Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([CH3:34])([C@@H:12]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[C:28]([F:31])([F:30])[F:29])[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:33])[C:19](=[O:32])[NH:20][N:21]=2)[CH3:13])[CH2:9]1)=O)(C)(C)C.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[CH3:33][C@H:18]1[N:17]2[C:22]([CH2:23][O:24][C:25]3[C:16]2=[CH:15][C:14]([C@H:12]([C:10]2([CH3:34])[CH2:9][NH:8][CH2:11]2)[CH3:13])=[C:27]([C:28]([F:29])([F:31])[F:30])[CH:26]=3)=[N:21][NH:20][C:19]1=[O:32]
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(C(F)(F)F)c([C@@H](C)C4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1C(=O)NN=C2COc3cc(C(F)(F)F)c([C@@H](C)C4(C)CNC4)cc3N21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
To a solution of 3-methyl-3-[(R)-1-((R)-4-methyl-3-oxo-7-trifluoromethyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-ethyl]-azetidine-1-carboxylic acid tert-butyl ester (diastereomer 1, 0.062 g, 0.128 mmol) in DCM (4 mL) was added TFA (1 mL) and the reaction mixture was stirred at ambient temperature for 1.5 h. The solvent was removed in vacuo to give (R)-4-methyl-6-[(R)-1-(3-methyl-azetidin-3-yl)-ethyl]-7-trifluoromethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid (Example #147-1, Enantiomer 1, 0.060 g, 94%) as a solid. 1H NMR (CD3OD-d4, 400 MHz): δ 7.46 (s, 1H), 7 (s, 1H), 4.95 (m, 1H), 4.70 (d, J=13.2 Hz, 2H), 4.3 (d, J=10.8 Hz, 1H), 3.95 (d, J=10.8 Hz, 1H), 3.65 (t, J=10.0 Hz, 2H), 3.26 (m, 1H), 1.55 (s, 3H), 1.49 (d, J=7.2 Hz, 3H), 1.44 (d, J=7.2 Hz, 3H). LC/MS (Table 1, Method 4) Rt=1.741 min; MS m/z: 383 [M+H]+. SFC (Table 1, Method 36) Rt=4.264 min.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[CH:20]1([C:23]([C:29]2[S:33][C:32]([SH:34])=[N:31][CH:30]=2)([OH:28])[C:24]([F:27])([F:26])[F:25])[CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[CH:20]1([C:23]([C:29]2[S:33][C:32]([S:34][C:2]3[CH:11]=[C:10]4[C:5]([C:6]([C:13]5[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=5)=[CH:7][C:8](=[O:12])[O:9]4)=[CH:4][CH:3]=3)=[N:31][CH:30]=2)([OH:28])[C:24]([F:26])([F:25])[F:27])[CH2:22][CH2:21]1
Reactant: OC(c1cnc(S)s1)(C1CC1)C(F)(F)F
Reactant: O=c1cc(-c2ccc(F)cc2)c2ccc(Br)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=c1cc(-c2ccc(F)cc2)c2ccc(Sc3ncc(C(O)(C4CC4)C(F)(F)F)s3)cc2o1

Procedure:
Employing the procedure described in Example 1, Step 3, with 7-bromo-4-(4-fluorophenyl)-2H-chromen-2-one, (+)-1-cyclopropyl-2,2,2-trifluoro-1-(2-mercapto-1,3-thiazol-5-yl)ethanol and potassium carbonate in NMP at 120° C., the title compound was obtained. 1H NMR (400 MHz, acetone-d6): δ 8.00 (s, 1H), 7.68 (m, 2H), 7.56-7.60 (m, 2H), 7.48 (dd, 1H), 7.39 (t, 2H), 6.43 (s, 1H), 5.88 (s, 1H), 1.65 (m, 1H), 0.82 (m, 1H), 0.54-0.71 (m, 3H); [α]D=+29.4° (c=1, EtOH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([O:21]C)=O)[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:3]=1.[NH3:30]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([NH2:30])=[O:21])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:3]=1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCNCC3)c2c1C
Reactant: N
Solvent: CO
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3OC3CCNCC3)c12
Temperature: 120 °C
Yield: 36 %

Procedure:
A suspension of methyl 4-(4-fluoro-2-(piperidin-4-yloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (0.1 g, 0.2 mmol) in 7N ammonia in MeOH (6 mL) was heated in a sealed tube at 120° C. for 18 hours. After cooling to ambient temperature the precipitated solid was collected by filtration, washed with cold MeOH and dried under vacuum to give beige solid (0.035 g, 36%).
