Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH2:16])=[N:11][CH:12]=[C:13](Br)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH:23]([N:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:28][C:27]1=[O:41])([CH3:25])[CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CCC=1>C(#N)C.Cl[Pd]Cl.[Fe].ClCCl>[NH2:16][C:10]1[N:11]=[CH:12][C:13]([C:30]2[CH:29]=[CH:28][C:27](=[O:41])[N:26]([CH:23]([CH3:25])[CH3:24])[CH:31]=2)=[N:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncc(Br)nc1OCc1ccccc1
Reactant: CC(C)n1cc(B2OC(C)(C)C(C)(C)O2)ccc1=O
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: C1=CC(P(c2ccccc2)c2ccccc2)=CC1
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)n1cc(-c2cnc(N)c(OCc3ccccc3)n2)ccc1=O
Temperature: 100 °C
Yield: 13.3 %

Procedure:
3-(benzyloxy)-5-bromopyrazin-2-amine (100 mg, 0.358 mmol) was dissolved in acetonitrile (4 mL). Aqueous Na2CO3 solution (462.3 μL of 2 M, 0.9247 mmol), 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (146.0 mg, 0.5548 mmol) and cyclopenta-1,4-dien-1-yl(diphenyl)phosphane; dichloromethane; dichloropalladium; iron (75.33 mg, 0.09247 mmol) was added and the reaction mixture was heated for 30 minutes at 100° C. under microwave conditions. The reaction mixture was concentrated in vacuo and the residue was partitioned between DCM and water. The layers were separated and the aqueous further extracted with DCM. The combined organic extract was dried (MgSO4), filtered and concentrated in vacuo. This material was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, and freeze-dried to give the title compound (16 mg, 6.13% Yield). H1 NMR (400.0 MHz, DMSO) δ 1.35 (d, J=6.8 Hz, 6H), 5.10 (m, J=6.8 Hz, 1H), 5.53 (s, 2H), 6.46 (d, J=9.5 Hz, 1H), 7.32 (m, J=7.3 Hz, 1H), 7.38-7.41 (m, 2H), 7.54 (d, J=7.2 Hz, 2H), 7.95 (dd, J=2.5, 9.5 Hz, 1H), 7.98 (s, 1H) and 8.06 (d, J=2.5 Hz, 1H). MS (ES+) 337.0
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:14]([O:16]CC)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].[OH-].[Na+]>C1COCC1.CO.O>[C:1]([C:3]1[CH:4]=[C:5]([C:14]([OH:16])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2]
Reactant: CCOC(=O)c1cc(C#N)c(N2CCOCC2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: N#Cc1cc(C(=O)O)sc1N1CCOCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.6 %

Procedure:
To a solution of ethyl 4-cyano-5-morpholin-4-ylthiophene-2-carboxylate (0.06 g, 0.23 mmol) in THF/MeOH/water (3:1:1) (5 mL) was added sodium hydroxide (0.095 g, 2.3 mmol). The reaction mixture was allowed to stir at rt for 20 h and was concentrated. The residue was acidified to pH 1-2 with 1N HCl and was extracted with EtOAc. The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated to give the title compound (0.048 g, 88%). LCMS: (FA) ES+ 239.1. 1H NMR (400 MHz, d6-DMSO) δ:7.67 (s, 1H), 3.72-3.75 (m, 4H) and 3.52-3.55 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9](Cl)(=[O:11])=[O:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].Cl>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([Cl:19])[CH:21]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=S(=O)(Cl)Cc1ccc(Br)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Cc1ccc(Br)cc1)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.3 %

