Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@H:10]1[C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=1[O:48][CH3:49])C1C=CC=CC=1>CO.O1CCCC1.[C].[Pd]>[CH3:49][O:48][C:41]1[CH:42]=[C:43]([O:46][CH3:47])[CH:44]=[CH:45][C:40]=1[C@@H:10]1[O:11][C@H:12]([CH2:31][OH:32])[C@@H:13]([OH:23])[C@H:14]([OH:15])[C@H:9]1[OH:8]
Reactant: COc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c(OC)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c(OC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94 %

Procedure:
To a solution of 1-deoxy-2,3,4,6-tetra-O-benzyl-1-(2,4-dimethoxyphenyl)-β-D-glucopyranose (1.1 g) in methanol (10 mL) and tetrahydrofuran (5 mL) was added 10% palladium-carbon powder (0.50 g), and the mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (0.47 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:24]3[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:30]([O:34][C:35]([NH:37][CH2:38][C:39](O)=[O:40])=[O:36])([CH3:33])([CH3:32])[CH3:31].Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CN(C)C1C=CN=CC=1>[C:30]([O:34][C:35]([NH:37][CH2:38][C:39]([O:29][CH:26]1[CH2:27][CH2:28][CH:24]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=3[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[CH:9]2)[CH2:25]1)=[O:40])=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)OC1CCC(n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentanol (50 mg, 0.129 mmol) and N-tert-butoxycarbonyl glycine (34 mg, 0.194 mmol) was mixed in N,N-dimethylformamide (1 ml). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31 mg, 0.155 mmol) and 4-dimethylamino pyridine (16 mg, 0.129 mmol) was added. The resulting mixture was stirred under nitrogen at ambient temperature for 24 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic extracts were washed with brine, dried (MgSO4), filtered and evaporated. The solid was purified by flash column chromatography on silica using ethyl acetate as the mobile phase to give 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl 2-[(tert-butoxycarbonyl)amino]acetate. The structure was confirmed by 1H NMR.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[CH2:11](Br)[CH:12]=[C:13]([CH2:15][CH2:16][CH:17]=[C:18]([CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH3:19])[CH3:14]>C1COCC1.CCCCCC>[O:4]=[C:3]([CH2:5][CH2:11][CH:12]=[C:13]([CH3:14])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:19])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH2:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCBr
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Methyl acetoacetate (225 μL, 2.1 mmol) was added dropwise to a stirred suspension of sodium hydride (50% oil suspension, prewashed with hexane) (100 mg, 2.1 mmol) in anhydrous THF (5 mL) at 0° C. under an Argon atmosphere. The resulting solution was stirred 15 minutes at 0° C. and then treated with a 1.6 M solution (1.3 mL, 2.1 mmol) of n-butylithium in hexane over 2 minutes. The yellow solution was stirred 15 min at 0° C. and then treated dropwise with farnesyl bromide (545 KL, 2.0 mmol). The cloudy orange solution was stirred at 20° C. for 1 1/2 hours and then quenched by dropwise addition of saturated aqueous NH4Cl solution. The resulting mixture was diluted with ethyl acetate and washed with water, dried, filtered and evaporated to give the crude product which was used in the next step without purification. Diagnostic peaks in the NMR (300 MHz, CDCl3): δ 1.600 (6H, s), 1.614 (3H,s), 1.68 (3H, s), 1.9-2.1 (8H, m), 2.2-2.33 (2H, m), 2.58 (2H, t, J=6Hz), 3.448 (2H, s), 3.740 (3H,s), 5.05-5.15 (3H, m).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][C:12]1[NH:13][CH:14]=[CH:15][N:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:11][C:12]1[N:13]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:14]=[CH:15][N:16]=1
Reactant: Cc1ncc[nH]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nccn1-c1ccc([N+](=O)[O-])cc1
Temperature: 120 °C
Reaction time: 48 h
Yield: 112.5 %

