Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]2[S:6][CH:7]=[C:8]([CH2:9][N:10]3[CH2:14][CH2:13][N:12]([C:15]4[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=4)[C:11]3=[O:24])[C:4]=2[CH:3]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.[NH2:57][CH2:58][C:59]1[CH:60]=[N:61][CH:62]=[CH:63][CH:64]=1>CN(C)C=O>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]2[S:6][CH:7]=[C:8]([CH2:9][N:10]3[CH2:14][CH2:13][N:12]([C:15]4[S:16][C:17]([C:21]([NH:57][CH2:58][C:59]5[CH:60]=[N:61][CH:62]=[CH:63][CH:64]=5)=[O:23])=[C:18]([CH3:20])[N:19]=4)[C:11]3=[O:24])[C:4]=2[CH:3]=1
Reactant: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
To a solution of 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid (0.55 g, 1.35 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added 1-hydroxy benzotriazole (0.22 g, 1.62 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.31 g, 1.62 mmol), diisopropylethylamine (0.85 mL, 4.87 mmol) and 3-(aminomethyl)pyridine (0.17 mL, 1.62 mmol). The resulting solution was stirred at ambient temperature for 16 hours, then concentrated in vacuo. The residue was dissolved in dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate solution (15 mL) and brine (15 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography eluted with 55-75% ethyl acetate in hexanes to afford the title compound as a colorless solid in 45% yield (0.30 g): mp 185-187° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.61 (s, 1H), 8.54 (d, J=6.0 Hz, 1H), 7.87 (s, 1H), 7.78 (d, J=6.0 Hz, 1H), 7.70 (d, J=9.0 Hz, 1H), 7.45 (s, 1H), 7.36-7.28 (m, 2H), 6.09 (br s, 1H), 4.70 (s, 2H), 4.60 (d, J=3.0 Hz, 2H), 4.06 (t, J=6.0 Hz, 2H), 3.47 (t, J=6.0 Hz, 2H), 2.61 (s, 3H); MS (ES+) m/z 498.1 (M+1).
Reaction SMILES: [C:1]([N:4]1[C@H:10]([CH3:11])[CH2:9][C:8]2[CH:12]=[C:13]3[O:18][CH2:17][O:16][C:14]3=[CH:15][C:7]=2[C:6]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)=[N:5]1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd].O.C(O)C>[C:1]([N:4]1[C@H:10]([CH3:11])[CH2:9][C:8]2[CH:12]=[C:13]3[O:18][CH2:17][O:16][C:14]3=[CH:15][C:7]=2[C:6]([C:19]2[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2C[C@H]1C)OCO3
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CC(=O)N1N=C(c2ccc(N)cc2)c2cc3c(cc2C[C@H]1C)OCO3
Yield: 88.4 %

Procedure:
(R)-7-acetyl-8,9-dihydro-8-methyl-5-(4-nitrophenyl)-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine (38.93 g) was hydrogenated in 730 mL (19 volumes) of 2B-3 ethanol using 7.79 g of 10% palladium on carbon and 1 atmosphere of hydrogen. When HPLC analysis indicated that starting material had been consumed, the catalyst was removed by filtration and the filtrate was evaporated to afford 38.7 g of crude product. The crude product was dissolved in 220 ML (5.7 volumes) of 1:1 water/ethanol by heating to reflux. The mixture was allowed to cool and the product precipitated near room temperature. The resulting thick, poorly stirring, slurry was stirred at room temperature and then cooled in an ice/water bath. The solid was isolated by filtration and dried in a vacuum oven at 55° C. overnight to afford 31.6 g of purified product. A second recrystallization using the same conditions afforded 28.7 g (30%) of product after drying under vacuum for 3 days at 65° C. and 3 days at room temperature. The product dried very slowly and 1.6% ethanol was still on the sample at this point. Analysis by X-ray diffraction (XRD), solid state NMR (SSNMR) and differential scanning calorimetry (DSC) indicated that the Form I polymorph was formed.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:25])[NH:15][C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=2[Br:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:28](I)[CH3:29]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:25])[N:15]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=2[Br:24])[CH2:28][CH3:29])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: COc1ccc(Br)c(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)C1CCN(C(=O)OC(C)(C)C)CC1)c1cc(OC)ccc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-(2-Bromo-5-methoxy-phenylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.21 mmol) was dissolved in dry N,N-dimethylformamide (5.0 mL). To the reaction mixture was then added at 0° C. sodium hydride (60% in mineral oil, 60.0 mg, 1.45 mmol) under nitrogen atmosphere and the reaction mixture was stirred at 0° C. for one hour. To the reaction mixture was then added at 0° C., ethyl iodide (0.226 g, 1.45 mmol). The reaction mixture was stirred at 0° C. for one hour, then at room temperature under nitrogen atmosphere for 18 hours. The reaction mixture was then added into an excess of water-ice and a solid precipitated. The solid was filtered by suction, washed with water and dried to yield a crude solid. The crude solid was purified via flash chromatography (25% ethyl acetate/hexanes) to yield the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]2[CH:20]=[CH:21][N:22]=[C:16]2[CH2:15]1)=[O:13].Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>O1CCOCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)C>[Cl:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]2[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[CH:21][N:22]=[C:16]2[CH2:15]1)=[O:13]
Reactant: Cc1ccccc1Br
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2ccnc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1ccccc1-c1cnc2n1CCN(C(=O)c1cccc(C(F)(F)F)c1Cl)C2
Temperature: 90 °C
Yield: 5.9 %

