Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[O:14][CH2:15][C:16]3[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:17]=3[N:18]=1)[CH2:9][CH2:8]2.[N:24]1([S:30](Cl)(=[O:32])=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[O:14][CH2:15][C:16]3[CH:22]=[C:21]([NH:23][S:30]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)(=[O:32])=[O:31])[CH:20]=[CH:19][C:17]=3[N:18]=1)[CH2:9][CH2:8]2
Reactant: COc1cccc2c1C(NC1=Nc3ccc(N)cc3CO1)CC2
Reactant: O=S(=O)(Cl)N1CCOCC1
Product: COc1cccc2c1C(NC1=Nc3ccc(NS(=O)(=O)N4CCOCC4)cc3CO1)CC2
Yield: 54 %

Procedure:
Prepared from rac-N2-(7-methoxy-indan-1-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 10) (100 mg, 0.323 mmol) and morpholin-4-sulfonyl chloride (66 mg, 0.356 mmol) according to the procedure described for Example 27. Obtained the title compound as a light yellow foam (80 mg, 54%), MS (ISP) m/e=459.2 [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[N:15][CH:16]=[C:11]2[C:10]([OH:26])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH:33](Br)([CH3:35])[CH3:34]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[N:15][CH:16]=[C:11]2[C:10]([O:26][CH:33]([CH3:35])[CH3:34])=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)Br
Reactant: CC(C)(C)OC(=O)n1nc(O)c2cnc(Oc3ccc(F)cc3F)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1nn(C(=O)OC(C)(C)C)c2nc(Oc3ccc(F)cc3F)ncc12
Temperature: 40 °C
Yield: 89.9 %

Procedure:
6-(2,4-Difluoro-phenoxy)-3-hydroxy-pyrazolo[3,4-d]pyrimidine-1-carboxylic acid tert-butyl ester (190 mg, 0.52 mmol) was mixed with K2CO3 (144 mg, 1 mmol) and isopropyl bromide (0.29 mL, 5.2 mmol) in DMF (3 mL). The mixture was heated at 40° C. for 4 hours, then cooled and diluted with water. The resulting mixture was extracted with EtOAc and the combined organic fractions were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified with flash column chromatography flushing with 30% ethyl acetate in hexanes to give 190 mg of 6-(2,4-difluoro-phenoxy)-3-isopropoxy-pyrazolo[3,4-d]pyrimidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@:5]([CH3:9])([CH:7]=O)[CH2:4][O:3]1.Cl.[NH2:12][OH:13].C([O-])([O-])=O.[Na+].[Na+]>O.CO>[CH3:1][C:2]1([CH3:10])[O:6][C@:5]([CH3:9])([CH:7]=[N:12][OH:13])[CH2:4][O:3]1
Reactant: NO
Reactant: CC1(C)OC[C@@](C)(C=O)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(C)OC[C@@](C)(C=NO)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
(S)-2,2,4-trimethyl-1,3-dioxolane-4-carbaldehyde (5.8 g, 40 mmol) was dissolved in 1:1 methanol water (100 mL) and hydroxylamine hydrochloride (2.8 g, 40 mmol) and Na2CO3 (2.4 g, 20 mmol). The reaction was stirred at ambient temperature overnight, then concentrated in vacuo. The aqueous layer was extracted with CH2Cl2, and the organic layer was dried over sodium sulfate, filtered and concentrated to afford (R)-2,2,4-trimethyl-1,3-dioxolane-4-carbaldehyde oxime (4.8 g, 30 mmol, 75% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:2]1=2.[CH3:11][C:12]([CH3:17])([CH3:16])[C:13](Cl)=[O:14]>N1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][C:8]([O:10][C:13](=[O:14])[C:12]([CH3:17])([CH3:16])[CH3:11])=[CH:9][C:2]1=2
Reactant: Oc1ccc2ccsc2c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccc2ccsc2c1
Yield: 95.5 %