Reaction SMILES: [CH3:1][C@:2]1([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:6][CH2:5][C@@H:4]([CH2:7][C:8]2N=C(C(F)(F)F)[O:10][N:9]=2)[C:3]1([CH3:18])[CH3:17].CC1C=CC(S(O)(=O)=O)=CC=1.[C:38](#[N:42])[CH:39]([CH3:41])[CH3:40]>[Cl-].[Cl-].[Zn+2]>[CH:39]([C:38]1[O:10][N:9]=[C:8]([CH2:7][C@@H:4]2[CH2:5][CH2:6][C@@:2]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:1])[C:3]2([CH3:18])[CH3:17])[N:42]=1)([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)N[C@@]1(C)CC[C@@H](Cc2noc(C(F)(F)F)n2)C1(C)C
Reactant: CC(C)C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(C)c1nc(C[C@@H]2CC[C@](C)(NC(=O)OC(C)(C)C)C2(C)C)no1
Temperature: 92.5 °C

Procedure:
To a solution of tert-butyl {(1S,3S)-3-[(2Z)-2-amino-2-(hydroxyimino)ethyl]-1,2,2-trimethylcyclopentyl}carbamate (prepared in Step-1 example 56) (0.300 g, 1.0 mmoles) in isobutyronitrile (7 mL), ZnCl2 (0.0410 g, 3.0 mmol), PTSA (0.057 g, 3.0 mmol) were added under N2 atmosphere. It was heated to 90-95° C. for six hours. After completion of reaction, isopropyl cyanide was removed under reduced pressure and diluted with water and ethyl acetate. The layers are separated and the organic layer was dried over Na2SO4, and concentrated on a rotavapor. The crude material is purified by column. 0.120 g, Off white sticky mass, 1H NMR (400 MHz, CDCl3) δ ppm: 0.81 (s, 3H), 0.97 (s, 3H), 1.21 (s, 3H), 1.34 (d, 6H), 1.43 (s, 9H), 1.70-1.73 (m, 1H), 1.95-2.00 (m, 2H), 2.22-2.25 (m, 2H), 2.55-2.59 (m, 1H), 2.79-2.83 (m, 1H), 3.17-3.19 (m, 1H), 4.51 (s, 1H). m/z (M−100)+H, 252.2.
Reaction SMILES: [CH:1]1([C:7]2[N:8]=[C:9]([NH:12][C:13]([C:15]([O:17]CC)=[O:16])=[O:14])[S:10][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH:1]1([C:7]2[N:8]=[C:9]([NH:12][C:13]([C:15]([OH:17])=[O:16])=[O:14])[S:10][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C(=O)Nc1nc(C2CCCCC2)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)C(=O)Nc1nc(C2CCCCC2)cs1
Reaction time: 0.17 h

Procedure:
Ethyl 4-cyclohexylthiazol-2-ylcarbamoylcarboxylate (1.41 g., 5 mmole) was combined with 40 ml. of water and 5 ml. of 1 N potassium carbonate (1 equivalent, 2.5 mmole) was heated on a steam bath for 15 minutes. After 10 minutes, tlc (chloroform-1% ethanol) indicated hydrolysis was almost complete. The hot reaction mixture was clarified by filtration, cooled in an ice-water bath and acidified with 10.5 ml. of 1 N hydrochloric acid. Product (1.02 g.) was recovered by filtration. Recrystallization from isopropyl alcohol gave purified 4-cyclohexylthiazol-2-ylcarbamoylcarboxylic acid [625 mg.; m.p. 198.5°-200.5° C. (dec)].
