Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:26])[C:10]([C:16]1[CH:23]=[C:22]([CH3:24])[C:19]([C:20]#[N:21])=[C:18]([CH3:25])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[C:34]([Cl:36])[C:33](Cl)=[N:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[C:34]([Cl:36])[C:33]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:26])[C:10]([C:16]3[CH:17]=[C:18]([CH3:25])[C:19]([C:20]#[N:21])=[C:22]([CH3:24])[CH:23]=3)([OH:15])[C:11]([F:14])([F:12])[F:13])=[C:2]([Cl:1])[CH:7]=2)=[N:32][CH:31]=1
Reactant: COC(=O)c1cnc(Cl)c(Cl)c1
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cc(C)c1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3cc(C)c(C#N)c(C)c3)C(F)(F)F)c(Cl)c2)c(Cl)c1

Procedure:
In analogy to Example 147, 4-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-2,6-dimethyl-benzonitrile (Example 141, step 5) was reacted with methyl-5,6-dichloro-nicotinate in the presence of cesium carbonate to give the title compound as a colorless solid. MS (m/e)=553.3 [M+H+].
Reaction SMILES: Br[C:2]1[C:19]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:18]([CH3:28])[C:5]2[CH:6]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=3)[CH2:7][O:8][C:4]=2[C:3]=1[CH3:29].CCCCCC.[C:36](OCC)(=[O:38])C>>[CH:15]([C:12]1[CH:11]=[CH:10][C:9]([CH:6]2[C:5]3[C:18]([CH3:28])=[C:19]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:24])([CH3:25])[CH3:26])[C:2]([O:38][CH3:36])=[C:3]([CH3:29])[C:4]=3[O:8][CH2:7]2)=[CH:14][CH:13]=1)([CH3:17])[CH3:16]
Reactant: Cc1c(Br)c(NC(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: COc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Yield: 37 %

Procedure:
Using N-(6-bromo-3-(4-isopropylphenyl)-4,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 87, the title compound was synthesized in the same manner as in Example 36. Yield: 37%. Melting point: 162-163° C. (hexane-ethyl acetate).
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][C:6]([NH2:8])=[NH:7].Cl[C:10]([C:12]1[C:16]([CH:17]2[CH2:19][CH2:18]2)=[CH:15][N:14]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[CH:22][CH:21]=2)[CH:13]=1)=[O:11]>COCCOC.C(Cl)(Cl)Cl.CO>[CH:17]1([C:16]2[C:12]([C:10]([NH:7][C:6]([NH2:8])=[NH:5])=[O:11])=[CH:13][N:14]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[CH:22][CH:21]=3)[CH:15]=2)[CH2:19][CH2:18]1
Reactant: N=C(N)N
Reactant: O=C(Cl)c1cn(-c2ccnc3ccccc23)cc1C1CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Solvent: CO
Product: N=C(N)NC(=O)c1cn(-c2ccnc3ccccc23)cc1C1CC1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
1.19 g (22 mmol) of sodium methoxide are added to 25 mL of methanol at a temperature in the region of 20° C. under an argon atmosphere. After total dissolution, 2.2 g (23 mmol) of guanidine hydrochloride are added. After stirring at a temperature in the region of 20° C. for 0.5 hour, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue, which is suspended in 50 mL of 1,2-dimethoxyethane and then concentrated to dryness again. The residue is suspended in a mixture of 100 mL of tetrahydrofuran and 100 mL of dichloromethane at a temperature in the region of 20° C. under an argon atmosphere, and 1.12 g (3.78 mmol) of 3-chlorocarbonyl-4-cyclopropyl-1-(quinolin-4-yl)-1H-pyrrole dissolved in 25 mL of chloroform are then added. After stirring for 17 hours at a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue, which is triturated in 100 mL of water. After filtration, a gum is obtained, which is dissolved in 50 mL of methanol. The solution is partially concentrated to a volume of from 5 to 10 mL and then purified by chromatography on silica gel [eluent: chloroform/methanol (75/25 by volume)]. After the fractions containing the expected product have been concentrated to dryness under reduced pressure, the residue is dissolved in 20 mL of methanol, and 2 mL of 6 N hydrochloric dioxane are added. The solution obtained is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is then triturated in a mixture of dichloromethane and diethyl ether and filtered, giving 0.77 g of 4-cyclopropyl-3-guanidinocarbonyl-1-(quinolin-4-yl)-1H-pyrrole in the form of a yellow solid melting at 185° C. Mass spectrum (EI): m/e 319 (M+.) (base peak), m/e 260, m/e 231.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH:35]=[O:36])=[C:19]([N:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]([C:32]([NH2:34])=[O:33])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.ClCCl.O.ClCCl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:35][OH:36])=[C:19]([N:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]([C:32]([NH2:34])=[O:33])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c5ccccc54)c3C=O)ncc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c5ccccc54)c3CO)ncc2c1
Reaction time: 0.17 h
Yield: 69.4 %

