Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[C:21]([F:29])[CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:33]O.Cl>CO.O>[F:29][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[C:25]([F:28])([F:27])[F:26])[CH2:18][C@H:10]1[CH2:9][C@H:8]([C:6]2[O:7][NH:33][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(C(F)(F)F)c(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(C(F)(F)F)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 93.6 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluoro-4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (0.781 g, 1.80 mmol) (from example 140, step 1) was dissolved in MeOH (15 mL) and cooled to −40° C. Sodium hydroxide (0.072 g, 1.80 mmol) dissolved in water (1 mL) was added over 1 min and the resulting solution was stirred at −40° C. for 20 min. Then hydroxylamine (50% by weight in water, 0.12 mL, 1.96 mmol) was added over 1 min and stirring continued at −40° C. for 2 h 15 min. The reaction mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30 mL, 180.00 mmol) and the mixture was continued to be stirred at 80° C. for 1 h. Then cooled to room temperature. Methanol was evaporated, then water was added. Extracted three times with DCM. Combined organic layers dried over MgSO4 and evaporated. Crude trans-methyl 2-(3-fluoro-4-(trifluoromethyl)-benzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (678 mg, 94%) was isolated as an off-white foam. MS m/z 403 (M+H)+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][CH:3]=1.O.[NH2:11][NH2:12]>C(O)(C)C>[F:9][C:5]1[C:6]([CH3:8])=[N:7][C:2]([NH:11][NH2:12])=[CH:3][CH:4]=1
Reactant: NN
Reactant: Cc1nc(Cl)ccc1F
Solvent: O
Solvent: CC(C)O
Product: Cc1nc(NN)ccc1F

Procedure:
To a mixture of 6-chloro-3-fluoro-2-methylpyridine (4.7 g, 32.3 mmol) in isopropanol (100 mL) was added hydrazine hydrate (5 g, 100 mmol). After the mixture was refluxed for 5 hrs, additional hydrazine hydrate (5 g, 100 mmol) was added, and the reaction was refluxed for 3 days. The mixture was then concentrated to dryness and stored under high vacuum overnight. This material was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:9])[C:3]=1[N+:15]([O-:17])=[O:16].[NH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:22]([NH:24][CH3:25])=[O:23].CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:12][C:11]([CH3:14])([CH3:13])[CH2:10][N:8]([CH3:9])[C:4]1[N:5]=[CH:6][N:7]=[C:2]([NH:18][C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=2[CH3:29])[C:22]([NH:24][CH3:25])=[O:23])[C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: CN(CC(C)(C)C)c1ncnc(Cl)c1[N+](=O)[O-]
Reactant: CNC(=O)c1ccc(C)c(N)c1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(C)c(Nc2ncnc(N(C)CC(C)(C)C)c2[N+](=O)[O-])c1
Temperature: 80 °C
Yield: 80.2 %

Procedure:
(6-Chloro-5-nitro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-methyl-amine (1.0 mmol) was dissolved in p-dioxane (2 mL), and 3-amino-4,N-dimethyl-benzamide (0.2 g, 1.2 mmol) and DIEA (0.3 mL) were added. The resulting mixture was heated to 80° C. for overnight. The product (0.31 g, yield 80%) was purified by column silica gel chromatography. MS (m/z): 387 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.N1CCCC1.[CH2:14]([OH:17])[C:15]#[CH:16]>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:16]#[C:15][CH2:14][OH:17])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: C#CCO
Solvent: C1CCNC1
Product: Nc1ccc(C#CCO)cn1
Temperature: 80 °C