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[CH3:8][N:9]([CH3:12])[CH:10]=[O:11].C(N(CC)CC)C>O>[CH3:8][N:9]([CH3:12])[C:10](=[O:11])[C:3]([C:2]([Cl:7])([Cl:6])[Cl:1])=[O:4]
Reactant: CN(C)C=O
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)C(=O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 273g (1.5 mole) portion of trichloroacetyl chloride was added over one hour to a stirred, cooled (5°C) portion of 330g (4.5 moles) of dimethylformamide. Nitrogen was passed over the solution throughout the reaction. A 152g (1.5 mole) portion of triethylamine was then added dropwise while keeping the temperature below 15°C. The mixture was stirred overnight at ambient temperature and then cooled to 5°C before 300 ml of water was added gradually. The organic products were extracted into ethyl ether, and the ethereal solution was washed with water, 10% hydrochloric acid, and with brine, dried over magnesium sulfate and concentrated. The residue was distilled under vacuum through a short-path still yielding 160g of pure N,N-dimethyl-3,3,3-trichloropyruvamide: Bp 80°-82° (0.2mm); ir(λmax, film) 5.7 (s), 6.0 (s), 9.45 (s), 11.6 (m) microns; nmr (δ , CDCl3) 3.0 and 3.05 (two singlets, 6H) ppm.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].Cl.N1C=CC=CC=1.[F:23][C:24]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[C:25]=1[NH2:26]>C(OCCO)C>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][C:3]([C:14]#[N:15])=[C:2]2[NH:26][C:25]1[C:24]([F:23])=[CH:30][C:29]([F:31])=[CH:28][C:27]=1[F:32]
Reactant: Nc1c(F)cc(F)cc1F
Reactant: COc1cccc2c(Cl)c(C#N)cnc12
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cccc2c(Nc3c(F)cc(F)cc3F)c(C#N)cnc12
Temperature: 100 °C

Procedure:
Using an analogous procedure to that described in Example 274. A reaction mixture of 200.0 mg (0.92 mmol) of 4-chloro-8-methoxy-3-quinolinecarbonitrile, 105.7 mg (0.92 mmol) of pyridine hydrochloride and 148.6 mg (1.0 mmol) of 2,4,6-trifluoro-aniline in 10 mL of 2-ethoxyethanol was heated at 100° C. for 2 hr. The work up gave 112.6 mg (37.4%) of the product as a yellow solid, m.p. 297° C. (dec.), mass spectrum (electrospray, m/e): M+H 330.0.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[CH:17]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]>>[F:16][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[N:7][C:2]([NH:24][C:23]2[CH:25]=[CH:26][C:20]([CH:17]([CH3:19])[CH3:18])=[CH:21][CH:22]=2)=[N:3][CH:4]=1
Reactant: CC(C)c1ccc(N)cc1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: CC(C)c1ccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine with 4-isopropylaniline gave 5-fluoro-N4-(3-hydroxyphenyl)-N2-(4-isopropylphenyl)-2,4-pyrimidinediamine. LCMS: ret. time: 23.08 min.; purity: 99%; MS (m/e): 439 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([C:12]1[N:16]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[N:15]=[C:14]([Br:24])[CH:13]=1)=[O:11].C(Cl)Cl.Cl[C:29]([O:31][CH3:32])=[O:30]>N1C=CC=CC=1>[Br:24][C:14]1[CH:13]=[C:12]([C:10]([NH:9][C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:29](=[O:30])[O:31][CH3:32])=[O:11])[N:16]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[N:15]=1
Reactant: COC(=O)Cl
Reactant: Cc1cccc(N)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1cccc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 0 °C
