Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[F:4][C:5]1[CH:29]=[CH:28][CH:27]=[CH:26][C:6]=1[CH2:7][C:8]1[N:12]2[N:13]=[CH:14][CH:15]=[CH:16][C:11]2=[C:10]([C:17]2[N:22]=[C:21]([NH2:23])[C:20]([NH2:24])=[C:19]([NH2:25])[N:18]=2)[N:9]=1.Cl[C:31]([O:33][CH2:34][CH2:35][Cl:36])=[O:32]>N1C=CC=CC=1.ClCCl>[NH2:25][C:19]1[C:20]([NH:24][C:31](=[O:32])[O:33][CH2:34][CH2:35][Cl:36])=[C:21]([NH2:23])[N:22]=[C:17]([C:10]2[N:9]=[C:8]([CH2:7][C:6]3[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=3[F:4])[N:12]3[C:11]=2[CH:16]=[CH:15][CH:14]=[N:13]3)[N:18]=1
Reactant: Nc1nc(-c2nc(Cc3ccccc3F)n3ncccc23)nc(N)c1N
Reactant: O=C(Cl)OCCCl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Nc1nc(-c2nc(Cc3ccccc3F)n3ncccc23)nc(N)c1NC(=O)OCCCl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
247 mg (0.623 mmol) of the compound prepared in Example 9A were initially charged in pyridine (2.5 ml) and dichloromethane (2.5 ml), 64 μl (0.623 mmol) of 2-chloroethyl chloroformate were added at 0° C. and the mixture was stirred at 0° C. for 10 min. After 16 hours of stirring at 20° C., another 64 μl (0.623 mmol) of 2-chloroethyl chloroformate were added, and the mixture was stirred at 20° C. for 16 hours. The reaction mixture was then poured onto ice-water and extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue (314 mg) was used for the next step without further purification.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:11]=[C:10]([CH3:12])[O:9][N:8]=1.[Br:13]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Br:13][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:11]=[C:10]([CH3:12])[O:9][N:8]=1
Reactant: Cc1cc(CCCCCO)no1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(CCCCCBr)no1
Yield: 77 %

Procedure:
3-(5-Bromopentyl)-5-methylisoxazole was prepared by reacting 3-(5-hydroxypentyl)-5-methylisoxazole with bromine and triphenylphosphine according to the procedure of part (f) above, and was obtained in 77% yield as an oil, b.p. 140°-150° C.(0.05 mm).
Reaction SMILES: C(C1[CH:4]=[C:5]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:30])[NH:22][C:23]([CH3:29])=[CH:24][C:25]=2[CH2:26][CH2:27][CH3:28])=[O:17])[C:6]2[C:7]([CH3:15])=[CH:8][N:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1)#N.[OH-].[K+].C(O)C.CC[O:38][C:39]([CH3:41])=[O:40]>>[CH3:15][C:7]1[C:6]2[C:10](=[CH:11][C:41]([C:39]([OH:38])=[O:40])=[CH:4][C:5]=2[C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:30])[NH:22][C:23]([CH3:29])=[CH:24][C:25]=2[CH2:26][CH2:27][CH3:28])=[O:17])[N:9]([CH:12]([CH3:13])[CH3:14])[CH:8]=1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(C#N)cc2c1c(C)cn2C(C)C
Reactant: CCOC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(C(=O)O)cc2c1c(C)cn2C(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 64.9 %

