Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[CH:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([C:4]([NH:24][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:6])=[CH:7][CH:8]=[C:9]([Cl:11])[N:10]=1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: NC1CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NC1CCCCC1)c1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,6-dichloronicotinic acid (5.005 g, 26.18 mmol) in DCM (60 ML) was added a few drops of DMF followed by the addition dropwise of oxalyl chloride (2.27 mL, 26.18 mmol). The reaction was stirred at room temperature for two hours until gas bubbling had stopped. The solvent was evaporated under reduced pressure to give an oil. DCM (60 mL) was added and the reaction mixture was cooled in an ice bath. Cyclohexylamine (5.98 mL, 52.36 mmol) was added slowly keeping the temperature below 15° C. The reaction was stirred at room temperature overnight.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[Cl:12][CH:13]([Cl:32])[C:14]([N:16]1[C@H:20]([CH2:21][F:22])[C@@H:19]([C:23]2[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=2)[O:18][C:17]1([CH3:31])[CH3:30])=[O:15].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:32][CH:13]([Cl:12])[C:14]([N:16]1[C@H:20]([CH2:21][F:22])[C@@H:19]([C:23]2[CH:28]=[CH:27][C:26]([C:6]3[CH:7]=[N:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=3)=[CH:25][CH:24]=2)[O:18][C:17]1([CH3:30])[CH3:31])=[O:15]
Reactant: CC1(C)O[C@H](c2ccc(I)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
Reactant: OCc1ccc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)O[C@H](c2ccc(-c3ccc(CO)nc3)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
Temperature: 80 °C
Yield: 41.8 %

Procedure:
A mixture of commercially available (6-(hydroxymethyl)pyridin-3-yl)boronic acid (1.020 g, 5.38 mmol), 2,2-dichloro-1-((4S,5R)-4-(fluoromethyl)-5-(4-iodophenyl)-2,2-dimethyloxazolidin-3-yl)ethanone (2.0 g mg, 4.48 mmol), Cs2CO3 (4.38 g, 13.4 mmol) in dioxane (40 mL) and water (25 mL) is bubbled with nitrogen gas for 2 minutes. To this mixture is added Pd(PPh3)4 (518 mg, 0.44 mmol) and the resulting reaction mixture heated to 80° C. in microwave reactor for 6 hours. The reaction is diluted with water (20 ml) and extracted with ethyl acetate (3×20 mL). The combined organic solution is dried over Na2SO4 and concentrated. The crude product is adsorbed on celite, and purified on silica gel column using 0 to 50% EtOAC/heptane to give the title compound (800 mg): LCMS m/z (Cl): 427 [M+H].
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:13][C:12]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>ClCCl>[NH:14]([C:12]1[O:13][C:9]([C:5]2[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=2)=[CH:10][N:11]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1cccc(-c2cnc(Nc3ccccc3)o2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(-c2cnc(Nc3ccccc3)o2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 1092.5 %

Procedure:
A solution of the title compound of Example 1 (0.110 g, 0.41 mmol) in dichloromethane (5 mL) was carefully treated with boron tribromide (0.516 g, 2.06 mmol). After stirring for 1 h, the reaction was carefully poured over ice. After the ice melted, the mixture was extracted with ethyl acetate (2×250 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The title compound was dried under vacuum at RT to afford a light brown solid (1.13 g, 47%). 1H NMR (400 MHz, d6-DMSO): δ 6.74 (dd, J1=8.1, J2=2.2 1H), 6.99 (d, J=2, 1H), 7.05 (d, J=7.9, 1H), 7.21 (t, J=7.9, 1H), 7.64 (s, 1H), 9.48 (bs, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:12]2[C:17]([C:18]#[N:19])=[C:16]([CH3:20])[N:15]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:14](=[O:31])[N:13]2[CH3:32])=[C:7]([S:9]([O-:11])=[O:10])[CH:8]=1)#[N:2].[Na+].Br[CH2:35][CH:36]1[CH2:39][CH2:38][CH2:37]1>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:12]2[C:17]([C:18]#[N:19])=[C:16]([CH3:20])[N:15]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:30])[F:28])[CH:22]=3)[C:14](=[O:31])[N:13]2[CH3:32])=[C:7]([S:9]([CH2:35][CH:36]2[CH2:39][CH2:38][CH2:37]2)(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: BrCC1CCC1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)[O-])N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)CC2CCC2)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 110 °C

