Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[CH2:22][C:21]([F:24])([F:23])[O:20][C:7]2([CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH2:6]1)[C:2]#[C:3][CH3:4].Cl.O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>ClCCl.C(Cl)Cl.C(#N)C>[CH2:1]([N:5]1[CH2:22][C:21]([F:23])([F:24])[O:20][C:7]2([CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)[CH2:6]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCN1CC(F)(F)OC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CC#N
Product: CC#CCN1CC(F)(F)OC2(CCNCC2)C1
Reaction time: 1 h
Yield: 96 %

Procedure:
Tert-butyl 8-but-2-ynyl-10,10-difluoro-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (50.0 mg, 0.145 mmol) was dissolved in dichloromethane (1 mL) and treated with HCl in dioxane (1.3 mL of 4 M, 5.1 mmol). The reaction mixture was stirred for 1 h then concentrated in vacuo several times with acetonitrile to yield a white solid. The solid was dissolved in 1:1 DCM/acetonitrile and stirred with solid K2CO3 for 1 h. The mixture was filtered and concentrated to provide 8-but-2-ynyl-10,10-difluoro-11-oxa-3,8-diazaspiro[5.5]undecane (34 mg, 96%). ESI-MS m/z calc. 244.1. Found 245.3 (M+1)+; Retention time: 0.79 minutes (3 min run).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:17](=O)[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:20][O:21][C:22]([NH2:24])=[NH:23].OS(O)(=O)=O.C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[CH3:20][O:21][C:22]1[NH:24][C:17]([CH3:18])=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:23]=1
Reactant: COC(=N)N
Reactant: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1=C(C)NC(OC)=NC1c1cccc([N+](=O)[O-])c1
Temperature: 70 °C
Yield: 61.6 %

Procedure:
A mixture of 2-[(3-nitrophenyl)methylene]-3-oxobutanoic acid, ethyl ester (16.46 g, 62.6 mmol), o-methylisourea hydrogen sulfate (14.00 g, 81.4 mmol), and sodium bicarbonate (15.8 g, 18.8 mmol) in dimethylformamide (9.4 ml) was heated at 70° C. (oil bath) under argon overnight. The cooled reaction was diluted with water and extracted with ethyl acetate. The organic phase was washed several times with water, washed with saturated sodium chloride, dried (potassium carbonate) and evaporated. The residue was passed through a pad of silica gel, crystallized from isopropyl ether/hexanes and then triturated with 60% isopropyl ether hexanes (50 ml) to give 1,4-dihydro-2-methoxy-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, ethyl ester as light yellow crystals (12.32 g), melting point 101°-103° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:20](=O)[CH3:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O.C([O-])([O-])=O.[Na+].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH3:21])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCCl
Product: CCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCOCC1
Reaction time: 0.5 h
Yield: 107.3 %

Procedure:
To a mechanically stirred solution of methyl 5-bromo-2-methyl-3-((tetrahydro-2H -pyran-4-yl)amino)benzoate (15.3 g, 46.6 mmol) and acetaldehyde (7.90 mL, 140 mmol) in 1,2-dichloroethane (DCE) (150 mL) under nitrogen was added acetic acid (16.01 mL, 280 mmol). After 30 min, sodium triacetoxyborohydride (29.6 g, 140 mmol) was added to the reaction mixture. The reaction was stirred overnight, at which time the nitrogen was removed and acetaldehyde (7.90 mL, 140 mmol) was added. After 2 h, the reaction mixture was diluted with water and Na2CO3 (sat′d) and extracted with EtOAc (3×). The ethyl acetate layers were dried over Na2SO4, filtered, and concentrated to obtain methyl 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoate (17.8 g, 50.0 mmol, 107% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.61 (d, J=2.02 Hz, 1 H), 7.54 (d, J=2.27 Hz, 1 H), 3.89-3.73 (m, 5 H), 3.26 (td, J=11.56, 1.89 Hz, 2 H), 3.15-2.86 (m, 3 H), 3.36 (s, 3 H). 1.66-1.55 (m, 2 H), 1.55-1.36 (m, 2 H), 0.79 (t, J=6.95 Hz, 3 H). MS(ES) [M+H]+ 358, 356.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.Cl.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[CH:39][CH:38]=1>C(#N)CC.CCO.O>[Cl:36][C:37]1[CH:38]=[CH:39][C:40]([N:43]2[CH2:48][CH2:47][N:46]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]5[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:45][CH2:44]2)=[CH:41][CH:42]=1
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2cc(CN3CCN(c4ccc(Cl)cc4)CC3)cnc2N2CCCC[C@@H]12
Temperature: 90 °C
Reaction time: 16 h
Yield: 38.1 %

Procedure:
(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (100 mg, 0.429 mmol) was suspended in propionitrile (1 mL) and (cyanomethyl)trimethylphosphonium iodide (125.0 mg, 0.51 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (225 ul, 1.3 mmol). To the stirred mixture was then added 1-(4-chlorophenyl)piperazine hydrochloride (110 mg, 0.472 mmol). The reaction was heated to 90° C. with stirring for 16 h. The reaction was then cooled to room temperature, diluted with EtOH (3 ml) and water (˜300 ul), then filtered. The solids were collected and refluxed in ethanol (5 mL) for 2 h. The suspension was cooled back to room temperature and filtered. The precipitate was filtered off and dried in vacuum to afford the title compound (67.3 mg, 43%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.47 (s, 1H), 7.65 (d, J=2.0 Hz, 1H), 7.21 (d, J=9.1 Hz, 2H), 6.97 (d, J=2.0 Hz, 1H), 6.88-6.95 (m, 2H), 4.45-4.55 (m, 1H), 3.83 (dd, J=11.4, 2.8 Hz, 1H), 3.35 (s, 2H), 3.05-3.16 (m, 5H), 2.60 (td, J=12.6, 2.5 Hz, 1H), 2.38-2.48 (m, 3H), 2.03 (d, J=12.6 Hz, 1H), 1.77-1.91 (m, 1H), 1.63 (d, J=12.6 Hz, 1H), 1.33-1.56 (m, 3H). [M+H] calc'd for C22H26ClN5O, 412; found, 412.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[N:9][NH:10][CH:11]=1)=[O:5].ClC1C=CC=C(Cl)C=1C(NC1C=NN(CC2C=CC(Cl)=CC=2Cl)C=1)=O.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].Br[CH2:51][C:52]1[CH:57]=[C:56]([Cl:58])[CH:55]=[CH:54][C:53]=1[O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>CN(C=O)C>[Cl:58][C:56]1[CH:55]=[CH:54][C:53]([O:59][CH2:60][C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)=[C:52]([CH2:51][N:10]2[CH:11]=[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:15][CH:14]=[CH:13][C:12]=3[F:16])[CH:8]=[N:9]2)[CH:57]=1
Reactant: O=C(Nc1cn[nH]c1)c1c(F)cccc1F
Reactant: Clc1ccc(OCc2ccccc2)c(CBr)c1
Agent: O=C(Nc1cnn(Cc2ccc(Cl)cc2Cl)c1)c1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: O=C(Nc1cnn(Cc2cc(Cl)ccc2OCc2ccccc2)c1)c1c(F)cccc1F
Reaction time: 8 h

Procedure:
2,6-Difluoro-N-1H-pyrazol-4-ylbenzamide (for a preparation see Intermediate 2; 86 mg, 0.385 mmol) was dissolved in DMF (2.5 ml), sodium iodide (21 mg, 0.140 mmol), potassium carbonate (169 mg, 1.22 mmol) and 2-(bromomethyl)-4-chloro-1-[(phenylmethyl)oxy]benzene (synthesised according to Bioorganic & Medicinal Chemistry Letters (2009), 19, 2599-2603; 121 mg, 0.388 mmol) were then added using further DMF (2.5 ml). The reaction was then stirred overnight. Further 2-(bromomethyl)-4-chloro-1-[(phenylmethyl)oxy]benzene (125 mg) was added and the reaction was stirred for 4 h. The reaction was concentrated in vacuo. The crude material was treated with water (50 ml) and the aqueous solution was extracted with ethyl acetate (3×50 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The sample was loaded in ethyl acetate and purified on silica (20 g) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound (70 mg) as a colourless gum; LCMS (System 1): MH+=454, tRET=3.59 min.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.C(O)(C(F)(F)F)=O.[C:29](Cl)(Cl)=[S:30].[OH-].[Na+]>O>[CH:17]([C:5]1[CH:4]=[C:3]([O:20][CH3:21])[C:2]([N:1]=[C:29]=[S:30])=[CH:16][C:6]=1[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)([CH3:19])[CH3:18]
Reactant: S=C(Cl)Cl
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1N=C=S
Yield: 31.7 %

Procedure:
To a solution of 5-(5-amino-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (0.100 g, 0.4 mmol) in 1 ml H2O and TFA (0.040 g, 0.4 mmol) was added thiophosgene (0.040 g, 0.4 mmol). After 1 h the mixture was neutralized with 2M NaOH and extracted with CH2Cl2. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford 5-(2-isopropyl-5-isothiocyanato4-methoxy-phenoxy)-pyrimidine-2,4-diamine (0.042 g, 36%) as brown foam [MH]+=334.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[Si:21]([O:28][CH:29]1[CH2:34][C:33]([CH3:36])([CH3:35])[C:32]([CH:37]=[CH:38][C:39](=[O:41])[CH3:40])=[C:31]([CH3:42])[CH2:30]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].CI.[Cl-].[NH4+]>C1COCC1.CN(C)P(=O)(N(C)C)N(C)C.CCCCCC>[Si:21]([O:28][CH:29]1[CH2:34][C:33]([CH3:35])([CH3:36])[C:32]([CH:37]=[CH:38][C:39](=[O:41])[CH2:40][CH3:1])=[C:31]([CH3:42])[CH2:30]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(=O)C=CC1=C(C)CC(O[Si](C)(C)C(C)(C)C)CC1(C)C
Reactant: CC(C)NC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: CI
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCC(=O)C=CC1=C(C)CC(O[Si](C)(C)C(C)(C)C)CC1(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To 3 ml of an anhydrous THF solution containing 375 mg of diisopropylamine was added 2.3 ml of a 1.6M n-hexane solution of n-butyl lithium at 0° C. in a nitrogen atmosphere to prepare LDA in the usual manner. The reaction mixture was cooled to -78° C., and 111 mg of hexamethylphosphoric triamide was added thereto. To the cooled mixture was dropwise added 10 ml of an anhydrous THF solution containing 1.0 g of 4-[4-(t-butyldimethylsilyl)oxy-2,6,6-trimethylcyclohex-1-enyl]-but-3-en-2-one. After the dropwise addition, the mixture was stirred under the same condition for 30 minutes. Then, 5 ml of an anhydrous THF solution of 659 mg of methyl iodide was added dropwise thereto. The reaction mixture was warmed to 0° C., followed by stirring overnight. After completion of the reaction, the reaction mixture was poured into a saturated ammonium chloride aqueous solution and extracted with diethyl ether. The organic layer was washed successively with a saturated sodium chloride aqueous solution and water, and dried over anhydrous magnesium sulfate. The solvent, etc. were removed by distillation under reduced pressure. Purification of the residue by silica gel column chromatography yielded 657 mg (63%) of 1-[4-(t-butyldimethylsilyl)oxy-2,6,6-trimethylcyclohex-1-enyl]pent-1-en-3-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([NH:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:10])[F:11])[C:5]([Cl:8])=[CH:6][CH:7]=1)(=[O:15])[CH3:14]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Yield: 98.5 %

Procedure:
A solution of 3-amino-6-chlorobenzotrifluoride (1.045 g, 5.34 mmol, Aldrich) in acetic anhydride (5 mL) was stirred at room temperature for 12 h to produce a white needle precipitate. It was filtered to give 1.250 g (98.5%) of 3-acetamido-6-chlorobenzotrifluoride. 1H NMR (CDCl3): δ 2.193 (s, 3H); 7.420 (d, 1H, J=8.7 Hz); 7.726 (m, 2H), 7.804 (s, 1H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]1[C:33]([OH:40])=[CH:34][CH:35]=[C:36]([CH:39]=1)[CH:37]=O)[CH3:30]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:37][C:36]3[CH:35]=[CH:34][C:33]([OH:40])=[C:32]([O:31][CH2:29][CH3:30])[CH:39]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: CCOc1cc(C=O)ccc1O
Product: CCOc1cc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)ccc1O

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 5-ethoxy-4-hydroxybenzaldehyde according to the procedure of step 1, Example 66. MS (ESI) m/z 529; MS (ESI) m/z 527.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].C1C(C(OO)=O)=CC=CC=1.BrN1C(=O)CCC1=O.Cl.[CH2:32]([O:34][C:35](=[O:38])[CH2:36][NH2:37])[CH3:33].C(=O)([O-])O.[Na+]>C(O)C.C(OCC)(=O)C.C1C=CC=CC=1>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([CH:3]=1)[CH2:1][NH:37][CH2:36][C:35]([O:34][CH2:32][CH3:33])=[O:38])#[N:6]
Reactant: Cc1cc(C#N)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C(OO)c1ccccc1
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CCO
Product: CCOC(=O)CNCc1cc(C#N)ccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 6 h