Procedure:
To a 5 ml microwave vial was added, 6-cyano-3-methyl-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indole-4-carboxamide (100 mg, 0.247 mmol), KOH (41.6 mg, 0.742 mmol) was ground and added followed by Ethanol (8 mL) the reaction was microwaved at 145° C. for 22 hr. The reaction was poured onto acidic Ice water (20 mL) and was stirred for 20 min. EtOAc was added and the mix was stirred an additional 10 min. The layers were separated and the majority of the product was in the EtOAc which was evaporated. The residue was dissolved in MeOH (1 mL) and material was crashed out with ice and was filtered to give product 3-methyl-1-(1-methylethyl)-4-({[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]amino}carbonyl)-1H-indole-6-carboxylic acid (70 mg, 0.160 mmol, 64.9% yield) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.49 (br. s., 1H) 8.18 (s, 1H) 8.10 (s, 1H) 7.53 (d, J=7.58 Hz, 2H) 5.90 (s, 1H) 4.76-4.90 (m, 1H) 4.36 (d, J=4.80 Hz, 2H) 2.55 (br. s., 1H) 2.18 (s, 3H) 2.13 (s, 3H) 1.52-1.61 (m, 2H) 1.44 (d, J=6.57 Hz, 6H) 0.94 (t, J=7.33 Hz, 3H) MS (ES) [M+H]+ 423.8
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:14]=2)[C:9]1=[O:21])[CH:5]=CC>ClCCl>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:14]=2)[C:9]1=[O:21]
Reactant: CC=CCC1Cc2ccc(C(=O)OC)cc2C1=O
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)C(=O)C(CC=O)C2
Reaction time: 0.75 h
Yield: 45 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 45 minutes while stirring through a solution, cooled to -70°, of 10.5 g of (RS)-2-(2-buten-1-yl)-6-methoxycarbonyl-1-indanone in 150 ml of anhydrous dichloromethane. Subsequently, the mixture was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 4.74 ml of dimethyl sulfide, the mixture was stirred at room temperature for 18 hours. The reaction mixture was evaporated in a vacuum and purified by column chromatography on silica get (diethyl ether). By recrystallization of the resulting solid, there were obtained 4.5 g (45%) of (RS)-2-(2-oxoethyl)-6-methoxycarbonyl-1-indanone as a light yellow solid with m.p. 92°.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH2:8])[O:4][N:3]=1.[O:9]1[C:13]([S:14](Cl)(=[O:16])=[O:15])=[CH:12][C:11]2[CH:18]=[CH:19][CH:20]=[CH:21][C:10]1=2>>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:14]([C:13]2[O:9][C:10]3[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=3[CH:12]=2)(=[O:15])=[O:16])[O:4][N:3]=1
Reactant: Cc1noc(N)c1C
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Product: Cc1noc(NS(=O)(=O)c2cc3ccccc3o2)c1C

Procedure:
N-(3,4-Dimethyl-5-isoxazolyl)benzo[b]furan-2-sulfonamide was prepared, in the same manner as described in Example 34B, from 3,4-dimethyl-5-amino isoxazole (78 mg, 0.70 mmol) and benzo[b]furan-2-sulfonyl chloride (0.46 g, 2.1 mmol). Flash chromatography (30% ethyl acetate/hexanes) provided 0.186 g of a light yellow solid, which was treated with 31 mg of NaOH in 10 ml of methanol at 25° C. for 30 minutes. Recrystallization from CHCl3/hexanes yielded a light tan solid (90 mg, 44% yield), m.p. 160.5-163° C.
Reaction SMILES: C(OC([N:11]1[CH2:20][CH2:19][C:18]2[N:17]=[CH:16][C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:14]([OH:26])[C:13]=2[CH2:12]1)=O)C1C=CC=CC=1>[Pd].C(O)(=O)C>[OH:26][C:14]1[C:13]2[CH2:12][NH:11][CH2:20][CH2:19][C:18]=2[N:17]=[CH:16][C:15]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1cnc2c(c1O)CN(C(=O)OCc1ccccc1)CC2
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc2c(c1O)CNCC2

Procedure:
The starting material is prepared as follows: Ethyl 6-benzyloxycarbonyl-4-hydroxy-5,6,7,8-tetrahydro[1,6]naphthyridine-3-carboxylate Example 1i) is hydrogenated with palladium on carbon as the catalyst in glacial acetic acid to obtain ethyl 4-hydroxy-5,6,7,8-tetrahydro[1,6]naphthyridine-3-carboxylate, which is treated with benzyl bromide in a mixture of triethylamine and DMF at 60° for 48 hr to obtain ethyl 6-benzyl-4-hydroxy-5,6,7,8-tetrahydro[1,6]naphthyridine-3-carboxylate. Treatment of this material with an excess of phosphorous oxychloride at reflux for 5 hr affords the required ethyl 6-benzyl-4-chloro-5,6,7,8-tetrahydro[1,6]naphthyridine-3-carboxylate.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14]C)=[O:13])[CH2:3]1.[CH3:21][C:22]1[CH:23]=[C:24]([C:28]2[O:29][C:30]([CH3:35])=[C:31]([CH2:33]I)[N:32]=2)[CH:25]=[CH:26][CH:27]=1>>[CH3:21][C:22]1[CH:23]=[C:24]([C:28]2[O:29][C:30]([CH3:35])=[C:31]([CH2:33][O:1][CH:2]3[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]4[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=4[C:12]([OH:14])=[O:13])[CH2:3]3)[N:32]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Cc1cccc(-c2nc(CI)c(C)o2)c1
Reactant: COC(=O)c1c(C)cccc1COC1CCCC(O)C1
Product: Cc1cccc(-c2nc(COC3CCCC(OCc4cccc(C)c4C(=O)O)C3)c(C)o2)c1