Procedure:
Dissolve benzo[b]thiophen-6-ol (10 g, 67 mmol) in pyridine (300 mL). Add 2,2-dimethyl-propionyl chloride (38 mL, 308 mmol) dropwise, and stir at room temperature for 8 hours. Concentrate in vacuo to ¼ volume, partition between ethyl acetate (250 mL) and water (250 mL). Separate layers, wash organic layer with water (250 mL) and brine (200 mL). Dry with magnesium sulfate, filter, and concentrate in vacuo to give 15 g of 2,2-dimethyl-propionic acid benzo[b]thiophen-6-yl ester (98%).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][CH:11]3[CH2:20][N:14]4[CH2:15][CH2:16][NH:17][C:18](=[O:19])[CH:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1>CN(C)C=O>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:20][N:14]4[CH2:15][CH2:16][N:17]([CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=5)[C:18](=[O:19])[C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C1NCCN2CC(Oc3cnc(C4CC4)cn3)CC12
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1[C@@H]2C[C@@H](Oc3cnc(C4CC4)cn3)CN2CCN1Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 26.9 %

Procedure:
To a solution of 7-(5-cyclopropylpyrazin-2-yloxy)hexahydro-pyrrolo[1,2-a]pyrazin-1(2H)-one (50 mg, 0.182 mmol) from Step 3 [3:1 (7R,8aS: 7R,8aR) diastereomer ratio] in N,N-dimethylformamide (0.7 mL) under nitrogen was added sodium hydride (60% weight suspension in mineral oil; 8.75 mg, 0.219 mmol), and the resulting suspension was stirred at room temperature. After 20 minutes, the suspension was treated with 1-(bromomethyl)-3-(trifluoromethyl)benzene (0.033 mL, 0.219 mmol) with stirring continued for 4 hours at room temperature. The reaction mixture was partitioned between water (3 mL) and ethyl acetate (3×2 mL), and the organic phase was dried over sodium sulfate. The solvent was concentrated under a stream of nitrogen, and the crude material was purified by flash chromatography on a 12 g silica gel cartridge eluted with a gradient 0-5% methanol/dichloromethane over 17 minutes to give the crude product as an oil. The crude oil (40 mg) was loaded onto a 2×0.25 mm silica gel prep plate and eluted with ethyl acetate to give the title compound (21 mg, 0.049 mmol, 26.6% yield) as the first of 2 diastereomers to elute as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 8.07 (d, J=1.0 Hz, 1H), 7.94 (d, J=1.1 Hz, 1H), 7.55 (dd, J=4.4, 3.4 Hz, 1H), 7.48 (t, J=9.0 Hz, 3H), 5.44 (dd, J=6.9, 5.7 Hz, 1H), 4.73 (d, J=14.8 Hz, 1H), 4.58 (d, J=14.8 Hz, 1H), 3.71 (t, J=8.0 Hz, 1H), 3.46 (dt, J=12.2, 7.1 Hz, 1H), 3.38 (dd, J=10.9, 5.7 Hz, 1H), 3.20 (dt, J=12.1, 3.9 Hz, 1H), 3.02 (dd, J=6.7, 3.8 Hz, 2H), 2.88 (dd, J=10.8, 2.9 Hz, 1H), 2.53 (dt, J=15.2, 7.6 Hz, 1H), 2.44 (dd, J=14.5, 7.8 Hz, 1H), 2.03-1.95 (m, 1H), 1.00-0.88 (m, 4H); MS (ESI+) m/z 433 (M+H)+.
Reaction SMILES: P([O-])([O-])([O-])=[O:2].C1C2C(=CC=CC=2)C=CC=1N[C:17](=[O:24])[C@H:18]([CH2:20][CH:21]([CH3:23])[CH3:22])[NH2:19]>CS(C)=O>[NH2:19][C@H:18]([C:17]([OH:24])=[O:2])[CH2:20][CH:21]([CH3:22])[CH3:23]
Reactant: O=P([O-])([O-])[O-]
Reactant: CC(C)C[C@H](N)C(=O)Nc1ccc2ccccc2c1
Solvent: CS(C)=O
Product: CC(C)C[C@H](N)C(=O)O
Reaction time: 72 h