Procedure:
7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (0.330 g, 1 mmol, Example 1), 1-bromo-2-methylbenzene (0.132 mL, 1.100 mmol), palladium(II)acetate (0.011 g, 0.050 mmol), triphenylphosphine (0.026 g, 0.100 mmol) and cesium carbonate (0.342 g, 1.050 mmol) were suspended in 1,4-dioxane (5 ml) under argon. The mixture was degassed 3 times and heated at 90° C. for 16 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (50 ml) and water (50 ml). The aqueous phase was extracted with ethyl acetate (2×50 ml), the combined organic extracts were washed with water (3×50 ml), brine (50 ml) dried over anhydrous sodium sulfate and concentrated to a crude oil. The crude oil was purified by mass-directed automated preparative HPLC to afford the free base that was dissolved in dichloromethane (5 ml) and treated with 4N HCl in dioxane. The solvents were removed in vacuo and the solid tritruated with diethyl ether to afford 7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (0.027 g, 0.059 mmol, 5.92% yield).
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([O:6][C:7]([C@:9]1([NH2:31])[C@H:14]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:13][C@@H:12]2[C@H:10]1[C@@:11]2([F:30])[C:25]([O:27]CC)=[O:26])=[O:8])[CH3:5].Cl>O1CCCC1.O>[CH3:5][CH2:4][O:6][C:7]([C@:9]1([NH2:31])[C@H:14]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:13][C@@H:12]2[C@H:10]1[C@@:11]2([F:30])[C:25]([OH:27])=[O:26])=[O:8]
Reactant: CCOC(=O)[C@@]1(N)[C@H]2[C@@H](C[C@H]1SCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@@]1(N)[C@H]2[C@@H](C[C@H]1SCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)O
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
17 mg of lithium hydroxide monohydrate was added to 150 mg of (1R,2S,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylsulfanyl)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in a mixture of 3.5 mL tetrahydrofuran and 1.7 mL of water, and the mixture was stirred for 30 minutes at ice-cooling. The mixture was acidified to pH 2 with 1N hydrochloric acid, diluted with 30 mL of water, and then stirred for 30 minutes at ice-cooling. This diluted solution was purified by ion exchange resin (AG 50W-X8 Resin (H form), eluent: water, a 30% aqueous solution of tetrahydrofuran and a 10% aqueous solution of pyridine), thereby yielding 73 mg of (1R,2S,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylsulfanyl)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[CH2:20][C:21]([OH:23])=[O:22])([O-:12])=[O:11].C(N(CC)CC)C>C(OC(=O)C)(=O)C>[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[C:20](=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)[C:21]([OH:23])=[O:22])([O-:12])=[O:11]
Reactant: Cc1ccc([N+](=O)[O-])c(CC(=O)O)c1
Reactant: O=Cc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc([N+](=O)[O-])c(C(=Cc2ccc(Br)cc2)C(=O)O)c1
Temperature: 40 °C
Yield: 98.6 %

