c1ccc(O)cc1)c1ccccc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCC(O)(c1ccc(OCc2cccc(C)n2)cc1)c1ccccc1OC

Procedure:
7.8 g of α-ethyl-α-(2-methoxyphenyl)-4-hydroxybenzyl-alcohol are dissolved in 65 ml. of methylisobutyl ketone, 9.1 g. of anhydrous potassium carbonate are added, and the reaction mixture is brought up to a boil. Thereafter, a solution of 4.7 g. of 2-methyl-6-chloromethyl-pyridine in 20 ml. of methylisobutyl ketone is added dropwise, and the reaction mixture is slightly boiled for 4 additional hours. After cooling, the reaction mixture is filtered off, and the filtrate is evaporated under reduced pressure. The residue is dissolved in benzene, the solution is washed with a 5% aqueous potassium hydroxide solution and then with water, dried over anhydrous magnesium sulfate and evaporated to dryness in vacuo. The crude product is crystallized from a mixture of ethyl acetate and cyclohexane. Melting point: 110° to 111° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].S(=O)(=O)(O)O.[S-:17][C:18]#[N:19].[Na+].C1OCCOCCOCCOCCOC1>ClC1C=CC=CC=1>[NH:1]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[C:18]([NH2:19])=[S:17]
Reactant: N#C[S-]
Reactant: COC(=O)c1cccc(N)c1
Agent: C1COCCOCCOCCOCCO1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Clc1ccccc1
Product: COC(=O)c1cccc(NC(N)=S)c1
Reaction time: 0.08 h
Yield: 85.9 %

Procedure:
11.3 g of methyl 3-aminobenzoate are initially introduced into the reaction vessel as a solution in 75 ml of chlorobenzene, 2.07 ml of concentrated sulfuric acid (96%) are added dropwise at −5 to 0° C. in the course of 15 minutes, stirring is continued for 5 minutes, 6.8 g of sodium thiocyanate are then introduced in portions at a maximum of 0° C. and the mixture is stirred for a further 15 minutes. 0.2 ml of 15-crown-5 is then added, the mixture is stirred at a bath temperature of 100° C. for 10 hours and cooled and the precipitate formed is filtered off and washed 3 times with water. 13.5 g (85.9%) of the title compound of melting point 171-172° C. result.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2.[CH3:20][O:21]C1C=CC=C2C=1C=CN2>>[CH3:20][O:21][C:5]1[CH:4]=[CH:3][CH:2]=[C:10]2[C:6]=1[CH:7]=[C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)[NH:9]2
Reactant: COc1cccc2[nH]ccc12
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Product: COc1cccc2[nH]c(B3OC(C)(C)C(C)(C)O3)cc12

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 4-methoxy-1H-indole.