Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].CC(C)([O-])C.[K+].[CH:18]([Si:21]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[O:22][CH2:23][CH:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)([CH3:20])[CH3:19].O>O1CCCC1>[CH:34]([Si:21]([CH:18]([CH3:20])[CH3:19])([CH:31]([CH3:33])[CH3:32])[O:22][CH2:23][CH:24]1[CH2:29][CH2:28][C:27](=[CH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:26][CH2:25]1)([CH3:35])[CH3:36]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CC(C)[Si](OCC1CCC(=O)CC1)(C(C)C)C(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C=C1CCC(CO[Si](C(C)C)(C(C)C)C(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
To a solution of 6.37 g (35 mmol) of tri methyl phosphonoacetate in 200 mL of tetrahydrofuran (THF) was added 4.28 g (35 mmol) of potassium tert-butoxide. The reaction mixture was stirred at room temperature for 10 minutes. To the resultant slurry was added a solution of 9.3 g (32.7 mmol) of ketone from step C in 20 mL of THF. The mixture was stirred at room temperature under nitrogen overnight, then poured into water and extracted with three 100 mL portions of ether. The combined organic phases were washed sequentially with water, aqueous saturated sodium bicarbonate, and brine, dried over magnesium sulfate, and concentrated to give 10.8 g (97%) of the title compound as a clear oil which was used without further purification. 1H NMR (500 MHz, CDCl3) δ 5.63 (s, 1H), 3.78 (m, 1H), 3.69 (s, 1H), 3.53 (m, 2H), 2.32 (m, 1H), 2.21(m, 1H), 1.97 (m, 2H), 1.76 (m, 1H), 1.10–1.03 (m 23H).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[S:8][C:7]=2[CH:6]=[CH:5][C:4]=1[C:17]#[N:18].Cl.C1(C)C=CC(S(O[CH:30]([CH3:37])[CH2:31][N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])(=O)=O)=CC=1.C(OCC)(=O)C>CN(C)C=O>[CH2:33]([N:32]([CH2:35][CH3:36])[CH2:31][CH:30]([N:15]1[C:16]2[CH:3]=[C:4]([C:17]#[N:18])[CH:5]=[CH:6][C:7]=2[S:8][C:9]2[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:37])[CH3:34]
Reactant: CCN(CC)CC(C)OS(=O)(=O)c1ccc(C)cc1
Reactant: N#Cc1ccc2c(c1)Nc1ccccc1S2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Temperature: 110 °C
Reaction time: 7 h

Procedure:
Sodium hydride (19.2 g; in 50% strength dispersion in vaseline) is added in the course of 20 minutes to a solution of 2-phenothiazinecarbonitrile (44.86 g) in N,N-dimethylformamide (600 cc). The mixture obtained is then heated to 110° C., after which the solution of 1-diethylamino-2-propyl p-toluenesulphonate hydrochloride prepared above is added in the course of 35 minutes. The reaction mixture is stirred at 110° C. for 7 hours and then diluted, after being cooled, with ethyl acetate (2 liters). The mixture is washed with distilled water (5 ×1 liter). The organic phase is extracted with 4 N hydrochloric acid (240 cc) and the acid aqueous phase is washed with ethyl acetate (750 cc) and then alkalinized medium is then extracted with ethyl acetate (1250 cc). The organic phase is washed with distilled water (3×300 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is stirred in the presence of ethyl ether (100 cc); a precipitate forms and this is filtered off, and the filtrate is purified by chromatography on a column of silica gel (0.2-0.063 mm) (height: 82 cm; diameter: 4.5 cm), eluting with an 80:20 (by volume) mixture (7 liters) of cyclohexane and ethyl acetate and collecting 100-cc fractions. After concentration to dryness under reduced pressure (30 mm Hg., 4 kPa) at 50° C., 10-[(2RS)-1-diethylamino-2-prop-yl]-2-phenothiazinecarbonitrile (6.76 g) is obtained from fractions 4 to 9, and a mixture (8.5 g) of 10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarbonitrile and 10-[(lRS)-2-diethylamino-1-propyl]-2-phenothiazinecarbonitrile is obtained from fractions 10 to 22. The mixture is purified by chromatography on a column of silica gel (0.2-0.063 mm) (height: 67 cm; diameter: 3.0 cm), eluting with an 85:15 (by volume) mixture (3 liters) cyclohexane and ethyl acetate and collecting 50-cc fractions. Fractions 22 to 29 are combined and concentrated to dryness at 50° C. under reduced pressure (30 mm Hg; 4 kPa) to give 10-[(2RS)-1-diethylamino2-propyl]-2-phenothiazinecarbonitrile (2.76 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:16]=[CH:17][CH:18]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2([CH3:13])[CH3:12].ClS([N:30]=[C:31]=O)(=O)=O.CN(C=O)C>C(OCC)(=O)C>[C:31]([C:16]1[N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([C:4]2[CH:5]=[C:6]3[C:10](=[C:2]([F:1])[CH:3]=2)[NH:9][C:8](=[O:11])[C:7]3([CH3:13])[CH3:12])=[CH:18][CH:17]=1)#[N:30]
Reactant: CC(C)(C)OC(=O)n1cccc1-c1cc(F)c2c(c1)C(C)(C)C(=O)N2
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1c(C#N)ccc1-c1cc(F)c2c(c1)C(C)(C)C(=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.5 %