Procedure:
A mixture of 50.0 g of p-fluoronitrobenzene, 85.93 g of 2-methylimidazole and 44.9 g of potassium carbonate in 860 ml of dimethylsulfoxide is heated at 120° C. for 24 hours. The mixture is poured into 2.5 liter of water and stored in a refrigerator for two days. The mixture is filtered and cake washed with copious volumes of water and vacuum dried. The cake is dissolved in 1500 ml of ethyl acetate, filtered through hydrous magnesium silicate and the filtrate reduced to about 500 ml, cooled and the resulting solid, filtered, and air dried to give 81.0 g of the desired product as brown crystals, m.p. 135°-137° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=3)[CH2:18][CH:17]([NH2:29])[CH2:16]2)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1.[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=3)[CH2:18][CH:17]([NH:29][C:37]([NH:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:38])[CH2:16]2)=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: O=C=Nc1ccccc1
Reactant: CCc1ccc(C2CC(N)CN(C(=O)C3CCCC3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)Nc3ccccc3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
108 mg (0.22 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-amine trifluoroacetate (Example 8A) and 31 mg (0.26 mmol, 1.2 eq.) of phenyl isocyanate were reacted according to General Method 4. Yield: 72 mg (79% of theory)
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[S:20]1[C:24]([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH:28]=O)=[CH:23][N:22]=[CH:21]1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([C:24]3[S:20][CH:21]=[N:22][CH:23]=3)[CH:26]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cccc(-c2cncs2)c1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2cncs2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 3-(thiazol-5-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.78 min.; [M+H]+: 409.08 g/mol.
Reaction SMILES: BrCC1CC1(F)F.Br[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.[CH3:17][C:18]1[N:19]=[C:20]([N:28]2[C:32](=[O:33])[NH:31][N:30]=[CH:29]2)[S:21][C:22]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:31]2[C:32](=[O:33])[N:28]([C:20]3[S:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:18]([CH3:17])[N:19]=3)[CH:29]=[N:30]2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Reactant: Fc1ccc(CBr)cc1
Agent: FC1(F)CC1CBr
Product: CCOC(=O)c1sc(-n2cnn(Cc3ccc(F)cc3)c2=O)nc1C
Yield: 84 %

Procedure:
Following the procedure as described in Preparation 13, making variation as required to replace bromomethyl-2,2-difluorocyclopropane with 1-(bromomethyl)-4-fluorobenzene to react with ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate in place of ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a white solid in 84% yield: 1H NMR (300 MHz, CDCl3) δ 8.27 (s, 1H), 7.47-7.30 (m, 2H), 7.11-6.97 (m, 2H), 4.98 (s, 2H), 4.32 (q, J=7.1 Hz, 2H), 2.65 (s, 3H), 1.34 (t, J=7.1 Hz, 3H); MS (ES+) m/z 363.1 (M+1).
Reaction SMILES: [CH:1]([CH:3]([NH:8][C:9](=[O:19])[C@H:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[NH:11][C:12](=[O:14])[CH3:13])[CH2:4][CH2:5][CH2:6][CH3:7])=[O:2].[CH2:20](O)[CH2:21][OH:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:2]1[CH2:20][CH2:21][O:22][CH:1]1[CH:3]([NH:8][C:9](=[O:19])[C@H:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[NH:11][C:12](=[O:14])[CH3:13])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCC(C=O)NC(=O)[C@H](CC(C)C)NC(C)=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCC(NC(=O)[C@H](CC(C)C)NC(C)=O)C1OCCO1

Procedure:
In 20 ml of benzene was dissolved 750 mg of N-acetyl-L-leucine-(1-formyl)pentylamide obtained in the same manner as in Example 16-(c), and 1.8 ml of ethylene glycol and a catalytic amount of p-toluenesulfonic acid were added thereto. The mixture was heated at reflux for 3.5 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was purified by medium-pressure column chromatography on silica gel to obtain 650 mg of the titled compound as a colorless crystal.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH:15]2[CH2:17][CH2:16]2)[C@H:10]([CH2:18][N:19]([C:23](=[O:37])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([O:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])[CH:25]=2)[CH:20]([CH3:22])[CH3:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].C(N([CH2:44][CH3:45])CC)C>>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([CH2:18][N:19]([C:23](=[O:37])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([O:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])[CH:25]=2)[CH:20]([CH3:22])[CH3:21])[C@H:11]([CH2:13][N:14]([CH:15]2[CH2:16][CH2:17]2)[C:1](=[O:5])[CH2:2][C:45]2[CH:44]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:12]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNC2CC2)C(C)C)ccc1C
Reactant: CCN(CC)CC
Agent: [Cl-]
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C(=O)Cc2ccccc2)C2CC2)C(C)C)ccc1C

Procedure:
From (3R,4R)-3-({[4-methyl-3-(3-methoxy-propoxy)-benzoyl]-isopropyl-amino}-methyl)-4-cyclopropylaminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.3 g, 0.579 mmol), phenylacethyl chloride (0.092 mL, 0.695 mmol) and triethylamine (0.12 mL, 0.869 mmol) and purification by flash chromatography (c-hexane/AcOEt 1:1 to 0:1) to give the title compound as colorless oil. TLC, Rf (AcOEt/c-hexane 4:1)=0.15. MS (LC-MS): 610.3 [M+H]+; (LC-MS Waters Symmetry C18, 2.1×30 mm, 20-100% CH3CN/5 min): 4.63 min.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:20]=[CH:19][C:18]2[NH:17][C:16]3[C:11](=[CH:12][C:13]([NH:21][C:22](=[O:26])[CH2:23][CH2:24]Cl)=[CH:14][CH:15]=3)[C:10](=[O:27])[C:9]=2[CH:8]=1)=[O:5].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([CH2:2][CH2:3][C:4]([NH:6][C:7]2[CH:20]=[CH:19][C:18]3[NH:17][C:16]4[C:11](=[CH:12][C:13]([NH:21][C:22](=[O:26])[CH2:23][CH2:24][N:17]5[CH2:18][CH2:9][CH2:10][CH2:11][CH2:16]5)=[CH:14][CH:15]=4)[C:10](=[O:27])[C:9]=3[CH:8]=2)=[O:5])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C1CCNCC1
Reactant: O=C(CCCl)Nc1ccc2[nH]c3ccc(NC(=O)CCCl)cc3c(=O)c2c1
Product: O=C(CCN1CCCCC1)Nc1ccc2[nH]c3ccc(NC(=O)CCN4CCCCC4)cc3c(=O)c2c1

Procedure:
Chloroamide 13 (400 mg, 1.0 mmol) was treated with piperidine (3 mL) according to the general aminolysis procedure to give the desired product BR-ACO-17 (300 mg, 61%) as a dark yellow solid.
Reaction SMILES: C(OC(=O)COC1C=CC(SC2C=C(OC3CCCC3)C=C(Br)C=2)=CC=1C)C.C1(C#C)C=CC=CC=1.[CH2:37]([O:39][C:40](=[O:77])[CH2:41][O:42][C:43]1[CH:48]=[CH:47][C:46]([S:49][C:50]2[CH:55]=[C:54]([C:56]#[C:57][C:58]3[CH:63]=[CH:62][C:61](CO)=[CH:60][CH:59]=3)[CH:53]=[C:52]([O:66][CH2:67][CH2:68][C:69]3C=C[C:72](Cl)=[CH:71][CH:70]=3)[CH:51]=2)=[CH:45][C:44]=1[CH3:76])[CH3:38]>>[CH2:37]([O:39][C:40](=[O:77])[CH2:41][O:42][C:43]1[CH:48]=[CH:47][C:46]([S:49][C:50]2[CH:55]=[C:54]([C:56]#[C:57][C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)[CH:53]=[C:52]([O:66][CH2:67][CH:68]3[CH2:72][CH2:71][CH2:70][CH2:69]3)[CH:51]=2)=[CH:45][C:44]=1[CH3:76])[CH3:38]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Agent: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OC3CCCC3)c2)cc1C
Solvent: C#Cc1ccccc1
Product: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccccc3)cc(OCC3CCCC3)c2)cc1C

Procedure:
The title product was prepared from [4-(3-Bromo-5-cyclopentyloxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (300 mg; 0.63 mmol), phenylacetylene (191.7 mg; 1.88 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 200 mg (64%). HPLC-MS: m/z: 500.8 (M)+; Rt: 3.30 min.
Reaction SMILES: [C:1]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:14]O.S(=O)(=O)(O)O>ClCCCl>[C:1]1([C:11]([O:13][CH3:14])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc2ccccc12
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: COC(=O)c1cccc2ccccc12
Temperature: 60 °C
Reaction time: 17 h
Yield: 87 %

Procedure:
The synthesis method of Example 7-(1) was applied. 1--Naphthoic acid (4.97 g), methanol (10 ml), 1,2-dichloroethane (12 ml) and concentrated sulfuric acid (0.6 ml) were used as reagents and the mixture was stirred at 60° C. for 17 hours. After the reaction, the mixture was extracted with ether to give 4.35 g of a pale-yellow transparent liquid (yield 87%).
Reaction SMILES: B(F)(F)F.CCOCC.[C:10]([CH2:12][C:13]1([N:33]2[CH:37]=[C:36]([C:38]3[C:39]4[CH:46]=[CH:45][N:44](COCC[Si](C)(C)C)[C:40]=4[N:41]=[CH:42][N:43]=3)[CH:35]=[N:34]2)[CH2:16][N:15]([C:17]2[N:18]=[CH:19][C:20]([C:23]([NH:25][C:26]3([C:29]([F:32])([F:31])[F:30])[CH2:28][CH2:27]3)=[O:24])=[N:21][CH:22]=2)[CH2:14]1)#[N:11].[OH-].[NH4+].C([O-])(O)=O.[Na+]>C(#N)C.O>[C:10]([CH2:12][C:13]1([N:33]2[CH:37]=[C:36]([C:38]3[C:39]4[CH:46]=[CH:45][NH:44][C:40]=4[N:41]=[CH:42][N:43]=3)[CH:35]=[N:34]2)[CH2:16][N:15]([C:17]2[N:18]=[CH:19][C:20]([C:23]([NH:25][C:26]3([C:29]([F:31])([F:30])[F:32])[CH2:27][CH2:28]3)=[O:24])=[N:21][CH:22]=2)[CH2:14]1)#[N:11]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5cnc(C(=O)NC6(C(F)(F)F)CC6)cn5)C4)c3)ncnc21
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CC#N
Solvent: CCOCC
Solvent: O
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(c2cnc(C(=O)NC3(C(F)(F)F)CC3)cn2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
Boron trifluoride etherate (0.52 mL, 4.1 mmol) was added to a solution of 5-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[1-(trifluoromethyl)cyclopropyl]pyrazine-2-carboxamide (0.90 g) in acetonitrile (20 mL) at 0° C. under N2. The reaction mixture was stirred at room temperature for 4 h. LCMS (M+H)+: m/z=539.2. The mixture was cooled to 0° C., water (10. mL) was added. After 30 min., 5.0 M ammonium hydroxide in water (2.5 mL) was added slowly at 0° C. in 5 min. Then the reaction mixture was stirred at room temperature overnight. The reaction mixture was worked up with saturated aqueous NaHCO3, extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with methanol in dichloromethylene (0-5%) to afford the desired product (0.69 g, 63%). LCMS (M+H)+: m/z=509.0. 1H NMR (300 MHz, DMSO-d6): δ 12.71 (br, 1H), 9.16 (s, 1H), 9.13 (s, 1H), 8.88 (s, 1H), 8.68 (d, J=1.2 Hz, 1H), 8.60 (s, 1H), 8.02 (d, J=1.2 Hz, 1H), 7.83 (dd, J=3.2, 2.5 Hz, 1H), 7.28 (dd, J=3.4, 1.4 Hz, 1H), 4.85 (d, J=9.8 Hz, 2H), 4.59 (d, J=10.0 Hz, 2H), 3.82 (s, 2H), 1.29 (m, 2H), 1.17 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14]C)=[O:13])[CH:6]=[CH:5]2.C1COCC1.O.[OH-].[Li+]>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2
Reactant: COC(=O)c1ccc2cc(Br)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of methyl 6-bromo-2-naphthoate (7.70 g, 29.0 mmol) in 2:1 THF:water (150 mL) was treated with lithium hydroxide hydrate (2.44 g, 58.1 mmol) followed by stirring at room temperature for 48 h. Concentrated under vacuum, diluted with water and cooled to 0° C. Acidified to pH3 with 4N HCl. Solids were collected by filtration, dissolved in toluene-EtOAc (ca. 2 L) and washed with brine. Dried over Na2SO4, filtered and concentrated under vacuum. Brown solid was triturated with ether, collected by filtration, and dried under vacuum to give the title compound as a nearly white solid (5.07 g, 70%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])(=[O:3])[CH3:2].CC(C)([O-])C.[K+].Br[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].[Cl-].[NH4+]>CN(C)C=O>[C:1]([N:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCCCBr
Reactant: CC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCN(C(C)=O)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 85 %

Procedure:
1.00 g (2.87 mmol) of Compound 27 obtained in Example 27 was dissolved in 10 ml of dimethylformamide under argon atmosphere, 355 mg of potassium tert-butoxide and 1.02 ml of ethyl 6-bromohexanoate were added under ice-cooling and the mixture was stirred at room temperature for 4.5 hours. An aqueous ammonium chloride solution was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride, dried over anhydrous sodium sulfate and purified by silica gel column chromatography (chloroform:methanol=30:1) to give 1.26 g (85%) of 2-[4-[N-acetyl-N-(5-ethoxycarbonylpentyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one.
Reaction SMILES: [OH:1][C@@H:2]([CH2:8][CH2:9][I:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:25]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:26][CH3:27])(=O)=O>C(Cl)Cl>[I:10][CH2:9][CH2:8][C@H:2]([O:1][Si:25]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:26][CH3:27])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)[C@@H](O)CCI
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCOC(=O)[C@H](CCI)O[Si](CC)(CC)CC
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a solution of 392 (15.5 g, 60.1 mmol), 2,6-lutidine (21.0 ml, 180 mmol) and DCM (125 mL) cooled to 0° C. and maintained under N2 was added dropwise triethylsilyl trifluoromethanesulfonate (17.5 g, 66.1 mmol). The reaction was stirred at 0° C. for 1 h then warmed to RT and stirred for 18 h. The reaction was quenched by adding satd. aq. NH4Cl and extracted with DCM. The organic extract was washed organic with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by SiO2 chromatography (SNAP 100) eluting with EtOAc/hexane (9:1) to afford 18.9 g (76%) of (S)-ethyl 4-iodo-2-(triethylsilyloxy)butanoate (396) as a yellow oil.
Reaction SMILES: [C:1]([CH:5]([CH3:21])[CH2:6][CH2:7][CH2:8][C:9]1([CH3:20])[CH:15]2[O:16][C:12]([CH2:17][CH2:18][OH:19])([CH2:13][CH2:14]2)[CH2:11][O:10]1)([O:3]C)=[O:2].CO.[OH-].[Na+]>O>[C:1]([CH:5]([CH3:21])[CH2:6][CH2:7][CH2:8][C:9]1([CH3:20])[CH:15]2[O:16][C:12]([CH2:17][CH2:18][OH:19])([CH2:13][CH2:14]2)[CH2:11][O:10]1)([OH:3])=[O:2]
Reactant: COC(=O)C(C)CCCC1(C)OCC2(CCO)CCC1O2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(CCCC1(C)OCC2(CCO)CCC1O2)C(=O)O
Temperature: 25 °C
Yield: 85.7 %

Procedure:
A mixture of (1RS,4SR,5RS)-4-(4-carbomethoxypentyl)-4-methyl-3,8-dioxabicyclo[3.2.1]octane-1-ethanol (71 mg, 0.24 mM), methanol (3 ml), water (1 ml) and 1 N sodium hydroxide (1 ml) is stirred at room temperature under nitrogen for twenty hours. Most of the methanol is removed in vacuo and the residue is treated with concentrated hydrochloric acid (1 ml) at 0° C. and extracted with ethyl acetate (3×30 ml). The combined organic layers are dried (Na2SO4) and evaporated in vacuo to give a colorless oil. This material is filtered through a silica gel column (3 g) and washed with ether (200 ml). The solvent is removed in vacuo to give (1RS,4SR,5RS)-4-(4-carboxypentyl)-4-methyl-3,8-dioxabicyclo[3.2.1]octane-1-ethanol (58 mg, 88%) as a colorless oil.
Reaction SMILES: C([Si]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH:16]2[CH2:18][CH2:17]2)=[CH:11][C:10]=1[CH3:19])(C)C)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>C1COCC1>[CH:16]1([C:12]2[CH:11]=[C:10]([CH3:19])[C:9]([OH:8])=[C:14]([CH3:15])[CH:13]=2)[CH2:18][CH2:17]1
Reactant: Cc1cc(C2CC2)cc(C)c1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc(C2CC2)cc(C)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
To a suspension of (4-bromo-2,6-dimethylphenoxy) tert-butyldimethylsilane (668 mg, 2.12 mmol) and tetrakis(triphenylphosphine)palladium (122 mg, 0.11 mmol) in THF (20 mL) was added cyclopropyl zinc chloride (28.0 mL, 11.2 mmol). The mixture was heated at 80° C. for 24 h and cooled to room temperature. The reaction was passed through a short pad of SiO2 to remove the catalyst and the solution was concentrated to oil. The resulting oil was diluted in EtOAc (100 mL), washed with brine (100 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=90:10) yielded 370 mg (63%) of tert-butyl(4-cyclopropyl-2,6-dimethylphenoxy)dimethylsilane. To tert-butyl(4-cyclopropyl-2,6-dimethylphenoxy)dimethylsilane (320 mg, 1.16 mmol) in THF (10 mL) was added a solution of tetrabutylammonium fluoride (5.0 mL, 1 M in THF, 5.0 mmol) and acetic acid (0.40 mL). The reaction was stirred at room temperature for 3 h and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=85:15) yielded 175 mg (93%) of 4-cyclopropyl-2,6-dimethylphenol as a light yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[CH3:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=1[NH2:35]>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH:35][C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:28])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Br)ccc2F)N=C1NC(=O)OC(C)(C)C
Reactant: Cc1ccccc1N
Product: Cc1ccccc1Nc1ccc(F)c([C@@]2(C)N=C(N)N(C)C(=O)C2(C)C)c1

Procedure:
The coupling of [(S)-4-(5-bromo-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate E8) and o-tolylamine according to procedure A followed by deprotection yielded the title compound as a white solid. MS (ESI): m/z=369.2 [M+H]+.