Procedure:
Assay mixtures were prepared containing 0.613 μg LAPM, 10 μg/mL bovine serum albumin (BSA). 0.1M phosphate buffer, pH 7.2, in a total volume of 2.7 mL. Measured amounts of compounds 5 to be tested for inhibitory activity were added in additional 0.1M phosphate buffer to a total volume of 3 mL. After 72 hours at 0°-5°, 1 mL of the enzyme/inhibitor mixture was treated with 4 μL of 0.2M (L)-leucine-β-napthylamide in dimethylsulfoxide, and the rate of increase of fluorescence at 410 nm, while exciting at 310 nm. was measured. Control experiments were performed identically, except no inhibitor was present. The concentration of the selected compound 5 observed to decrease reaction rates by one-half was used to determine the value of IC50 for each compound. This was accomplished by subtracting one-half the concentration of enzyme present in the sample mixtures (1.6×10-9M) from the inhibitor concentration observed to decrease reaction rates by one-half. The results of these experiments are set forth in Table 2, above.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:11][C@@H:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:9]1CC1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([C@H:8]1[CH2:11][C@@H:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@@H](C(=O)OC(C)(C)C)N1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H](C(=O)OC(C)(C)C)N1
Yield: 65.5 %

Procedure:
307 mg (884 μmol) of cis-N-benzylazetidine-2,4-dicarboxylic acid di-tert.butyl ester in 25 ml of methanol is hydrogenated in a Parr shaker over 100 mg of 20% Pd(OH)2 /C (containing 31% water) under 4 atm of hydrogen for 7.5 h. The catalyst is filtered off through a double paper filter and thoroughly washed with methanol. Evaporation and filtration over SiO2 (EtOAc/hexanes 1:1) affords 149 mg (66%) of cis-azetidine-2,4-dicarboxylic acid di-tert.butyl ester as a yellowish oil which solidifies spontaneously. mp. 47°-48.5° C. 1H NMR (CDCl3): δ4.04 (dd, 2H, J=5.5, 9), 3.2 (br., 1H), 2.97 (dt, 1H, J=12 (d), 9 (t)), 2.38 (dt, 1H, J=12 (d), 5.5 (t)), 1.48 (s, 18H). IR (neat): 3328, 2979, 2934, 1731, 1480, 1458, 1394, 1369, 1280, 1257, 1156, 1103, 1048, 1031, 892, 846, 734 cm-1.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([CH3:31])[CH3:30]>>[CH3:28][N:2]([CH3:1])[C:3]([C:5]1[N:22]([CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:35]4[CH2:36][CH2:37][N:32]([CH:29]([CH3:31])[CH3:30])[CH2:33][CH2:34]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C=O)cn3)nc2n1C1CCCC1
Reactant: CC(C)N1CCNCC1
Product: CC(C)N1CCN(Cc2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Yield: 53 %

Procedure:
Following General Procedure B, 7-cyclopentyl-2-(5-formyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (150 mg, 0.396 mmol) and N-isopropylpiperazine (56 mg, 0.436 mmol) gave 7-cyclopentyl-2-[5-(4-isopropyl-piperazin-1-ylmethyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (103 mg, 53%) [following SiO2 chromatography, eluting with 0-10% (2M NH3 in MeOH)/dichloromethane]. MS (ESI) m/z 491.3 (M+H)+ (method A).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:8]1[O:17][C:11]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:10][CH2:9]1>CC1C=CC(C)=CC=1>[N:5]1[CH:6]=[CH:7][C:2]([N:14]2[CH2:15][CH2:16][C:11]3([O:17][CH2:8][CH2:9][O:10]3)[CH2:12][CH2:13]2)=[CH:3][CH:4]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Clc1ccncc1
Solvent: Cc1ccc(C)cc1
Product: c1cc(N2CCC3(CC2)OCCO3)ccn1
Yield: 90.5 %