Procedure:
To a stirred solution of tert-butyl 2-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1H-pyrrole-1-carboxylate (1.0 g, 2.9 mmol) was added chlorosulfonylisocyanate (0.28 mL, 3.2 mmol). The mixture was stirred at 25° C. for 2 h then DMF (0.21 mL, 2.9 mmol) was added and the mixture was stirred for an additional 1 h. The mixture was diluted with ethyl acetate and washed with NaHCO3, water, saturated aqueous NaCl, dried over MgSO4, and concentrated. Flash chromatography (2% MeOH/CH2Cl2) afforded 0.23 g (21%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[CH3:11][O:12][C:13](=[O:20])[CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:17]2[CH2:18][CH2:19][CH:14]([C:13]([O:12][CH3:11])=[O:20])[CH2:15][CH2:16]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COC(=O)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C1CCN(Cc2ccc(OC)cc2)CC1
Reaction time: 72 h

Procedure:
4-Methoxybenzyl chloride (1.10 g, 6.98 mmol) was added dropwise to a solution of isonipecotic acid methyl ester (1.00 g, 6.98 mmol) and triethylamine (1.40 g, 14 mmol) in THF (30 ml), and stirring was carried out for 72 h at 60° C. 5% sodium hydrogen carbonate solution (50 ml) was then added to the reaction mixture, and extraction with ethyl acetate (3×50 ml) was carried out. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography with cyclohexane/ethyl acetate (2:1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(N2CCN(c3cnccc3C)C2=O)cc1
Yield: 87.3 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.84650 mmol) was reacted with 4-bromo-benzoic acid methyl ester (182 mg, 0.84650 mmol), 1,4-dioxane (50 mL), copper iodide (16 mg, 0.084650 mmol), trans-1,2-diamino cyclohexane (29 mg, 0.2539 mmol) and potassium carbonate (468 mg, 3.3860 mmol) to afford the crude product. Purification by column chromatography on silica gel (5% MeOH in DCM) afforded 230 mg of 4-[3-(4-Methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzoic acid methyl ester (91.6% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][OH:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:20][C:5]1[C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[N:7][C:2]([NH:21][C:22]2[CH:23]=[C:24]([CH2:25][OH:26])[CH:27]=[CH:28][CH:29]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(CO)c1
Reactant: COc1cccc(CCCNc2nc(Cl)ncc2Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(CCCNc2nc(Nc3cccc(CO)c3)ncc2Cl)c1
Temperature: 100 °C
Yield: 80.9 %

Procedure:
To a solution of 2,5-dichloro-N-[3-(3-methoxyphenyl)propyl]pyrimidin-4-amine (0.70 g, 2.2 mmol) and 3-aminobenzyl alcohol (0.38 g, 3.0 mmol) in 1,4-dioxane (19.1 mL) was added p-toluenesulfonic acid monohydrate (0.16 g, 0.82 mmol). The mixture was heated at 100° C. for 16 hours and the reaction was complete. After cooling, the mixture was filtered under vacuum. The cake was washed with cold EtOAc and then H2O to give the desired product as an off-white powder (0.71 g, 79%). LCMS for C21H24ClN4O2 (M+H)+: m/z=399.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=1[F:20].[F:22][C:23]([F:38])([F:37])[C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[N:32]=1)[C:27](O)=[O:28]>>[F:20][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:12]=1[C:11]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:21])[C:27](=[O:28])[C:26]1[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[N:32]=[C:24]([C:23]([F:38])([F:22])[F:37])[CH:25]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: COC(=O)CNc1cnccc1-c1c(F)cccc1OC
Product: COC(=O)CN(C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1)c1cnccc1-c1c(F)cccc1OC

