Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1.[H-].[Na+].[H-].[H][H].[O:26]1[CH2:31][CH2:30][N:29]([P:32](Cl)([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[O:33])[CH2:28][CH2:27]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([O:12][P:32]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)([N:29]3[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)=[O:33])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1
Reactant: O=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Reactant: [H][H]
Reactant: O=P(Cl)(N1CCOCC1)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=P(OC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1)(N1CCOCC1)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 915 mg (3.0 mmoles) of 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one in 10 ml of dry tetrahydrofuran was added 173 mg of a 50% dispersion as sodium hydride in oil (3.6 mmoles of hydride). The mixture was stirred at room temperature approximately 1 hr until hydrogen evolution stopped. Dimorpholinophosphinic chloride (1.5 g; 6.0 mmoles) was added and the resulting mixture was stirred at room temperature for 2 hrs. Insoluble salts were removed by filtration. Tetrahydrofuran was evaporated. The residue was crystallized from ethyl acetate to give colorless needles, mp 185°-187°.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][O:29][C:28]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:27]1=2.O1CCOCC1>CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([C:33]3[CH:34]=[CH:35][C:27]4[N:26]([CH3:25])[CH2:31][CH2:30][O:29][C:28]=4[CH:32]=3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: CN1CCOc2cc(B(O)O)ccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(-c3ccc4c(c3)OCCN4C)n2n1
Temperature: 110 °C
Yield: 58.9 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 60 mg, 0.174 mmol), 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ylboronic acid (62 mg, 0.226 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg, 13.6 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.58 mL of 1,4-dioxane and 0.29 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (50-50% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (46.9 mg, 59%). 1H NMR (DMSO-d6) δ: 10.99 (s, 1H), 7.95 (d, J=8.6 Hz, 2H), 7.89 (s, 1H), 7.57-7.62 (m, 2H), 7.54 (d, J=8.3 Hz, 2H), 6.81 (d, J=8.8 Hz, 1H), 6.25 (s, 1H), 4.20-4.24 (m, 2H), 3.32-3.35 (m, 2H), 2.91 (s, 3H), 2.35 (s, 3H), 1.39 (s, 6H); ESI-MS: m/z 458.2 (M+H)+.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:28](O)=[O:29])[N:18]([CH3:27])[C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[CH:11][CH:10]=1>>[N:2]1([NH:1][C:28]([C:17]2[N:18]([CH3:27])[C:19]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([CH3:8])=[CH:14][CH:13]=3)[N:16]=2)=[O:29])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: Cc1ccc(-c2nc(C(=O)O)n(C)c2-c2ccc(C)cc2)cc1
Reactant: NN1CCOCC1
Product: Cc1ccc(-c2nc(C(=O)NN3CCOCC3)n(C)c2-c2ccc(C)cc2)cc1

Procedure:
Using essentially the same procedure as Example 9, Step B, but using 4-aminomorpholine (0.025 mL), 4,5-di-(4-methylphenyl)-1-methylimidazole-2-carboxylic acid (25 mg, 0.08 mmol) from Example 9, Step A was converted to the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][C:16]=2[F:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:24]=[C:25]1[NH:29][C@H:28]([CH2:30][O:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:27][O:26]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([N:29]3[C@H:28]([CH2:30][O:31][C:32](=[O:39])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:27][O:26][C:25]3=[O:24])=[CH:17][C:16]=2[F:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3COC(=O)c3ccccc3)cc2F)CC1
Yield: 49.9 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 91 and using 4-(4-bromo-2-fluorobenzoyl)piperazine-1-carboxylic acid tert-butyl ester (3.49 g) described in Preparation Example 154 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (1.99 g), the title compound (2.37 g) was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[C:12]3[NH:14][N:15]=[CH:16][C:11]3=[CH:10][N:9]=2)[CH:4]=[N:3]1.Br[CH2:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[C:21]#[N:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[C:12]3[N:14]([CH2:18][C:19]4[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=4[C:21]#[N:22])[N:15]=[CH:16][C:11]3=[CH:10][N:9]=2)[CH:4]=[N:3]1
Reactant: N#Cc1ccccc1CBr
Reactant: Cn1cc(Nc2ncc3cn[nH]c3n2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1cc(Nc2ncc3cnn(Cc4ccccc4C#N)c3n2)cn1

