Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].IC.[CH3:27]N(C)C(=O)C>C1COCC1>[CH3:27][CH:8]([CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10]
Reactant: CC(=O)N(C)C
Reactant: O=C(CC(c1ccccc1)c1ccccc1)c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C(=O)c1ccncc1)C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3,3-diphenyl-1-pyridin-4-yl-propan-1-one (200 mg, example 14, step 1) in THF (11 ml) was added NaH (33 mg as a 55% suspension in mineral oil) at room temperature. The mixture was stirred for 1.5 h and placed in an ice bath. Iodomethane (109 mg) was added. The mixture was stirred for 1 h at 0° C. and for 2 h at room temperature. N,N-dimethylacetamide (0.5 ml) was added and the mixture was stirred overnight at room temperature. Ice water was added and the mixture was extracted with ethyl acetate. The organic phase was dried using MgSO4, filtered and concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 1:0 to 0:1) to give the title compound (148 mg) as an off-white solid, MS (ESI+): m/z=302.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([F:22])([F:21])[C:6]([F:20])([F:19])[C:7]([F:18])([F:17])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH3:2].[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:27](O)=[O:28]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:27]([O:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:8][C:7]([F:17])([F:18])[C:6]([F:19])([F:20])[C:5]([F:21])([F:22])[CH2:4][O:3][CH2:1][CH3:2])=[CH:11][CH:12]=1)=[O:28]
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1Cl
Reactant: CCOCC(F)(F)C(F)(F)C(F)(F)COc1ccc(O)cc1
Product: CCCCCCCCOc1ccc(C(=O)Oc2ccc(OCC(F)(F)C(F)(F)C(F)(F)COCC)cc2)cc1Cl

Procedure:
4-(5-Ethoxy-2,2,3,3,4,4-hexafluoropentoxy)phenyl 3-chloro-4-octyloxybenzoate (Compound 5, Table 1) was prepared by esterification of 4-(5-ethoxy-2,2,3,3,4,4-hexafluoropentoxy)phenol (prepared essentially as in Example 4) with 3-chloro-4-octyloxybenzoic acid.
Reaction SMILES: Cl.[CH:2]1([NH:8][CH2:9][C:10]([OH:12])=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([O:23][C:24](Cl)=[O:25])[CH:20]([CH3:22])[CH3:21]>C(#N)C.O>[CH2:19]([O:23][C:24]([N:8]([CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)[CH2:9][C:10]([OH:12])=[O:11])=[O:25])[CH:20]([CH3:22])[CH3:21]
Reactant: O=C(O)CNC1CCCCC1
Reactant: CC(C)COC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)COC(=O)N(CC(=O)O)C1CCCCC1
Reaction time: 17 h
Yield: 93.6 %

Procedure:
To a solution of the commercially available cyclohexylglycine hydrochloride (15 g, 77.4 mmol) in acetonitrile (320 ml) and water (320 ml) was added potassium carbonate. Isobutylchloroformate (11.1 ml, 85.1 mmol) was added to the clear solution over 15 minutes and the reaction was stirred for 17 hours. The acetonitrile was removed under reduced pressure and the remaining aqueous layer was extracted twice with ether (100 ml). The aqueous layer was then acidified to pH 1 with 6N hydrochloric acid and extracted with dichloromethane (3×300 ml). The organic layer was dried over sodium sulfate, filtered and concentrated to yield 18.64 g (94%) product as a white solid.