Procedure:
The title compound was prepared in analogy to example 90, from [4-(2-fluoro-6-methoxy-phenyl)-pyridin-3-ylamino]-acetic acid methyl ester and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 72 hours. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 20:80). Light yellow solid (48%). MS (ESI): m/z=532.109 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([NH2:17])[C:10]([NH2:16])=[CH:11][CH:12]=2)[O:7]1)=[O:5])[CH3:2].[F:18][C:19]([F:24])([F:23])[C:20](O)=O>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[O:7][C:8]2[C:13](=[CH:12][CH:11]=[C:10]3[NH:16][C:20]([C:19]([F:24])([F:23])[F:18])=[N:17][C:9]3=2)[CH2:14][CH2:15]1)=[O:5])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)C1CCc2ccc(N)c(N)c2O1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCc2ccc3[nH]c(C(F)(F)F)nc3c2O1
Yield: 65 %

Procedure:
A solution of ethyl-7,8-diamino-chroman-2-carboxylate (927 mg, 3 mmol) in trifluoroacetic acid (20 mL) was heated to reflux for 6 hours and then concentrated in vacuo to give a residue. The residue was dissolved in ethyl acetate (100 mL) and then washed with saturated NaHCO3 solution (30 mL) and water (2×30 mL), dried over anhydrous Na2SO4. Purification by flash chromatography (30% CH2Cl2-hexanes) afforded 612 mg (65% yield) of the title compound as white solid: mp 134° C.; 1H NMR (400 MHz, CDCl3) :[tautamer a]: δ:1.19 (t, J=7.1, 3H), 2.22 (m, 2H), 2.40 (m, 1H), 2.70 (m, 1H), 4.15 (q, J=7 Hz, 2H), 5.14 (m, 1H), 7.02 (d, J=8.0 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 14.09 (bs, 1H). [tautamer b]: δ1.19 (t, J=7.1, 3H), 2.22 (m, 2H), 2.40 (m, 1H), 2.70 (m, 1H), 4.15 (q, J=7 Hz, 2H), 5.03 (m, 1H), 7.07 (s, 2H), 13.77 (bs, 1H); IR 3450, 3250, 2980, 2600, 1730, 1600, 1500, 1230 cm−1. MS 315 [M+H]+.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]([C@@H:21]2[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[N:22]2[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:18](O)=[O:19])=[CH:13][C:12]=1[F:35].Cl.Cl.[CH3:38][C@H:39]1[C:47]2[C:46]([N:48]3[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]3)=[N:45][CH:44]=[N:43][C:42]=2[C@@H:41]([OH:54])[CH2:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]([C@H:21]2[N:22]([C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])[C:23]([CH3:26])([CH3:27])[CH2:24][CH2:25]2)[C:18]([N:51]2[CH2:52][CH2:53][N:48]([C:46]3[C:47]4[C@H:39]([CH3:38])[CH2:40][C@@H:41]([OH:54])[C:42]=4[N:43]=[CH:44][N:45]=3)[CH2:49][CH2:50]2)=[O:19])=[CH:13][C:12]=1[F:35]
Reactant: C[C@@H]1C[C@H](O)c2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)O)c2ccc(Br)c(F)c2)CCC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Br)c(F)c4)[C@@H]4CCC(C)(C)N4C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
N-Ethyl-N-isopropylpropan-2-amine (0.045 mL, 0.26 mmol) was added to a solution of (S)-2-(4-bromo-3-fluorophenyl)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)acetic acid (0.035 g, 0.081 mmol; prepared analogously to that described in Example B), (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.025 g, 0.081 mmol; see Example 3, Step 12), and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.031 g, 0.081 mmol) in DCM (5 mL). The reaction was stirred overnight at room temperature. The reaction was then quenched with H2O, washed with H2O (3×30 mL), dried with MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography to give (S)-tert-butyl 5-((S)-1-(4-bromo-3-fluorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (23% yield). LCMS (APCI+) 648.2 m/z [M+H]+; Retention time=4.28 minutes.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH2:31]([NH:33][CH2:34][CH2:35][CH3:36])[CH3:32]>>[CH2:31]([N:33]([CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)[CH2:34][CH2:35][CH3:36])[CH3:32]
Reactant: CCCNCC
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1
Product: CCCN(CC)CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1