Procedure:
The reaction was carried out under argon. Sodium 5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfinate (150 mg, 101 μmol; purity 32%) was suspended in DMF (1 ml). 1-(Bromomethyl)cyclobutane (164.1 mg) was then added, and the mixture was heated in a closed tube at 110° C. for 72 h. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The title compound was obtained as a solid (40.2 mg, 75% of theory).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:22]([OH:24])=O)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[CH2:32]([O:39][C:40](=[O:48])[CH2:41][CH2:42][NH:43][C:44](=[O:47])[CH2:45][NH2:46])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([O:39][C:40](=[O:48])[CH2:41][CH2:42][NH:43][C:44](=[O:47])[CH2:45][NH:46][C:22](=[O:24])[CH:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]#[N:21])=[CH:18][CH:19]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: NCC(=O)NCCC(=O)OCc1ccccc1
Reactant: N#Cc1ccc(CC(NC(=O)OCc2ccccc2)C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(CC(NC(=O)OCc2ccccc2)C(=O)NCC(=O)NCCC(=O)OCc2ccccc2)cc1

Procedure:
For the preparation of the ester starting material, N-(benzyloxycarbonyl)-3-(p-cyanophenyl)-DL-alanine and N-glycyl-β-alanine benzyl ester trifluoroacetate are coupled to give N-[N-[N-(benzyloxycarbonyl)-3-(p-cyanophenyl)-DL-alanyl]glycyl]-β-alanine benzyl ester, m.p. 134°-135° C. Therefrom with hydrogen sulphide and triethylamine in pyridine there is obtained N-[N-[N-(benzyloxycarbonyl)-3-[p-(thiocarbamoyl)phenyl]-DL-alanyl]glycyl]-β-alanine benzyl ester m.p.150°-151° C. Reaction with methyl iodide in acetone, subsequent reaction with ammonium acetate in methanol and treatment with benzyl chloroformate and triethylamine in THF give N-[N-[N-(benzyloxycarbonyl)-3-[p-[N-(benzyloxycarbonyl)-amidino]phenyl]-DL-alanyl]glycyl]-β-alanine benzyl ester, MS: 694 (100, M+H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[F:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH:5][C:10](=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(N)cccc1F
Product: CC(=O)Nc1cccc(F)c1C

Procedure:
3-Fluoro-2-methylaniline was acetylated with acetic acid anhydride to give 3-fluoro-2-methyl-N-acetylaniline. Displacing fluorine of the 3-fluoro-2-methyl-N-acetylaniline with methylamine followed by nitration, deacetylation and reduction of the nitro group with palladium or charcoal gave 1,2-diamino-3-methyl-4-methylaminobenzene. Condensation of 4,4′-dibromobenzil with the 1,2-diamino-3-methyl-4-methylaminobenzene in refluxing methanol gave 2,3-bis(4-bromophenyl)-5-methyl-6-methylaminoquinoxaline which upon acetylation with acetic acid anhydride, nitration, reduction with palladium on charcoal and cyclization gave the title compound.
Reaction SMILES: O1CCCC1.[NH2:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:40])[CH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(N(CC)CC)C>[OH:9][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][NH:6][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:40])[CH2:31][CH2:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: NCC(O)c1ccccc1
Reactant: O=C(CCCc1ccccc1)OCCCCCCCCCCCCBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCCc1ccccc1)OCCCCCCCCCCCCNCC(O)c1ccccc1