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]1[NH:21][CH:22]=[C:23]([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[CH:31]=[C:30]([C:35]2[CH:40]=[CH:39][C:38]([C:41]4[NH:45][C:44]([C@@H:46]5[CH2:50][CH2:49][CH2:48][N:47]5C(OC(C)(C)C)=O)=[N:43][CH:42]=4)=[CH:37][CH:36]=2)[CH:29]=[CH:28]3)[N:24]=1)=O)(C)(C)C>C(Cl)Cl>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[NH:47]1[CH2:48][CH2:49][CH2:50][C@H:46]1[C:44]1[NH:45][C:41]([C:38]2[CH:39]=[CH:40][C:35]([C:30]3[CH:29]=[CH:28][C:27]4[C:32](=[CH:33][CH:34]=[C:25]([C:23]5[NH:24][C:20]([C@@H:16]6[CH2:17][CH2:18][CH2:19][NH:15]6)=[N:21][CH:22]=5)[CH:26]=4)[CH:31]=3)=[CH:36][CH:37]=2)=[CH:42][N:43]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)c[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc(-c2cnc([C@@H]3CCCN3)[nH]2)ccc1-c1ccc2cc(-c3cnc([C@@H]4CCCN4)[nH]3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of a TFA salt of (S)-tert-butyl 2-(5-(4-(6-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (50 mg) in DCM (10 mL) was added TFA (2.0 mL, 26 mmol) in one portion. The mixture was agitated at room temperature for 2 h. The reaction was concentrated under vacuum to yield a TFA salt of 2-((S)-pyrrolidin-2-yl)-5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazole (51.5 mg) as orange solid, which was used without further purification. LC-MS retention time 0.978 min; m/z 475.19 [M+H]+. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min and an analysis time of 4 min where Solvent A was 10% acetonitrile/90% water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. HPLC-MS (TFA) 78457-087 using a Waters Sunfire C18 column 4 6×50 mm 5u showed the reaction was complete peak found at RT=0.978 min. MH+=475.19. 1H NMR (500 MHz, MeOD) δ ppm 8.34 (s, 1H), 8.20 (s, 1H), 8.03 (dd, J=14.2, 8.7 Hz, 2H), 7.84-7.96 (m, 7H), 7.79-7.84 (m, 1H), 4.99-5.11 (m, 2H), 3.48-3.63 (m, 4H), 2.57-2.70 (m, 2H), 2.41-2.55 (m, 2H), 2.29-2.41 (m, 2H), 2.15-2.29 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]2[CH2:12][NH:11][C:10](=[O:13])[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.I[CH3:15].[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[C:7]([CH:8]2[CH2:12][N:11]([CH3:15])[C:10](=[O:13])[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C1CC(c2cccnc2F)CN1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CC(c2cccnc2F)CC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
To a solution of 4-(2-fluoropyridin-3-yl)pyrrolidin-2-one (0.254 g, 1.41 mmol) in DMF (5 mL) at 0° C. was added iodomethane (0.090 mL, 1.4 mmol) and sodium hydride (60% weight dispersion in mineral oil, 0.056 g, 1.4 mmol). The reaction mixture was stirred at 0° C. for 30 min, warmed to room temperature, and stirred for 30 min. The reaction mixture was diluted with EtOAc, quenched with water, and diluted with brine and water. The aqueous phase was extracted with EtOAc (6×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (50% to 100% EtOAc (10% MeOH) in hexanes) gave 4-(2-fluoropyridin-3-yl)-1-methylpyrrolidin-2-one (0.226 g, 1.16 mmol, 83% yield) as a pale yellow oil. MS (ESI, pos. ion) m/z: 195.1 (M+1).