Procedure:
To a cooled (ice bath) flask containing 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-formylphenyl)-1H-indole-3-carboxamide (51 mg, 0.11 mmol) dissolved in methanol/dichloromethane (1.35 ml, 2.9:1) was added a solution of sodium borohydride (20 mg, 0.53 mmol) in water (0.35 ml), via slow drop-wise addition. The mixture was stirred for 10 minutes and then taken up in dichloromethane (20 ml) and water (20 ml). The contents were poured into a separatory funnel and agitated. The organic phase was collected and washed with a solution of 50% diluted brine (20 ml). The dichloromethane layer was collected and the aqueous phases were back extracted with methylene chloride (2×20 mL). The organic phases were combined, dried over magnesium sulfate, filtered and stripped. The crude material was purified by filtration through a short column of silica gel, eluting with 7.5% methanol/dichloromethane. The desired fraction was collected and then the material was crystallized from a solution of hot dichloromethane/hexanes to provide white crystalline product as 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-1H-indole-3-carboxamide (37 mg). LC/MS calcd for C28H25FN4O3 (m/e) 484.54, obsd 485.0 (M+H, ES+): 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.44 (s, 9H) 4.03-4.37 (m, 2H) 5.49-6.00 (br. s, 2H) 7.18-7.38 (m, 3H) 7.49-7.71 (m, 5H) 8.13-8.28 (m, 2H) 8.32 (d, J=2.64 Hz, 1H).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(=O)(O)[O-:18].[Na+].C(OO)(=O)C.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH:5]1([CH2:4][CH2:3][C@@H:2]([CH3:1])[CH2:11][CH2:12][CH:13]2[O:18][C:14]2([CH3:15])[CH3:16])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CC(C)=CCC[C@H](C)CCC1CCCCC1
Reactant: O=C([O-])O
Agent: CC(=O)OO
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H](CCC1CCCCC1)CCC1OC1(C)C
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A flask was charged with 11.48 g (51.6 mmol) of crude (3R)-(3,7-dimethyl-oct-6-enyl)-cyclohexane, 100 mL of dichloromethane, and 9.33 g (111 mmol) of sodium bicarbonate. The mixture was cooled in a 0° C. bath. Slowly 11.6 mL (55.2 mmol) 32% peracetic acid was added. The mixture was stirred for 4 hours at 0° C. Then 10% aqueous sodium sulfite was added slowly until bubbling ceased. The layers were separated, and the organic layer was washed twice with 10% aqueous sodium sulfite and dried over magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure. The remaining residue was 10.65 g (87%) of a clear oil: 1H NMR (400 MHz, CDCl3) ppm 0.86 (m, 5 H) 1.00 (d, J=6.59 Hz, 2 H) 1.14 (m, 7 H) 1.25 (s, 3 H) 1.29 (s, 3 H) 1.35 (m, 2 H) 1.50 (m, 3 H) 1.65 (m, 5 H) 2.68 (td, J=6.16, 1.83 Hz, 1 H). MS (APCl) m+1/z=239.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C@H:10]([CH2:13][NH2:14])[O:9][C:8]=2[CH:15]=1.Br[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][C:27](=[O:31])[O:28]2)=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C@H:10]([CH2:13][NH:14][CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]4[CH:25]=[CH:26][C:27](=[O:31])[O:28][C:29]=4[CH:30]=3)[O:9][C:8]=2[CH:15]=1
Reactant: COc1ccc2c(c1)O[C@@H](CN)CO2
Reactant: O=c1ccc2ccc(OCCCBr)cc2o1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)O[C@@H](CNCCCOc1ccc3ccc(=O)oc3c1)CO2
Temperature: 90 °C
Yield: 30.8 %