Procedure:
According to method I (tetrahydrofuran, reflux 4 days) from 2-amino-1-phenylethanol and (12-bromo-1-dodecyl)4-phenylbutanoate. Working up by means of chromatography (ethyl acetate/petroleum ether 60-80/triethylamine 6:4:1). Recrystallized from diethyl ether. Melting point: 73°-74° C.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]O)[CH:16]=1>>[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)[CH:16]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1cccnc1
Product: N#Cc1ccnc(-n2nccc2OCc2cccnc2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and pyridin-3-ylmethanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.27 (2H, s), 5.78 (1H, d, J=2.0 Hz), 7.41 (1H, dd, J=1.2 Hz, J=5.2 Hz), 7.36 (1H, dd, J=4.8 Hz, J=7.6 Hz), 7.58 (1H, d, J=2.0 Hz), 7.80 (1H, d, J=8.0 Hz), 8.03 (1H, s), 8.63 (1H, dd, J=1.2 Hz, J=4.8 Hz), 8.69-8.72 (2H, m). [M+H] Calc'd for C15H11N5O, 278. Found, 278.
Reaction SMILES: Cl[S:2]([C:5]1[S:6][C:7]([C:10]2[S:11][C:12]([CH2:15][CH3:16])=[CH:13][CH:14]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3].[NH2:17][C:18]1[O:22][N:21]=[C:20]([CH3:23])[C:19]=1[Br:24]>>[Br:24][C:19]1[C:20]([CH3:23])=[N:21][O:22][C:18]=1[NH:17][S:2]([C:5]1[S:6][C:7]([C:10]2[S:11][C:12]([CH2:15][CH3:16])=[CH:13][CH:14]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: Cc1noc(N)c1Br
Reactant: CCc1ccc(-c2ccc(S(=O)(=O)Cl)s2)s1
Product: CCc1ccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Br)s2)s1
Yield: 59 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(5-ethyl-2-thienyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2. Reaction of 2-chlorosulfonyl-5-(5-ethyl-2-thienyl)thiophene (200 mg, 0.68 mmol) with 5-amino-4-bromo-3-methyl isoxazole (121 mg, 0.68 mmol) yielded 174 mg N-(4-bromo-3-methyl-5-isoxazolyl)-5-(5-ethyl-2-thienyl)-thiophene-2-sulfonamide (59% yield). After passing through a small plug of silica gel with elution using 10% MeOH/CHCl3, a small fraction of the product was further purified using preparative HPLC to give the sulfonamide as a light tan colored powder, m.p. 126° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH:5]=[C:4]([CH3:19])[N:3]=1.ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)(Cl)Cl>[CH3:19][C:4]1[CH:5]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH:7]=[C:2]([CH3:1])[N+:3]=1[O-:28]
Reactant: Cc1cc(CCc2ccc([N+](=O)[O-])cc2)cc(C)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(CCc2ccc([N+](=O)[O-])cc2)cc(C)[n+]1[O-]
Reaction time: 2 h

Procedure:
Compound (3) (22.82 g, 84.5 mmol) was dissolved in chloroform (100 ml), and 16 g (94 mmol) of m-chloroperbenzoic acid (mCPBA) was addedin small portions at RT over a period of 30 min. The mixture was stirred for an additional 2 h and after a negative TLC test for the starting material it was worked up by partitioning between sat. sodium hydrogen carbonate and chloroform. The combined chloroform extracts (3×200 ml) were evaporated yielding a light yellow solid material that was TLC pure.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]2[N:51]([C:52]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[N:50]=[N:49][N:48]=2)=[CH:37][CH:36]=1>O1CCCC1.C(OCC)(=O)C>[CH2:1]([C:5]1[N:14]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[C:47]3[N:51]([C:52]([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)([C:59]4[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=4)[C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[N:50]=[N:49][N:48]=3)=[CH:39][CH:40]=2)[C:13](=[O:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:16]=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(=O)c2cc(C=CC(=O)OCC)ccc2[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nc2ccc(C=CC(=O)OCC)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 38.3 %