Reaction SMILES: Cl[CH2:2][C@@:3]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15])([OH:7])[C@H:4]([OH:6])[CH3:5].C[O-].[Na+].O>CO>[O:7]1[C@@:3]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[F:15])([C@H:4]([OH:6])[CH3:5])[CH2:2]1
Reactant: C[C@@H](O)[C@](O)(CCl)c1ccc(F)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A solution of 0.12 g (0.45 mmol) of (2S,3R)-1-chloro-2-(2,4-difluorophenyl)butane-2,3-diol in 3 mL of methanol was cooled in ice, and 0.12 g (0.6 mmol) of a 28% solution of NaOMe in methanol was added. Reaction was performed for 2 hours, and 10 mL of water was added to stop the reaction. Extraction was performed with ethylacetate (10 mL). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain a crude product. The resulting crude product was purified by column on silica gel to obtain 0.09 g of the title compound (yield: 96%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:24]2[CH2:28][CH:27]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[O:26][C:25]2=[O:34])[CH:5]=[CH:6][C:7]=1[C:8]([CH2:10][O:11][CH:12]1[CH2:17][O:16][C:15]2=[N:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][N:14]2[CH2:13]1)=C.C[OH:36]>O=[Os](=O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]([N:24]2[CH2:28][CH:27]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[O:26][C:25]2=[O:34])[CH:5]=[CH:6][C:7]=1[C:8](=[O:36])[CH2:10][O:11][CH:12]1[CH2:17][O:16][C:15]2=[N:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][N:14]2[CH2:13]1
Reactant: CO
Reactant: C=C(COC1COc2nc([N+](=O)[O-])cn2C1)c1ccc(N2CC(CNC(C)=O)OC2=O)cc1F
Agent: O=[Os](=O)(=O)=O
Product: CC(=O)NCC1CN(c2ccc(C(=O)COC3COc4nc([N+](=O)[O-])cn4C3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-(3-{3-Fluoro-4-[1-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxymethyl)-vinyl]-phenyl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide (48 mg) was dissolved in 1.5 mL methanol, followed by addition of NaIO4 (54 mg) and OsO4 (0.02 mL, 2.5% in water). The solution was stirred at room temperature for 4 hours and then Celite (500 mg) was added. The resulting mixture was stirred for 30 min before it was filtered and washed with EtOAc. The organic layer was dried over Na2SO4 and purified with preparative TLC (CH2Cl2/MeOH, v/v, 10/1). The titled compound was obtained as yellow solid (8 mg). ESI MS m/z 478 (M+H). 1H NMR (400 MHz, MeCN-d3) 8.06 (t, J=8.4 Hz, 1H), 7.74 (s, 1H), 7.69 (dd, J=14.0, 2.0 Hz, 1H), 7.52 (dd, J=8.8, 2.4 Hz, 1H), 6.84 (b, 1H), 4.95-5.00 (m, 2H), 4.83-4.92 (m, 1H), 4.78 (dt, J=12.0, 2.8 Hz, 1H), 4.53 (d, J=12.8 Hz, 1H), 4.41 (dt, J=12.8, 2.0 Hz, 1H), 4.30-4.35 (m, 1H), 4.29 (dd, J=12.8, 3.2 Hz, 1H), 4.21 (t, J=9.2 Hz, 1H), 3.89 (dd, J=9.2, 6.4 Hz, 1H), 3.58-3.68 (m, 2H), 3.39 (d, J=5.2 Hz, 1H), 1.98 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH:18]([NH:21][CH2:22][CH2:23][NH2:24])([CH3:20])[CH3:19]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:24][CH2:23][CH2:22][NH:21][CH:18]([CH3:20])[CH3:19])[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: CC(C)NCCN
Solvent: COCCOC
Product: CC(C)NCCNc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and N-isopropylethylenediamine in DME. ES-MS m/e (%): 287 (M+H+, 100), 228 ([M+H-iPrNH2]+, 40).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:9]([CH3:12])([O-:11])=[O:10].[OH-].[Na+].Cl.O>CO>[N+:9]([CH:12]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([O-:11])=[O:10]
Reactant: O=Cc1ccccc1
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])C=Cc1ccccc1
Temperature: 0 °C

Procedure:
Benzaldehyde (2, 52.35 g, 0.493 mol) and nitromethane (30.11 g, 0.493 mol) were dissolved in methanol (100 mL) in a two-necked flask equipped with a thermometer and a pressure-equalizing dropping funnel. NaOH (25.6 g, 0.641 mol) in ice/water (50 mL) was added dropwise to the solution keeping the temperature below 15° C. A fine slurry formed during the addition and methanol was added to allow stirring. After the addition the slurry was diluted with ice/water and the resulting clear solution was added dropwise to a solution of conc. HCl/H2O (200/300 ml); a yellow precipitate was formed during the addition. The precipitate was filtered on a buchner funnel, washed with water and crystallized from methanol obtaining pure 3 (58.78 g, 80%). Yellow needles. M.p. 57-58° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:11])[CH3:10].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[F:24][C:25]([F:32])([F:31])[C:26](OCC)=[O:27]>C1COCC1>[F:24][C:25]([F:32])([F:31])[C:26](=[O:27])[CH2:10][C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:12])([F:13])[F:1])=[O:11]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1ccccc1C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(CC(=O)C(F)(F)F)c1ccccc1C(F)(F)F
Temperature: -78 °C
Yield: 98.5 %

Procedure:
To a stirred solution of 2′-trifluoromethyl-acetophenone (225 mL, 15.0 mmol) in THF (20 mL, anhyd) at −78° C. added dropwise a 1.0M solution of lithium hexamethyldisilazide (LiHMDS) (15.8 mL, 15.8 mmol). After 1 h the reaction mixture was cooled to −78° C. and charged dropwise with ethyl trifluoroacetate (3.6 mL, 30 mmol). After addition was complete, the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was quenched by slow addition of H2O (20 mL) and concentrated under reduced pressure. The resulting material was transferred to a separatory funnel, diluted with Et2O (60 mL), washed with 1N HCl and brine, then dried (MgSO4) and concentrated to yield the title compound (4.2 g, 99%) as an amber liquid, which was used in the next step without purification. Rf: 0.15 (20% EtOAc/Hex).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:20])([CH3:19])[CH2:9][C@@:10]([C:15]([F:18])([F:17])[F:16])([OH:14])[CH2:11][CH2:12][OH:13])=[C:4]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:20])([CH3:19])[CH2:9][C@:10]([OH:14])([C:15]([F:17])([F:16])[F:18])[CH2:11][CH:12]=[O:13])=[C:4]([S:21]([CH3:24])(=[O:22])=[O:23])[CH:3]=1
Reactant: CC(C)(C[C@@](O)(CCO)C(F)(F)F)c1ccc(Cl)cc1S(C)(=O)=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C[C@@](O)(CC=O)C(F)(F)F)c1ccc(Cl)cc1S(C)(=O)=O
Temperature: 50 °C
Yield: 87.9 %

Procedure:
(R)-5-(4-Chloro-2-methanesulfonylphenyl)-5-methyl-3-trifluoromethylhexane-1,3-diol (27.6 g, 0.07 mol) was dissolved in methylene chloride (400 mL) with mild heating (50° C.). Dess-Martin periodinane (33.1 g, 0.08 mol) was added and the mixture was stirred at room temperature. After 1 hour the reaction was concentrated in vacuo, diluted with 300 mL of diethyl ether and filtered through a plug of CELITE® filter aid. The organic layer was washed with six 100 mL portions of saturated aqueous sodium bicarbonate solution followed by brine and drying over magnesium sulfate. The solution was filtered through CELITE® filter aid and the solvent was evaporated to give a viscous oil. The oil was dissolved in 30% Et2O/hexanes and passed through a plug of silica. Evaporation of the eluent provided (R)-5-(4-chloro-2-methanesulfonylphenyl)-3-hydroxy-5-methyl-3-trifluoromethylhexanal as a viscous oil (23.8 g, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]3[C:14]([CH:21]4[O:25][CH2:24][CH2:23][O:22]4)=[C:15]([C:17]([O:19][CH3:20])=[O:18])[S:16][C:10]=3[C:9]=2[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:4][CH:3]=1.[H-].[Na+].BrC[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>CN(C=O)C>[C:39]([O:38][C:36](=[O:37])[CH2:13][N:12]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:9]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:10]2[S:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[C:14]([CH:21]3[O:25][CH2:24][CH2:23][O:22]3)[C:11]1=2)([CH3:42])([CH3:41])[CH3:40]
Reactant: COC(=O)c1sc2c(C3CCCCC3)c(-c3ccc(Cl)cc3)n(C)c2c1C1OCCO1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc2c(C3CCCCC3)c(-c3ccc(Cl)cc3)n(CC(=O)OC(C)(C)C)c2c1C1OCCO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution (0.23 M) of methyl 5-(4-chlorophenyl)-6-cyclohexyl-3-(1,3-dioxolan-2-yl)-4-methyl-4H-thieno[3,2-b]pyrrole-2-carboxylate in DMF at 0° C. was treated with NaH (2 eq., 60% dispersion in mineral oil), and the suspension was stirred at RT for 30 min, then tert-butyl bromoacetate (4 eq.) was added. The reaction mixture was heated at 50° C. for 3.5 h then it was quenched by addition of aqueous NH4Cl (saturated solution) and diluted with Et2O. The aqueous phase was separated and extracted with Et2O. The combined organic phase was washed sequentially with aqueous HCl (1 N), aqueous NaHCO3 (saturated solution) and brine then dried and evaporated. The residue was purified by flash chromatography on silica gel (1:19 to 1:1 AcOEt/petroleum ether) to afford methyl 4-(2-tert-butoxy-2-oxoethyl)-5-(4-chlorophenyl)-6-cyclohexyl-3-(1,3-dioxolan-2-yl)-4H-thieno[3,2-b]pyrrole-2-carboxylate. This compound was dissolved in DCM and the resulting solution (0.1 M) was treated with TFA (16 eq.). The reaction was stirred at RT for 3 h then solvents were evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel (1:99 to 1:19 MeOH/DCM) to afford the title compound (55%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:13]3[N:12]=[C:11]([NH2:14])[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[N:15]=1.Cl[C:17]([O:19][CH2:20][CH2:21][CH:22]=[CH2:23])=[O:18].[Cl-].[NH4+]>N1C=CC=CC=1>[CH2:20]([O:19][C:17](=[O:18])[NH:14][C:11]1[N:10]=[CH:9][C:8]2[CH2:7][CH2:6][C:5]3[N:15]=[C:2]([CH3:1])[S:3][C:4]=3[C:13]=2[N:12]=1)[CH2:21][CH:22]=[CH2:23]
Reactant: C=CCCOC(=O)Cl
Reactant: Cc1nc2c(s1)-c1nc(N)ncc1CC2
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Product: C=CCCOC(=O)Nc1ncc2c(n1)-c1sc(C)nc1CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.8 %

Procedure:
To 2-methyl-4,5-dihydro-thiazolo[4,5-h]quinazolin-8-ylamine (100 mg, 0.46 mmol) in pyridine (3 mL) was added 3-butenyl chloroformate (68 μL, 74 mg, 0.55 mmol). The mixture was stirred at room temperature for 16 h. Ammonium chloride solution was added (50 mL) and the product was extracted with CH2Cl2 (3×50 mL). The organic extracts were combined, dried, filtered, and concentrated under vacuum to give a yellow solid. Crystallisation from EtOAc afforded the pure title product as yellow crystals (122 mg, 84%): mp 204° C. (dec). Anal. RP-HPLC: tR 14.1 min (0-60% MeCN, purity 100%). 1H-NMR (CDCl3): δ 8.36 (s, 1H, Py-H), 7.49 (brs, 1H, NH), 5.90-5.75 (m, 1H, CH), 5.19-5.07 (m, 2H, CH2), 4.27 (t, 2H, J 6.6, CH2), 3.06 (m, 4H, CH2—CH2), 2.77 (s, 3H, CH3), 2.45 (m, 2H, CH2). MS (ESI+): m/z 339.00 (M+Na)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:16]1[N:17]=[C:18]2[CH:25]=[CH:24][CH:23]=[N:22][C:19]2=[N:20][CH:21]=1)=O)(C)(C)C.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>ClCCl>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:16]1[N:17]=[C:18]2[CH:25]=[CH:24][CH:23]=[N:22][C:19]2=[N:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CNc1cnc2ncccc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cnc2ncc(NCC3CCCCN3)nc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(Pyrido[2,3-b]pyrazin-2-ylaminomethyl)-piperidine-1-carboxylic acid tert butyl ester (0.48 g) was dissolved in dichloromethane (3 ml), cooled (ice bath) and treated with trifluoroacetic acid (2 ml). The mixture was stirred for 3 hours at room temperature, solvent removed at reduced pressure and the residue co-evaporated with toluene to give the title compound (0.45 g).
