Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][C:35]([C:41]#[N:42])([C:38]([OH:40])=O)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([C@H:50]([NH2:52])[CH3:51])=[CH:46][CH:45]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([C@H:50]([NH:52][C:38]([C:35]2([C:41]#[N:42])[CH2:34][CH2:33][N:32]([C:30]([O:29][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:31])[CH2:37][CH2:36]2)=[O:40])[CH3:51])=[CH:46][CH:45]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(C(=O)O)CC1
Reactant: C[C@@H](N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)C1(C#N)CCN(C(=O)OC(C)(C)C)CC1)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 93.6 %

Procedure:
O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.255 g, 3.30 mmol) was added in one portion to 1-(tert-butoxycarbonyl)-4-cyanopiperidine-4-carboxylic acid (Intermediate 43) (0.763 g, 3 mmol), (R)-1-(4-chlorophenyl)ethanamine (0.462 mL, 3.00 mmol) and DIPEA (1.572 mL, 9.00 mmol) in DMA (20 mL) at 25° C. under nitrogen. The resulting solution was stirred at 60° C. for 4 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (150 mL), and washed sequentially with 1M aqueous citric acid (50 mL), water (50 mL), and saturated sodium hydrogen carbonate (100 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product thus obtained was concentrated, then purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in isohexane. Pure fractions were evaporated to afford (R)-tert-butyl 4-(1-(4-chlorophenyl)ethylcarbamoyl)-4-cyanopiperidine-1-carboxylate (1.100 g, 94%) as a colourless gum which solidified on drying under high vacuum. This material was then redissolved in DCM (20.00 mL), and trifluoroacetic acid (2.311 mL, 30.00 mmol) was added. The solution was stirred at room temperature for 3 hours, after which the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness to afford (R)—N-(1-(4-chlorophenyl)ethyl)-4-cyanopiperidine-4-carboxamide (0.720 g, 82%) as a colourless gum. This material was used directly in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH2:13])(=[O:12])=[O:11].[C:16](=S)=[S:17].[OH-].[K+].C(OCC)(=O)C>CN(C)C=O>[F:15][C:2]([F:1])([F:14])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]=[C:16]=[S:17])(=[O:11])=[O:12]
Reactant: NS(=O)(=O)c1ccccc1OC(F)(F)F
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S(=O)(N=C=S)c1ccccc1OC(F)(F)F
Temperature: 35 °C

Procedure:
24.1 g (0.1 mole) of 2-trifluoromethoxy-benzene-sulphonic acid amide are dissolved in 100 ml of dimethylformamide. 7.6 g (0.1 mole) of carbon disulphide and 5.6 g (0.1 mole) of potassium hydroxide powder are added and the reaction mixture is stirred at 35° C. until a clear solution has formed. A further 5.6 g (0.1 mole) of potassium hydroxide powder are then added and stirring is continued until a clear solution is formed. 100 ml of ethyl acetate are then added dropwise at 20° C. The product thereby obtained as crystals is isolated by filtration with suction and dried under reduced pressure. The dried product is suspended in 100 ml of toluene; 20 g of liquid phosgene are added dropwise at 0° C. and the mixture is stirred at 5° C. to 10° C. for one hour and at 20° C. for two hours. After filtration, the filtrate is concentrated to give an oily residue, which essentially contains 2-trifluoromethoxy-phenylsulphonyl isothiocyanate. Because of its low stability, the product is reacted as quickly as possible--without further purification--in the process according to the invention.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[C:5](=[O:13])[CH2:4][CH2:3]1.[OH-].[K+].[CH3:17][N:18]([CH3:22])[C:19](Cl)=[S:20]>O.O1CCCC1>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([O:12][C:19]([N:18]([CH3:22])[CH3:17])=[S:20])=[CH:9][CH:10]=2)[C:5](=[O:13])[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(=O)c2cc(O)ccc21
Reactant: CN(C)C(=S)Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=S)Oc1ccc2c(c1)C(=O)CCC2(C)C
Reaction time: 0.17 h