Procedure:
A solution of 46 g (0.4 mol) 4-chloropyridine and 123.5 g (0.86 mol) 4-piperidone ethylene ketal is heated for 48 hours to reflux in 400 ml p-xylene. Subsequently the reaction mixture is cooled, the precipitated precipitate is removed by filtration, the mother liquor is concentrated to dryness and the residue is purified by column chromatography on silica gel (ethyl acetate/saturated ammonia-alkaline methanol 9/1). In this way 79.7 g (90%) 8-pyridin-4-yl-1,4-dioxa-8-aza-spiro[4.5]decane is obtained as a white powder. m/e=220; f.p.=65° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[SH:13][C:14]1[C:15]2[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:16]=2[S:17][C:18]=1[C:19]([NH2:21])=[O:20].C([O-])(O)=O.[Na+]>C1COCC1.C(OCC)(=O)C>[NH2:21][C:19]([C:18]1[S:17][C:16]2[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:15]=2[C:14]=1[S:13][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=[O:20]
Reactant: COc1ccc2sc(C(N)=O)c(S)c2c1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CSc2c(C(N)=O)sc3ccc(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
Methyl 4-(bromomethyl)benzoate (479 mg, 2.09 mmol) is added to a room temperature solution of 3-mercapto-5-methoxybenzo[b]thiophene-2-carboxamide (200 mg, 0.84 mmol) in 12 mL of THF followed by NaHCO3 (351 mg, 4.18 mmol) and the reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with ethyl acetate and washed with 1N HCl, saturated NaHCO3, and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. Chromatography eluting with ethyl acetate:dichloromethane (1:9 to 1:1) followed by recrystallization from ethyl acetate:hexane provides methyl 4-[[[2-(aminocarbonyl)-5-methoxybenzo[b]thien-3-yl]thio]methyl]-benzoate in 68% yield; mp=150°-152° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:23]1([CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])=[CH:6][CH:7]=1
Reactant: O=C(O)CCCc1ccccc1
Reactant: NC(Cc1ccccc1C(F)(F)F)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(CCCc1ccccc1)NC(Cc1ccccc1C(F)(F)F)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(2-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in acetonitrile (30 ml) were added 4-phenyl-n-butyric acid (236 mg, 1.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (358 mg, 1.87 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2) The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:acetone=1:1). Recrystallization from ethyl acetate-hexane gave the title compound (501 mg, 76%).
Reaction SMILES: [CH3:1][C:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:21])[CH2:3][C:4](=[O:20])[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[O:17])[O:15][N:14]=[C:13]([CH3:18])[C:12]=2[CH:19]=1)=[O:6].[CH3:28][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[OH:20][C:4]([CH3:28])([CH2:3][C:2]([CH3:1])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH3:21])[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[O:17])[O:15][N:14]=[C:13]([CH3:18])[C:12]=2[CH:19]=1)=[O:6]
Reactant: C[Mg]Br
Reactant: Cc1noc(=O)c2ccc(NC(=O)C(=O)CC(C)(C)c3ccccc3)cc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1noc(=O)c2ccc(NC(=O)C(C)(O)CC(C)(C)c3ccccc3)cc12
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
72 mg of 6-(4-methyl4-phenyl-2-oxo-valeroylamino)-4-methyl-2,3-benzoxazin-1-one in 4 ml of tetrahydrofuran is mixed with 3 ml of methylmagnesium bromide (3 mol) at 0° C. After 30 minutes, ammonium chloride solution is added, the organic phase is separated, dried and concentrated by evaporation. After chromatography on silica gel (hexane/ethyl acetate 1:1), 39 mg of 6-(2-hydroxy-2,4-dimethyl4-phenyl-valeroylamino)-4-methyl-2,3-benzoxazin-1-one, melting point 173-175° C., is obtained.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][OH:7])(=[O:3])[CH3:2].N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][Cl:19])=[O:16]>O1CCCC1>[C:15](=[O:16])([O:17][CH2:18][Cl:19])[O:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)NCCO
Reactant: O=C(Cl)OCCl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)NCCOC(=O)OCCl
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.4 %