Procedure:
The product from Example 23D and ethyl(propyl)amine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.84 (m, 1H), 7.74 (d, J=8.1, 2H), 7.58 (m, 2H), 7.53 (d, J=8.1 Hz, 2H), 6.82(s, 1H), 3.32-3.8 (m, 14H), 3.20 (m, 2H), 1.80 (m, 2H), 1.38 (t, J=7.5 Hz, 3H), 1.05 (t, J=7.5 Hz, 3H); MS (DCI) m/z 421 (M+H)+;
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([O:23][CH3:24])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[F:25][C:26]1[CH:34]=[C:33]2[C:29]([C:30]([C:35]3[CH2:36][CH2:37][NH:38][CH2:39][CH:40]=3)=[CH:31][NH:32]2)=[CH:28][CH:27]=1>CS(C)=O.C(OCC)(=O)C>[F:25][C:26]1[CH:34]=[C:33]2[C:29]([C:30]([C:35]3[CH2:36][CH2:37][N:38]([CH2:12][C@H:13]4[CH2:22][CH2:21][C:20]5[C:15](=[C:16]([O:23][CH3:24])[CH:17]=[CH:18][CH:19]=5)[O:14]4)[CH2:39][CH:40]=3)=[CH:31][NH:32]2)=[CH:28][CH:27]=1
Reactant: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: COc1cccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CC2
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1cccc2c1O[C@@H](CN1CC=C(c3c[nH]c4cc(F)ccc34)CC1)CC2
Temperature: 80 °C
Yield: 61.9 %

Procedure:
To a solution of [(2R)-8-methoxy-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.348 g, 1.00 mmol) in methyl sulfoxide (20 mL) was added 6-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.865 g, 4.00 mmol) and the reaction mixture was heated to 80° C. for 12 h. The reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (200 mL), washed with water (2×100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 4:1) followed by recrystallization from ethanol provided 0.243 g (62%, 40% ee) of 6-fluoro-3-(1-{[(2R)-8-methoxy-3,4-dihydro-2H-chromen-2-yl]methyl}-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole as a tan crystalline powder. [α]D25=−27.14 (c 9.95 in chloroform, 40% ee); Rf=0.47 (silica, ethyl acetate:hexanes 4:1); mp >170° C. dec; Anal. Calcd. for C24H25FN2O2.0.1 H2O: C, 73.11; H, 6.44; N, 7.11. Found: C, 72.81; H, 6.36; N, 7.06.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][N:10]([C:19](=S)[NH:20][S:21]([N:24]([CH2:28][CH3:29])[CH2:25][CH2:26][CH3:27])(=[O:23])=[O:22])[N:9]=2)=[CH:4][CH:3]=1.[CH3:31][NH2:32]>C(#N)C.Cl[Hg]Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][N:10]([C:19]([NH:32][CH3:31])=[N:20][S:21]([N:24]([CH2:28][CH3:29])[CH2:25][CH2:26][CH3:27])(=[O:23])=[O:22])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: CCCN(CC)S(=O)(=O)NC(=S)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Agent: Cl[Hg]Cl
Solvent: CC#N
Product: CCCN(CC)S(=O)(=O)N=C(NC)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Reaction time: 4 h
Yield: 77 %