Procedure:
2-Amino5-bromopyridine (7-1), 10.0 g (57.8 mmol) was stirred in pyrrolidine (96.5 mL, 1.16 mol, 20 equiv) in a flame dried round bottom flask under argon. Propargyl alcohol (10.1 mL, 173 mmol) and tetrakis triphenylphosphine palladium(0) (1.34 g, 1.16 mmol) were added and the solution was degassed 3×by alternating vacuum/Ar. Heat to 80° C. After 18 h the bulk of the pyrrolidine was removed in vacuo and the residue was diluted with water. Extract with CH2Cl2 three times, and the extracts were dried over Na2SO4, filtered and concentrated to provide impure product. The aqueous layer was further extracted ten times with CH2Cl2/nBuOH (95:5). The extracts were dried over Na2SO4, filtered and concentrated. The two samples were combined and were purified in two batches by flash column chromatography (gradient: CH2Cl2 to CH2Cl2/MeOH, 90:10). The product was triurated with ice cold CH2Cl2, filtered, and washed with ice cold CH2Cl2. Afforded the titled compound as a pale yellow solid. 1H NMR (CD3OD) δ7.96 (d, 1H, J=2.2 Hz), 7.45 (dd, 1H, J=2.4, 8.8 Hz), 6.51 (d, 1H, J=8.8 Hz), 4.36 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[Na].[CH2:22]([CH:24]1[O:29][CH2:28][CH2:27][N:26]([C:30]2[N:31]=[C:32]([CH2:37][C:38](O)=[O:39])[NH:33][C:34](=[O:36])[CH:35]=2)[CH2:25]1)[CH3:23]>CN(C)C=O.N1C=CC=CC=1>[CH2:22]([CH:24]1[O:29][CH2:28][CH2:27][N:26]([C:30]2[N:31]=[C:32]([CH2:37][C:38]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=3)=[O:39])[NH:33][C:34](=[O:36])[CH:35]=2)[CH2:25]1)[CH3:23]
Reactant: CCC1CN(c2cc(=O)[nH]c(CC(=O)O)n2)CCO1
Reactant: Nc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCC1CN(c2cc(=O)[nH]c(CC(=O)Nc3ccc(F)cc3)n2)CCO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4 ml of pyridine, 472 mg of 4-fluoroaniline and 815 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are successively added to a solution of 410 mg of the sodium salt of [4-(2-ethylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetic acid in 4 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 16 hours, and then concentrated under reduced pressure. The residue is taken up in 25 ml of water and then the pH is brought back to about 7 with a 2M hydrochloric acid solution. 30 ml of ethyl acetate are added and then the resulting mixture is allowed to stir at ambient temperature for 1 hour. The precipitate formed is filtered off, and then rinsed successively with water and diethyl ether. 300 mg of (±)-2-[4-(2-ethylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-(4-fluorophenyl)-acetamide are thus obtained in the form of an off-white powder, the characteristics of which are the following:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[OH:21][CH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1>>[OH:28][CH2:27][C:26]1[CH:30]=[CH:31][C:23]([C:22]([NH:20][C:3]2[CH:4]=[CH:5][C:6]([N:8]3[CH2:12][CH2:11][CH:10]([CH2:13][N:14]4[CH2:18][CH2:17][CH2:16][CH:15]4[CH3:19])[CH2:9]3)=[CH:7][C:2]=2[CH3:1])=[O:21])=[CH:24][CH:25]=1
Reactant: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1N
Reactant: O=C(O)c1ccc(CO)cc1
Product: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1NC(=O)c1ccc(CO)cc1

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine with 4-hydroxymethyl-benzoic acid. MS: 408.5 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([NH:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([Br:1])=[C:3]([CH3:12])[CH:4]=1)(=[O:15])[CH3:14]
Reactant: Cc1cc(C(=O)NN)ccc1Br
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NNC(=O)c1ccc(Br)c(C)c1
Temperature: 25 °C

Procedure:
4-Bromo-3-methylbenzoic hydrazide (D30, 7.5 g) was suspended in acetic anhydride (7 ml) giving rise to an exothermic reaction. The reaction mixture was cooled to room temperature and the product collected. The solid was washed with ethanol and diethyl ether to afford the title compound as a white powder (5.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[CH:17][C:18]=3[O:20][CH2:21][CH:22]3[CH2:26][CH2:25][NH:24][CH2:23]3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:29](O)(=[O:32])[CH2:30][OH:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:27][CH3:28])=[CH:17][C:18]=2[O:20][CH2:21][CH:22]2[CH2:26][CH2:25][N:24]([C:30](=[O:31])[CH2:29][OH:32])[CH2:23]2)[N:13]=[CH:12][N:11]=1
Reactant: O=C(O)CO
Reactant: COc1cc(OCC2CCNC2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Product: COc1cc(OCC2CCN(C(=O)CO)C2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Yield: 45 %