Procedure:
(S)-2,3-Dihydro-7-methoxy-1,4-benzodioxin-2-methanamine hydrochloride (11.5 g, 49.8 mmole), 7-(3-bromopropoxy)coumarin (14.2 g, 50.0 mmole), and diisopropylethylamine (12 ml, 68.9 mmole) were combined in 350 ml of DMF and heated at 90° C. for 24 hours uunder a nitrogen atmosphere. The solvent was then removed in vacuum and replaced with 300 ml of dichloromethane. Upon addition of an equal volume of saturated aqueous sodium bicarbonate, a white solid precipitated. This was filtered and redissolved in 550 ml of warm methanol and 35 ml of 4N isopropanolic HCl was added. The solution was boiled on a hot plate and the solvent gradually replaced with isopropanol. Upon cooling, 0.54 g of the title compound precipitated as a white solid, monohydrochloride, quarter hydrate, m.p. 225°-227° C. Subsequent crops yielded as additional 6.1 g of product.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]([CH3:10])[CH2:8][NH2:9])=[CH:5][N:4]=[C:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[F:17][C:18]([F:34])([F:33])[C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:32]=2)[C:29](O)=[O:30])[N:20]=1>>[CH3:1][N:2]1[C:6]([CH:7]([CH3:10])[CH2:8][NH:9][C:29](=[O:30])[C:28]2[CH:32]=[C:24]([C:21]3[N:20]=[C:19]([C:18]([F:34])([F:33])[F:17])[O:23][N:22]=3)[CH:25]=[N:26][CH:27]=2)=[CH:5][N:4]=[C:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(CN)c1cnc(-c2ccccc2)n1C
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Product: CC(CNC(=O)c1cncc(-c2noc(C(F)(F)F)n2)c1)c1cnc(-c2ccccc2)n1C
Yield: 28 %

Procedure:
This compound was synthesized from 2-(1-methyl-2-phenyl-1H-imidazol-5-yl)propan-1-amine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (35 mg, yield 28%). 1H NMR (400 MHz, DMSO-d6) δ 9.36 (d, J=2.1 Hz, 1H), 9.28-9.26 (m, 2H), 8.84-8.83 (t, J=2.0 Hz, 1H), 7.65-7.63 (m, 2H), 7.50-7.42 (m, 4H), 6.92 (s, 1H), 3.70 (s, 3H), 3.66-3.61 (m, 1H), 3.32-3.28 (m, 1H), 3.22-3.17 (m, 1H), 1.33-1.32 (d, J=6.7 Hz, 3H). MS (ESI) m/z: Calculated for C22H19F3N6O2: 456.15. found: 457.2 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH:8][C:5]=1[CH:6]=[O:7]>CO.O>[Br:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:21])([CH3:20])[CH3:22])=[CH:8][C:5]=1[CH2:6][OH:7]
Reactant: COc1cc(Br)c(C=O)cc1OCOCC[Si](C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(Br)c(CO)cc1OCOCC[Si](C)(C)C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
Sodium borohydride (275 mg, 7.2 mmol) was added in portions over 10 min to a solution of 2-bromo-4-methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-benzaldehyde (1.3 g, 3.6 mmol) in MeOH (20 mL) at 0° C. After 30 min, the reaction was diluted with H2O (40 mL) and extracted with EtOAc (2×30 mL). Organics were washed with brine (30 mL), dried (Na2SO4) and concentrated in vacuo to give 1.31 g of (2-bromo-4-methoxy-5-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-methanol as a clear oil. 1H NMR (300 MHz, CDCl3) δ 7.29 (s, 1H), 7.05 (s, 1H), 5.27 (s, 2H), 4.66 (d, 2H, J=6.6 Hz), 3.87 (s, 3H), 3.79 (t, 2H, J=8.4 Hz), 1.92 (t, 1H, J=6.6 Hz), 0.96 (t, 2H, J=8.4 Hz), 0.01 (s, 9H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=1)[N:9]=[C:8]2[NH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[N:29]=[CH:28]2)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1)[N:9]=[C:8]2[NH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[N:29]=[CH:28]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2nc(-c3cccc([N+](=O)[O-])c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2c1
Agent: [Pd]
Solvent: CO
Product: CC(=O)Oc1ccc2nc(-c3cccc(N)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 102.6 %