Procedure:
To a solution of 4,4-dimethyl-7-hydroxy-1-tetralone (XIV) (3.07 g, 16.16 mmol) in water (10.77 mL) containing potassium hydroxide (904 mg) cooled below 10° C. was added N,N-dimethylthiocarbamoyl chloride (2.67 g, 21.6 mmol) in tetrahydrofuran (4.30 mL); the reaction temperature kept below 12° C. After 10 minutes, reaction mixture is made basic by the addition of a 10% aqueous KOH solution (5.39 mL). Product is extracted with ethyl acetate (2×50 mL), organic phases concentrated in vacuo and the residue chromatographed on silica gel (eluted with 10% ethyl acetate in hexane) to give 3.74 g (Y: 84%) of title product; 1H-NMR (CDCl3): δ 7.68 (d, J=2.6 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.27 (dd, J=8.5, 2.6 Hz, 1H), 3.46 (s, 3H), 3.34 (s, 3H), 2.73 (t, J=6.8 Hz, 2H), 2.04 (t, J=6.8 Hz, 2H), 1.41 (s, 6H); MS (DCI) m/e: 278 (MH+).
Reaction SMILES: I.[NH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([N:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:19])[C:13]=3[C:12]3=[N:20][O:21][C:22]([CH3:23])=[C:11]3[C:10]2=[O:24])[CH2:4]1.[C:25]1([S:31]([N:34]([CH2:41][C:42](O)=[O:43])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:25]1([S:31]([N:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[CH2:41][C:42]([NH:2][CH:3]2[CH2:8][CH2:7][CH2:6][CH:5]([N:9]3[C:18]4[CH:17]=[CH:16][CH:15]=[C:14]([Cl:19])[C:13]=4[C:12]4=[N:20][O:21][C:22]([CH3:23])=[C:11]4[C:10]3=[O:24])[CH2:4]2)=[O:43])(=[O:33])=[O:32])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)CN(c1ccccn1)S(=O)(=O)c1ccccc1
Reactant: Cc1onc2c1c(=O)n(C1CCCC(N)C1)c1cccc(Cl)c21
Agent: CN(C)c1ccncc1
Agent: I
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1onc2c1c(=O)n(C1CCCC(NC(=O)CN(c3ccccn3)S(=O)(=O)c3ccccc3)C1)c1cccc(Cl)c21
Temperature: 25 °C
Reaction time: 144 h
Yield: 47 %

Procedure:
To a solution of 5-(3-amino-cyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one hydroiodide, 130 mg (0.28 mmol) in 10 mL of DMF was added 82 mg (0.28 mmol) of (benzenesulfonyl-pyridin-2-yl-amino)-acetic acid (Bionet), 46 mg (0.34 mmol) of 1-hydroxy-7-azabenzo-triazole, 66 mg (0.34 mmol) of EDC, 5 mg of DMAP and 120 μL (0.84 mmol) of TEA. The reaction mixture was stirred six days at rt. and was concentrated to dryness. The residue was dissolved in 20% isopropanol/chloroform, washed with saturated NaHCO3, washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by radial chromatography using a MeOH/chloroform gradient and concentrated to dryness. The residue was slurried in ether/hexanes and concentrated to dryness to yield 79 mg (47%) of the title compound as a tan foam. MS (ion spray) 606.1 (M+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(NC(C)C)(C)C.[CH:15]([OH:18])([CH3:17])[CH3:16]>>[CH:15]([O:18][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1)([CH3:17])[CH3:16]
Reactant: Clc1ncccn1
Reactant: CC(C)O
Solvent: CC(C)NC(C)C
Product: CC(C)Oc1ncccn1
Temperature: 130 °C

Procedure:
A 2-chloropyrimidine was dissolved in isopropyl alcohol to which was added diisopropylamine. The reaction was heated in a sealed tube for ten days at 130° C. The cooled reaction mixture was concentrated, and the product purified via silica gel column chromatography to yield the 2-isopropoxypyrimidine.
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([CH3:18])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:30]([C:29]1[CH:28]=[CH:27][C:26]([CH:23]2[CH2:24][CH2:25][N:20]([C:9]([C:8]3[C:7]([CH3:18])=[CH:6][C:5]([CH:1]4[CH2:2][CH2:3][CH2:4]4)=[C:13]([CH:12]=3)[C:14]([O:16][CH3:17])=[O:15])=[O:11])[CH2:21][CH2:22]2)=[CH:33][CH:32]=1)#[N:31]
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: COC(=O)c1cc(C(=O)O)c(C)cc1C1CCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)c(C)cc1C1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a round-bottom flask was added a solution of 4-cyclobutyl-5-(methoxycarbonyl)-2-methylbenzoic acid (compound 230.2, 2.10 g, 8.46 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL). 4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 1.88 g, 8.44 mmol, 1.00 equiv), EDC.HCl (3.22 g, 16.8 mmol, 2.00 equiv), and 4-dimethylaminopyridine (3.10 g, 25.4 mmol, 3.00 equiv) were added to the reaction. The resulting solution was stirred overnight at 25° C., then diluted with 100 mL of ethyl acetate. The mixture was washed with 2×30 mL of NH4Cl (aq., sat.) and 2×30 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (0:1-1:3) as eluent to yield 3.20 g (91%) of methyl 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzoate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Cl:10][CH2:11][C:12](Cl)=[O:13]>C(Cl)Cl.N1C=CC=CC=1>[Cl:10][CH2:11][C:12]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9])=[O:13]
Reactant: O=C(Cl)CCl
Reactant: Nc1cc(Cl)ccc1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCl)Nc1cc(Cl)ccc1O
Reaction time: 18 h
Yield: 55 %