Procedure:
The procedure described in Example 1 was repeated using N-(3-chloro-4-fluoro-phenyl)-7-methoxy-5-(pyrrolidin-3-ylmethoxy)quinazolin-4-amine (100 mg) and glycolic acid (21 mg) to give the title product in 45% yield; NMR spectrum (DMSO-d6 at 373 K) 9.69 (s, 1H), 8.52 (s, 1H), 8.21-8.20 (m, 1H), 7.66-7.63 (m, 1H), 7.40 (t, 1H), 6.90 (d, 1H), 6.83 (d, 1H), 4.41-4.39 (m, 2H), 4.20-4.10 (m, 1H), 4.05-4.00 (m, 2H), 3.97 (s, 3H), 3.73 (dd, 1H), 3.61-3.58 (m, 1H), 3.51-3.47 (m, 1H), 3.42 (dd, 1H), 2.26-2.14 (br m, 1H), 2.00-1.87 (br m, 1H); Mass spectrum MH+ 461.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].C(N(CC)CC)C.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:27][CH:26]([CH2:28][NH:29][C:30]([C:32]3[S:33][C:34]([Cl:37])=[CH:35][CH:36]=3)=[O:31])[O:25][C:24]2=[O:38])=[CH:19][CH:18]=1>ClCCl>[Cl:37][C:34]1[S:33][C:32]([C:30]([NH:29][CH2:28][CH:26]2[O:25][C:24](=[O:38])[N:23]([C:20]3[CH:19]=[CH:18][C:17]([NH:16][S:5]([CH2:4][CH2:3][CH2:2][Cl:1])(=[O:7])=[O:6])=[CH:22][CH:21]=3)[CH2:27]2)=[O:31])=[CH:36][CH:35]=1
Reactant: Nc1ccc(N2CC(CNC(=O)c3ccc(Cl)s3)OC2=O)cc1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1CN(c2ccc(NS(=O)(=O)CCCCl)cc2)C(=O)O1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An ice-cooled solution of 26.4 mg (0.15 mmol) of 3-chloro-1-propanesulphonyl chloride and 0.03 ml (0.2 mmol) of triethylamine in 3.5 ml of absolute dichloromethane is admixed with 35 mg (0.1 mmol) of N-{[3-(4-aminophenyl)-2-oxo-1,3-oxazolidin-5-yl]-methyl}-5-chloro-2-thiophene-carboxamide (from Example 149). After 30 min, ice-cooling is removed and the mixture is stirred at room temperature overnight, and 150 mg (about 5.5 eq.) of PS-trisamine (Argonaut Technologies) and 0.5 ml of dichloromethane are then added. The suspension is stirred gently for 2 h and filtered (the resin is washed with dichloromethane/methanol), and the filtrate is concentrated. The product is purified by preparative RP-HPLC. Yield: 19.6 mg (40% of theory),
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].S(O[CH2:18][CH2:19][CH2:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1)(C)(=O)=O>CN(C=O)C>[C:1]1(=[O:11])[N:5]([CH2:18][CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]#[N:26])=[CH:27][CH:28]=2)[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: CS(=O)(=O)OCCCc1ccc(C#N)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
To 100 ml of DMF suspension of 21.1 g (0.114 mol) of potassium phthalimide was added 50 ml of DMF solution of 13.6 g (57 mmols) of crude 4-(3-mesyloxypropyl)benzonitrile. The reaction mixture was stirred at 90° C. for 3 hours, then cooled to room temperature and poured into 200 ml of ice-water, followed by extraction with ether-benzene (1:1). The organic layer was dried over Na2SO4 and concentrated, giving 14.0 g (yield 85%) of 4-(3-phthalimidopropyl)benzonitrile.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=[O:15])[N:5]=1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=[O:18].FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C(I)C=CC=1)=O>CC#N.O>[OH:18][CH2:2][C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=[O:15])[N:5]=1)=[O:3]
Reactant: CC(=O)c1nn(CC(=O)O)c2ccccc12
Reactant: O=C(O)C(F)(F)F
Agent: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: O=C(O)Cn1nc(C(=O)CO)c2ccccc21
Temperature: 90 °C