Procedure:
A solution of N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine (100 mg, 0.46 mmol), 2-(bromomethyl)benzonitrile (1.1 eq) and potassium carbonate (2 eq) in DMF (2 mL) was stirred at rt for 18 h. The resultant mixture was diluted with EtOAc and washed with H2O, then brine. The organic phase was collected, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by column chromatography (petroleum ether: EtOAc) to give the title product. 1H NMR (d6-DMSO) δ 9.94 (s, 1H), 8.93 (s, 1H), 8.09 (s, 2H), 7.91 (dd, 1H), 7.67 (td, 1H), 7.51-7.54 (m, 2H), 7.36-7.38 (m, 1H), 5.76 (s, 2H), 3.82 (s, 3H); LC-MS method B, (ES+) 331.0, RT=8.04 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:16]([C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[S:26])=[CH:20][CH:19]=1)#[N:17].CCOCC>C1(C)C=CC=CC=1>[CH2:9]([O:8][C:7]1[C:2]([NH:1][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([C:16]#[N:17])=[CH:19][CH:20]=2)=[S:26])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N#Cc1ccc(N=C=S)cc1
Reactant: Nc1ncccc1OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: N#Cc1ccc(NC(=S)Nc2ncccc2OCc2ccccc2)cc1

Procedure:
A stirring mixture of 2-amino-3-benzyloxy pyridine (5.68 g, 0.0284 mol) and 4cyanophenyl isothiocyanate (5 g, 0.0312 mol) in toluene (20 ml) was heated under reflux for 2 h. After allowing to cool, the solution was treated with ether, and the resulting solid filtered off, washed and dried. Yield 9.4 g (92%), m.p. 163°-165 ° C.
Reaction SMILES: C(OC(NC(C(C)(C)C)C(O)=O)=O)(C)(C)C.C1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C@H](N)[C@@H]1O.C(O[C:33](=[O:53])[NH:34][CH:35]([C:40](=[O:52])[NH:41][CH:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44][CH:43]1[OH:51])[C:36]([CH3:39])(C)C)(C)(C)C.ClNC(=O)[O-].C([O:61][C:62]([C:64]1([NH:69][C:70]([CH:72]2[CH2:76][CH:75]([O:77][C:78]3[C:87]4[C:82](=[CH:83][C:84]([O:88][CH3:89])=[CH:85][CH:86]=4)[N:81]=[C:80]([C:90]4[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=4)[CH:79]=3)[CH2:74][N:73]2C(=O)NC(C(=O)NC2C3C(=CC=CC=3)CC2O)C(C)(C)C)=[O:71])[CH2:66][CH:65]1[CH:67]=[CH2:68])=[O:63])C>>[OH:51][C@@H:43]1[CH2:44][C:45]2[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=2)[C@@H:42]1[NH:41][C:40]([C@@H:35]([NH:34][C:33]([N:73]1[CH2:74][C@H:75]([O:77][C:78]2[C:87]3[C:82](=[CH:83][C:84]([O:88][CH3:89])=[CH:85][CH:86]=3)[N:81]=[C:80]([C:90]3[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=3)[CH:79]=2)[CH2:76][C@H:72]1[C:70]([NH:69][C@:64]1([C:62]([OH:63])=[O:61])[CH2:66][C@H:65]1[CH:67]=[CH2:68])=[O:71])=[O:53])[CH2:36][CH2:39][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:52]
Reactant: CC(C)(C)OC(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C)C(=O)OCC
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Agent: CC(C)(C)OC(=O)NC(C(=O)O)C(C)(C)C
Agent: O=C([O-])NCl
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)N[C@@H](CCc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(=O)O