Procedure:
To a cooled (0° C.) solution of 2-amino-4-chlorophenol (30 g, 209 mmol) in DCM (200 mL) and pyridine (17 mL) was added a solution of chloroacetyl chloride in DCM (23.6 g, 230 mmol in 75 mL). The mixture was allowed to reach rt slowly and was subsequently stirred for 18 h. The precipitate was filtered, washed with DCM, and dried overnight at 50° C. to give crude 2-chloro-N-(5-chloro-2-hydroxyphenyl)acetamide (intermediate 56) (26 g, 55%), as a brown solid which was used in the next step without any further purification.
Reaction SMILES: [C:1]([C@:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].I[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1>>[CH3:17][C@@:3]1([C:1]#[C:2][C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: C#C[C@]1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: Ic1cccs1
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(C#Cc1cccs1)O2

Procedure:
This enantiomer was obtained as described in Example 4 by reacting the (S)-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol from Example 11 with 2-iodothiophene. It was isolated by chromatography as above and was crystallized from ether/hexane to yield colorless crystals with m.p. 131°-134° C. [α]D25 =+34.9° (c=1.145 in MeOH).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:18][C:19]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:20]=1[NH2:21]>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:21][C:20]1[C:22]([CH3:26])=[CH:23][CH:24]=[CH:25][C:19]=1[CH3:18])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cccc(C)c1N
Reactant: CCCC(=O)c1cnc2c(C)cccc2c1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(C)cccc2c1Nc1c(C)cccc1C

Procedure:
3-Butyryl-4-chloro-8-methylquinoline (2.48 g, 10 mmol) and 2,6-dimethylaniline (1.85 ml, 15 mmol) in dioxan (10 ml) were heated at reflux for 30 minutes, then the solvent evaporated and the product converted to free base. Recrystallisation from aqueous ethanol gave 3-butyryl-4-(2,6-dimethylphenylamino)-8-methylquinoline, m.p. 100°-101°.
Reaction SMILES: C(N(CC)CC)C.Br[C:9]([F:21])([F:20])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[C:22]([NH:32][CH2:33][C:34](=[O:40])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(#N)C>[C:22]([NH:32][CH2:33][C:34](=[O:40])[CH2:35][CH2:36][C:37]([O:39][C:9]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])([F:21])[F:20])=[O:38])([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]
Reactant: O=C(OCc1ccccc1)C(F)(F)Br
Reactant: O=C(O)CCC(=O)CNC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(CCC(=O)OC(F)(F)C(=O)OCc1ccccc1)CNC(=O)OCc1ccccc1
Yield: 74.5 %