Procedure:
The title compound was prepared in a similar manner as described by N. Yoshikawa et al., J. Org. Chem., 2002, 67, 2556-2565: A mixture of 2-(3-acetyl-1H-indazol-1-yl)acetic acid (100 mg, 0.46 mmol), TFA (0.71 mL, 0.92 mmol) and bis-(trifluoroacetoxy)-iodobenzene (394 mg, 0.92 mmol) in CH3CN (4 mL) and water (0.6 mL) was heated to reflux (90° C.) for 16 h. Solvents were evaporated and the crude product was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA) to give after lyophilization of the purified fractions the title compound. MS (LC-MS): 233 [M+H]+; tR (HPLC conditions k): 2.41 min.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH3:7][SiH:8]([CH3:10])[Cl:9]>>[CH2:1]([Si:8]([CH3:10])([CH3:7])[Cl:9])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C[SiH](C)Cl
Reactant: C=CCCC=C
Product: C=CCCCC[Si](C)(C)Cl
Reaction time: 48 h
Yield: 68 %

Procedure:
5-Hexenyldimethylchlorosilane was prepared by combining 1,5-hexadiene (164 g) and 0.05 g of platinum complex ##STR8## in a flask equipped with a condenser, addition-funnel and a thermometer. Dimethylchlorosilane (92 g) was added at such a rate that the pot temperature did not rise above 40° C. The mixture was allowed to stand at room temperature for 48 hours. The product was isolated in 68% yield by distillation under reduced pressure (bp 39°-40° C./2.2 mm Hg).
Reaction SMILES: O[CH:2]1[C:7]2([CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[O:6][C:5]2[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:4]=2[CH:3]1[C:20](=[S:23])[NH:21][CH3:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH3:22][NH:21][C:20]([C:3]1[C:4]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:5]=2[O:6][C:7]2([CH2:8][CH2:9][O:10][CH2:11][CH2:12]2)[CH:2]=1)=[S:23]
Reactant: CNC(=S)C1c2cc([N+](=O)[O-])ccc2OC2(CCOCC2)C1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CNC(=S)C1=CC2(CCOCC2)Oc2ccc([N+](=O)[O-])cc21
Yield: 59.2 %

Procedure:
A mixture of 1.66 g of 3,4-dihydro-3-hydroxy-N-methyl-6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydropyran]-4-carbothioamide, 1.0 g of p-toluenesulfonic acid monohydrate and 100 ml of toluene was refluxed with heating for 1.5 hours. Water was added therein and the mixture was extracted with methylene chloride. An organic layer was washed and dried, and the solvent was distilled. The obtained residue was purified according to silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 0.93 g of N-methyl-6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydropyran]-4-carbothioamide with a melting point of 223°-225° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[NH:8][C:9]([CH:13]=[O:14])=[C:10]([Cl:12])[N:11]=1)[CH2:4][CH2:5][CH3:6].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:24]([O-:26])=[O:25])=[CH:19][CH:18]=1>CN(C=O)C>[CH2:3]([C:7]1[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]([CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[C:24]([O:26][C:17]([CH3:22])([CH3:18])[CH3:16])=[O:25])=[CH:19][CH:18]=2)[C:9]([CH:13]=[O:14])=[C:10]([Cl:12])[N:11]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Reactant: O=C([O-])C(c1ccc(CBr)cc1)C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(C(C(=O)OC(C)(C)C)C2CCCC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
1.6 g (0.053 mol) of sodium hydride (80% strength) are suspended in 50 ml of DMF under protective gas, 10 g (0.053 mol) of 2-butyl-5-formyl-4-chloroimidazole (preparation according to EP 324,377) in 100 ml of DMF are added dropwise at 0° C., the mixture is then stirred at 0° C. for 15 min and 18.9 g (0.053 mol) of tert-butyl 2-(4-bromomethylphenyl-2-cyclopentylacetate in 100 ml of DMF are added dropwise. The mixture is stirred at 0° C. for 2 h, the solvent is evaporated, the residue is taken up in diethyl ether and filtered and, after concentration, chromatographed on silica gel 60 using dichloromethane.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Cl[CH2:6][C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1>>[N:8]1[CH:9]=[CH:10][N:11]=[CH:12][C:7]=1[CH2:6][NH:3][CH2:2][CH2:1][NH2:4]
Reactant: ClCc1cnccn1
Reactant: NCCN
Product: NCCNCc1cnccn1