Procedure:
A mixture of tert-butyl 5-(6-acetoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.84 g, 1.55 mmol) in MeOH (200 mL) was added 10% Pd/C under an atmosphere of N2. The mixture was stirred under an atmosphere of H2 (balloon pressure) for 48 h at RT. The mixture was filtered through a pad of Celite® washing with MeOH. The volatiles were removed in vacuo to give tert-butyl 5-(6-acetoxy-2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.811 g, 1.59 mmol). HPLC retention time 5.51 min.
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[CH:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+]>CO.C(O)(=O)C.O>[CH3:3][C:2](=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:1]=[O:4]
Reactant: O=Cc1ccccc1
Reactant: CCC=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(C=O)=Cc1ccccc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
Propionaldehyde (87 gms 15 moles) was added at 50° C. over a period of 5 hours to a stirred mixture of benzaldehyde (318 gms, 3 moles), methanol (500 mls), water (500 mls) and sodium hydroxide (25 gms). After a further 1 hour stirring at 50° C., the reaction mixture was brought to neutrality with acetic acid and the methanol fractionated out of the reaction. The organic layer was then separated from the aqueous layer and fractionated to recover the excess of benzaldehyde (109 gms, b.pt. 36°-40° C./2 mm Hg) and obtain the -methylcinnamaldehyde (167 gms, b.pt. 100°-102° C./2 mm).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[Cl:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>>[Cl:16][CH2:17][CH2:18][CH2:19][C:20]([C:4]1[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=1)=[O:21]
Reactant: O=C(Cl)CCCCl
Reactant: COc1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)CCCCl)cc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 97802.9 %

Procedure:
To a cooled solution of 10.8 g (0.1 mol) anisole in 100 ml anhydrous toluene 13.3 g (0.1 mol) aluminium trichloride was added in portions over 15 minutes at −10° C. then 15.5 g (12.3 ml, 0.1 mmol) 4-chloro-butyryl chloride were added over 15 minutes keeping the temperature at −10° C. After stirring for additional 30 minutes at −10° C. the reaction mixture was hydrolyzed and the layers were separated. The aqueous layer was extracted with toluene (three times 100 ml) and the combined organic layers were dried and evaporated to yield 20.8 g (97%) 4-chloro-1-(4-methoxy-phenyl)-butan-1-one as a light beige liquid that solidified on standing. The product was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=2)[N:17]=1)=[O:11]>CCO.CC(O)=O.[Pd]>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=2)[N:17]=1)=[O:11]
Reactant: COC(=O)CCCCCCC(=O)Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)CCCCCCC(=O)Nc1nc(-c2cccc(N)c2)cs1
Yield: 72.2 %