Procedure:
Triethylamine (3.5 mL; 2.5 g; 25 mmol) was added using a syringe to a stirred mixture of the crude product of 3a (8.6 g; 20 mmol) and 5-(Cbz-amino)-4-oxopentanoic acid (6.63 g; 25 mmol) in dry acetonitrile (100 mL). The mixture was refluxed for 18 h, then the solvent was evaporated and the dark red residue was dissolved in diethyl ether (100 mL) and 0.5 M HCl (100 mL). After mixing thoroughly, the ether layer was washed with water (2×15 mL), saturated NaHCO3 (2×15 mL), and saturated NaCl solution (1×15 mL), then dried (MgSO4). After filtration and evaporation, the residue was purified by flash chromatography on a 60×55 mm silica gel 60 column eluted with dichloromethane-diethyl ether (9:1) (1000 mL), collecting 10×75 mL fractions. After evaporation of fractions 2-5 and vacuum-drying (0.02 mm Hg), 6.7 g (74%) product was obtained (red-orange solid mp 48-50° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9][CH2:10][N:11]([CH3:15])[CH2:12][CH2:13][NH2:14])=[CH:4][CH:3]=1.[C:22]([NH:24][C:25](=[N:33][CH2:34][CH2:35][CH2:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)[CH:39]=1)OC1C=CC=CC=1)#[N:23]>>[C:22]([NH:24][C:25]([NH:14][CH2:13][CH2:12][N:11]([CH2:10][CH2:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH3:15])=[N:33][CH2:34][CH2:35][CH2:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][N:45]2[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]2)[CH:39]=1)#[N:23]
Reactant: N#CNC(=NCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Reactant: CN(CCN)CCC(c1ccc(F)cc1)c1ccccn1
Product: CN(CCNC(=NCCCOc1cccc(CN2CCCCC2)c1)NC#N)CCC(c1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.7 g (2.4 mmol) of N-[3-(4-fluorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,2-ethanediamine and 0.95 g (2.4 mmol) of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int.[%])=586 ([M+H]+, 1), 214 (100).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([OH:21])=[O:20]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([C:16]3[CH:24]=[CH:23][CH:22]=[C:18]([C:19]([OH:21])=[O:20])[CH:17]=3)[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Product: O=C(O)c1cccc(N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)c1
Yield: 73.9 %

Procedure:
4-nitrophthalic anhydride (0.25 g, 0.0013 mol) and m-aminobenzoic acid (0.18 g, 0.0013 mol) were refluxed as above overnight. The clear solution was purified as per 120 to yield 0.30 g (74%) 146 as a very pale dull yellow powder: mp=368-370° C.; Rf0.83 (A): Rf0.93 (C): Rf0.53 (D): IR (cm−1): 2700-3280 (OH), 3122 (C═CH), 2687 (C—H), 1781 (C═O), 1727 (bs, C═O), 1622 (C═C), 1588 (C═C), 1546 (N═O), 1461 (C═C), 1420 (C═C), 1386 (C—O), 1350 (N═O), 1113 (C—O), 727 (C═CH); MS m/z (rel intensity) 311 (68), 285 (46), 267 (46), 191 (100).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21](/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26])[N:22]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C1COCC1.CO.[C].[Pd]>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])[N:22]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: COc1ccc(-c2c(-c3nc(/C=C/C(=O)O)cs3)cnn2C(C)(C)C)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2c(-c3nc(CCC(=O)O)cs3)cnn2C(C)(C)C)cc1
Yield: 89.4 %

Procedure:
A mixed solution of (E)-3-(2-(1-(tert-butyl)-5-(4-methoxyphenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acrylic acid (70 mg, 0.18 mmol) and 10% palladium carbon (19.43 mg, 0.18 mmol) in THF (2 mL) and methanol (2 mL) was stirred under 1 atm hydrogen atmosphere at room temperature for 14 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was crystallized from diethyl ether to give 3-(2-(1-(tert-butyl)-5-(4-methoxyphenyl)-1H-pyrazol-4-yl)thiazol-4-yl)propanoic acid (62.0 mg, 0.161 mmol, 88%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][C:8]([CH3:13])([CH3:12])[CH2:7][C:5]=2[N:6]=1.C1N=[CH:17][N:16]([C:19](N2C=NC=C2)=[O:20])[CH:15]=1.C1CCN2C(=NCCC2)CC1.CNC>C(#N)C>[CH3:12][C:8]1([CH3:13])[CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:19](=[O:20])[N:16]([CH3:17])[CH3:15])[S:3][C:4]=2[C:10](=[O:11])[CH2:9]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC1(C)CC(=O)c2sc(N)nc2C1
Agent: CNC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CN(C)C(=O)Nc1nc2c(s1)C(=O)CC(C)(C)C2
Temperature: 100 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a solution of 2-amino-5,5-dimethyl-5,6-dihydro-4H-benzothiazol-7-one (151 g, 0.768 mol) in acetonitrile (5 L) are added CDI (249 g, 1.53 mol) and DBU (233 g, 1.53 mol). The reaction mixture is stirred overnight at 100° C. Dimethylamine (310 g, 3.83 mol) is added at RT and the stirring is continued overnight at 100° C. After cooling to RT, the reaction mixture is concentrated in vacuo and the residue is poured into ice water. The pH of the mixture is adjusted to pH 5 with HCl (6 M). The aqueous mixture is extracted with ethyl acetate (4×500 mL). The combined organic layers are washed with brine (500 mL) and dried over anhydrous Na2SO4. The solvent is evaporated in vacuo to give crude product. The crude product is washed with water to give 3-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-1,1-dimethyl-urea (169 g, 82% yield).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3].Br[CH2:13][C:14]([C:16]1C=CC=C[CH:17]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+].Cl>CC(=O)CC.C(OCC)(=O)C>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([O:11][CH2:13][C:14]([CH2:16][CH3:17])=[O:15])[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cccc(O)c1
Reactant: O=C(CBr)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: C=CCOc1cccc(OCC(=O)CC)c1

