Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:46])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:43]=[CH:42][C:34]([C:35]([O:37][CH2:38][C:39]([OH:41])=O)=[O:36])=[CH:33][C:32]=2[O:44][CH3:45])=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:80][CH2:81][CH2:82][O:83][CH2:84][CH2:85][OH:86]>O1CCCC1>[OH:86][CH2:85][CH2:84][O:83][CH2:82][CH2:81][NH:80][C:39]([CH2:38][O:37][C:35](=[O:36])[C:34]1[CH:42]=[CH:43][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:46])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:29])=[C:32]([O:44][CH3:45])[CH:33]=1)=[O:41]
Reactant: COc1cc(C(=O)OCC(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: NCCOCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)OCC(=O)NCCOCCO)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reaction time: 0.5 h
Yield: 14.2 %

Procedure:
In a 20 mL round-bottomed flask, 2-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)acetic acid (Example 69, 150 mg, 152 μL, 222 μmol), HATU (84.6 mg, 222 μmol) and Hunig's base (86.2 mg, 117 μL, 667 μmol) were combined with dry tetrahydrofuran (2 mL) to give an off-white suspension at room temperature. It was stirred for 30 min and the solution became clear. 2-(2-Aminoethoxy)ethanol (23.4 mg, 16.0 μL, 222 μmol) was added. After stirring at room temperature overnight, the reaction mixture was concentrated. The residue was reconstituted with ethyl acetate. It was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was absorbed on small amount of silica gel and loaded on a 24 g pre-packed silica gel column. Eluting the column with ethyl acetate gave 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid [2-(2-hydroxy-ethoxy)-ethylcarbamoyl]-methyl ester as an off-white solid (24 mg, 15% yield). LCMS (ES+) m/z calcd. for C37H41Cl2F2N4O7 [(M+H)+]: 761. found: 761.
Reaction SMILES: [ClH:1].C(OC(=O)[N:8]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:9][CH2:10][N:11]1[CH2:18][CH:17]2[O:19][CH:13]([CH2:14][N:15]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)[CH2:16]2)[CH2:12]1)(C)(C)C>O1CCOCC1.C(OCC)C>[ClH:1].[CH2:29]([NH:8][CH2:9][CH2:10][N:11]1[CH2:12][CH:13]2[O:19][CH:17]([CH2:16][N:15]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=3)[CH2:14]2)[CH2:18]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N(CCN1CC2CN(Cc3ccc(C#N)cc3)CC(C1)O2)Cc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: N#Cc1ccc(CN2CC3CN(CCNCc4ccccc4)CC(C2)O3)cc1

Procedure:
Dioxane saturated with HCl gas (10 ml) was added to a solution of benzyl-{2-[7-(4-cyano-benzyl)-9-oxa-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-ethyl}-carbamic acid tert-butyl ester (0.65 g, from step (ii) above in 5 ml of dioxane and stirred for 1 h at RT under nitrogen atmosphere. The reaction mixture was diluted with dry diethylether, and the solvent was decanted. Precipitated solid was washed with dry diethylether (4 times) and dried under vacuum to give HCl salt of the sub-title compound (0.5 g) as a powder.
Reaction SMILES: [CH3:1][C:2]([CH3:30])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:29])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:28])=[CH:11]/[CH:12]=[CH:13]\[CH:14]=[C:15](/[CH3:27])\[CH2:16][CH2:17]/[CH:18]=[C:19](\[CH3:26])/[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24]>[Pd]>[CH3:25][CH:23]([CH2:22][CH2:21][CH2:20][CH:19]([CH2:18][CH2:17][CH2:16][CH:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([CH2:9][CH2:8][CH2:7][CH:6]([CH2:5][CH2:4][CH2:3][CH:2]([CH3:30])[CH3:1])[CH3:29])[CH3:28])[CH3:27])[CH3:26])[CH3:24]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/C=C\C=C(/C)CC/C=C(\C)CCC=C(C)C
Agent: [Pd]
Product: CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C
Temperature: 40 °C
Reaction time: 47 h
Yield: 83.4 %

Procedure:
Dehydrosqualene prepared above was placed in a one liter Parr pressure reactor and 1.1 g of 5% Pd/C was added. The vessel was sealed and evacuated under house vacuum for twenty minutes (ca. 20 ton) and then pressurized with hydrogen gas up to 950 psi. The reaction is initially exothermic. After the initial exothermic stage of the reaction was complete the reaction temperature was maintained at 40° C. by external heating and later at 60° C. Hydrogen gas was added as needed to maintain the reaction rate. After 47 hours the reaction was judged complete by GCMS analysis so the crude reaction product was filtered through a silica gel pad 3 inches in diameter×3 inches high and the silica gel was washed with 550 mL 5% ethyl acetate in hexanes. After removal of the solvent by rotary evaporation the crude squalane weighed 332.6 g. The product was distilled in 3 batches using a Kugelrohr bulb to bulb apparatus to give 282.4 g squalane (83.4% yield over both steps).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:15])[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[CH3:14])=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:24][CH2:25][CH:26]=[C:27]1[C:33]2[CH:34]=[CH:35][CH:36]=[N:37][C:32]=2[CH2:31][O:30][C:29]2[CH:38]=[CH:39][C:40]([OH:42])=[CH:41][C:28]1=2>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:15])[CH2:13][CH2:12][N:11]([CH2:24][CH2:25][CH:26]=[C:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[N:37][C:32]=4[CH2:31][O:30][C:29]4[CH:38]=[CH:39][C:40]([OH:42])=[CH:41][C:28]3=4)[CH2:10][CH:9]2[CH3:14])=[CH:4][CH:3]=1
Reactant: Oc1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: CC1CNCCC1(O)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1CN(CCC=C2c3cc(O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-Chloro-phenyl)-3-methyl-piperidin-4-ol (1.0 g, 4.6 mmol) in DMF (10 mL) with triethylamine (1.75 mL, 12.54 mmol), was added 5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-ol (1.38 g, 4.18 mmol) dropwise for over a period of about 1.5 hours at about 50° C. The reaction was stirred overnight at about 50° C. The reaction was quenched with water, extracted with ethyl acetate, and evaporated in vacuo. The residue was purified by silica gel chromatography (87:10:3 ethyl acetate:methanol:triethylamine) to yield a brown solid of the title compound.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]#[N:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.Cl.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1.C(Cl)(Cl)Cl>C(O)C>[NH2:12][C:11]1[N:21]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)[N:22]=[CH:4][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: NNc1ccc(Cl)cc1
Reactant: CCOC=C(C#N)C(=O)OCC
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnn(-c2ccc(Cl)cc2)c1N
Temperature: 25 °C
Yield: 47.8 %

Procedure:
A solution of ethyl ethoxymethylenecyanoacetate (3 g, 17.7 mmol) and 4-chlorophenylhydrazine hydrochloride (3.33 g, 18.6 mmol) in ethanol (60 mL) was refluxed for 2 days, following the procedure described in Schmidt, P. et al. Helv.Chim.Acta, 1959, 349. The reaction mixture was then allowed to cool to room temperature, whereupon a precipitate was formed. Cold CHCl3 was added, the precipitate was filtered and washed with more CHCl3. The filtrate and the washings were evaporated to dryness, precipitated with ether, filtered and dried to give ethyl 5-amino-1-(4-chlorophenyl)-1H-pyrazole-4-carboxylate (2.25 g, 48%) as a white solid: mp 150°-156° C.; 1H NMR (80 MHz, CDCl3) δ (TMS) 7.77 (s, 1H, pyrazole), 7.48 (s, 4H, arom), 4.30 (q, J=7, 2H, OCH2), 1.36 (t, J=7, 3H, OCH2CH3). Analysis calculated for C12H12ClN3O2 : C 54.25; H 4.55; N 15.81. Found: C 54.77; H 4.49; N 15.65.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:35]=[N:34][CH:33]=[CH:32][N:31]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])[C:13]([NH:29][C:30]2[CH:35]=[N:34][CH:33]=[CH:32][N:31]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2=O)C(=O)O)cc1Cl
Reactant: Nc1cnccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2=O)C(=O)Nc2cnccn2)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 51.1 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(2-oxo-cyclopentyl)-propionic acid (125 mg, 0.36 mmol) in methylene chloride (3.62 mL) cooled to 0° C. was treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.20 mL, 0.39 mmol) and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 10 min and at 25° C. for 20 min. The reaction mixture was then treated with a solution of 2-aminopyrazine (76 mg, 0.80 mmol) and pyridine (0.06 mL, 0.80 mmol) in tetrahydrofuran (1.81 mL). This solution was stirred at 25° C. for 1 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 75/25 ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(2-oxo-cyclopentyl)-N-pyrazin-2-yl-propionamide (77.6 mg, 50.7%) as a white foam: EI-HRMS m/e calcd for C19H20ClN3O4S (M+) 421.0863, found 421.0868.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH:9]([O:12][C:13]1[CH:18]=[C:17]([O:19][CH:20]([CH3:22])[CH3:21])[N:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[C:14]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28])([CH3:11])[CH3:10].Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34].O>COCCOC>[CH:20]([O:19][C:17]1[C:18]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:13]([O:12][CH:9]([CH3:10])[CH3:11])[C:14]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:15]([C:23]([F:24])([F:26])[F:25])[N:16]=1)([CH3:22])[CH3:21]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)c1c(OC(C)C)cc(OC(C)C)nc1C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1c(OC(C)C)nc(C(F)(F)F)c(C(=O)OCC)c1OC(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.2 %

Procedure:
To a -78° C. solution of 0.021 mol of LDA in DME (30 ml) was added a solution of 4.65 g (0.014 mol) of product of Example 6 in 20 ml of DME. The resulting solution was stirred for 10 minutes and treated with 2.7 ml (0.035 mol) of ethyl chloroformate. After stirring at -78° C. for 30 minutes the reaction mixture was warmed to room temperature in 30 minutes and poured into 50 ml of water. The mixture was extracted with ether. The ether extract was washed with 10% K2CO3, dried over CaSO4 and concentrated. The residue was first kugelrohr distilled at 0.15 torr (pot temperature 55° C.) to remove low boiling material (1.08 g), then distilled at 164°-173° C. (0.15 torr) to give 1.95 g (34.5%) of product as an oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.Cl.C1(C2C=CC=CC=2)C=CC=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[CH:26]=[CH:25][C:24]2[C:23](=[O:27])[CH:22](CCN3CCC(C4C=CC=CC=4)CC3)[CH2:21][CH2:20][C:19]=2[CH:18]=1)=[O:16].[CH3:48][C:49](C)([CH3:53])[CH2:50]CN.C(Cl)Cl.O>C1(C)C=CC=CC=1.CN(C=O)C>[CH3:48][C:49]([CH3:53])([CH3:50])[CH2:10][CH2:9][NH:14][C:15]([C:17]1[CH:26]=[CH:25][C:24]2[C:23](=[O:27])[CH2:22][CH2:21][CH2:20][C:19]=2[CH:18]=1)=[O:16]
Reactant: CC(C)(C)CCN
Reactant: O=C(Nc1ccccc1-c1ccccc1)c1ccc2c(c1)CCC(CCN1CCC(c3ccccc3)CC1)C2=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)CCNC(=O)c1ccc2c(c1)CCCC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 119.1 %

Procedure:
Oxalyl chloride (2M in CH2Cl2, 4.3 mL, 8.6 mmol) was added to a stirring suspension of acid 2 (0.90 g, 4.3 mmol) in toluene (20 mL). DMF (1 drop) was added and the reaction began bubbling. After 2 hours, the reaction was evaporated in vacuo. The residue was dissolved in CH2Cl2 (21 mL) and 3,3-dimethylbutylamine (0.87 g, 1.2 mL, 8.6 mmol) was added. After stirring at ambient temperature for 4 hours, the reaction was transferred to a separatory funnel with CH2Cl2 /H2O. Extraction with CH2Cl2 (3×30 mL) and drying over MgSO4 afforded 1.4 g of product after evaporation of the solvent. Flash chromatography (silica gel, 37 mm dia, 40% EtOAc/hexane) afforded 1.2 g of product. Recrystallization from EtOAc/hexane (10 mL/10 mL) afforded 0.89 g (75%) of pure crystalline title compound.
Reaction SMILES: [OH-].[NH4+].[N+:3]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=2)([O-])=O.[ClH:21]>[Pd].CO.C(OCC)C>[ClH:21].[NH2:3][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([C:17]([F:20])([F:18])[F:19])[CH:10]=2
Reactant: O=[N+]([O-])c1cnc2cc(C(F)(F)F)ccc2c1O
Agent: [Pd]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Solvent: CCOCC
Product: Nc1cnc2cc(C(F)(F)F)ccc2c1O
Reaction time: 4 h

Procedure:
A Parr flask was charged with methanol (40 mL), ammonium hydroxide (10 mL), 3-nitro-7-(trifluoromethyl)-4-quinolinol (12.8 g, 49.6 mmol) and palladium on carbon (1.0 g of 10%). The mixture was placed on a Parr apparatus under a hydrogen atmosphere at 40 psi (2.8 Kg/cm2) for 4 hours. The mixture was filtered and the catalyst was washed with methanol and dichloromethane. The combined organics were concentrated under vacuum to provide a green solid. The solid was dissolved in methanol and then combined with 1 N hydrochloric acid in anhydrous diethyl ether (150 mL). A precipitate formed almost immediately. The reaction mixture was allowed to stir for 16 hours. The precipitate was isolated by filtration, washed with diethyl ether and then dried in a vacuum oven at 80° C. to provide 9.3 g of 3-amino-7-(trifluoromethyl)-4-quinolinol hydrochloride as an off-white solid.
Reaction SMILES: CS[C:3]1[C@@:8]([O:14][C:15]2[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=2)([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][CH2:5][N:4]=1.[CH3:24][O:25][C:26]1[N:31]=[C:30]([C:32]([NH:34][NH2:35])=O)[CH:29]=[CH:28][C:27]=1[N:36]1[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]1.C(O)(=O)C>C(OCC)(=O)C>[CH3:24][O:25][C:26]1[N:31]=[C:30]([C:32]2[N:4]3[CH2:5][CH2:6][CH2:7][C@:8]([O:14][C:15]4[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=4)([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:3]3=[N:35][N:34]=2)[CH:29]=[CH:28][C:27]=1[N:36]1[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]1
Reactant: CCOC(=O)[C@@]1(Oc2cc(F)c(F)c(F)c2)CCCN=C1SC
Reactant: COc1nc(C(=O)NN)ccc1-n1cnc(C)c1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)[C@@]1(Oc2cc(F)c(F)c(F)c2)CCCn2c(-c3ccc(-n4cnc(C)c4)c(OC)n3)nnc21
Temperature: 100 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
To ethyl (3S)-2-(methylsulfanyl)-3-(3,4,5-trifluorophenoxy)-3,4,5,6-tetrahydropyridine-3-carboxylate (702 mg) and 6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-2-carbohydrazide (500 mg) was added acetic acid (3 mL), and the mixture was stirred at 100° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 10% aqueous potassium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (NH, ethyl acetate). The crudely-purified product was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (1.02 g).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31](=[O:33])[NH2:32])=[CH:27][N:26]=3)[CH:21]=2)[CH2:16]1)(C)(C)C>C(Cl)Cl>[NH2:14][CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([NH2:32])=[O:33])=[CH:27][N:26]=3)[CH:21]=2)[CH2:16]1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(Oc3ccc(C(N)=O)cn3)cc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CC(N)C3)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
Add TFA (5.37 g, 47.1 mmol) to a suspension of [5-(5-carbamoyl-pyridin-2-yloxy)-indan-2-yl]-carbamic acid tert-butyl ester (870 mg, 2.35 mmol) in DCM (30 ml) and stir at ambient temperature overnight. Concentrate mixture on rotary evaporator and purify on cation exchange column (5 g, Varian) to give the title compound (479 mg) as a white solid. Mass spectrum (ion spray): m/z=270 (M+1); 1HNMR (MeOH-d4): 8.61 (s, 1H), 8.22 (d, 1H), 7.24 (d, 1H), 6.98 (s, 1H), 6.94 (d, 1H), 6.90 (d, 1H), 3.80 (m, 1H), 3.18 (m, 2H), 2.72 (m, 2H).
Reaction SMILES: [CH3:1][Si:2]([CH3:26])([CH3:25])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[N:17]3[CH:18]=[CH:19][N:20]=[C:16]3[CH:15]=[C:14]([C:21]([NH:23][NH2:24])=[O:22])[N:13]=2)[CH:9]=[N:8]1.C(Cl)Cl.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>CCOC(C)=O>[C:37]([NH:24][NH:23][C:21]([C:14]1[N:13]=[C:12]([C:10]2[CH:9]=[N:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:26])([CH3:25])[CH3:1])[CH:11]=2)[N:17]2[CH:18]=[CH:19][N:20]=[C:16]2[CH:15]=1)=[O:22])(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: C[Si](C)(C)CCOCn1cc(-c2nc(C(=O)NN)cc3nccn23)cn1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)NNC(=O)c1cc2nccn2c(-c2cnn(COCC[Si](C)(C)C)c2)n1
Temperature: 0 °C
Yield: 81.3 %

Procedure:
In a 20 mL flask, 5-(1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine-7-carbohydrazide (45.1 mg, 0.121 mmol) was dissolved in DCM (604 μL, 0.121 mmol). After cooling to 0° C., triethylamine (20.2 μL, 0.145 mmol) and acetyl chloride (9.45 μL, 0.133 mmol) were added. The reaction mixture was allowed to warm to ambient temperature for 15 hours. This was then diluted in EtOAc and washed with water and brine. The organic layer was then dried with MgSO4, filtered and concentrated down to afford N′-acetyl-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine-7-carbohydrazide (40.9 mg, 81.5% yield) as a light yellow solid. MS (apci) m/z=416.2 (M+H).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1.[CH2:23]1COC[CH2:24]1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[CH:23][CH3:24])[CH:15]=1
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: C1CCOC1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Product: CC=Cc1cccc(C(=O)OC)c1
Reaction time: 0.5 h

Procedure:
A suspension solution of ethyltriphenylphosphonium bromide (1079.3 mg, 2.907 mmol) in THF (10 mL) was cooled to 0° C. LHMDS (2.781 mL, 2.781 mmol, 1.0 M in THF) was added dropwise, and the mixture was stirred for 30 minutes. A solution of 3-formyl-benzoic acid methyl ester (415.0 mg, 2.528 mmol) in THF (2.5 mL) was then added dropwise, and the mixture was stirred for 10 minutes and then stirred at room temperature overnight. The reaction mixture was quenched by adding a saturated aqueous ammonium chloride solution and then extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, and then dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 3-propenyl-benzoic acid methyl ester as a yellow transparent oily substance (218.2 mg, 49%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]([C:9]([F:12])([F:11])[F:10])[CH:4]([C:6](O)=[O:7])[NH2:5].B.C1COCC1.CCOC(C)=O.CCO>C1COCC1.O>[F:1][C:2]([F:13])([F:14])[CH:3]([C:9]([F:10])([F:11])[F:12])[CH:4]([NH2:5])[CH2:6][OH:7]
Reactant: NC(C(=O)O)C(C(F)(F)F)C(F)(F)F
Agent: B
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: NC(CO)C(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 4,4,4,4′,4′,4′-hexafluoro-DL-valine (0.500 g, 2.22 mmol) in THF (20 mL) was stirred under nitrogen at 25° C. Borane-THF complex (6.66 mL, 1.0 M in THF) was added dropwise and the resulting solution stirred for 4 h at 25° C. After this time period, the reaction was complete by TLC (10:2:1 EtOAc:EtOH:H2O). The reaction mixture was quenched by slow addition of 10% HOAc in MeOH (23 mL). After concentration, the residue was dissolved in Et2O (200 mL) and washed with saturated aqueous NaHCO3 (3×20 mL) and brine (20 mL), and then dried using Na2SO4. After concentration, the resulting residue was used directly in the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[C@H:10]([CH2:28]O)[NH:11][C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:20]([O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[S:40][CH2:28][C@H:10]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:30])[N:11]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(N[C@@H](CO)C(=O)OCc1ccccc1)c1ccccc1OCc1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CSC(c2ccccc2OCc2ccccc2)=N1

Procedure:
N-[2-(Benzyloxy)benzoyl]-L-serine benzyl ester (20 mg, 0.05 mmol) and Lawesson's reagent [2,4-bis(p-methoxyphenyl)-1,3-dithiadiphosphetane-2,4-disulfide] (20 mg, 0.05 mmol, 1 equiv.) were dissolved in toluene (15 mL). After being refluxed overnight under nitrogen, the reaction mixture was diluted with EtOAc (20 mL), washed with brine, dried over MgSO4, filtered, concentrated and chromatographed on silica gel eluting with hexanes/EtOAc (6/1) to yield thiazoline (7) as a clear oil. Rf=0.3 (hexanes/EtOAc, 6:1); 1H NMR (300 MHz, CDCl3) δ8.00 (dd, 1H, ArH), 7.51-7.49 (m, 2H, ArH), 7.42-7.25 (m, 9H, ArH), 7.02-6.95 (m, 2H, ArH), 5.28 (d, 1H, PhCHH), 5.20 (d, 1H, PhCHH), 5.18 (s, 2H, CH2Ph), 5.12 (dd, 1H, CHCH2), 3.60-3.47 (m, 2H, CHCH2); MS (FAB) m/z 404 MH+, measured exact mass: 404.1313, calculated exact mass: 404.1320.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=5[NH2:38])=[CH:27][CH:26]=4)=[O:24])(=[O:21])=[O:20])=[CH:15][C:14]=3[N+:39]([O-:41])=[O:40])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl[C:43]([O:45][CH3:46])=[O:44].C(N(CC)C(C)C)(C)C.Cl>CN(C1C=CN=CC=1)C.ClCCl>[C:1]12([CH2:11][NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=5[NH:38][C:43]([O:45][CH3:46])=[O:44])=[CH:27][CH:26]=4)=[O:24])(=[O:21])=[O:20])=[CH:15][C:14]=3[N+:39]([O-:41])=[O:40])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: Nc1cc(F)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(NCC34CC5CC(CC(C5)C3)C4)c([N+](=O)[O-])c2)cc1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Nc1cc(F)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(NCC34CC5CC(CC(C5)C3)C4)c([N+](=O)[O-])c2)cc1

Procedure:
A room temperature solution of Example 43B (30 mg, 0.051 mmol), methyl chloroformate (0.05 mL, 0.65 mmol), N,N-diisopropylethylamine (0.1 mL, 0.57 mmol) and DMAP (3 mg, 0.02 mmol) in dichloromethane (1 mL) was stirred for 16 hours, treated with 4M HCl (0.3 mL), and concentrated. The concentrate was purified by flash column chromatography on silica gel with 50-100% ethyl acetate/hexanes to provide the desired product. MS (ESI(−)) m/e 635 (M−H)−; 1H NMR (400 MHz, DMSO-d6) δ 8.89 (br s, 1H), 8.65 (d, 1H), 8.56 (t, 1H), 7.92 (, 3H), 7.43 (d, 2H), 7.35 (m, 3H), 7.12 (dt, 1H), 3.50 (s, 3H), 3.18 (d, 2H), 1.98 (m, 3H), 1.72-1.55 (m, 12H).