Procedure:
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and 2-(3-methylphenyl)-4-iodomethyl-5-methyloxazole as starting materials in the procedure of Example XXXI, gave the product 59 of molecular weight 449.55 (C27H31NO5), MS(ESI): 450.53 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[C:4](=O)[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=O.O.[NH2:18][NH2:19]>C(O)C>[CH3:1][O:2][CH:3]([O:15][CH3:16])[C:4]1[NH:19][N:18]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=1
Reactant: COC(OC)C(=O)CC(=O)c1ccccn1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COC(OC)c1cc(-c2ccccn2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a stirred slurry of 4,4-dimethoxy-1-(pyridin-2-yl)butane-1,3-dione (9a) (5.11 g, 22.9 mmol) in ethanol (200 mL) was dropwise added hydrazine monohydrate (1.28 mL, 26.3 mmol). The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. A saturated solution of sodium hydrogenocarbonate (30 mL) was added to the residue. The aqueous layer was extracted with ethyl acetate (2×50 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide 2-[5-(dimethoxymethyl)-1H-pyrazol-3-yl]pyridine (9b) (3.51 g, 16.0 mmol, 70%) which was used without further purification.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].C(N(CC)C(C)C)(C)C>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.[Cu]I.CN(C=O)C>[CH:9]1([NH:8][C:5]2[N:6]=[N:7][C:2]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])=[CH:3][CH:4]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1ccc(NC2CCC2)nn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccc(NC2CCC2)nn1
Temperature: 80 °C
Reaction time: 16 h
Yield: 74.4 %

Procedure:
6-Bromo-N-cyclobutylpyridazin-3-amine (0.60 g, 2.63 mmol), trimethylsilylacetylene (TMSA) (1.29 g, 13.1 mmol), Pd(PPh3)4 (0.15 g), and CuI (0.04 mg) were placed in a vial with a rubber septum. After the mixture underwent 3 cycles of vacuum/filling with Ar2, DMF (3.0 mL) and N,N-diisopropylethylamine (DIPEA) (0.41 g, 3.2 mmol) were added. The mixture was then stirred at 80° C. for 16 hrs. The reaction mixture was concentrated and the resulting residue was purified by silica gel chromatography (eluent: 30% ethyl acetate in n-hexane, ethyl acetate was added 0.5% Et3N) to give an off-white solid (0.48 g, 74.5%). 1H NMR (300 MHz, CDCl3) δ: 7.26-7.29 (1H, d, J=9.0 Hz), 6.50-6.53 (1H, d, J=9.0 Hz), 5.55 (1H, s), 4.17-4.24 (1H, m), 2.40-2.46 (2H, m), 1.89-1.98 (2H, m), 1.77-1.85 (2H, m), 0.28 (9H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[O:15][CH:14]([CH2:17]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:13][C:12]=3[CH:11]=[C:10]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:35][NH2:36]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[O:15][CH:14]([CH2:17][NH:36][CH3:35])[CH2:13][C:12]=3[CH:11]=[C:10]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(-c4ccccc4)cc(-c4ccc(F)cc4)c3O2)cc1
Product: CNCC1Cc2cc(-c3ccccc3)cc(-c3ccc(F)cc3)c2O1

Procedure:
The title compound was prepared (0.040 g, 51%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(4-fluorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.10 g, 0.21 mmol) and methylamine (0.30 g, 9.8 mmol). mp >250° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Br:16][CH:17](O)[CH3:18].N1C(C)=CC=CC=1C>C(Cl)Cl>[Br:16][CH2:17][CH2:18][O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:4])=[O:5]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(O)Br
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: O=S(=O)(OCCBr)C(F)(F)F
Temperature: -5 °C
Yield: 72 %