Procedure:
N-(tert.butoxycarbonyl)-L-phenethylglycine was attached to the resin as described for the preparation of compound 16 followed by reaction with (1S,2R)-cis-1-amino-2-indanol as described for the preparation of 17 and removal of the Boc group as described for 18. The afforded compound was then reacted with the chlorocarbamate achieved from 12 as described for the preparation of 13 which gave the title compound. Purity by HPLC>95%. M+H+810.4.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][CH2:13][OH:14])[CH:8]=[CH:9][CH:10]=1)[CH3:3].CC(C)([O-])C.[K+].Cl.Cl[CH2:23][CH2:24][NH2:25]>CN(C)C=O>[NH2:25][CH2:24][CH2:23][O:14][CH2:13][CH2:12][CH2:11][C:7]1[CH:6]=[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])[CH:10]=[CH:9][CH:8]=1
Reactant: NCCCl
Reactant: CN(C)Cc1cccc(CCCO)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)Cc1cccc(CCCOCCN)c1
Reaction time: 24 h
Yield: 6.1 %

Procedure:
A suspension of 3-[(N,N-dimethylamino)methyl] benzene propanol (2.5 g), potassium tertiary butoxide (0.56 g), 2-chloroethylamine hydrochloride (0.59 g) in dimethylformamide (10 ml) was stirred at 0°-5° under a nitrogen atmosphere for 24 h. The mixture was poured onto water (1 1) and extracted with ethyl acetate. The organic extract was evaporated to leave a yellow oil which was purified by column chromatography using methanol followed by methanol: 0.880 ammonia; (20:1) to give the title compound as a brown oil (73 mg). T.l.c. system B Rf 0.2.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH3:19])[C:9]=1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([Cl:18])[N:12]=1)=[O:4].S(Cl)([Cl:23])(=O)=O>C(Cl)Cl>[CH3:1][NH:2][C:3]([C:5]1[S:6][C:7]([Cl:23])=[C:8]([CH3:19])[C:9]=1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([Cl:18])[N:12]=1)=[O:4]
Reactant: O=S(=O)(Cl)Cl
Reactant: CNC(=O)c1scc(C)c1Nc1nc(Cl)ncc1Cl
Solvent: ClCCl
Product: CNC(=O)c1sc(Cl)c(C)c1Nc1nc(Cl)ncc1Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 9 %

Procedure:
An ice-cold solution of 3-(2,5-dichloro-pyrimidin-4-ylamino)-4-methyl-thiophene-2-carboxylic acid methylamide (0.105 g, 0.33 mmol) in methylene chloride (4 mL) was treated with sulfuryl chloride (33 μL). The mixture was stirred for 16 hours and concentrated. Chromatography on preparative TLC plate (hexanes/ethyl acetate/methanol (50:25:1)) gave 5-chloro-3-(2,5-dichloro-pyrimidin-4-ylamino)-4-methyl-thiophene-2-carboxylic acid methylamide (10.4 mg, 9%): 1H NMR (300 MHz, CDCl3) δ 9.9 (s, 1H), 8.33 (s, 1H), 5.82 (br, 1H), 3.05 (d, 3H), 2.22 (s, 3H); MS (m/e): 351.1 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH2:8].[I:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](O)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C(Cl)Cl>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][S:16]([C:13]1[CH:14]=[CH:15][C:10]([I:9])=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: O=S(=O)(O)c1ccc(I)cc1
Reactant: N[C@@H]1CCCC[C@@H]1N
Solvent: ClCCl
Product: N[C@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(I)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34.6 %