Procedure:
To a mixture of 4-bromobenzaldehyde (19.5 g, 106 mmol) and 2-nitro-5-methyl-phenylacetic acid (20.6 g, 106 mmol; J. G. Atkinson et. al., Tetrahedron Lett., 2857, 1979) in 100 ml of acetic anhydride was added triethylamine (14.7 ml, 106 mmol) and the resulting reddish solution was heated at 40° C. for 70 hours. Most of the acetic anhydride was evaporated under vacuum and the residue was diluted with ethyl acetate and washed with sat. NH4Cl, H2O, and brine. Drying (MgSO4) and evaporation yielded 37.87 g (99%) of product as a yellow solid which was used in the next reaction without purification.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[OH:8].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>C(OC(C)C)(C)C>[CH:9](=[N:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[OH:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: O=Cc1ccccc1
Solvent: O
Solvent: CC(C)OC(C)C
Product: O[C@@H]1CCCC[C@H]1N=Cc1ccccc1

Procedure:
In a 250 ml round bottom flask equipped with a reflux condenser and a Dean-Stark trap, 6.91 g of racemic trans-2-aminocyclohexanol (60 mmol) obtained according to (b) were dissolved under argon in 70 ml of diisopropyl ether and 6.1 ml of benzaldehyde (60 mmol) were added to the solution which was refluxed under argon at 110° C. during 50 min until about 1 ml of water separated. The solvent was removed in a rotary evaporator (45° C./250-10 mbar) to obtain 12.11 g of white-beige crystals of racemic trans-2-(benzylidenamino)-cyclohexanol, m.p. 86° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]3=[N:10][C:9]=2[C:18]2[CH:19]=[C:20]([CH:32]=[CH:33][CH:34]=2)[C:21]([NH:23][C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[O:22])[CH:5]=[CH:4][N:3]=1.[F:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][N:41]([CH:44]2[CH2:49][CH2:48][N:47]([C:50]3[CH:56]=[CH:55][C:53]([NH2:54])=[C:52]([O:57][CH3:58])[CH:51]=3)[CH2:46][CH2:45]2)[CH2:40][CH2:39]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>FC(F)(F)CO.CO.C(Cl)Cl.CCCCCC>[F:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([F:30])[C:24]=1[NH:23][C:21](=[O:22])[C:20]1[CH:32]=[CH:33][CH:34]=[C:18]([C:9]2[N:10]=[C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:54][C:53]3[CH:55]=[CH:56][C:50]([N:47]4[CH2:46][CH2:45][CH:44]([N:41]5[CH2:40][CH2:39][N:38]([CH2:37][CH2:36][F:35])[CH2:43][CH2:42]5)[CH2:49][CH2:48]4)=[CH:51][C:52]=3[O:57][CH3:58])[N:7]=2)[CH:19]=1
Reactant: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)ccc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3cc(F)ccn3c2-c2ccnc(Cl)n2)c1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3cc(F)ccn23)n1
Temperature: 150 °C
Yield: 52.6 %