Procedure:
To a mixture of 2-acetylaminoethanol (20.0 g), pyridine (15.3 g) and tetrahydrofuran (100 ml), a solution of chloromethyl chloroformate (25.2 g) in tetrahydrofuran (50 ml) was added dropwise under ice cooling over the period of 30 minutes. After stirring at room temperature for 16 hours, the resulting solid was removed off by filtration and washed with tetrahydrofuran (30 ml). The filtrate and the washing were combined, and concentrated under reduced pressure. To the residue, ethyl acetate (300 ml) and water (100 ml) were added and the organic layer was separated. The aqueous layer was extracted twice with a mixture of ethyl acetate (150 ml) and tetrahydrofuran (50 ml). The organic layers were combined, washed with a saturated sodium chloride aqueous solution (100 ml), and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by subjecting to silica gel chromatography (silica gel 240 g, eluent: ethyl acetate-hexane=1:1→ethyl acetate) to obtain [2-(acetylamino)ethyl] chloromethyl carbonate (32.4 g) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH:8]1[CH2:11][C:10](=[CH2:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:22])C=1>ClCCl>[C:1]([O:5][C:6](=[O:13])[NH:7][CH:8]1[CH2:9][C:10]2([O:22][CH2:12]2)[CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C1CC(NC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CC2(CO2)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 61.2 %

Procedure:
A solution of (3-methylene-cyclobutyl)-carbamic acid tert-butyl ester (4.27 g, 23.3 mmol) in dichloromethane (95 mL) was cooled to 0° C. in an ice/water bath. 3-Chloroperbenzoic acid (77% technical grade, 5.84 g, 26 mmol) was added in small portions. After stirring at 0° C. for 1.5 hours, the mixture was transferred to a separatory funnel and washed sequentially with 10% aqueous Na2SO3 (50 mL), saturated aqueous NaHCO3 (30 mL), and saturated aqueous NaCl (30 mL). The organic layer was dried over magnesium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluting with 30-100% ethyl acetate in heptane), affording the title compound (2.84 g, 61%) as a white solid. NMR showed a 1:1 mixture of N,O-cis/trans isomers. 1H NMR (400 MHz, chloroform-d) δ ppm 1.46 (d, J=1.26 Hz, 9H) 2.35-2.45 (m, 2H) 2.67-2.83 (m, 4H) 3.97-4.36 (m, 1H) 4.77 (br. s., 1H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]([CH3:17])([CH3:16])[C:14]#[N:15])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH:8]=[CH:7]2.[Br:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23](Br)[C:20]=1[CH:21]=[O:22].C(=O)(O)[O-].[Na+]>CS(C)=O.[Cu](I)I>[Br:18][C:19]1[C:20]([CH:21]=[O:22])=[C:23]([N:9]2[CH:8]=[CH:7][C:6]3[C:11](=[C:2]([F:1])[CH:3]=[C:4]([C:13]([CH3:17])([CH3:16])[C:14]#[N:15])[CH:5]=3)[C:10]2=[O:12])[CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C#N)c1cc(F)c2c(=O)[nH]ccc2c1
Reactant: O=Cc1c(Br)cccc1Br
Agent: I[Cu]I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C#N)c1cc(F)c2c(=O)n(-c3cccc(Br)c3C=O)ccc2c1
Temperature: 110 °C
Reaction time: 3.5 h
Yield: 63.3 %