Procedure:
Part B: To a stirred suspension of 3-(4-chlorophenyl)-N-(((ethyl)propyl-amino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-thiocarboxamide (2.32 gram, 5 mmol) in acetonitrile (20 mL) is added cold methylamine (4 mL). To the resulting solution is added a solution of HgCl2 (1.5 gram) in acetonitrile (10 mL). The resulting black suspension is stirred for four hours. The precipitate is removed by filtration. The filtrate is concentrated in vacuo, dissolved in dichloromethane and successively washed with aqueous 0.5 N NaOH solution and water, dried over Na2SO4, filtered and concentrated in vacuo. The resulting oil is crystallized from diethyl ether to give 3-(4-chlorophenyl)-N′-(((ethyl)propylamino)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine (1.78 gram, 77% yield). Melting point (MP):129-131° C.
Reaction SMILES: C[Al](C)C.[CH:5]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6]1.[CH3:11][C:12]1[C:13]2[CH:37]=[C:36]([CH3:38])[O:35][C:14]=2[N:15]=[C:16]([NH:18][C:19]([NH:21][S:22]([C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27](OC)=[O:28])(=[O:24])=[O:23])=[O:20])[N:17]=1.Cl>C1(C)C=CC=CC=1.C(Cl)Cl.C(OCC)(=O)C>[CH3:11][C:12]1[C:13]2[CH:37]=[C:36]([CH3:38])[O:35][C:14]=2[N:15]=[C:16]([NH:18][C:19]([NH:21][S:22]([C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([O:10][CH:5]2[CH2:9][CH2:8][CH2:7][CH2:6]2)=[O:28])(=[O:23])=[O:24])=[O:20])[N:17]=1
Reactant: OC1CCCC1
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)c2cc(C)oc2n1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc2c(C)nc(NC(=O)NS(=O)(=O)c3ccccc3C(=O)OC3CCCC3)nc2o1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 30 ml of dry methylene chloride was added 7.5 ml of 2M trimethylaluminum in toluene under a nitrogen atmosphere. Subsequently, 2.0 g of cyclopentanol in 2 ml methylene chloride was added via syringe and the mixture stirred at ambient temperature for 15 minutes. After addition of 2.0 g of methyl 2-{[(4,6-dimethylfuro[2,3-d]pyrimidin-2-yl)aminocarbonyl]aminosulfonyl}benzoate to the mixture, the reaction was heated to reflux for 48 hours. The mixture was then cooled and poured into excess dilute hydrochloric acid and mixed with ethyl acetate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:15]=3)[CH:11]=[C:10]([C:30]([F:33])([F:32])[F:31])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][N:36]=1>>[F:27][C:26]([F:29])([F:28])[CH2:25][O:24][C:16]1[CH:15]=[C:14]([C:12]2[CH:11]=[C:10]([C:30]([F:33])([F:32])[F:31])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:38]4[CH:39]=[CH:40][C:35]([NH2:34])=[N:36][CH:37]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)[CH:19]=[CH:18][C:17]=1[C:20]([F:23])([F:22])[F:21]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)COc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)ccc1C(F)(F)F
Product: Nc1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)cc(C(F)(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-6-trifluoromethyl-pyrimidine (example E.55) (0.273 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.13 g, 0.6 mmol) according to the general procedure VI. Obtained as an off-white solid (0.20 g, 73%). MS (ISP) 559.2 [(M+H)+]; mp 220° C.
Reaction SMILES: C(OC(N1CC[C@H]([C@@H](C2CCCCC2)O)C1)=O)(C)(C)C.[C:21]([O:25][C:26]([N:28]1[CH2:32][CH2:31][C@H:30]([CH:33]=[O:34])[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:45][C:46]1([F:55])[CH2:51][CH2:50][CH:49](C(Cl)=O)[CH2:48][CH2:47]1.S(C)C>C1COCC1>[C:21]([O:25][C:26]([N:28]1[CH2:32][CH2:31][CH:30]([CH:33]([CH:49]2[CH2:50][CH2:51][C:46]([F:55])([F:45])[CH2:47][CH2:48]2)[OH:34])[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(Cl)C1CCC(F)(F)CC1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C=O)C1
Agent: CC(C)(C)OC(=O)N1CC[C@H]([C@H](O)C2CCCCC2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)C2CCC(F)(F)CC2)C1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
The title compound was prepared in a manner similar to that described in Preparation 9 for the synthesis of (S)-3-((R)-cyclohexylhydroxymethyl)pyrrolidine-1-carboxylic acid t-butyl ester. (S)-3-Formylpyrrolidine-1-carboxylic acid t-butyl ester and LiHMDS were dissolved in THF under nitrogen and cooled at −78° C. 4,4-Difluoro-cyclohexanecarbonyl chloride (prepared by treatment of 4,4-difluorocyclohexane carboxylic acid with thionyl chloride in THF at 50° C. for 2 hours), was then added and the resulting mixture was stirred at −78° C. then allowed to reach room temperature overnight. BH3.Me2S in THF was added and the resulting mixture stirred at room temperature for 1 hour, then refluxed for 1 hour. The solids (1.03 g) were separated and dissolved in 1:1 AcOH:H2O (20 mL) and purified by preparative HPLC (BDS, 40-60%). This was repeated twice to yield:
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])=[C:2]=[O:3].[N:11]1[C:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:13][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]=12.CCN(C(C)C)C(C)C>CN(C=O)C>[C:5]1([CH3:10])[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH:1][C:2]([N:17]1[CH2:18][CH2:19][N:14]2[CH:13]=[C:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:11]=[C:15]2[CH2:16]1)=[O:3]
Reactant: Cc1ccccc1N=C=O
Reactant: CCOC(=O)c1cn2c(n1)CNCC2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cn2c(n1)CN(C(=O)Nc1ccccc1C)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a vial containing 1-isocyanato-2-methylbenzene (0.0166 g, 0.125 mmol) was added ethyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate (0.024 g, 0.125 mmol), DIPEA (0.0762 mL, 0.438 mmol), and DMF (1.5 mL). The solution was shaken at room temperature for 16 h, then concentrated to give crude ethyl 7-(o-tolylcarbamoyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate.