Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:18]([C:19](=[O:25])[C:20]=2[O:21]COC)=[CH:17][CH:16]=[C:15]([O:26]COC)[CH:14]=3)=[CH:7][C:6]=1[O:30]COC.Cl>O1CCOCC1>[F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:18]([C:19](=[O:25])[C:20]=2[OH:21])=[CH:17][CH:16]=[C:15]([OH:26])[CH:14]=3)=[CH:7][C:6]=1[OH:30]
Reactant: COCOc1ccc2c(=O)c(OCOC)c(-c3ccc(OCCF)c(OCOC)c3)oc2c1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1c(O)c(-c2ccc(OCCF)c(O)c2)oc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
To 2-(4-(2-fluoroethoxy)-3-(methoxymethoxy)phenyl)-3,7-bis(methoxymethoxy)-4H-chromen-4-one (19 mg, 0.041 mmol) was added 1 mL of 4 M HCl solution in dioxane. The mixture was stirred at rt for 3 h. Volatiles were removed under reduced pressure and the residue was washed with ether (2×1 mL) and dried under high vacuum to afford 2-(4-(2-fluoroethoxy)-3-hydroxyphenyl)-3,7-dihydroxy-4H-chromen-4-one (AD-F-001S-WZ01067) as a yellow solid (11 mg, 81%). 1H NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1H), 9.39 (s, 1H), 9.17 (s, 1H), 7.89 (d, J=9.6 Hz, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.59 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 6.87 (m, 2H), 4.80 (m, 1H), 4.68 (m, 1H), 4.30 (m, 1H), 4.23 (m, 1H); MS (ESI) m/z 333 (M+H+), 355 (M+Na+).
Reaction SMILES: [C:1]1([C:7]2[N:12]3[N:13]=[C:14]([OH:16])[CH:15]=[C:11]3[CH2:10][CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:27][C:28]([F:43])([S:39](F)(=[O:41])=[O:40])[C:29]([F:38])([F:37])[C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32]>C1COCC1.CCOC(C)=O>[F:43][C:28]([F:27])([S:39]([O:16][C:14]1[CH:15]=[C:11]2[CH2:10][CH2:9][CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:12]2[N:13]=1)(=[O:41])=[O:40])[C:29]([F:37])([F:38])[C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Oc1cc2n(n1)C(c1ccccc1)=CCC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(Oc1cc2n(n1)C(c1ccccc1)=CCC2)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 0.17 h
Yield: 85.9 %

Procedure:
Step AAH (7): To a soln of 7-phenyl-4,5-dihydropyrazolo[1,5-a]pyridin-2-ol (500 mg, 2.356 mmol) in THF (15 mL) was added NaHMDS (1.0 M in THF, 2.94 mL, 2.94 mmol) at −78° C. under nitrogen. After stirring for 10 min, 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (1281 mg, 4.24 mmol) was added. The mixture was allowed to warm from −78° C. to rt over 3 h. The reaction was diluted with EtOAc (200 mL) and washed sequentially with 0.1 N aqueous sodium hydroxide, water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography (30% EtOAc/hexanes) to afford 7-phenyl-4,5-dihydropyrazolo[1,5-a]pyridin-2-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (1.0 g, 86% yield). LC-MS (M+H)+ 495.12.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=[O:14].[Br:15]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:15][C:11]1[CH:10]=[C:9]([CH:13]=[O:14])[N:8]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])[CH:12]=1
Reactant: O=Cc1cccn1-c1ccncc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)cn1-c1ccncc1Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 29.4 %

Procedure:
To a solution of 2.95 g of 1-(3-chloro-4-pyridinyl)-1H-pyrrole-2-carbaldehyde in 20 ml of N,N-dimethylformamide was added 2.66 g of N-bromosuccinimide. The resulting mixture was stirred at room temperature for 10 hours. Water was poured into the reaction mixture, and a deposited precipitate was collected by filtration to obtain 1.2 g of 4-bromo-1-(3-chloro-4-pyridinyl)-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: Br[CH:2]([CH3:21])[C:3]([NH:5][C:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:15][CH:16]=2)[N:7]=1)=[O:4].[CH3:22][NH:23][CH3:24]>C1C=CC=CC=1>[CH3:22][N:23]([CH3:24])[CH:2]([CH3:21])[C:3]([NH:5][C:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:15][CH:16]=2)[N:7]=1)=[O:4]
Reactant: CC(Br)C(=O)NC1=NN(c2cccc(C(F)(F)F)c2)CC1
Reactant: CNC
Solvent: c1ccccc1
Product: CC(C(=O)NC1=NN(c2cccc(C(F)(F)F)c2)CC1)N(C)C

Procedure:
A 1.0 g. amount of 2-bromo-N-[1-(α,α,α-trifluoro-m-tolyl)-2-pyrazolin-3-yl]propionamide (Example 12) is dissolved in 50 ml. of benzene in a pressure bottle, then 2.0 ml. of dimethylamine is added and the bottle is sealed for 1/2 hour at room temperature with the separation of crystals. The mixture is heated on a steam bath for 6 hours, then is cooled. The reaction mixture is partitioned between water and benzene. The benzene layer is dried over anhydrous magnesium sulfate and evaporated to a dark gum. The gum is dissolved in hexane and filtered through a hydrous magnesium silicate. The filtrate is evaporated to a gum (0.9 g.). A 210 mg. amount of this gum is chromatographed by thick layer chromatography on one mm Silica Gel G plates using the upper phase of a mixture of 2 parts benzene, 1 part acetone and 2 parts water to give 180 mg. of the desired product as a light yellow gum.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]([C:14](=O)[CH3:15])[NH2:13].[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(O)(=O)C>[C:17]([NH:13][N:12]1[C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=2[N:1]=[C:14]1[CH3:15])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)N(N)c1ccc(C(F)(F)F)cc1N
Solvent: CC(=O)O
Product: CC(=O)Nn1c(C)nc2cc(C(F)(F)F)ccc21
Yield: 90 %

Procedure:
After boiling 23.3 g of 2-amino-4-trifluoromethyl-N-acetylphenylhydrazine [prepared as described in: J. Org. Chem. 42, 542 (1977)] with 120 ml of acetic acid and 20 ml of acetic anhydride for 6 hours, the orange-red solution obtained was evaporated under reduced pressure and the residue was triturated with water. The separated crystals were filtered by suction, washed with water and dried at 80° C. to yield 23.2 g (90%) of 1-acetylamino-2-methyl-5-trifluoromethylbenzimidazole, m.p.: 214°-216° C. after recrystallization from acetone.
Reaction SMILES: [Br:1][C:2]1[C:6]([CH2:7]Cl)=[C:5]([CH2:9]Cl)[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].[S-2:15].[Na+].[Na+]>CO>[Br:1][C:2]1[C:6]2[CH2:7][S:15][CH2:9][C:5]=2[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: [S-2]
Reactant: COC(=O)c1sc(CCl)c(CCl)c1Br
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1sc2c(c1Br)CSC2
Yield: 75 %

Procedure:
Compound (3) from the previous step was dissolved into 500 ml slightly boiling methanol, and a solution of sodium sulfide in 500 ml methanol was added drop-wise over about 1 hour at boiling temperature. The reactant was then kept at boiling temperature for about 1 hour. Methanol was removed by rotary evaporation and the sticky residue was absorbed by silica gel. The purification of product was performed by column chromatography using petroleum ether/ethyl acetate (30:1) as the eluent. Methyl 3-bromo-4,6-dihydrothieno[3,4-b]thiophene-2-carboxylate was obtained as colorless oil. The yield was about 75%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[CH2:13][CH:14]([CH3:19])[C:15](OC)=[O:16])([O-])=O>[Pd].CC(O)(C)C>[NH2:10][C:8]1[CH:9]=[C:4]2[C:5]([CH2:13][CH:14]([CH3:19])[C:15](=[O:16])[NH:1]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(C)(C)O
Product: CC1Cc2ccc(N)cc2NC1=O
Temperature: 50 °C
Reaction time: 72 h
Yield: 96.9 %

Procedure:
A flask was charged with methyl 3-(2,4-dinitrophenyl)-2-methylpropanoate (1.1 g, 4.1 mmol), 10 wt % Pd on carbon (0.25 g, 2.3 mmol), and t-BuOH (15 mL). The mixture was degassed with H2 three times and was stirred for about 72 h at about 50° C. The mixture was filtered and the filtrate was concentrated under reduced pressure to give 7-amino-3-methyl-3,4-dihydroquinolin-2(1H)-one (0.70 g, 92%): LC/MS (Table 2, Method g) Rt=1.04 min; MS m/z: 177 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][CH2:24][CH:25]=[O:26])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][Mg+].[Br-]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)([CH2:23][CH2:24][CH:25]([OH:26])[CH3:28])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCC=O)(c2ccc(F)cc2)OC1=O
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanal (300 mg, 0.69 mmol) in THF (4 ml) was added dropwise MeMgBr (0.7 ml, 3 mol/L) at −78° C. The mixture was stirred for 2 h and the temperature was allowed to be warm to rt at this stage. The reaction was quenched with aqueous NH4Cl. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated to give the crude product, which was purified by HPLC and chiral HPLC to give two isomers.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[CH3:14][N:15]=[C:16]=[O:17].O>C(Cl)Cl>[CH3:14][NH:15][C:16]([NH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)=[O:17]
Reactant: CN=C=O
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Solvent: ClCCl
Solvent: O
Product: CNC(=O)N[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 3.5 h

Procedure:
tert-Butyl (3R)-3-aminopyrrolidine-1-carboxylate 6-2 (1.813 g, 9.73 mmol) was dissolved in 10 mL CH2Cl2. A solution of methylisocyanate (0.555 g, 9.73 mmol) in 10 mL CH2Cl2 was added. The solution was stirred for 3.5 hours. 50 mL H2O was added and the precipitate was extracted with CH2Cl2 (2×). The combined organic layers were dried (Na2SO4), filtered, and concentrated to afford tert-butyl (3R)-3-{[(methylamino)carbonyl]amino}pyrrolidine-1-carboxylate 6-3 as a white semi-solid. Free base: 1H NMR (DMSO-d6) δ 6.15 (bs, 1H), 5.63 (bd, 1H, J=4.22 Hz), 4.02 (m, 1H), 3.42-3.34 (m, 1H), 3.28-3.19 (m, 2H), 2.93-2.98 (m, 1H), 2.53 (d, 3H, J=4.58 Hz), 1.99-1.93 (m, 1H), 1.68-1.63 (m, 1H), 1.39 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=O)[C:9](=[O:22])[N:10]2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][C:4]=1[C:24]([O:26][CH3:27])=[O:25].O=P(Cl)(Cl)[Cl:30].CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:30][C:8]1[C:9](=[O:22])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6]([N:7]=1)=[CH:5][C:4]([C:24]([O:26][CH3:27])=[O:25])=[C:3]([O:2][CH3:1])[CH:12]=2
Reactant: COC(=O)c1cc2[nH]c(=O)c(=O)n(Cc3ccc(OC)cc3)c2cc1OC
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2nc(Cl)c(=O)n(Cc3ccc(OC)cc3)c2cc1OC
Temperature: 110 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To a solution of methyl 7-methoxy-1-[(4-methoxyphenyl)methyl]-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (24 g, 64.80 mmol) in toluene (300 mL) was added POCl3 (14.8 g, 96.52 mmol) and N,N-dimethylaniline (15.7 g, 129.75 mmol). The resulting solution was stirred overnight at 110° C. and concentrated in vacuo. The product was precipitated by the addition of methanol (150 mL) and collected by filtration to afford methyl 3-chloro-7-methoxy-1-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a green solid (17 g, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)O)=[C:7]([CH3:18])[C:6]=2[CH:19]=1.S(Cl)([Cl:22])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([Cl:22])[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[C:7]([CH3:18])[C:6]=2[CH:19]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(C(O)C2CCCCC2)oc2ccc(Cl)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1c(C(Cl)C2CCCCC2)oc2ccc(Cl)cc12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution (10 mL) of (5-chloro-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methanol (518 mg) synthesized above in toluene was added thionyl chloride (163 μL), and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (553 mg, quantitative) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH3:20])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C([Li])CCC.[C:26](Cl)([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])[N:11]([CH3:20])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: Cn1cnc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(C(=O)OCc2ccccc2)nc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4,5-di-(4-chlorophenyl)-1-methylimidazole (0.25 gm, 0.825 mmol) from Step B in THF (5 mL) cooled to −70° C. in a dry ice/acetone bath was added via syringe n-butyl lithium (1.6 N in hexanes, 0.62 mL, 1.0 mmol). The reaction was stirred at −70° C. for 30 min and then a solution of CBZ-Cl (0.42 mL, 1.65 mmol) in THF (2 mL) was added rapidly. The reaction was warmed to rt over 1 hr. The reaction was poured into an aq. sodium bicarbonate solution and then extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by flash chromatography (15% ethyl acetate in hexanes) to provide the title compound as a white solid. HPLC/MS: 437 (M+1), 439 (M+3); Rt=4.37 min.
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:10]=[C:9]([CH3:19])[C:5]=2[C:6]([OH:8])=O)[CH2:3][CH2:2]1.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C.[NH2:50][CH2:51][CH2:52][C@@H:53]([OH:58])[C:54]([CH3:57])([CH3:56])[CH3:55]>ClCCl.O>[CH:1]1([C:4]2[CH:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:10]=[C:9]([CH3:19])[C:5]=2[C:6]([NH:50][CH2:51][CH2:52][C@@H:53]([OH:58])[C:54]([CH3:57])([CH3:56])[CH3:55])=[O:8])[CH2:2][CH2:3]1
Reactant: Cc1cc(N2CCOCC2)cc(C2CC2)c1C(=O)O
Reactant: CC(C)(C)[C@H](O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: Cc1cc(N2CCOCC2)cc(C2CC2)c1C(=O)NCC[C@@H](O)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 39 %

Procedure:
To a stirred solution of 2-cyclopropyl-6-methyl-4-morpholin-4-yl-benzoic acid (synthesized according to the methods described in sections a) to f)) (0.34 g, 1.3 mmol) in dichloromethane (10 ml) are added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.30 g, 1.56 mmol), hydroxybenzotriazole (0.21 g, 1.56 mmol) and diisopropylethylamine (0.65 ml, 3.9 mmol) at 0° C. and stirred for 15 min before the addition of (3R)-1-amino-4,4-dimethyl-pentan-3-ol (synthesized according to the methods described in sections g) to k)) (0.28 g, 1.69 mmol). The resulting mixture is stirred at room temperature for 16 h. Water (20 ml) is added to the mixture and extracted with dichloromethane (3×20 ml). The combined organic layers are washed with 10% sodium hydrogen carbonate solution (30 ml), brine (30 ml), dried over sodium sulfate and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, 55% ethyl acetate/dichloromethane) yielding 2-cyclopropyl-N-[(3R)-3-hydroxy-4,4-dimethyl-pentyl]-6-methyl-4-morpholin-4-yl-benzamide (example 28) (0.19 g, 0.51 mmol, 39%). [M+H]+ 375.3. [α]D25=+30.0° (c 1.0, methanol).
Reaction SMILES: [C:1]1([P:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]1([CH:23]=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(O)C>[CH:17]1([CH:23]=[N:10][CH2:9][CH2:8][P:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NCCP(c1ccccc1)c1ccccc1
Reactant: O=CC1CCCCC1
Solvent: CCO
Product: C(=NCCP(c1ccccc1)c1ccccc1)C1CCCCC1
Yield: 98 %

Procedure:
Under argon, a solution of 2-diphenylphosphino-ethylamine (619.0 mg, 2.7 mmol) and cyclohexane carbaldehyde (306.2 mg, 2.73 mmol) in ethanol (15 mL) was heated at 65° C. (oil bath) for 4 h. Then, the solvent was removed in-vacuo to give the desired product (>98% by 1H-NMR) as a colourless liquid (880.5 mg, 2.7 mmmol, quantitative).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([F:15])[CH:14]=1)[O:5][CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9]>[Pd].CO>[F:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([F:15])[CH:14]=1)[O:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C=COc1cc(F)cc(F)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCOc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.8 %

Procedure:
A mixture of methyl 3-(3,5-difluorophenoxy)acrylate (60.0 g, 280 mmol, STEP 5), and 10% palladium on carbon (1.0 g) in methanol (300 mL) was stirred under hydrogen gas (1 atmosphere) at room temperature for 18 hours. The reaction mixture was filtered through a pad of Celite, and washed with toluene (100 mL). The filtrate was concentrated in vacuum to afford the title compound (61.0 g, quant) as a colorless oil, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:12]([C:13]([OH:15])=O)=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][S:9][C:4]=2[CH:3]=1.[CH3:16][O:17][C:18]1[CH:27]=[C:26]2[C:21]([N:22]=[CH:23][C:24]([S:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]3)=[N:25]2)=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[CH:27]=[C:26]2[C:21]([N:22]=[CH:23][C:24]([S:28][CH2:29][CH2:30][N:31]3[CH2:32][CH2:33][CH:34]([NH:37][C:13]([C:12]4[C:2]([Cl:1])=[CH:3][C:4]5[S:9][CH2:8][C:7](=[O:10])[NH:6][C:5]=5[CH:11]=4)=[O:15])[CH2:35][CH2:36]3)=[N:25]2)=[CH:20][CH:19]=1
Reactant: O=C1CSc2cc(Cl)c(C(=O)O)cc2N1
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Product: COc1ccc2ncc(SCCN3CCC(NC(=O)c4cc5c(cc4Cl)SCC(=O)N5)CC3)nc2c1