Procedure:
Cis-1,2-diaminocyclohexane (0.70 g, 6.86 mmol) was stirred in CH2Cl2 (40 mL) at 0° C. under N2. A solution of 4-iodobenzenesulfonic acid (0.85 g, 2.81 mmol) in CH2Cl2 (20 mL) was added dropwise to the above solution. It was stirred for 30 min at 0° C. LC/MS showed completion of the reaction. It was washed with 1N HCl. The aqueous solution was basified with 1N NaOH until formation of a cloudy solution. It was extracted with CH2Cl2 (3×), washed with brine, dried (MgSO4), and concentrated to dryness to give cis-N-(2-amino-cyclohexyl)-4-iodobenzenesulfonamide (0.37 g, yield: 35%). 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J=6.8 Hz, 2H), 7.60 (d, J=6.7 Hz, 2H), 3.15 (m, 1H), 2.84 (m, 1H), 1.48 (m, 10H) ppm.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[CH3:13][S-:14].[Na+]>CO>[CH3:12][O:11][C:4]1[N:3]=[C:2]([S:14][CH3:13])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: C[S-]
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Agent: [Na+]
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(SC)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 60.5 %

Procedure:
A methanol (100 ml) solution of 2-chloro-6-methoxy-3-nitropyridine (2.0 g, 10.4 mmol) was added dropwise to a methanol (20 ml) solution of sodium thiomethoxide (805 mg, 10.9 mmol) while being cooled with ice, and the temperature thereof was raised to the room temperature and the mixed solution was stirred for 17 hours and the precipitated crystal was filtered to obtain 1.26 g (yield 59%) of 6-methoxy-2-methylthio-3-nitropyridine as a yellow powdery crystal.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[C:9]=1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].OS(O)(=O)=O.[CH3:22]O>>[C:1]([NH:5][C:6]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[C:9]=1[C:14]([O:16][CH3:22])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CO
Reactant: Cc1noc(C(=O)NC(C)(C)C)c1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1c(C)noc1C(=O)NC(C)(C)C
Reaction time: 48 h

Procedure:
5.0 g of 5-tert-butylaminocarbonyl-3-methylisoxazole-4-carboxylic acid are dissolved in 200 ml of methanol, and 5 ml of concentrated H2SO4 are added. After 2 days, the mixture is evaporated down, the residue is partitioned between ethyl acetate and water and the organic phase is evaporated down. 4.0 g of methyl 5-tert-butylaminocarbonyl-3-methylisoxazole-4-carboxylate are obtained as a colorless oil (compound No. 1007). H-NMR (CDCl3): d=1.48 (s; 9H), 2.50 (s; 3H), 3.99 (s; 1H), 9.42 (bs; 1H, NH).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[F:24][C:25]1([F:32])[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1>>[F:24][C:25]1([F:32])[CH2:30][CH2:29][CH:28]([NH:31][C:21]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:20][N:19]=2)=[O:23])[CH2:27][CH2:26]1
Reactant: Cc1onc(-c2ccccc2)c1COc1cnc(C(=O)O)cn1
Reactant: NC1CCC(F)(F)CC1
Product: Cc1onc(-c2ccccc2)c1COc1cnc(C(=O)NC2CCC(F)(F)CC2)cn1
Yield: 27 %

Procedure:
As described for example 2b, 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyrazine-2-carboxylic acid (100 mg, 0.32 mmol) was converted, using 4,4-difluorocyclohexylamine instead of aminomethylcyclopropane to the title compound (SiO2, heptane:ethyl acetate=90:10 to 60:40, 37 mg, 27%) which was obtained as a white solid. MS: m/e=429.2 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([CH2:37][O:38]C(=O)C)=[O:36]>>[OH:38][CH2:37][C:35]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:36]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)cc1F
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)CO)CC4)c[nH]c23)cc1F