Procedure:
Ethylenediamine is reacted with 2-chloromethylpyrazine by the procedure of Example 34 to give N-(2-pyrazinylmethyl)ethylenediamine. Heating this compound with S-methylisothiourea in water under reflux for 3 hours by the procedure of Example 1 gives 2-(2-pyrazinylmethylamino)ethylguanidine.
Reaction SMILES: N1C=CC=CC=1.[F:7]N1N=C(F)C=C(F)N1.[NH2:16][CH2:17][CH2:18][C:19]1[N:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22]>ClCCl>[NH2:16][CH2:17][CH2:18][C:19]1[N:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21]([F:7])=[O:22]
Reactant: FC1=CC(F)=NN(F)N1
Reactant: NCCc1nc(Cl)ccc1C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: NCCc1nc(Cl)ccc1C(=O)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
2 ml (24.8 mmol) of pyridine and 4.2 ml (49.8 mmol) of 2,4,6-trifluorotriazine are added to a suspension of 5.0 g (24.8 mmol) of 2-(aminoethyl)-6-chloronicotinic acid in 125 ml of dichloromethane. The mixture is stirred for 3 hours at ambient temperature and then filtered. The solid is rinsed with 50 ml of dichloromethane and the filtrate is washed twice with 60 ml of ice-cold water. The organic phase is dried over Na2SO4 and the solvent is evaporated off under reduced pressure. 5.01 g of product are obtained in the form of an orange oil. Yield=99%.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:14])[C:7]2=[O:12].[F:21][C:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:32][C:33](O)=[O:34].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:21][C:22]1[C:27]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:32][C:33]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:14])[C:7]2=[O:12])=[O:34]
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1F
Reactant: CC(c1ccccn1)n1ccc2c(N)cccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(c1ccccn1)n1ccc2c(NC(=O)Cc3cccc(C(F)(F)F)c3F)cccc2c1=O
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of 5-amino-2-(1-(pyridin-2-yl)ethyl)isoquinolin-1(2H)-one (100 mg, 0.0004 mol) in N,N-Dimethylformamide (1 mL, 0.01 mol) was added 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid (178 mg, 0.000801 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (468.3 mg, 0.001232 mol) and N,N-diisopropylethylamine (300 uL, 0.002 mol). The reaction mixture was stirred for 16 hours at 50° C. LC/MS indicated that the reaction was completed. The DMF reaction solution was directly applied to prep. HPLC. The final product was obtained as a solid (102.4 mg). MS m/z=470.3 (M+1). 1H NMR (DMSO) δ 10.17 (s, 1 H), 8.54 (d, J=6.4 Hz, 1 H), 8.10 (d, J=8.0 Hz, 1 H), 7.82 (dd, J=7.8, 0.7 Hz, 1 H), 7.78 (td, J=9.5, 1.8 Hz, 2 H), 7.70 (t, J=7.1 Hz, 1 H), 7.55 (d, J=7.8 Hz, 1 H), 7.48 (t, J=7.9 Hz, 1 H), 7.40 (t, J=7.7 Hz, 1 H), 7.35 (d, J=8.0 Hz, 1 H), 7.31 (qd, J=4.8, 0.9 Hz, 1 H), 6.74 (d, J=7.8 Hz, 1 H), 6.28 (q, J=7.2 Hz, 1 H), 3.98 (s, 2 H), 1.78 (d, J=7.2 Hz, 3 H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][CH2:18][CH3:19])[C:11](=[O:20])[N:10]([CH2:21][CH2:22][CH3:23])[C:9]=3[N:8]=2)[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C)C=O>[CH2:30]([N:15]1[C:14]2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][CH3:19])[C:11](=[O:20])[N:10]([CH2:21][CH2:22][CH3:23])[C:9]=2[N:8]=[C:7]1[CH:4]1[CH2:5][CH2:6][C:2](=[O:1])[CH2:3]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCCn1c(=O)c2[nH]c(C3CCC(=O)C3)nc2n(CCC)c1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c(=O)c2c(nc(C3CCC(=O)C3)n2Cc2ccccc2)n(CCC)c1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