Procedure:
240 g of trifluoromethanesulfonic anhydride (0.85 mol) are added in 1.5 h, under inert atmosphere, to a solution of bromoethanol (57 mL; 0.80 mol) and 2,6-lutidine (104 mL; 0.89 mol) in CH2Cl2 cooled at −5° C. After 10 min the mixture is concentrated to one fourth the volume, then eluted through a small layer of silica gel (eluent n-hexane/EtOAc=9:1). By evaporation and drying, the desired product is obtained (147.2 g; 0.57 mol).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18]([O:19][CH2:20][C:21]2[O:22][C:23]([CH:26]=O)=[CH:24][CH:25]=2)=[N:17][C:16]([Cl:28])=[CH:15][N:14]=1)(=[O:11])=[O:10].[CH:29]1([NH2:32])[CH2:31][CH2:30]1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18]([O:19][CH2:20][C:21]2[O:22][C:23]([CH2:26][NH:32][CH:29]3[CH2:31][CH2:30]3)=[CH:24][CH:25]=2)=[N:17][C:16]([Cl:28])=[CH:15][N:14]=1)(=[O:11])=[O:10]
Reactant: NC1CC1
Reactant: O=Cc1ccc(COc2nc(Cl)cnc2NS(=O)(=O)c2cccc(Cl)c2Cl)o1
Product: O=S(=O)(Nc1ncc(Cl)nc1OCc1ccc(CNC2CC2)o1)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 107b using 2,3-dichloro-N-[5-chloro-3-(5-formyl-2-furanylmethoxy)-2-pyrazinyl]benzenesulphonamide (Example 209) (0.3 g) and cyclopropylamine (0.1 g). Yield 0.1 g.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.S(C1C=CC(C)=CC=1)(O[CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:1].[O:22]([CH2:21][CH2:20][N:10]1[CH2:11][CH2:12][CH:7]([CH2:6][C:5]2[CH:13]=[CH:14][CH:15]=[C:3]([F:2])[CH:4]=2)[CH2:8][CH2:9]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccccc2)cc1
Reactant: Fc1cccc(CC2CCNCC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Fc1cccc(CC2CCN(CCOc3ccccc3)CC2)c1
Yield: 50 %

Procedure:
From a mixture of 4-(3-fluorobenzyl)piperidine hydrochloride (229.5 mg, 1.0 mmol), 2-phenoxyethyl tosylate (350.4 mg, 1.2 mmol), potassium carbonate (414 mg, 3.0 mmol) in 15 mL of ethanol was 175 mg (50%) of the title compound, mp 175-177° C. 1H NMR (DMSO-d3) 1.696 (m, 1 H), 1.582 (m, 2 H), 2.096 (m, 2 H), 2.617 (m, 2 H), 2.781 (m, 2 H), 3.395 (m, 2 H), 3.687 (m, 2 H), 4.547 (s, 2 H), 6.756-6.999 (m, 6 H), 7.288 (m, 3 H), 12.556 (s, 1 H). Anal. Calcd for C20H25ClFNO: C, 68.66; H, 7.20; N, 4.00. Found: C, 68.37; H, 7.09; N, 3.98.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17](I)[S:18][C:11]=12)[NH2:5].[CH2:20]([NH:23][C:24](=[O:31])[CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[C:21]#[CH:22]>>[NH2:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[CH:16]=[C:17]([C:22]#[C:21][CH2:20][NH:23][C:24](=[O:31])[CH2:25][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[S:18][C:11]=23)=[C:2]([F:1])[CH:3]=1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: C#CCNC(=O)CN1CCCC1
Product: Nc1ccc(Oc2ccnc3cc(C#CCNC(=O)CN4CCCC4)sc23)c(F)c1
Reaction time: 3 h
Yield: 65 %