Procedure:
To 3-[3-(2-chloro-4-pyrimidinyl)-7-fluoroimidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluoro-phenyl)benzamide (100 mg, 0.21 mmol) and 4-{4-[4-(2-fluoroethyl)-1-piperazinyl]-1-piperidinyl}-2-(methyloxy)aniline (Example 59, step E) (63 mg, 0.19 mmol) in 2,2,2-trifluoroethanol (2 mL) was added p-toluenesulfonic acid monohydrate (135 mg, 0.71 mmol). The mixture was stirred and heated on a microwave at 150° C. for 30 minutes, then cooled to room temperature. The mixture was neutralized with 0.5M sodium methoxide in MeOH. The mixture was concentrated under vacuum and the residue purified by silica gel chromatography to give a yellow oil. The oil was dissolved in minimal DCM, then hexane was added until a precipitate was formed. The slurry was cooled at −10° C. for 30 min, then poured through a Teflon filter, washing the solids with cold hexanes. The solids were dried under vacuum to give the title compound (81 mg, 0.10 mmol, 55%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ10.24 (s, 1H), 9.47 (brs, 1H), 8.51 (s, 1H), 8.32 (s, 1H), 8.20 (d, 1H, J=5.32 Hz), 8.06 (d, 1H, J=7.70 Hz), 7.81 (d, 1H, J=7.70 Hz), 7.59-7.64 (m, 2H), 7.34-7.44 (m, 2H), 7.21 (t, 2H, J=8.06 Hz), 7.02-7.08 (m, 1H), 6.69 (d, 1H, J=2.20 Hz), 6.43-6.51 (m, 2H), 4.57 (t, 1H, J=4.95 Hz), 4.45 (t, 1H, J=4.86 Hz), 3.80 (s, 3H), 3.71-3.77 (m, 2H), 2.59-2.70 (m, 4H), 2.40-2.46 (m, 8H), 2.26-2.34 (m, 1H), 1.81-1.87 (m, 2H), 1.46-1.56 (m, 2H). MS (ESI): 780 [M+H]+.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:32])[C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([N:14]2[CH2:19][CH2:18][C@:17]([CH2:26][C:27]([OH:30])([CH3:29])[CH3:28])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:16][C:15]2=[O:31])[CH3:13])=[CH:8][CH:7]=1>O1CCCC1>[OH:30][C:27]([CH3:28])([CH3:29])[CH2:26][C@@:17]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:16][C:15](=[O:31])[N:14]([C@H:12]([C:9]2[CH:10]=[CH:11][C:6]([C:5]([OH:32])=[O:4])=[CH:7][CH:8]=2)[CH3:13])[CH2:19][CH2:18]1
Reactant: COC(=O)c1ccc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(C(=O)O)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1 M aqueous NaOH solution (5 mL) was added to a solution of 4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-benzoic acid methyl ester (0.73 g) in tetrahydrofuran (5 mL). The resulting solution was stirred at room temperature overnight. Then, the solution was concentrated and the residue was taken up in water and filtered. The aqueous filtrate was acidified with 1 M hydrochloric acid and the resulting mixture was extracted with ethyl acetate. The combined extracts were washed with brine and dried (MgSO4). The solvent was removed to afford the title compound as a foam-like solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[S:6][C:7]([C:11]([OH:13])=O)=[C:8]([CH3:10])[N:9]=2)[CH2:3][CH2:2]1.C1(NC2SC(C(Cl)=O)=C(C)N=2)CC1.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.[NH2:34][CH:35]([C:38]1[S:39][CH:40]=[CH:41][CH:42]=1)[C:36]#[N:37]>C(N(CC)CC)C>[C:36]([CH:35]([NH:34][C:11]([C:7]1[S:6][C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[N:9][C:8]=1[CH3:10])=[O:13])[C:38]1[S:39][CH:40]=[CH:41][CH:42]=1)#[N:37]
Reactant: Cc1nc(NC2CC2)sc1C(=O)O
Reactant: N#CC(N)c1cccs1
Agent: Cc1nc(NC2CC2)sc1C(=O)Cl
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc(NC2CC2)sc1C(=O)NC(C#N)c1cccs1
Yield: 36.6 %

Procedure:
1.7g of 2-cyclopropylamino-4-methyl-thiazole-5-carboxylic acid was converted into 2-cyclopropylamino-4-methyl-thiazole-5-carboxylic acid chloride using 1.9g of phosphorus pentachloride according to the same procedure as EXAMPLE 1. Then 1.7g of amino-thiophen-2-yl-acetonitrile hydrochloride and 3.9ml of triethylamine were added thereto and the reaction mixture was treated according to the same procedure as EXAMPLE 1 to obtain 1.0g (Yield 39%) of the title compound.
Reaction SMILES: C([O:5][C@@H:6]1[C@:14]2([CH2:15][CH3:16])[C@H:9]([C@@H:10]3[CH2:24][CH2:23][C:22]4[CH:21]=[C:20]([O:25][CH3:26])[CH:19]=[CH:18][C:17]=4[C@H:11]3[CH2:12][CH2:13]2)[CH2:8][CH2:7]1)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[OH:5][C@@H:6]1[C@:14]2([CH2:15][CH3:16])[C@H:9]([C@@H:10]3[CH2:24][CH2:23][C:22]4[CH:21]=[C:20]([O:25][CH3:26])[CH:19]=[CH:18][C:17]=4[C@H:11]3[CH2:12][CH2:13]2)[CH2:8][CH2:7]1
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@H]2OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Yield: 103.4 %