Procedure:
To a suspension of 1.75 g of ethyl 3-(2-butyl-1,4-dihydro-4-oxo-6-quinazolinyl)-2-propenoate in 25 ml of dry tetrahydrofuran at room temperature is rapidly added 6.70 g of a 1.0M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran. After stirring for 20 minutes at room temperature 3.899 g of 5-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl]-1-(triphenylmethyl)-1H-tetrazole is rapidly added in one portion and the reaction mixture heated at reflux for 48 hours. After cooling to room temperature, the reaction mixture is diluted with ethyl acetate and the organic layer washed with 5% HCl, water and brine. The organic layer is dried with MgSO4 and concentrated in vacuo to a residue which is purified by column chromatography on silicagel by eluting with 1:4 ethyl acetate-hexanes to give 1.732 g of the desired product as a solid. FAB MASS SPEC 799 (M+Na)
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10].[OH-].[Na+]>>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(Cc1nc2cc(C(=O)N(CCC(=O)O)c3ccccn3)ccc2n1C)c1ccc(C(=N)N)cc1
Yield: 66 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. Yield: 66% of theory, C26H27N7O3 (485.6) ##EQU46##
Reaction SMILES: Br[CH:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([O:5][C@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])=[O:4].C(N(CC)CC)C.Cl.[F:28][C:29]1([F:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:28][C:29]1([F:35])[CH2:34][CH2:33][N:32]([CH:2]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]([O:5][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:7])=[O:4])[CH2:31][CH2:30]1
Reactant: FC1(F)CCNCC1
Reactant: C[C@H](OC(=O)C(Br)c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H](OC(=O)C(c1ccccc1)N1CCC(F)(F)CC1)c1ccccc1
Temperature: 55 °C
Reaction time: 0.08 h
Yield: 92.4 %

Procedure:
To a solution of the product from Example 138A (1.00 g, 3.13 mmol) in tetrahydrofuran (20 mL) at room temperature was added triethylamine (1.75 mL, 12.5 mmol) and tetrabutylammonium iodide (0.46 g, 1.25 mmol). The mixture was stirred for 5 minutes and then 4,4-difluoropiperidine hydrochloride (0.74 g, 4.70 mmol) was added as the free base in THF. The mixture was stirred for 1 hour at room temperature and then heated to 55° C. overnight. The cooled mixture was washed with brine, concentrated, then purified by column chromatography (EtOAc-hexane) to provide the title compound (1.04 g, 92% yield).
Reaction SMILES: CC(OC([N:8]1[C@H:17]([C:18]([OH:20])=O)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)C.[CH3:21][C:22]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:21][C:22]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:23]=1[NH:24][C:18]([C@@H:17]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][NH:8]1)=[O:20]
Reactant: Cc1cccc(N)c1C
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(NC(=O)[C@@H]2Cc3ccccc3CN2)c1C

Procedure:
N-Boc-L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Bachem) was coupled with 2,3-dimethyl aniline using standard peptide coupling procedures. The product was deprotected using TFA in CH2Cl2 to give the title compound.
Reaction SMILES: C(S[C:9](=[S:18])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=1)C1C=CC=CC=1.[CH3:19][NH2:20].O>C(O)C>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:9]([NH:20][CH3:19])=[S:18])=[N:12][CH:13]=1
Reactant: Cc1ccc(NC(=S)SCc2ccccc2)nc1
Reactant: CN
Solvent: CCO
Solvent: O
Product: CNC(=S)Nc1ccc(C)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl(5-methyl-2-pyridyl)dithiocarbamate (3 g.) was suspended in ethanol (30 ml.). Methylamine (33% ethanolic solution, 10 ml.) was added and the mixture stirred at room temperature for 1 hour. On the addition of water, the thiourea separated and was collected by filtration, dried and recrystallised from ethanol-petrol ether. Yield 2.5 g., m.pt. 161° C.
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10](Cl)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>C(O)CCC.Cl>[NH:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([OH:15])=[CH:17][CH:18]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nccc(Nc2ccccc2)n1
Reactant: Nc1ccc(O)cc1
Agent: Cl
Solvent: CCCCO
Product: Oc1ccc(Nc2nccc(Nc3ccccc3)n2)cc1
Temperature: 80 °C

Procedure:
4-Anilino-2-chloropyrimidine (Reference Example A-9, 0.921 g, 4.48 mmol) was dissolved in butanol (6 ml) and treated with 4-hydroxyaniline (0.489 g, 4.48 mmol) and conc. HCl (9 drops). The reaction was heated to 80° C. for 4 hours. The solvent was removed by evaporation at reduced pressure to give the title product as a solid which was used without further purification (1.4 g) NMR (300 MHz): 6.43 (d, 1H), 6.68 (d, 2H) 7.14 (t, 1H), 7.25 (m, 4H), 7.64 (m, 2H), 7.88 (s, 1H) 9.53 (brs, 1H), 10.27 (brs, 1H). 10.88 (brs, 1H); m/z: (ES−) 279 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCCCCCCOCCCc1ccccn1
Reactant: NCc1ccccc1
Product: c1ccc(CNCCCCCCOCCCc2ccccn2)cc1