Procedure:
A solution of 3-allyloxyphenol (1.19 g), 2-bromoacetophenone (1.0 g) and potassium carbonate (1.10 g) in 2-butanone (15 ml) was refluxed for four hours. The mixture was partioned between 0.2N HCl and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, concentrated in vacuo. Column Chromatography (silica gel 60, 50% methylene chloride in hexane) gave the title compound.
Reaction SMILES: N[C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](N4N=NC(CC)=N4)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1.[ClH:45].[C:46]1([CH:52]([C:94]2[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=2)[CH2:53][NH:54][C:55]2[N:63]=[C:62]([N:64]3[CH2:68][CH2:67][C@@H:66]([NH:69][C:70](NCC4C=CC=CN=4)=[O:71])[CH2:65]3)[N:61]=[C:60]3[C:56]=2[N:57]=[CH:58][N:59]3[C@@H:80]2[CH2:84][C@H:83]([N:85]3[N:89]=[N:88][C:87]([CH2:90][CH3:91])=[N:86]3)[C@@H:82]([OH:92])[C@H:81]2[OH:93])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[C:100]1([C:106]2[S:107][CH:108]=[C:109]([CH2:111][NH2:112])[N:110]=2)[CH:105]=[CH:104][CH:103]=[CH:102][CH:101]=1>>[ClH:45].[C:94]1([CH:52]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:53][NH:54][C:55]2[N:63]=[C:62]([N:64]3[CH2:68][CH2:67][C@@H:66]([NH:69][C:70]([NH:112][CH2:111][C:109]4[N:110]=[C:106]([C:100]5[CH:101]=[CH:102][CH:103]=[CH:104][CH:105]=5)[S:107][CH:108]=4)=[O:71])[CH2:65]3)[N:61]=[C:60]3[C:56]=2[N:57]=[CH:58][N:59]3[C@@H:80]2[CH2:84][C@H:83]([N:85]3[N:89]=[N:88][C:87]([CH2:90][CH3:91])=[N:86]3)[C@@H:82]([OH:92])[C@H:81]2[OH:93])[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=1
Reactant: NCc1csc(-c2ccccc2)n1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccccn6)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: Cl
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6csc(-c7ccccc7)n6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from ((1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Example 48) using a procedure analogous to that of 1-((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-2-ylmethyl-urea hydrochloride (Example 113) by replacing 2-aminomethyl pyridine with C-(2-phenyl-thiazol-4-yl)-methylamine. MS (ES+) m/e 812.46 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH:5]([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][C:11]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[CH2:10][CH2:9]1)[CH3:2].[H-].[Na+].FC(F)(F)S(O[CH2:45][CH3:46])(=O)=O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:36])[C:5]([CH2:45][CH3:46])([S:32]([CH3:35])(=[O:33])=[O:34])[CH2:6][CH2:7][CH:8]1[CH2:9][CH2:10][C:11]([S:22]([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)(=[O:24])=[O:23])([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[CH2:12][CH2:13]1)[CH3:2]
Reactant: CCOS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)C(CCC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1)S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC)(CCC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1)S(C)(=O)=O
Reaction time: 0.75 h
Yield: 12.3 %

Procedure:
A solution of the product from Example 108 (620 mg, 1.10 mmol) in N,N-dimethylformamide (2.5 mL) was added dropwise to a solution of sodium hydride (60% dispersion in mineral oil, 48 mg, 1.21 mmol) in N,N-dimethylformamide (2.5 mL), and stirred for 45 minutes. Ethyl trifluoromethanesulfonate (0.140 mL, 1.10 mmol) was added dropwise and stirred for 14 hours at room temperature. The reaction was partitioned between diethyl ether (150 mL) and 1M aqueous hydrochloric acid (150 mL), the phases were separated and the aqueous layer extracted with diethyl ether. The combined organic layers were washed with 1N aqueous sodium hydrogencarbonate and brine, dried over MgSO4 and concentrated. The residue was chromatographed using a Biotage™ 40S column, eluting with 70/30 iso-hexane/acetone to give the title compound (80 mg).