Procedure:
Prepared from 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A; 72 mg, 0.186 mmol) and N-(prop-2-ynyl)-2-(pyrrolidin-1-yl)acetamide (34 mg, 0.205 mmol; prepared according to the method described in WO 04/076412A) according to the procedure described for Example 6, Step B, except the reaction was executed at room temperature for 3 hours. The product was purified by preparative TLC (10% MeOH/CH2Cl2). The product was obtained as a waxy solid (69 mg, 65%). 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J=6 Hz, 1H), 7.60 (s, 1H), 7.52 (br s, 1H), 7.03 (t, J=9 Hz, 1H), 6.54 (m, 2H), 6.48 (m, 1H), 4.39 (d, J=6 Hz, 2H), 3.86 (br s, 2H), 3.28 (s, 2H), 2.69 (m, 4H), 1.85 (m, 4H). LRMS (ESI pos) m/e 425 (M+1).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19](O)=[C:18]([F:23])[C:17]=2[F:24])=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:25][C:26]([F:53])([C:49]([F:52])([F:51])[F:50])[C:27]([F:48])([F:47])[C:28]([F:46])([F:45])[O:29][C:30]([F:44])([F:43])[C:31]([F:42])([F:41])[C:32]([F:40])([F:39])[CH2:33][O:34][CH2:35][CH2:36][CH2:37]Br>>[CH2:1]([O:9][C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:37][CH2:36][CH2:35][O:34][CH2:33][C:32]([F:39])([F:40])[C:31]([F:41])([F:42])[C:30]([O:29][C:28]([F:45])([F:46])[C:27]([F:47])([F:48])[C:26]([F:25])([F:53])[C:49]([F:51])([F:52])[F:50])([F:44])[F:43])=[C:18]([F:23])[C:17]=2[F:24])=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1cnc(-c2ccc(O)c(F)c2F)nc1
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)COCCCBr
Product: CCCCCCCCOc1cnc(-c2ccc(CCCOCC(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c2F)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-octyloxy-2-[4-hydroxy-2,3-difluorophenyl]pyrimidine (1.5 g, 4.7 mmol) with 3-(4-(nonafluorobutoxy)-2,2,3,3,4,4-hexafluorobutoxy)propyl bromide (2.45 g, 5.1 mmol, prepared from 1,3-dibromopropane and 4-(nonafluorobutoxy)-2,2,3,3,4,4-hexafluorobutanol). The reaction mixture was quenched with water, and the resulting crude product was further purified by recrystallization from ethanol, followed by Kugelrohr distillation (210° C. at 0.5 torr), to provide a yield of 2.6 g.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[CH3:13][NH2:14]>CO>[NH2:1][C:2]1[C:3]([C:9]([NH:14][CH3:13])=[O:11])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: COC(=O)c1nc(Br)cnc1N
Reactant: CN
Solvent: CO
Product: CNC(=O)c1nc(Br)cnc1N
Temperature: 25 °C
Yield: 88 %

Procedure:
An ice-cooled solution of 50 g of methyl 3-amino-6-bromo-pyrazine-2-carboxylate in 500 mL of MeOH was saturated with methylamine gas. The reaction was then heated at 85° C. in a sealed, stainless steel Parr pressure vessel for 2 h, and cooled to room temperature, and then on an ice water bath. The mixture was concentrated to an oil on a rotary evaporator under reduced pressure. The crude oil was dissolved in EtOAc and washed with water, dried (Na2SO4), filtered, and concentrated to give 43.9 g (88.0% yield) of product as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19](Cl)=[O:20])[CH2:15][CH2:14]1)([CH3:12])([CH3:11])[CH3:10].N1C=CC=CC=1>ClCCl>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:19]([C@H:16]2[CH2:17][CH2:18][C@H:13]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:14][CH2:15]2)=[O:20])=[CH:3][CH:4]=1
Reactant: Nc1ccc(O)cc1
Reactant: CC(C)(C)[C@H]1CC[C@H](C(=O)Cl)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[C@H]1CC[C@H](C(=O)Nc2ccc(O)cc2)CC1
Reaction time: 8 h