Reaction SMILES: C([N:5]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6])(C)(C)C.[C:15]([C:23]([OH:25])=O)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:8]([N:6]([C:23]([C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:25])[NH:5][C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:13])([CH3:9])[CH3:7]
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: CC(C)(C)N(N)C(=O)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
N'-t-butyl-N'-benzoylhydrazine (1 g), benzoyl formic acid (0.7 g) and methanesulfonyl chloride (0.7 g) were stirred in toluene (30 ml) and saturated sodium bicarbonate (10 ml) at approximately 5° C. Triethylamine was added slowly, dropwise to the reaction mixture and stirred 1 hour at room temperature. After stirring for 1 hour, the reaction mixture was diluted with toluene (25 ml) and washed with water several times. The organic layers were dried over magnesium sulfate, filtered and the toluene rotavapped off to afford a white solid. After column chromatography, the product was obtained as a white solid in approximately 70% yield.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][N:7]([CH3:29])[C:8]1[N:28]=[C:11]2[CH:12]=[CH:13][C:14]([NH:16][C:17]([C:19]3[N:23]([CH3:24])[N:22]=[CH:21][C:20]=3[C:25](O)=[O:26])=[O:18])=[CH:15][N:10]2[N:9]=1>>[CH3:6][N:7]([CH3:29])[C:8]1[N:28]=[C:11]2[CH:12]=[CH:13][C:14]([NH:16][C:17]([C:19]3[N:23]([CH3:24])[N:22]=[CH:21][C:20]=3[C:25]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:26])=[O:18])=[CH:15][N:10]2[N:9]=1
Reactant: C1CCNC1
Reactant: CN(C)c1nc2ccc(NC(=O)c3c(C(=O)O)cnn3C)cn2n1
Product: CN(C)c1nc2ccc(NC(=O)c3c(C(=O)N4CCCC4)cnn3C)cn2n1

Procedure:
Using pyrrolidine and 5-(2-dimethylamino-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. Light brown solid (120 mg, 61%). MS: m/z=383 (M+H+).
Reaction SMILES: [C:1]1([NH:7][C:8]([CH2:10][C:11]#[N:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[CH3:19][N:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26]>CN(C)C=O>[CH3:19][N:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](=[O:26])[CH:10]([C:8](=[O:9])[NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:11]#[N:12]
Reactant: Cn1cccc1C(=O)Cl
Reactant: N#CCC(=O)Nc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cccc1C(=O)C(C#N)C(=O)Nc1ccccc1
Temperature: 0 °C

Procedure:
To the solution of 4.0 g of phenylcarbamoyl-acetonitrile in 50 ml of dimethylformamide 28 g of potassium tert. butoxide are added while stirring under nitrogen. After 2 hours the resulting suspension is cooled to 5° and 4.0 g of 1-methylpyrrol-2-carboxylic acid chloride (U.S. Pat. No. 3,551,571) are added during 10 minutes. The mixture is stirred for 18 hours at room temperature, poured into 300 ml of ice water and the precipitate formed filtered off. It is washed with water, dried and recrystallized from ethanol, to yield the 1-methyl-β-oxo-α-phenylcarbamoyl-2-pyrrolpropionitrile melting at 172°-174°; it is identical with that obtained according to Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6](/[CH:7]=[CH:8]/[S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6](/[CH:7]=[CH:8]/[S:9]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([F:15])=[CH:17][CH:18]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(/C=C/S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(F)cc1
Product: COc1ccc(/C=C/S(=O)(=O)Nc2ccc(F)cc2)cc1
Yield: 86.4 %

Procedure:
A solution of (E)-4-methoxystyrylsulfonyl chloride (10 mmol) and 4-fluoroaniline (10 mmol) was subjected to General Procedure 1, part B. The title compound, melting point 115-117° C., was obtained 86.4% yield.