Yield: 31.6 %

Procedure:
N-(2-amino-6-methylphenyl)-3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide prepared in Step 2 (1.18 g, 2.91 mmol), CH2Cl2 (2 M, 1.46 mL) and pyridine (1 M, 2.91 mL) were introduced to a 50 mL round flask. The mixture thus obtained was cooled down to 0° C., added with methyl chloroformate (2.25 mL, 29.1 mmol, 10.0 eq), and refluxed at 80° C. for 15 hours. Upon completion of the reaction, the solvent was removed under reduced pressure. The residue was extracted with 1 M HCl (20 mL) and ethyl acetate (20 mL x 2), washed with brine (20 mL). The organic layer thus obtained was dried over MgSO4 and concentrated under reduced pressure. Subsequently, the residue was purified by silica gel column chromatography (EA:Hex=2:3→EA:Hex=1:1) to obtain the title compound (426.7 mg, yield: 32%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C(Cl)Cl>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:22][CH:19]2[CH2:18][CH2:17][N:16]([CH2:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)[CH2:21][CH2:20]2)=[O:32])=[CH:26][CH:25]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COc1cc2nccc(CN3CCC(N)CC3)c2cc1OC
Solvent: ClCCl
Product: COc1cc2nccc(CN3CCC(NC(=O)Nc4ccc(Cl)cc4)CC3)c2cc1OC
Yield: 22 %

Procedure:
1-((6,7-Dimethoxyquinolin-4-yl)methyl)piperidin-4-amine (150 mg, 0.50 mmol) was dissolved in DCM (5 mL). While stirring, 4-chlorophenyl isocyanate (84 uL, 0.65 mmol) was added dropwise at rt, and the reaction was allowed to stir for 15 hours. The solvent was removed and the crude compound was columned using 100% DCM to 5% MeOH to give the desired product 1-(4-chlorophenyl)-3-(1-((6,7-dimethoxyquinolin-4-yl)methyl)piperidin-4-yl)urea (50 mg, 0.11 mmol, 22% yield). MS (ESI pos. ion) m/z: 455.2 (MH+). Calc'd exact mass for C24H27ClN4O3: 454.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH:16]([C:20]([NH:22][NH2:23])=[O:21])[CH2:17][CH2:18][CH3:19])(=[O:14])=[O:13])=[CH:8][CH:7]=1>C(O)C>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([NH:15][CH:16]([CH2:17][CH2:18][CH3:19])[C:20]([NH:22][NH:23][C:3](=[S:4])[NH:2][CH3:1])=[O:21])(=[O:14])=[O:13])=[CH:10][CH:11]=1
Reactant: CN=C=S
Reactant: CCCC(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)NN
Solvent: CCO
Product: CCCC(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)NNC(=S)NC
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
Methyl isothiocyanate (683 mg) was added, at room temperature, to an ethanol (85 ml) solution of the 4-chloro-N-[1-(hydrazinocarbonyl)butyl]benzenesulfonamide (2.596 g) obtained in Example 1-(2). The mixture was stirred for 30 minutes, and then stirred for 2 hours under reflux conditions. The solvent was distilled off from the reaction mixture to obtain a solid. The solid was washed with chloroform (100 ml), and then dried to obtain 2-(2-{[(4-chlorophenyl)sulfonyl]amino}pentanoyl)-N-methylhydrazine carbothioamide (2.868 g).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][N:16]([C:17]4[N:22]=[C:21]([N:23]5[CH2:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)[CH:20]=[N:19][CH:18]=4)[C:10]=3[CH:9]=2)=[CH:6][C:5]([CH3:37])=[CH:4][N:3]=1.Cl.C[OH:40]>O1CCOCC1>[N:23]1([C:21]2[N:22]=[C:17]([N:16]3[C:10]4[CH:9]=[C:8]([C:7]5[C:2]([OH:40])=[N:3][CH:4]=[C:5]([CH3:37])[CH:6]=5)[N:13]=[CH:12][C:11]=4[CH:14]=[N:15]3)[CH:18]=[N:19][CH:20]=2)[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1