Procedure:
To a solution of 4-aminophenol (3.08 g, 28.2 mmol) in dichloromethane (50 ml) were added cis/trans-4-tert-butyl-cyclohexanecarbonyl chloride (11.43 g, 56.4 mmol) and pyridine (4.56 ml, 56.4 mmol), while cooling the reaction mixture in an ice bath. After the addition was completed, the cooling bath was removed and stirring was continued overnight at room temperature. The solvent was removed by evaporation and the residue was dissolved in THF (300 ml). 6N NaOH (aq, 33 ml) was added and the mixture was stirred at room temperature overnight. The organic phase was removed by evaporation. Water (200 ml) was added and the solid material collected by filtration, washed with water, dried and dissolved in methanol (100 ml). A solution of KOH (2.4 g) in methanol (50 ml) was added. After stirring for 2 h at room temperature water (200 ml) was added and the organic solvent was removed by evaporation. The aqueous phase was acidified with 1 N HCl and extracted with ethyl acetate (3×300 ml). The combined organic phases were dried and evaporated, yielding a pink oil, which was dried in vacuo. The solid material was crystallised from ethyl acetate/heptane yielding the title compound (2.03 g, 26%) as pink crystals. From the first aqueous extract a second portion of product was isolated by extraction with ethyl acetate (3×250 ml). The combined organic layers were washed with water (400 ml), saturated sodium bicarbonate (2×400 ml), dried, filtered and evaporated, yielding a pink thick oil. Crystallisation from ethyl acetate/heptane yielded a second amount of the title compound (2.75 g, 35%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH2:11][CH2:10][CH:9]([C:17](O)=[O:18])[CH2:8][C:7]2=1.C(N1C=CN=C1)([N:24]1C=CN=C1)=O>O1CCCC1>[F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH2:11][CH2:10][CH:9]([C:17]([NH2:24])=[O:18])[CH2:8][C:7]2=1
Reactant: O=C(O)C1CCc2[nH]c3ccc(OC(F)(F)F)cc3c2C1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: NC(=O)C1CCc2[nH]c3ccc(OC(F)(F)F)cc3c2C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.6 %

Procedure:
A stirred solution of 6-(trifluoromethoxy)-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid of Step 2 (1.722 g, 5.75 mmol) in anhydrous tetrahydrofuran (37 mL) was treated under nitrogen with carbonyldiimidazole (1.37 g, 8.61 mmol). The yellow solution was stirred at room temperature for 5 hours and then anhydrous ammonia was bubbled through the solution for 30 minutes. The suspension was diluted with ethyl acetate and the organic phase was washed with 1:1 water/saturated aqueous sodium bicarbonate and 1:1 water/brine. The extracts were dried over anhydrous magnesium sulfate and evaporated to dryness to yield a pale yellow glass. The residue was purified by chromatography on silica gel Merck-60 using a 1% to 3% gradient of methanol in dichloromethane to provide the title compound (1.33 g, 77%) as an off white solid, m.p. 177-178° C. MS [(+)ES, m/z]: 299 [M+H]+. HRMS [(+)ESI, m/z]: 299.1004 [M+H]+. Calc'd for C14H14F3N2O2: 299.1007. HPLC: Chromolith Monolith column, 0.46×10 cm, gradient of acetonitrile in water (0.01% TFA), 4 mL/min, detection at 254 nm; Rt 1.8 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9]1.[NH2:22][C:23]1[C:24]([C:31](O)=[O:32])=[N:25][C:26]([Cl:30])=[C:27]([NH2:29])[N:28]=1>>[NH2:22][C:23]1[C:24]([C:31]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:9]2)=[O:32])=[N:25][C:26]([Cl:30])=[C:27]([NH2:29])[N:28]=1
Reactant: Nc1nc(N)c(C(=O)O)nc1Cl
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2ccncc2N)C1
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2NC(=O)c2nc(Cl)c(N)nc2N)C1
Yield: 57 %

Procedure:
Following method 11, tert-butyl 1-(3-aminopyridin-4-yl)piperidin-3-ylcarbamate was coupled to 3,5-diamino-6-chloropyrazine-2-carboxylic acid yielding (S)-tert-butyl 1-(3-(3,5-diamino-6-chloropyrazine-2-carboxamido)pyridin-4-yl)piperidin-3-ylcarbamate (57%). LCMS (m/z): 463.1 (MH+); LC Rt=2.36 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11](=[O:13])[N:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:26][C:27]3[CH:28]=[C:29]([C:30]([O:32][CH3:33])=[O:31])[CH:34]=[CH:35][CH:36]=3)[C:11](=[O:13])[N:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: COC(=O)Cn1nc(-c2ccc(Cl)cc2)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2cccc(C(=O)OC)c2)c1=O

Procedure:
200 mg (0.75 mmol) of methyl [3-(4-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetate [preparation according to WO 2007/134862 Example 222A] were suspended in 7.5 ml of acetone, 365 mg (1.12 mmol) of cesium carbonate and 223 mg (0.97 mmol) of methyl 3-bromomethylbenzoate were added and the mixture was heated at the boil for 1 h. After cooling, the mixture was filtered through Extrelut and the filter cake was rinsed with acetone. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1→1:1). The target compound was obtained as a colorless foam (165 mg, 53% of theory).