Procedure:
A solution of 2-(8-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-propionitrile (250 mg, 1.09 mmol), 2,6-dibromobenzaldehyde (459 mg, 1.74 mmol) and sodium bicarbonate (182 mg, 2.17 mmol) in dry dimethylsulfoxide (8 ml) was placed under vacuum and back-filled with argon (repeat twice more). To this was added copper iodide (207 mg, 1.09 mmol) and the flask was evacuated and back-filled with argon (repeat twice more). The mixture was heated in an oil bath to 110° C. and stirred for 3.5 hours. The reaction mixture was cooled to ambient and taken up in ethyl acetate (40 ml) and water (40 ml). The biphasic material was filtered through a plug of celite, rinsing well with ethyl acetate. The filtrate and washes were transferred to a separatory funnel and the organic phase was collected. This was washed with an equal volume of 50% diluted brine solution and the ethyl acetate phase collected. The aqueous phases were back extracted with ethyl acetate (2×30 ml). The combined organic phase was dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by HPLC on silica gel, eluting with 1% methanol/dichloromethane to provide the desired product as a light yellow solid (285 mg). (M+H)+=413/415 m/e.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[C:14]([C:19](O)=[O:20])=[N:15][N:16]([CH3:18])[CH:17]=3)=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:60][C:61]1([CH3:66])[CH2:65][CH2:64][CH2:63][NH:62]1>CN(C=O)C>[CH:1]1([C:4]2[N:9]=[C:8]([C:10](=[N:12][C:13]3[C:14]([C:19]([N:62]4[CH2:63][CH2:64][CH2:65][C:61]4([CH3:66])[CH3:60])=[O:20])=[N:15][N:16]([CH3:18])[CH:17]=3)[OH:11])[C:7]([NH:22][C:23]3[CH:28]=[N:27][CH:26]=[N:25][CH:24]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: Cn1cc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)O)n1
Reactant: CC1(C)CCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cn1cc(N=C(O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)N2CCCC2(C)C)n1
Reaction time: 8 h
Yield: 7.2 %

Procedure:
To stirred solution of 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid (70 mg, 0.18 mmol) in DMF were sequentially added N-methylmorpholine (0.12 ml, 0.9 mmol), HBTU (210 mg, 0.55 mmol), and 2,2-dimethylpyrrolidine (35 mg, 0.36 mmol) at rt, and the reaction mixture was allowed to stirr overnight. The solvent was removed in vacuo, and the residue was dissolved in EtOAc (10 ml), and was washed with aqueous NaHCO3 solution and water. The aqueous layer was back-extracted with EtOAc, and the combined organic layer was dried (Na2SO4), filtered, and evaporated in vacuo. The crude product was purified by prep. HPLC (column: Gemini C18 (250×21.2 mm, 5μ); elution with a gradient of 0.05% aqueous TFA solution/acetonitrile) to give the title compound (6 mg, 6%) as sticky yellow solid.
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)C(C)C)(C)C.[C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:23]([C:26](Cl)=[O:27])=[CH:22][CH:21]=1>ClCCl>[C:20]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:21]=[CH:22][C:23]([C:26]([N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[S:1][CH:2]=[CH:3][C:4]2=3)=[O:27])=[CH:24][CH:25]=1
Reactant: c1cc2c(s1)CCCCN2
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(-c2ccccc2)cc1)N1CCCCc2sccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
A solution of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine of Step A (0.300 g) and N,N-diisopropylethyl amine (0.5 mL) in dichloromethane (25 mL) was cooled to 0°. To this was added a solution of 4-biphenyl carbonyl chloride (0.518 g) in dichloromethane (5 ml). The solution was stirred overnight as it warmed to room temperature, then washed with 0.1N hydrochloric acid, aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to an oil. Flash chromatography of the residue on silica gel provided the title compound as a white solid (0.490 g), m.p. 164-166° C.