Procedure:
The title compound is prepared as an off-white solid (42 mg, 60% yield) following Scheme 3 and in analogy to Example 35 using 7-chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (31 mg, 0.12 mmol 1.0 eq) and 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (40 mg, 0.12 mmol, 1.0 eq) as starting materials.
Reaction SMILES: ClC1C=CC(C[N:7]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][CH:20]([F:22])[F:21])[CH:14]=3)[N:9]([CH:23]3[CH2:28][CH2:27][N:26](C=O)[CH2:25][CH2:24]3)[C:8]2=[O:31])=CC=1>C(O)=O>[F:22][CH:20]([F:21])[CH2:19][O:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:23]1[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]1)[C:8](=[O:31])[NH:7][C:16]2=[O:17]
Reactant: O=CN1CCC(n2c(=O)n(Cc3ccc(Cl)cc3)c(=O)c3cc(OCC(F)F)ccc32)CC1
Solvent: O=CO
Product: O=c1[nH]c(=O)n(C2CCNCC2)c2ccc(OCC(F)F)cc12
Yield: 159.9 %

Procedure:
A solution of 5.63 g of 1,1-dimethylethyl 4-[6-(2,2-difluoroethoxy)-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carboxylate obtained in stage 3.5 in 70 ml of formic acid is stirred at AT for 2 h 00. The solvent is evaporated under reduced pressure to give 6.13 g of the expected product in the form of the formic acid salt.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[O:8][C:9]3[C:14]([C:15](=O)[CH:16]=2)=[CH:13][CH:12]=[CH:11][C:10]=3[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[O:8][C:9]3[C:14]([C:15](=[S:33])[CH:16]=2)=[CH:13][CH:12]=[CH:11][C:10]=3[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:3][CH2:2]1
Reactant: O=c1cc(N2CCOCC2)oc2c(-c3ccccc3)cccc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: S=c1cc(N2CCOCC2)oc2c(-c3ccccc3)cccc12
Temperature: 130 °C
Yield: 135.1 %

Procedure:
A 2 mL conical microwave vial was charged with a magnetic stirring bar, 2-morpholino-8-phenyl-4H-chromen-4-one (LY294002) (150 mg, 488 μmol), Lawesson's reagent (118 mg, 293 μmol), and toluene (2 mL). The reaction mixture was sealed, and the reaction mixture was magnetically stirred and heated via microwave irradiation to 130° C. for 20 minutes. The final mixture was poured onto water (approximately 30 mL), extracted with dichloromethane (3×5 mL), the combined extracts dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. Purification via column chromatography (silica gel; hexanes/ethyl acetate (1:1), then 100% ethyl acetate) afforded pure 2-morpholino-8-phenyl-4H-chromene-4-thione (68) (128 mg, 81% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][NH:6][CH2:5]2.C(N(CC)C(C)C)(C)C.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:5]2
Reactant: Brc1ccc2c(c1)CNC2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1Cc2ccc(Br)cc2C1
Reaction time: 2 h

Procedure:
To a cooled solution of 5-bromoisoindoline (1.1 g, 5.5 mmol) in dichloromethane (15 mL) was added N,N-diisopropylethylamine (1.16 mL, 6.6 mmol) followed by benzyl chloroformate (942 μL, 6.6 mmol). The cold bath was removed and stirring continued for 2 hr. The reaction mixture was then diluted with dichloromethane, washed with water, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by silica chromatography (25 g silica eluted with 0-50% ethyl acetate in hexane) to give the title compound as a white solid.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.C(O)(=O)C.[C:14]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)([O:16][CH2:17][CH3:18])=[O:15]>ClCCCl>[CH2:17]([O:16][C:14]([N:19]1[CH2:24][CH2:23][CH:22]([N:1]2[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]2)[CH2:21][CH2:20]1)=[O:15])[CH3:18]
Reactant: O=C(O)C1CCNCC1
Reactant: CCOC(=O)N1CCC(=O)CC1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)N1CCC(N2CCC(C(=O)O)CC2)CC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
A solution of Isonipecotic acid (8.0 g, 61.0 mmol) in DCE (80 mL) was treated with acetic acid (10.7 mL, 185 mmol) and 1-carbethoxy-4-piperidone (12.7 g, 74.3 mmol). The reaction mixture was stirred for 1 hr at 40° C. Then STAB (29.2 g, 92.8 mmol) was added, the reaction mixture was stirred at 70° C. for 6 h, cooled to rt and the solvent was removed in vacuo. The residue was purified by column chromatography (gradient 0% to 50% MeOH in CHCl3) to give 1′-(ethoxycarbonyI)-1,4′-bipiperidine-4-carboxylic acid (16.0 g, 92.2%), Intermediate 1, as an off white solid.