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A139) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[Br:14]C1C(=O)C(Br)=CC(Br)(Br)C=1>C(Cl)Cl>[Br:14][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([O:2][CH3:1])[C:9]=1[C:10]([F:11])([F:12])[F:13]
Reactant: O=C1C(Br)=CC(Br)(Br)C=C1Br
Reactant: COc1c(N)cccc1C(F)(F)F
Solvent: ClCCl
Product: COc1c(N)ccc(Br)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
To a solution of compound 17C (200 mg, 1.05 mmol) in CH2Cl2 (2 mL) cooled to −20° C. was added dropwise a solution of 2,4,4,6-tetrabromo-2,5-cyclohexadienone (429 mg, 1.05 mmol) in CH2Cl2 (2 mL). After the addition, the reaction was stirred at rt overnight, then additional amount of 2,4,4,6-tetrabromo-2,5-cyclohexadienone (429 mg, 1.05 mmol) was added. The reaction was continued for 2 more days, then concentrated under reduced pressure. The residue was chromatographed (silica gel) eluting with 10%-20% EtOAc/hexane to yield the title compound (47 mg, 16% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15].[CH3:17][N:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[Sn](CCCC)(CCCC)CCCC>O1CCOCC1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:19]2[N:18]([CH3:17])[CH:22]=[CH:21][CH:20]=2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15]
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cccn2C)c(C(F)(F)F)cc1N
Temperature: 100 °C
Reaction time: 1 h
Yield: 14.5 %

Procedure:
2-Amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (400 mg, 1.16 mmol) and 1-methyl-2-tributylstannanyl-1H-pyrrole (643 mg, 1.5 equiv) were weighed in air and added in a flame-dried flask. [Bistriphenylphosphine]dichloropalladium (124.5 mg, 0.15 equiv) was added and the flask was closed by a septum. Dioxane (16 mL) was added and the mixture was stirred for 1 h (TLC control) at 100° C. After 1 h, 1-methyl-2-tributylstannyl-1H-pyrrole (429 mg, 1 equiv) was added and the mixture was stirred for 35 h (TLC control) at 100° C. The solvent was removed in vacuo, the residue was taken in DCM and washed with a saturated solution of NaHCO3, water and brine. The organic phase was dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography (hexanes to EtOAc/hexanes (4:6)) to furnish 2-amino-5-(1-methyl-1H-pyrrol-2-yl)-4-trifluoromethyl-benzoic acid methyl ester (50 mg, 14.5%) as a yellow oil. ESI-MS: m/z 299 [M+H]+, rt 5.78 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:18]=[CH:17][C:9]([O:10][CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])=[CH:8][CH:7]=1.I.[NH2:20][C:21]1[C:22]([C:29]([NH:31][C:32](=[NH:35])SC)=[O:30])=[N:23][C:24]([Cl:28])=[C:25]([NH2:27])[N:26]=1>C(O)C>[NH2:20][C:21]1[C:22]([C:29]([N:31]=[C:32]([NH2:35])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:18]=[CH:17][C:9]([O:10][CH2:11][C:12]([N:14]([CH3:15])[CH3:16])=[O:13])=[CH:8][CH:7]=2)=[O:30])=[N:23][C:24]([Cl:28])=[C:25]([NH2:27])[N:26]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CN(C)C(=O)COc1ccc(CCCCN)cc1
Agent: I
Solvent: CCO
Product: CN(C)C(=O)COc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
A solution of 2-[4-(4-aminobutyl)phenoxy]-N,N-dimethylacetamide 29 (67 mg, 0.27 mmol) in absolute ethanol (1 mL) was stirred at 65° C. for 30 min, after which 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (110 mg, 0.29 mmol) was added in one portion. The reaction mixture was stirred at that temperature for 3 h and then cooled to room temperature. The reaction mixture was concentrated by rotary evaporation. The crude residue was triturated with water and filtered. The filter cake was purified by flash silica gel column chromatography eluting with dichloromethane/methanol/concentrated ammonium hydroxide (200:10:0, 200:10:1, v/v) to give 2-(4-{-4-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}-phenoxy)-N,N-dimethylacetamide as a yellow solid (35 mg, 28% yield). This solid was dissolved in methanol (2 mL) and added to 4 N aqueous HCl (4 drops). Concentration in vacuo gave 2-(4-{4-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)-guanidino]butyl}phenoxy)-N,N-dimethylacetamide hydrochloride (30, PSA 16313). mp 130-132° C. (decomposed). 1H NMR (300 MHz, CD3OD) δ 1.69 (m, 4H), 2.60 (m, 2H), 2.95 (s, 3H), 3.10 (s, 3H), 3.35 (m, 2H), 4.75 (s, 2H), 6.80 (d, 2H), 7.10 (d, 2H). m/z (EST): 463 [C20H27ClN8O3+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([CH2:24][CH3:25])(C3C=CC(O)=C(C)C=3)[CH2:14][CH3:15])=[CH:10][C:9]=2[CH:26]=1)=[O:4].Br[CH2:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].[C:35]([O-:38])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:26]=[CH:9][C:8]2[O:12][C:11]([CH:13]([CH:14]([C:5]3[CH:6]=[CH:7][C:35]([O:38][CH2:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[C:9]([CH3:8])[CH:26]=3)[CH3:15])[CH2:24][CH3:25])=[CH:10][C:7]=2[CH:6]=1)=[O:4]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1cc2cc(C(=O)OC)ccc2o1
Reactant: CC(C)(C)C(=O)CBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(c1cc2cc(C(=O)OC)ccc2o1)C(C)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 179.8 %