Procedure:
A solution of 0.4 g (1.12 mmoles) of (+)-17β-tert.butoxy-13 β-ethyl-3-methoxygona-1,3,5(10)-triene and 0.1 g of p-toluenesulfonic acid monohydrate in 10 ml of toluene was stirred and heated at reflux for 1 hr. The resulting solution was cooled and treated with saturated aqueous sodium bicarbonate solution then extracted twice with ether. The combined organic extracts were dried, filtered and concentrated in vacuo giving 0.348 g of (+)-17β-hydroxy-13β-ethyl-3-methoxygona-1,3,5(10)-triene as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[C:3]1[CH:10]=[O:11].[BH4-].[Na+].O>C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[C:3]1[CH2:10][OH:11]
Reactant: Cn1cc([N+](=O)[O-])cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cn1cc([N+](=O)[O-])cc1CO
Reaction time: 0.33 h
Yield: 97.9 %

Procedure:
1-Methyl-4-nitro-1H-pyrrole-2-carbaldehyde (0.400 g, 2.08 mmol; see step (i) above) was placed in 50 mL of anhydrous ethanol under N2. NaBH4 (0.040 g, 1.04 mmol) was added in small portions over 5 min and the solution allowed to stir for 20 min. Water (10 mL) was added slowly to quench the reaction. The organics were then extracted with ethyl acetate (2×20 mL) and the resultant organic fractions dried (MgSO4), filtered and the solvent removed under reduced pressure to yield the sub-title compound as a light brown solid (0.318 g, 98%).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:16][CH3:17])=[C:13]([F:15])[CH:14]=2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20](=[O:43])[CH2:21][CH:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[CH3:18][O:19][C:20](=[O:43])[CH2:21][CH:22]1[CH2:23][CH2:24][CH:25]([C:28]2[CH:29]=[CH:30][C:31]([C:2]3[CH:3]=[CH:4][C:5]([NH:8][C:9]4[CH:10]=[N:11][C:12]([O:16][CH3:17])=[C:13]([F:15])[CH:14]=4)=[CH:6][N:7]=3)=[CH:32][CH:33]=2)[CH2:26][CH2:27]1
Reactant: COC(=O)CC1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: COc1ncc(Nc2ccc(Br)nc2)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)CC1CCC(c2ccc(-c3ccc(Nc4cnc(OC)c(F)c4)cn3)cc2)CC1
Temperature: 80 °C

Procedure:
To a solution of (6-bromo-pyridin-3-yl)-(5-fluoro-6-methoxy-pyridin-3-yl)-amine (0.17 g, 0.6 mmol, 1.0 equiv) and {4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (0.22 g, 0.6 mmol, 1.0 equiv) in 15 Ml DME was added 1 Ml saturated sodium carbonate solution followed by 10 mg Pd(PPh3)4 catalyst. The reaction was then heated to 80° C. overnight. Removal of volatiles in vacuo followed by silica gel chromatography (20% EtOAc in hexanes) afforded the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93-1.08 (m, 1 H) 1.01 (d, J=2.78 Hz, 1 H) 1.31-1.52 (m, 3. H) 1.62 (s, 2 H) 1.69 (d, J=9.85 Hz, 4 H) 2.02 (d, J=7.07 Hz, 2 H) 3.81 (s, 3 H) 7.28 (d, J=8.34 Hz, 2 H) 7.58 (d, J=13.89 Hz, 1 H) 7.75 (d, J=8.34 Hz, 3 H) 7.70 (d, J=8.59 Hz, 1 H) 7.81 (d, J=2.27 Hz, 1 H) 7.89 (d, J=8.84 Hz, 1 H) 8.15 (s, 1 H) 9.04 (br. S., 1 H); (M+H)+ 450.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:14]([C:15]([OH:17])=O)[CH2:13][CH2:12][CH:11]2[CH:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:19][C@H:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)[CH3:21]>>[CH3:29][O:28][C:26]([C:25]1[CH:30]=[CH:31][C:22]([C@@H:20]([NH:19][C:15]([C@H:14]2[CH2:13][CH2:12][CH:11]3[CH:9]([CH2:10]3)[N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:17])[CH3:21])=[CH:23][CH:24]=1)=[O:27]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: CC(C)(C)OC(=O)N1C2CC2CC[C@@H]1C(=O)O
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCC3CC3N2C(=O)OC(C)(C)C)cc1
Yield: 27.6 %