Procedure:
A suspension of compound 14 (0.391 g, 1 mmol) and Pd/C (10 wt. %, 50 mg) in EtOH and AcOH (20 ml+1 ml) was reacted under hydrogen atmosphere at 50° C. for 2 hours. The catalyst was removed by filtration through a pad of Celite. After removal of the solvent in vacuo, the crude material was dissolved in EtOAc and washed with NaHCO3 solution and brine and dried over Na2SO4. The solvent was removed by rotary evaporation. The crude solid was purified by flash chromatography (EtOAc/hexane, 2:1) to give compound 20 (0.261 g, 72.4%). 1H NMR (300 MHz, CDCl3) δ 11.2 (1H, s), 7.22 (1H, s), 7.20 (1H, s), 7.16 (1H, brs), 7.10 (1H, s), 6.70-6.66 (1H, m), 3.69 (3H, s), 2.28 (2H, t, J=7.4 Hz), 2.06 (2H, dd, J=7.3, 4.7 Hz), 1.61-1.45 (4H, m), 1.22-1.08 (4H, m). 13C NMR (75 MHz, CDCl3) δ 174.6, 171.8, 159.6, 150.1, 147.3, 135.7, 130.2, 116.9, 115.3, 113.0, 108.1, 51.9, 36.1, 34.3, 29.07, 29.01, 25.09, 25.00, 21.4.
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH3:13])[N:12]=1)[C:7](O)=O)[CH3:3].CC[N:16](C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.N.N1C=CC=CC=1>CN(C=O)C.O1CCOCC1.C(Cl)Cl>[CH2:2]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH3:13])[N:12]=1)[C:7]#[N:16])[CH3:3]
Reactant: CCc1cc(C(=O)O)cc(C)n1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1cc(C#N)cc(C)n1
Reaction time: 0.25 h
Yield: 50.3 %

Procedure:
To a solution of 2-ethyl-6-methyl-isonicotinic acid hydrochloride (1.85 g, 9.18 mmol, Example J) in DMF (90 mL), DIPEA (6.3 mL, 4.75 g, 36.7 mmol)) is added. The mixture is cooled to 0° C. before PyBOP (5.25 g, 10.1 mmol) is added. Stirring is continued at 0° C. for 15 min, then NH3 (64 mL of a 0.5 M solution in dioxane) is added. Stirring is continued for 2 h at rt before the solvent is evaporated under reduced pressure. The residue is dissolved in DCM (80 mL) and pyridine (4.5 mL, 4.39 g, 55.5 mmol) followed by TFA anhydride (6.32 mL, 9.39 g, 44.7 mmol) is added at 0° C. The mixture is stirred at rt for 2 h, before it is diluted with DCM, washed sat. aq. Na2CO3. The organic phase is dried over MgSO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 2-ethyl-6-methyl-isonicotinonitrile (0.675 g) as a yellow oil; 1H NMR (CDCl3): δ 1.33 (t, J=7.5 Hz, 3 H), 2.61 (s, 3 H), 2.86 (q, J=7.5 Hz, 2 H), 7.21 (s, 2H).
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH2:23]([CH2:25][NH2:26])[OH:24]>>[CH2:18]([C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:26][CH2:25][CH2:23][OH:24])=[O:22])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Reactant: NCCO
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NCCO)cn1
Yield: 60 %

Procedure:
As described for example 9, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (500 mg, 1.4 mmol) was converted, using ethanolamine instead of rac-2-amino-1-propanol, to the title compound (280 mg, 60%) which was obtained as a colourless oil after purification by chromatography (silica, 0 to 5% methanol in dichloromethane). MS: m/e=334.3 [M+H]+.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[C:15]([CH:24]=[CH:25][CH:26]=3)[CH2:16][NH:17][CH2:18][CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])[N:6]2[N:5]=1)=O.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1.COCC(O)C.C(N(CC)C(C)C)(C)C>>[CH3:23][S:20]([CH2:19][CH2:18][NH:17][CH2:16][C:15]1[CH:14]=[C:13]([C:12]2[N:6]3[C:7]([CH:8]=[N:9][C:4]([NH:40][C:37]4[CH:36]=[CH:35][C:34]([N:31]5[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]5)=[CH:39][CH:38]=4)=[N:5]3)=[CH:10][CH:11]=2)[CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CS(=O)c1ncc2ccc(-c3cccc(CNCCS(C)(=O)=O)c3)n2n1
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5cccc(CNCCS(C)(=O)=O)c5)n4n3)cc2)CC1

Procedure:
Into a microwave vial, [3-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzyl]-(2-methanesulfonyl-ethyl)-amine (0.100 g, 0.000255 mol), 4-(4-Methyl-piperazin-1-yl)-phenylamine (0.214 g, 0.00112 mol), 1-Methoxy-2-propanol (0.613 mL) and N,N-Diisopropylethylamine (0.133 mL, 0.000764 mol) were added. The reaction was microwaved on 300 watts, 170° C. for 50 minutes. The solvent was removed under vacuum. The desired product was isolated via ISCO column chromatography with DCM and methanol as eluant (0 to 15% methanol). The collected fractions afforded (7-{3-[(2-Methanesulfonyl-ethylamino)-methyl]-phenyl}-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine a yellow solid (41 mg, 31%). LCMS (E/I+) 520.16 (M+H). NMR 1H (DMSO-d6)-9.76 (ns, 1H), 9.37 (s, 1H), 9.20 (bs, 2H), 8.99 (s, 1H), 8.42 (d, 2H, J=7.45 Hz), 8.16 (s, 1H), 7.61-7.72 (m, 3H), 7.51 (d, 1H, J=7.45 Hz), 7.15 (d, 1H, J=4.47 Hz), 6.91-7.04 (m, 4H), 4.31 (s, 2H), 3.76 (d, 2H, J=12.66 Hz), 3.34-3.63 (m, 6H0, 3.08-3.24 (m, 5H), 2.82-3.00 (m, 5H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[S-:11][C:12]#[N:13].[NH4+]>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10][C:12]([NH2:13])=[S:11])=[CH:5][CH:4]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: N#C[S-]
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Product: NC(=S)NNc1ccc(Cl)cc1

Procedure:
Fifty g of 4-chlorophenylhydrazine hydrochloride and 40 g of ammonium thiocyanate were added to 250 ml of denatured ethanol and the mixture was stirred under reflux for 16 hours. It was then filtered while still hot and the filter cake was washed with about 100 ml of hot ethanol. As the filtrate cooled, the product began to crystallize, and it was collected and recrystallized from denatured ethanol to obtain 32.7 g of the desired intermediate, m.p. 200°-201°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[F:12][C:13]1([F:27])[CH2:17][CH2:16][C@@H:15]([NH:18][CH2:19][C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22])[CH2:14]1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([N:18]([C@@H:15]2[CH2:16][CH2:17][C:13]([F:12])([F:27])[CH2:14]2)[CH2:19][C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: COC(=O)C(C)(C)CN[C@@H]1CCC(F)(F)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C(C)(C)CN(c1nc(Cl)ncc1[N+](=O)[O-])[C@@H]1CCC(F)(F)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62 %

Procedure:
2,4-Dichloro-5-nitropyrimidine (2.18 g, 11.25 mmol) was added to a mixture of (R)-methyl 3-(3,3-difluorocyclopentylamino)-2,2-dimethylpropanoate (2.65 g, 11.25 mmol) and sodium bicarbonate (3.78 g, 44.98 mmol) in dichloromethane (10 mL) and petroleum ether (40 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane and dried over magnesium sulfate. The solids were filtered off, rinsing with more dichloromethane. The mother liquors were adsorbed on silica gel and concentrated in vacuo. The residue was purified by flash column chromatography to afford the title compound as yellow solid (2.74 g, 62% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:18])OC2C=CC=CC=2)=[CH:7][C:6]([CH3:19])=[C:5]([CH2:20][CH2:21][CH3:22])[N:4]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([CH3:30])[CH:29]=1>>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[C:28]([CH3:30])[CH:29]=[C:24]([CH3:23])[CH:25]=3)[CH2:32][CH2:33]2)=[O:18])=[CH:7][C:6]([CH3:19])=[C:5]([CH2:20][CH2:21][CH3:22])[N:4]=1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: CCCc1nc(OC)c(NC(=O)Oc2ccccc2)cc1C
Product: CCCc1nc(OC)c(NC(=O)N2CCN(c3cc(C)cc(C)c3)CC2)cc1C
Yield: 54 %

Procedure:
Phenyl N-(2-methoxy-5-methyl-6-propylpyridin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.