Procedure:
A solution of 2-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-benzofuran-5-carboxylic acid methyl ester (4.25 g, 12.1 mmol) and 1-bromopinacolone (2.70 g, 15.1 mmol) in acetone (80 mL) is treated with K2CO3 (3.33 g, 24.1 mmol) and stirred at RT for 18 h. The solid is filtered and the filtrate is concentrated, the residue is purified on column chromatography with 10-15% EtOAc/Hexane to provide the title compound (4.90 g, 90%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[OH:9][C@H:10]1[CH2:14][CH2:13][NH:12][CH2:11]1.CCN(CC)CC>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:12]2[CH2:13][CH2:14][C@H:10]([OH:9])[CH2:11]2)=[N:6][CH:7]=1
Reactant: Fc1ccc(Br)cn1
Reactant: O[C@H]1CCNC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O[C@H]1CCN(c2ccc(Br)cn2)C1
Yield: 72.6 %

Procedure:
Heat 5-bromo-2-fluoro-pyridine (10.33 g, 57.39 mmmol) in THF (50 mL) with (S)-3-hydroxypyrrolidine (5.00 g, 57.39 mmol) and Et3N (9.2 mL, 68.87 mmol) in a microwave reactor at 120° C. for 45 min. Dilute with EtOAc (150 mL), and wash with saturated NaHCO3 (2×50 mL) and water (100 mL). Dry with Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 100% EtOAc to give 10.13 g (72%) of the title compound. MS/ES m/z (79Br) 244.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1.[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[CH:16][CH:15]=1>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]#[N:27])=[CH:18][CH:19]=2)[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1
Reactant: Clc1cc(Cl)n2nccc2n1
Reactant: N#Cc1ccccc1-c1ccc(CN)cc1
Solvent: CCO
Product: N#Cc1ccccc1-c1ccc(CNc2cc(Cl)nc3ccnn23)cc1

Procedure:
5.7 g (30.3 mmol) 5,7-dichloropyrazolo[1,5-a]pyrimidine (prepared according to T. Novinson, B. Bhooshan, T. Okabe, G. R. Revankar, R. K. Robins, K. Senga, H. R. Wilson, J. Med. Chem. 1976, 19, 512) and 6.3 g (30.25 mmol) 4-aminomethyl-2'-cyanobiphenyl were dissolved in 150 ml dry ethanol and heated with reflux for 10 h. The solvent was removed in vacuo, the residue dissolved in ethyl acetate, washed with 10% aqueous sodium carbonate solution, and dried over sodium sulfate. After evaporation in vacuo the title compound crystallized from ethyl acetate/ether in colorless crystals, m.p. 162°-163° C.