Procedure:
2-[3-[(6-Bromohexyl)oxy]propyl]pyridine (17.0 g) was added to benzylamine (50 ml) at 140° under nitrogen. After 1 h at 140° the reaction mixture was cooled and partitioned between 2N sodium hydroxide (250 ml) and ether (250 ml). The organic layer was washed with water and brine, dried and concentrated to a yellow oil. The excess benzylamine was removed by distillation to give the title compound as a yellow oil (18.5 g), t.l.c. (System A 80:20:2) Rf 0.42.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:17]4[CH2:24][CH2:23][CH2:22][C:18]=4[N:19]([CH3:21])[N:20]=3)[N:14]=2)[N:9](COCC[Si](C)(C)C)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:17]4[CH2:24][CH2:23][CH2:22][C:18]=4[N:19]([CH3:21])[N:20]=3)[N:14]=2)[NH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4c3CCC4)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4c3CCC4)nc12
Reaction time: 15 h
Yield: 92666.7 %

Procedure:
To a solution of N-isopropyl-2-(1-methyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (68 mg, 150 μmol) in dichloromethane (5 mL) was added TFA (1.48 g, 1.00 mL, 13.0 mmol) and the reaction mixture stirred for 15 h then concentrated. The residue was re-dissolved in 5 mL of a solution of dichloromethane/MeOH/ammonium hydroxide (60:10:1) and stirred at 25° C. for 3 h, then evaporated and purified by chromatography (40 g column, 50 μm from Analogix, 0 to 5% MeOH containing 10% ammonium hydroxide in dichloromethane). The pure product was suspended in dichloromethane and cyclohexane added to promote solid formation, which was separated by decantation and dried under high vacuum to give N-isopropyl-2-(1-methyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (45 mg, 139 mmol, 93%) as a white solid. MS (M+H)+=325; 1H NMR (DMSO-d6) δ: 12.68 (br. s., 1H), 8.87 (s, 1H), 8.31 (s, 1H), 8.00 (d, J=7.9 Hz, 1H), 4.02-4.46 (m, 1H), 3.79 (s, 3H), 2.92 (t, J=6.4 Hz, 2H), 2.73 (t, J=6.4 Hz, 2H), 2.60 (t, J=6.4 Hz, 2H), 1.24 (d, J=6.4 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][O-:10].[Na+]>CO.CCCCCC>[Cl:1][C:2]1[N:7]=[C:6]([O:10][CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: Clc1ccnc(Cl)n1
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Product: COc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 50 %

Procedure:
To a solution of 2,4-dichloro pyrimidine (20 gm) in methanol (200 ml) was added sodium methoxide (8.7 gm) at 0 to 5° C. The resulting mixture was stirred for 14 hours at room temperature and then concentrated under reduced pressure to obtain a residual mass. The residual mass obtained was extracted with ethyl acetate and water. The combined organic layers were washed with water and sodium chloride solution, and then concentrated under vacuum to obtain a crude solid. The crude solid obtained was dissolved in hexane (40 ml) at 0 to 5° C. and stirred for 1 hour. The solid obtained was collected by filtration and then dried to obtain 9.7 gm of 2-chloro-4-methoxypyrimidine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14]([CH3:22])[CH:13]=2)[N:3]=1.[I:23][C:24]1[N:25]=[CH:26][NH:27][CH:28]=1>>[I:23][C:24]1[N:25]=[CH:26][N:27]([C:2]2[N:3]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14]([CH3:22])[CH:13]=3)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=2)[CH:28]=1
Reactant: Ic1c[nH]cn1
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(Cl)n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-chloro-6-(3-methyl-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidine (example A.38) (2.04 g, 6.0 mmol) and commercially available 4-iodo-imidazole (1.28 g, 6.6 mmol) according to the general procedure IVa. Obtained as an off-white solid (2.83 g, 95%). MS (ISP) 499.3 [(M+H)+]; mp 190° C.