Procedure:
4.0 g (24.6 mmol) of 3-methyl-4-nitrobenzonitrile was added to a mixture of 100 ml of benzene, 100 ml of perbenzoic acid and 5.3 g (29 mmol) of N-bromosuccinimide, and they were heated under reflux for 2 days. 100 mg of perbenzoic acid and 4.0 g (22.5 mmol) of N-bromosuccinimide were added to the reaction mixture, and they were heated under reflux for 2 days. Thereafter, 100 mg of perbenzoic acid and 4.0 g (22.5 mmol) of N-bromosuccinimide were added to the reaction mixture, and they were heated under reflux for 2 days. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the obtained crude product was dissolved in 50 ml of ethanol. 6.9 g (49.2 mmol) of glycine ethyl ester hydrochloride and 6.2 g (73.8 mmol) of sodium hydrogencarbonate were added to the obtained solution, and they were stirred at 70° C. for 6 hours. The solvent was evaporated. After the extraction with ethyl acetate, the extract was washed with 1 N hydrochloric acid. The obtained aqueous layer was made basic with 1 N sodium hydroxide. After the extraction with ethyl acetate, the obtained organic layer was washed with saturated aqueous sodium chloride solution and then dried. The solvent was evaporated to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2(O)[CH2:12][CH2:11][O:10][CH2:9]2)[CH:5]=[C:4]([F:14])[C:3]=1[C:15]1[S:16][CH:17]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:19]=1.FC1C=C(C2(O)CCOC2)C=C(F)C=1C1SC=C(C(O)=O)N=1.FC(F)(F)C(O)=O>ClCCl>[O:10]1[CH2:11][CH:12]=[C:8]([C:6]2[CH:7]=[C:2]([F:1])[C:3]([C:15]3[S:16][CH:17]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:19]=3)=[C:4]([F:14])[CH:5]=2)[CH2:9]1
Reactant: COC(=O)c1csc(-c2c(F)cc(C3(O)CCOC3)cc2F)n1
Agent: O=C(O)c1csc(-c2c(F)cc(C3(O)CCOC3)cc2F)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1csc(-c2c(F)cc(C3=CCOC3)cc2F)n1
Temperature: 120 °C
Yield: 24.1 %

Procedure:
To a solution of methyl 2-[2,6-difluoro-4-(3-hydroxytetrahydrofuran-3-yl)phenyl]thiazole-4-carboxylate (250 mg, 0.732 mmol, precursor to Intermediate 144) in dichloromethane (1 mL) was added TRIFLUOROACETIC ACID (1 mL) The mixture was heated at 120° C. in microwave for 2 h. After in vacuo concentration, purification by CombiFlash (0 to 100% EtOAC in heptane) provided methyl 2-(4-(2,5-dihydrofuran-3-yl)-2,6-difluorophenyl)thiazole-4-carboxylate (57 mg, 24% yield) as a mixture of olefin isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][CH:10]=[C:9]([O:21][CH3:22])[C:8]=2[C:7]1=[O:23].OO.NC(N)=O.P([O-])([O-])(O)=O.[K+].[K+].S(=O)(O)[O-].[Na+].[C:46]([O:49]C(=O)C)(=[O:48])[CH3:47]>ClCCl.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C1(C)C=CC=CC=1>[C:46]([O:49][C:10]1[N:11]=[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:13]2[CH2:14][CH2:15][N:6]([CH2:5][C:4]3[CH:24]=[CH:25][C:26]([F:27])=[C:2]([Cl:1])[CH:3]=3)[C:7](=[O:23])[C:8]=2[C:9]=1[O:21][CH3:22])(=[O:48])[CH3:47]
Reactant: CCOC(=O)c1ncc(OC)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Reactant: CC(=O)OC(C)=O
Agent: NC(N)=O
Agent: O=P([O-])([O-])O
Agent: O=S([O-])O
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(OC(C)=O)c(OC)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a cold (5° C.) mixture of ethyl 6-(3-chloro-4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate (199 g, 0.51 mol) and urea hydrogen peroxide (100 g, 1.06 mol) in dichloromethane (1.5 L), trifluoroacetic anhydride was added dropwise over a period of 45 minutes. The resultant homogeneous solution was stirred at 20° C. for 30 minutes and cooled back to 5° C. The reaction mixture was treated with aqueous potassium hydrogen phosphate (pH of aqueous extract increased to 8), followed by slow addition of freshly prepared aqueous sodium bisulfite solution with the temperature of the product mixture maintained below 25° C. The organic extract was separated and the aqueous fraction extracted with toluene (2×). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Without further purification, a solution of this intermediate N-oxide (˜280 g) and acetic anhydride (239 mL, 2.5 mol) in toluene (2 L) was heated at 110° C. for 16 hours. The product mixture was concentrated under vacuum. The resultant oil was concentrated from toluene (300 mL, twice) and stored under vacuum overnight. The acetate product was used in the following step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]([Cl:8])[CH2:6][CH2:5][CH2:4][CH:3]=1.[C:9]1(=[O:19])[NH:13][C:12](=[O:14])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.[K].[I-].[K+].C(OCC)C>CN(C)C=O>[Cl:8][C:7]1[CH:2]([N:13]2[C:9](=[O:19])[C:10]3[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:12]2=[O:14])[CH2:3][CH2:4][CH2:5][CH:6]=1
Reactant: ClC1=CCCCC1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1C1CCCC=C1Cl
Yield: 73.5 %

Procedure:
A solution of 11.0 g (72.8 mmol) 1,6-dichlorocyclohexene, 20.0 g (108 mmol) potassium phthalimide and 1.0 g (6.0 mmol) potassium iodide in 50 ml dry dimethylformamide was stirred 24 hours at 110° C. under an atmosphere of nitrogen. The reaction mixture was allowed to cool then poured into 30 ml diethyl ether. The dark mixture was filtered, then the ether and DMF removed in vacuo. The dark crystalline residue was dissolved in ethyl acetate then chromatographed on 500 g flash silica eluting with 10% to 20% ethyl acetate/hexane. Concentration of appropriate fractions followed by recrystallization from ethyl acetate/hexane gave 14.0 g (73.5%) of the desired phthalimide, mp 99°-103° C.
Reaction SMILES: [CH:1]([Si:4]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[O:5][C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[N:16]3[CH:17]=[C:18]([O:21][C@H:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C@@H:25]([NH2:32])[CH2:24][CH2:23]4)[CH:19]=[CH:20][C:15]3=[N:14][N:13]=2)[CH2:7]1)([CH3:3])[CH3:2].ClC(Cl)(Cl)C[O:42][C:43](=O)[NH:44][C:45]1[N:46]([C:54]2[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][CH:55]=2)[N:47]=[C:48]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH:49]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:50]([C:48]1[CH:49]=[C:45]([NH:44][C:43]([NH:32][C@@H:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@H:22]([O:21][C:18]3[CH:19]=[CH:20][C:15]4[N:16]([C:12]([N:8]5[CH2:9][CH2:10][CH2:11][C@H:6]([O:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:33]([CH3:35])[CH3:34])[CH:36]([CH3:38])[CH3:37])[CH2:7]5)=[N:13][N:14]=4)[CH:17]=3)[CH2:23][CH2:24]2)=[O:42])[N:46]([C:54]2[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][CH:55]=2)[N:47]=1)([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)[Si](O[C@H]1CCCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)C1)(C(C)C)C(C)C
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC[C@H](O[Si](C(C)C)(C(C)C)C(C)C)C5)n4c3)c3ccccc32)cc1
Yield: 60 %

Procedure:
A solution of Intermediate 63c (140 mg, 0.261 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 106 mg, 0.261 mmol) in 1,4-dioxane (3 mL) and DIPEA (70 μL, 0.4 mmol) was stirred at 90° C. for 3 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give the title compound as a pale brown gum (124 mg, 60%). LCMS (Method 3): Rt 5.43 min, m/z 791 [MH+].
Reaction SMILES: C([O:5][C:6]([C@@H:8]([C@@H:20]([CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22])[CH2:9][N:10]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[N:12]([CH3:18])[C:11]1=[O:19])=[O:7])(C)(C)C.Br>C(O)(=O)C.C(Cl)Cl>[C:6]([C@H:8]([C@@H:20]([CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22])[CH2:9][N:10]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[N:12]([CH3:18])[C:11]1=[O:19])([OH:7])=[O:5]
Reactant: CN1C(=O)N(C[C@@H](C(=O)OC(C)(C)C)[C@@H](CC2CCCC2)C(=O)N2CCCCC2)C(=O)C1(C)C
Agent: Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1C(=O)N(C[C@H](C(=O)O)[C@@H](CC2CCCC2)C(=O)N2CCCCC2)C(=O)C1(C)C
Reaction time: 4 h

Procedure:
A solution of 15.11 g of the 9:1 mixture from Example 4 in 15 ml of acetic acid was treated at 0° with 15 ml of 33% hydrogen bromide in acetic acid and stirred at 0° for 4 hrs. The solution was diluted with methylene chloride, washed with water and the organic phase was dried, filtered and evaporated. The residue was crystallized from 26 ml of tert-butyl methyl ether and 26 ml of hexane, after which 6.90 g (70%) of diastereomer-pure (de>98%) 1-[2(R)-[1(R)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl]piperidine (IX), m.p. 111-114°, was obtained. IR (KBr): 1770m and 1715s (C=O).