Procedure:
To a solution of (4-bromo-phenyl)-methanesulfonyl chloride (1.4 g, 5.2 mmol) in DCM (20 mL) at room temperature was added pyridine (1.26 mL, 15.6 mmol) followed by 3-chloroaniline (1.1 mL, 10.4 mmol) and the reaction was stirred at room temperature for 3 hours. 1 M aqueous HCl was added and then extracted with DCM, filtered through a separator, concentrated, dry loaded onto silica and purified by silica gel column chromatography (0-100% DCM in cyclohexane) to give C-(4-bromo-phenyl)-N-(3-chloro-phenyl)-methanesulfonamide (0.61 g, 1.68 mmol). 1H NMR (300 MHz, CDCl3): δ 7.49 (d, 2H), 7.26 (m, 1H), 7.13-7.15 (m, 4H), 6.96-6.98 (m, 1H), 6.31 (s, 1H), 4.31 (s, 2H).
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:4][CH:3]1[CH2:5][C:6]([OH:8])=[O:7].Br[CH2:11][C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13].[I-].[Na+].C(N(CC)CC)C>CN(C)C=O.O>[F:1][C:2]1([F:9])[CH2:4][CH:3]1[CH2:5][C:6]([O:8][CH2:11][C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])=[O:7]
Reactant: O=C(O)CC1CC1(F)F
Reactant: O=C(CBr)N1CCCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CC1CC1(F)F)OCC(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A solution of 2.72 g (0.02 mol) 2,2-difluorocyclopropyl-acetic acid and 3.84 g (0.02 mol) N-(bromoacetyl)-pyrrolidine in 10 ml dimethylformamide was treated, at room temperature, with 0.3 g sodium iodide and 2.8 ml (0.02 ml) triethylamine and the mixture stirred at room temperature for 10 hours. It was then poured into water and extracted three times with ethyl acetate. The combined ethyl acetate phases were washed with first with aqueous 2% sodium hydrogen carbonate and then with water, dried over magnesium sulphate and concentrated. The crude product was purified by silica gel column chromatography using hexane/ethyl acetate (1:1) as eluent. A sample was analysed by thin layer chromatography using hexane/ethyl acetate (1:1) as eluent (Rf :0.18). 3.3 g (66% of theory) of product was obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.[H-].[Na+].[CH2:10](Br)[C:11]#[CH:12].O>O1CCCC1>[CH2:12]([N:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1)[C:11]#[CH:10]
Reactant: C#CCBr
Reactant: O=Cc1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCn1ccc(C=O)c1
Reaction time: 0.17 h

Procedure:
2.924 g of pyrrole-3-carboxaldehyde (J. Org. Chem. 1981, Vol. 46, p. 839) dissolved in 45 ml of tetrahydrofuran and 1.488 g of sodium hydride as 50% in oil were admixed and then were stirred for 10 minutes cold, then for 40 minutes at room temperature. After cooling, 2.5 ml of propargyl bromide were added with stirring at 5 C. for 90 minutes. A further 2 ml of propargyl bromide were added with stirring at 5° C. for 1 hour and the mixture was poured into water and extracted with methylene chloride. The solvent was distilled off at atmospheric pressure to obtain 2.868 g of 1-(2-propynyl)-1H-pyrrole-3-carboxaldehyde which was purified by chromatography on silica gel and elution with a 65-35 hexane-ethyl acetate mixture to obtain 2.868 g of the said product.
Reaction SMILES: ClC1C=NC=CC=1C#N.ClC1C=CC(CO)=CC=1.[H-].[Na+].C([Li])CCC.[Cl:26][C:27]1[CH:46]=[CH:45][C:30]([CH2:31][O:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][C:38]=2[C:39](=[O:44])[CH2:40][CH2:41][CH2:42][CH3:43])=[CH:29][CH:28]=1.B.[Na]>CN(C)C=O.ClC1C=CC(COC2C=NC=CC=2C#N)=CC=1.C(OCC)C>[Cl:26][C:27]1[CH:46]=[CH:45][C:30]([CH2:31][O:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][C:38]=2[CH:39]([OH:44])[CH2:40][CH2:41][CH2:42][CH3:43])=[CH:29][CH:28]=1
Reactant: CCCCC(=O)c1ccncc1OCc1ccc(Cl)cc1
Agent: B
Agent: N#Cc1ccncc1Cl
Agent: N#Cc1ccncc1OCc1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCC(O)c1ccncc1OCc1ccc(Cl)cc1

Procedure:
Starting from 3-chloro-4-pyridine carbonitrile, by reaction with 4-chlorobenzyl alcohol in the presence of sodium hydride in dimethylformamide, 3-(4-chlorobenzyloxy)-4-pyridine carbonitrile is obtained, which is reacted with butyllithium in diethyl ether to 3-(4-chlorobenzyloxy)-4-valeryl pyridine. The keto group of this 4-valeryl derivative is reduced with sodium boron hydride to the hydroxyl group; 1-[3-(4-chlorobenzyloxy)-4-pyridyl]-1-pentanol is obtained. The hydroxyl group of the pentanol derivative is exchanged with thionyl chloride in methylene chloride for a chlorine group, 3-(4-chlorobenzyloxy)-4-(1-chloropentyl)-pyridine is obtained. By subsequent reaction with imidazole in the presence of sodium hydride (analogously to example 13), the 3-(4-chlorobenzyloxy)-4-[1-(1-imidazolyl)-pentyl]-pyridine is obtained.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][N:31]=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][NH:28][C:23](=[O:24])[C:22]2[CH:21]=[CH:20][C:19]([S:16]([N:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8]3)(=[O:18])=[O:17])=[CH:27][CH:26]=2)=[N:31][CH:32]=1
Reactant: NCc1ccc(F)cn1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NCc1ccc(F)cn1)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add to a stirring mixture of 4-(3-phenyl-indole-1-sulfonyl)-benzoic acid (5.0 g, 13.25 mmol) and 2-aminomethyl-5-fluoropyridine (dihydrochloride) (2.9 g, 14.57 mmol) in anhydrous methylene chloride (60 mL), EDCI (3.8 g, 19.82 mmol) and 4-DMAP (6.0 g, 49.10 mmol). Stir the resulting solution overnight at room temperature, concentrate to a paste, and partition between ethyl acetate (100 mL), water (100 mL), and brine (100 mL). Dry the organic layer over sodium sulfate and concentrate to an oil. Dissolve the oil in methylene chloride and add to a biotage 65 cartridge. Elute with 1:1 ethyl acetate/hexanes to provide isolation of the pure 3 (N-(5-Fluoro-pyridin-2-ylmethyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamide as a solid, 5.7 g (89%): 1H NMR(DMSO-d6) δ 9.32 (t, J=5.9 Hz, 1H), 8.46 (d, J=2.9 Hz, 1H), 8.20 (d, J=8.3 Hz, 2H), 8.12 (s, 1H), 8.03 (m, 3H), 7.82 (d, J=7.8 Hz, 1H), 7.72 (d, J=6.8 Hz, 2H), 7.62 (dt, J=2.9, 8.8 Hz, 1H), 7.50(t, J=7.3 Hz, 2H), 7.39 (m, 4H), 4.50 (d, J=5.9 Hz, 2H); MS(ESI) m/z 486 (m+H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([NH2:10])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:11][C:12]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:13]=1[C:14](Cl)=[O:15]>N1C=CC=CC=1.ClCCl>[Cl:11][C:12]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:13]=1[C:14]([NH:10][C:8]1[CH:9]=[C:4]2[CH:3]=[CH:2][NH:1][C:5]2=[N:6][CH:7]=1)=[O:15]
Reactant: Nc1cnc2[nH]ccc2c1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cnc2[nH]ccc2c1)c1cc([N+](=O)[O-])ccc1Cl

Procedure:
1.87 g 1H-Pyrrolo[2,3-b]pyridin-5-ylamine in 60 ml dry pyridine were treated dropwise at RT with a solution of 6.79 g 2-chloro-5-nitrobenzoyl chloride in 10 ml dichloromethane. Stirring was continued over night. The mixture was evaporated and the residue was treated with 25 ml methanol and 10 ml conc. ammonia for 2 hrs at RT. The solvents are again evaporated and the residue is dispersed in water. The crude product is isolated by filtration and washed thoroughly with water and diethylether.
Reaction SMILES: FC1C=C(NC(C2(C(NC3C=CC(F)=CC=3)=O)CC2)=O)C=CC=1OC1C2C(=CC(OC)=C(OC)C=2)[N:12]=[C:11](NC)C=1.[CH3:41][O:42][C:43]1[CH:44]=[C:45]([NH:51][C:52](SC)=[C:53]2[C:58](=[O:59])[O:57][C:56]([CH3:61])([CH3:60])[O:55][C:54]2=[O:62])[CH:46]=[CH:47][C:48]=1[O:49][CH3:50].CN>C1COCC1.Cl[Hg]Cl>[CH3:41][O:42][C:43]1[CH:44]=[C:45]([NH:51][C:52]([NH:12][CH3:11])=[C:53]2[C:58](=[O:59])[O:57][C:56]([CH3:61])([CH3:60])[O:55][C:54]2=[O:62])[CH:46]=[CH:47][C:48]=1[O:49][CH3:50]
Reactant: COc1ccc(NC(SC)=C2C(=O)OC(C)(C)OC2=O)cc1OC
Reactant: CNc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)c2cc(OC)c(OC)cc2n1
Agent: CN
Agent: Cl[Hg]Cl
Solvent: C1CCOC1
Product: CNC(Nc1ccc(OC)c(OC)c1)=C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Synthesis of ′N-(3-fluoro-4-{[2-(methylamino)-6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide. A mixture of 5-[(3,4-dimethoxy-phenylamino)-methylsulfanyl-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione (0.50 g, 1.4 mmol), methylamine (2 M in THF, 0.75 mL. 1.5 mmol), HgCl2 (0.38 g, 1.4 mmol) in THF (5 mL) was stirred at room temperature for 30 minutes. The mixture was extracted with DCM and water (3×) and dried with Na2SO4. Concentration in vacuo afforded 5-[(3,4-dimethoxy-phenylamino)-methylamino-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione as a yellow solid (0.48 g, 99% yield) and this compound was used without further purification. LCMS: m/z 335 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][C@H:10]([OH:13])[CH2:11][OH:12])[N:5]=1)([O-:3])=[O:2].O.[C:15]1(C)[CH:20]=CC(S(O)(=O)=O)=C[CH:16]=1>COC(OC)(C)C.O1CCCC1>[CH3:16][C:15]1([CH3:20])[O:13][C@@H:10]([CH2:9][N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]2)[CH2:11][O:12]1
Reactant: O=[N+]([O-])c1ccn(C[C@H](O)CO)n1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OC[C@H](Cn2ccc([N+](=O)[O-])n2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 269.1 %

Procedure:
A solution of (S)-3-(3-nitro-pyrazol-1-yl)-propane-1,2-diol (1 g, 5.34 mmol) in 2,2-dimethoxypropane (8.5 mL, 0.63M) and tetrahydrofuran (10 mL, 0.53 M) was treated with para-toluenesulfonic acid monohydrate (0.11 g, 0.57 mmol). The reaction was stirred under nitrogen at 25° C. overnight. After this time, the reaction was concentrated in vacuo. Silica gel column chromatography (Aspire 40 g, 20-45% ethyl acetate/hexanes) afforded 1-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-3-nitro-1H-pyrazole (348.5 mg, 29%) as a viscous yellow/orange oil. The material was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([NH:8][C@@:9]([C:21]2[CH:26]=[C:25]([O:27][C:28]([F:33])([F:32])[CH:29]([F:31])[F:30])[CH:24]=[C:23]([F:34])[CH:22]=2)([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:10][C:11]([OH:13])=[O:12])=[O:7])=[CH:4][C:3]=1[C:37]([F:40])([F:39])[F:38].[CH:41]1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CO.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([NH:8][C@@:9]([C:21]2[CH:26]=[C:25]([O:27][C:28]([F:32])([F:33])[CH:29]([F:31])[F:30])[CH:24]=[C:23]([F:34])[CH:22]=2)([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH2:10][C:11]([O:13][CH3:41])=[O:12])=[O:7])=[CH:4][C:3]=1[C:37]([F:40])([F:39])[F:38]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)C[C@@](NC(=O)c1ccc(F)c(C(F)(F)F)c1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C[C@@](NC(=O)c1ccc(F)c(C(F)(F)F)c1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 100 °C
Yield: 15.2 %

Procedure:
To a solution of (R)-3-(4-fluoro-3-(trifluoromethyl)benzamido)-3-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-3-(4-fluorophenyl)propanoic acid (32 mg, 0.055 mmol) in toluene (0.5 mL) was added DPPA (18 mg, 0.066 mmol) and TEA (7 mg, 0.066 mmol). The reaction mixture was heated at 100° C. for 1 h followed by the addition of MeOH and TEA. The reaction was heated at 65° C. overnight. Excess K2CO3 was added and the reaction was heated to reflux for 3 h. The reaction mixture was concentrated and the resulting residue was purified by preparative HPLC (phenominex 30×100 mm column, 30-100% MeOH (90% in water, 0.1% TFA) gradient over 12 min with flow rate 40 mL/min and UV detection at 220 nm) to yield (R)-methyl 3-(4-fluoro-3-(trifluoromethyl)benzamido)-3-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-3-(4-fluorophenyl)propanoate (Example 318) as a white solid (5 mg, 15% yield). LCMS: RT=3.92 min [M+H] 613.3 (4 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) ppm 3.74 (s, 3H), 3.87-4.11 (m, 2H), 4.89 (m, 1H), 5.86 (t, 1H), 6.95 (d, 1H), 6.99-7.13 (m, 5H), 7.28-7.40 (m, 3H), 8.09-8.16 (m, 1H), 8.26 (d, 1H), 8.94 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[O:11][C:10]([NH2:12])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[CH:15]1([CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([OH:24])=O)[CH2:20][CH2:19][CH2:18][CH2:17]C1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[O:11][C:10]([NH:12][C:22](=[O:24])[CH:21]([CH:15]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[N:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)C(c1ccccc1)C1CCCCC1
Reactant: Nc1ncc(Cc2ccc(Cl)cc2)o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ncc(Cc2ccc(Cl)cc2)o1)C(c1ccccc1)C1CCCC1
Reaction time: 16 h

Procedure:
5-(4-Chloro-benzyl)-oxazol-2-ylamine (42 mg, 0.20 mmol) and cyclohexyl-phenyl-acetic acid (44 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (84.1 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (9.6 mg, 0.023 mmol, 12%). ESI-MS m/z calc. 408.9. found 409.4 (M+1)+ Retention time 3.76 minutes.
Reaction SMILES: C(O[CH:5]1[CH:9]([N+:10]([O-:12])=[O:11])[CH:8]([CH:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH3:14])[S:7][CH2:6]1)(=O)C.S(Cl)(Cl)(=O)=O.O>C1(C)C=CC=CC=1>[CH3:17][CH:16]([CH3:18])[CH2:15][CH:13]([C:8]1[S:7][CH:6]=[CH:5][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:14]
Reactant: CC(=O)OC1CSC(C(C)CC(C)C)C1[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=S(=O)(Cl)Cl
Product: CC(C)CC(C)c1sccc1[N+](=O)[O-]
Temperature: 4 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
After dissolving 1.1 g of 5-(4-methylpentan-2-yl)-4-nitrotetrahydrothiophen-3-yl acetate in 7 ml of toluene, the solution was cooled to 4° C. A solution prepared by dissolving 0.8 g of sulfuryl chloride in 2 ml of toluene was added thereto. The temperature of the solution was allowed to rise room temperature, and the solution was stirred for 2 hours. Water was added to stop reaction, and the organic layer was washed with 1 mol/l aqueous sodium hydroxide and saturated saline. The organic layer was dried with magnesium sulfate and concentrated, and then purified by silica gel chromatography (hexane/ethyl acetate=10/1), thereby obtaining 0.8 g of 2-(4-methylpentan-2-yl)-3-nitrothiophene (yield: 85.0%).
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][C:5]([C:6](OCC)=[O:7])=[CH:4][N:3]=1.[BH4-].[Na+].O>C(O)C.C(OCC)C>[I:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(I)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: OCc1ccc(I)nc1
Temperature: 6 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
40 g (145 mmol) of ethyl 6-iodonicotinate diluted in 400 mL of ethanol are added dropwise to a solution at 0° C. of 27.3 g (−722 mmol) of sodium borohydride in 270 mL of ethanol. For the addition, the temperature of the reaction mixture is maintained from 2 and 6° C., and then at 0° C. for 1 hour and at room temperature for 20 hours. The reaction is worked up by addition of 200 mL of water, and a white precipitate forms. The reaction mixture is filtered off; the filtrate is evaporated under vacuum to give the product in the form of a yellow paste. The product is placed in 300 mL of diethyl ether and then filtered to give 23.2 g (68%) of (6-iodopyrid-3-yl)methanol in the form of a pale yellow solid.
Reaction SMILES: [OH-].[Na+].[CH3:3]I.[OH:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:18])[CH2:11][C:12]([CH3:17])([CH3:16])[O:13]2)=[CH:8][CH:7]=1>ClCCl.[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[CH3:3][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:18])[CH2:11][C:12]([CH3:16])([CH3:17])[O:13]2)=[CH:8][CH:7]=1
Reactant: CC1(C)CC(=O)c2ccc(O)cc2O1
Reactant: CI
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2c(c1)OC(C)(C)CC2=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.6 %

Procedure:
In 40 ml of 5% sodium hydroxide solution 3.84 g (20 millimoles) of 7-hydroxy-2,2-dimethyl-4-chromanone are dissolved whereupon 80 ml of dichloro methane and 0.5 g of triethyl benzyl ammonium chloride are added and the mixture is intensively stirred at room temperature for 20 minutes. After addition of 4.25 g (1.9 ml, 30 millimole) of methyl iodide the reaction mixture is stirred for 2 hours. The organic layer is separated, washed twice with 50 ml of water each, dried over sodium sulfate and evaporated. The residue is crystallized from 80% methanol. Thus 3.9 g of the desired compound are obtained, yield 94.6%. Mp.: 77°-78° C.
Reaction SMILES: C(=O)(O)O.[Cl:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]([NH2:21])=[NH:20])[CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.CN(C)/[CH:24]=[C:25](\[F:37])/[C:26]([C:28]1[N:32]([CH:33]([CH3:35])[CH3:34])[C:31]([CH3:36])=[N:30][CH:29]=1)=O>>[Cl:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]2[N:21]=[C:26]([C:28]3[N:32]([CH:33]([CH3:34])[CH3:35])[C:31]([CH3:36])=[N:30][CH:29]=3)[C:25]([F:37])=[CH:24][N:20]=2)[CH:9]=[CH:10][C:11]=1[N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: Cc1ncc(C(=O)/C(F)=C/N(C)C)n1C(C)C
Reactant: N=C(N)Nc1ccc(N2CCOCC2)c(Cl)c1
Agent: O=C(O)O
Product: Cc1ncc(-c2nc(Nc3ccc(N4CCOCC4)c(Cl)c3)ncc2F)n1C(C)C

Procedure:
The title compound was prepared using the procedure described in Example 112, employing N-(3-chloro-4-morpholin-4-yl-phenyl)-guanidine carbonate (Method 17; 500 mg, 1.97 mmol), and (2Z)-3-(dimethylamino)-2-fluoro-1-(1-isopropyl-2-methyl-1H-imidazol-5-yl)prop-2-en-1-one (Method 14; 392 mg, 1.64 mmol). Yield: 203 mg, 30% as a white solid; NMR: 1.41 (d, 6H), 2.49 (s, 3H), 2.90 (t, 4H), 3.72 (t, 4H), 5.35 (m, 1H), 7.10 (d, 1H), 7.34 (d, 1H), 7.50 (dd, 1H), 7.73 (d, 1H), 8.52 (d, 1H), 9.51 (s, 1H); m/z 431.
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)C(C)C)(C)C.[N:30]1([C:38](OC2C=CC([N+]([O-])=O)=CC=2)=[O:39])[CH2:35][CH2:34][S:33](=[O:37])(=[O:36])[CH2:32][CH2:31]1.O>CN1CCCC1=O.C(OCC)(=O)C>[F:20][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:15][N:14]([C:38]([N:30]3[CH2:35][CH2:34][S:33](=[O:37])(=[O:36])[CH2:32][CH2:31]3)=[O:39])[CH2:13][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]2)=[CH:8][CH:9]=1
Reactant: COC(=O)C1CNCC(c2ccc(OC(F)F)cc2)C1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCS(=O)(=O)CC1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C1CC(c2ccc(OC(F)F)cc2)CN(C(=O)N2CCS(=O)(=O)CC2)C1
Reaction time: 0.12 h

Procedure:
2.2 g (7.7 mmol) of methyl 5-[4-(difluoromethoxy)phenyl]piperidine-3-carboxylate were dissolved in 14 ml of N-methyl-2-pyrrolidone, and admixed with 4.0 ml (3.0 g, 23.0 mmol) of N,N-diisopropylethylamine and 3.5 g (11.5 mmol) of 4-nitrophenyl thiomorpholine-4-carboxylate 1,1-dioxide. The reaction mixture was converted in the microwave at 180° C. for seven minutes. Subsequently, water and ethyl acetate were added, and the aqueous phase was removed and extracted repeatedly with ethyl acetate. The combined organic extracts were washed with water and saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was taken up in diethyl ether and filtered, and the filtrate was purified by means of preparative HPLC. Yield: 2.0 g (51% of theory)