10.0 g (0.031 mol) of 8-(3-oxocyclopentyl)-1,3-dipropyl-7H-purine-2,6-dione are dissolved in 30 ml of absolute dimethylformamide and after the addition of 4.6 g (0.033 mol) of potassium carbonate the mixture is stirred for 20 minutes at ambient temperature. 5.7 g (0.033 mol) of benzylbromide are added dropwise, the mixture is stirred for a further 40 minutes and the reaction is ended by the addition of water. The solution is evaporated down, the residue is taken up in water and extracted with dichloromethane. After drying and evaporation, the combined organic phases yield an oily residue which is purified on silica gel with a mixture of dichloromethane/methanol in the ratio 99:1 and then recrystallised from ethanol. 9.4 g (73.3% of theory) of the title compound are obtained in the form of colourless crystals, melting point: 145° C.
Reaction SMILES: FC(F)(F)S([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([N:17]3[CH2:22][CH2:21][CH2:20][C@@H:19]4[C:23]5[CH:24]=[C:25](OS(C(F)(F)F)(=O)=O)[CH:26]=[CH:27][C:28]=5[CH2:29][C@H:18]34)=[O:16])=[CH:14][C:9]=2[N:8]=[CH:7]1)(=O)=O.N1[C:44]2C=CC=C[C:43]=2NC=1>CN(C)C=O>[NH:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([N:17]3[CH2:22][CH2:21][CH2:20][C@@H:19]4[C:23]5[CH:24]=[C:25]([C:43]#[CH:44])[CH:26]=[CH:27][C:28]=5[CH2:29][C@H:18]34)=[O:16])=[CH:14][C:9]=2[N:8]=[CH:7]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: O=C(c1ccc2c(c1)ncn2S(=O)(=O)C(F)(F)F)N1CCC[C@@H]2c3cc(OS(=O)(=O)C(F)(F)F)ccc3C[C@@H]21
Solvent: CN(C)C=O
Product: C#Cc1ccc2c(c1)[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1C2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A flask charged with a stir bar, trifluoromethanesulfonic acid cis-1-(1-trifluoromethane-sulfonyl-1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-6-yl ester (mixture of isomers regarding sulfonyl group attachment to N-1 or N-3 of the benzimidazole, 0.20 g) and N,N-dimethylformamide (2 mL) is sparged with argon for 5 min. Copper(I) iodide (13 mg), Pd(PPh3)2Cl2 (25 mg), triethylamine (0.31 mL), and trimethylsilylacetylene (0.14 mL) are added in the given order, the vessel is sealed, and the resulting mixture is heated to 60° C. After stirring the mixture at 60° C. overnight, it is cooled to room temperature and aqueous K2CO3 solution is added. The resulting mixture is extracted with ethyl acetate, the combined extract is dried (Na2SO4), and the solvent is evaporated. The residue is chromatographed on silica gel (dichloromethane/methanol 1:09:1) to afford the trimethylsilylated title compound which is taken up in methanol (3 mL) and treated with saturated aqueous K2CO3 solution at room temperature for 2 h. The mixture is then concentrated, water is added to the residue, and the resulting mixture is extracted with ethyl acetate. The combined extract is dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (dichloromethane/methanol 1:0→9:1) to afford the title compound. Yield: 0.03 g (26% of theory); LC (method 1): tR=2.65 min; Mass spectrum (ESI+): m/z=342 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:10][CH3:11])=[N+:4]([O-])[C:5]([CH3:8])=[CH:6][CH:7]=1.[C:12]([O:15][C:16](=O)C)(=[O:14])C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:12]([O:15][CH3:16])=[O:14])=[N:4][C:3]=1[O:10][CH3:11]
Reactant: COc1c(Br)ccc(C)[n+]1[O-]
Reactant: CC(=O)OC(C)=O
Product: COC(=O)Cc1ccc(Br)c(OC)n1

Procedure:
step c—A solution of 357b (0.47 g) and acetic anhydride (4.0 mL) was heated at 120° C. for 2 h, The reaction mixture was concentrated in vacuo and purified on a SiO2 column eluting with 5% EtOAc/hexane to afford methyl 5-bromo-6-methoxy-pyridin-2-yl-acetate (357c).