Procedure:
The title compound (D71) (46 mg) was prepared according to the general procedure for amides preparation (Method C) starting from (3R)-2-(tert-butoxycarbonyl)-2-azabicyclo[4.1.0]heptane-3-carboxylic acid (D22) (100 mg) and (S)-methyl 4-(1-aminoethyl)benzoate hydrochloride (115 mg). Reaction time: 1 h
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18]([O:20]CCC)=O.[NH2:24][C:25]1[S:26][C:27]2[CH2:33][CH2:32][CH2:31][CH2:30][C:28]=2[N:29]=1>>[OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:15])(=[O:16])[N:4]([CH3:17])[C:3]=1[C:18]([NH:24][C:25]1[S:26][C:27]2[CH2:33][CH2:32][CH2:31][CH2:30][C:28]=2[N:29]=1)=[O:20]
Reactant: CCCOC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Reactant: Nc1nc2c(s1)CCCC2
Product: CN1C(C(=O)Nc2nc3c(s2)CCCC3)=C(O)c2sc3ccccc3c2S1(=O)=O
Yield: 58 %

Procedure:
Prepared analogous to Example 1 from propyl 4-hydroxy-2-methyl-2H-[1] benzothieno [2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 2-amino-4,5,6,7-tetrahydrobenzothiazole with a yield of 58% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[N:15]1([CH2:20][CH2:21][NH2:22])[CH:19]=[CH:18][CH:17]=[CH:16]1>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]2[NH:22][CH2:21][CH2:20][N:15]3[CH:19]=[CH:18][CH:17]=[C:16]23)[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]
Reactant: NCCn1cccc1
Reactant: COc1cc(C=O)cc(OC)c1OC
Solvent: CC(=O)O
Product: COc1cc(C2NCCn3cccc32)cc(OC)c1OC
Yield: 62.5 %

Procedure:
A solution of 3,4,5-trimethoxybenzaldehyde (19.6 g) and 2-(1H-pyrrol-1-yl)ethanamine (11 g, described in Example 7) in acetic acid (250 ml) is stirred at room temperature for 48 hr and evaporated under reduced pressure. The residue is partitioned between chloroform and 10% sodium carbonate and the organic phase is separated, washed with water, dried over magnesium sulfate, filtered and evaporated to give 18 g of the title compound, nmr(CDCl3) δ (2.40(s), 3.35(m), 3.84(s), 3.92(m), 5.03(s), 5.65(m), 6.12(t), 6.61(m) and 6.70(s).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[N:12]=[C:11]2[C:6]([C:7](O)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:7]1[CH:8]=[CH:9][N:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:14])[F:1])=[N:12]2
Reactant: Oc1ccnc2nc(C(F)(F)F)ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Temperature: 25 °C
Yield: 77 %

Procedure:
7-Trifluoromethyl[1,8]naphthyridin-4-ol (2.00 g, 9.34 mmol) was added in portions to phosphorus oxychloride with stirring at room temperature—a mild exotherm was observed. The mixture was stirred at room temperature under nitrogen overnight. The solvent was removed in vacuo, and saturated sodium hydrogencarbonate solution was added with ice-bath cooling to the residual material with stirring, until the pH of the mixture was ˜7. The mixture was extracted with dichloromethane (3×50 mL), then the combined organic layers were dried over magnesium sulfate, and were concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, eluting with 25% ethyl acetate in dichloromethane, yielding 5-chloro-2-trifluoromethyl-[1,8]naphthyridine as an off-white solid (1.67 g, 77%). δH (360 MHz, CDCl3) 7.72 (1H, d, J 4.6), 7.96 (1H, d, J 8.8), 8.86 (1H, d, J 8.4), 9.15 (1H, d, J 4.6). m/z (ES+) 233, 235 [MH]+.