Reactant: CO
Reactant: Cc1cnc(F)c(-c2cc3c(cn2)cnn3-c2cncc(N3CCCN(C(=O)OC(C)(C)C)CC3)n2)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cnc(O)c(-c2cc3c(cn2)cnn3-c2cncc(N3CCCNCC3)n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-[6-[6-(2-fluoro-5-methyl-3-pyridyl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-yl]-1,4-diazepane-1-carboxylate (0.2113 mmol; 106.6 mg) in Methanol (5 mL) was added hydrochloric acid, 4.0 M in 1,4-Dioxane (5 mL). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 164 as a by-product (18.7 mg, 22%). 1H NMR (400 MHz, DMSO) δ 9.89-9.85 (s, 1H), 9.25-9.20 (s, 1H), 8.64-8.60 (s, 1H), 8.56-8.52 (d, J=2.6 Hz, 1H), 8.41-8.38 (s, 1H), 8.08-8.05 (s, 1H), 7.33-7.30 (s, 1H), 3.95-3.84 (m, 4H), 2.99-2.93 (m, 2H), 2.71-2.66 (m, 2H), 2.15-2.13 (s, 3H), 1.88-1.81 (m, 2H); MS (ESI) m/z: 403.2 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:18]4([NH:21][C:22](=[O:31])[C:23](=[O:30])[N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]4)[CH2:14][N:13]3[C:32](=[O:35])[C:33]=2[OH:34])=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:47][C:48]1[O:52][N:51]=[C:50]([C:53](Cl)=[O:54])[CH:49]=1.CNC>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:18]4([NH:21][C:22](=[O:31])[C:23]([N:24]5[CH2:25][CH2:26][N:27]([C:53]([C:50]6[CH:49]=[C:48]([CH3:47])[O:52][N:51]=6)=[O:54])[CH2:28][CH2:29]5)=[O:30])[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]4)[CH2:14][N:13]3[C:32](=[O:35])[C:33]=2[OH:34])=[O:9])=[CH:36][CH:37]=1
Reactant: O=C(NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O)C(=O)N1CCNCC1
Reactant: Cc1cc(C(=O)Cl)no1
Agent: CNC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCN(C(=O)C(=O)NC34CCC(CC3)Cn3c4nc(C(=O)NCc4ccc(F)cc4)c(O)c3=O)CC2)no1
Reaction time: 0.08 h
Yield: 51.2 %

Procedure:
To a suspension N-(4-fluorobenzyl)-3-hydroxy-4-oxo-10-((oxo(1-piperazinyl)acetyl)amino)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamide (0.024 g, 0.038 mmol) in dichloromethane (1 mL) was added diisopropyl ethylamine (0.027 mL, 0.153 mmol). After stirring for 5 min, 5-methylisoxazole-3-carbonyl chloride (0.011 g, 0.077 mmol) was added and the solution stirred at room temperature for 1 h. Dimethylamine (0.192 mL, 0.383 mmol) (2 M in methanol) was added and the solution stirred at room temperature for 1 h then concentrated. The residue was purified by preparative HPLC: Solvent A=10% methanol/90% H2O/0.1% trifluoroacetic acid; Solvent B=90% methanol/10% H2O/0.1% trifluoroacetic acid; Start % B=10; Final % B=100; Gradient time=20 min; Stop time=25 min; Column=XTERRA® 19×50 mm, C18, 5 μm (product elutes at 12.6 min) to give the title compound as a pale lavender solid (12.1 mg, 49% yield). 1H NMR (500 MHz, CDCl3) δ: 12.00 (1 H, brs), 8.51 (1 H, d, J=5.80 Hz), 8.40 (1 H, d, J=5.19 Hz), 7.28-7.50 (2 H, m), 6.88-7.12 (2 H, m), 6.33 (1 H, d, J=2.14 Hz), 4.55 (2 H, t, J=6.26 Hz), 4.16 (2 H, brs), 4.02-4.14 (2 H, m), 3.89-4.00 (2 H, m), 3.80 (2 H, dt, J=18.08, 5.00 Hz), 3.50-3.68 (2 H, m), 2.53-2.77 (2 H, m), 2.48 (4 H, d, J=7.93 Hz), 1.87-2.15 (4 H, m), 1.72 (2 H, brs). LCMS (M+H) calcd for C30H33FN7O7: 622.24; found: 622.78.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[C:15]([CH:16]=O)=[CH:14][NH:13][C:12]1=[S:18].Cl.[NH2:20][OH:21].[OH-].[Na+]>C(O)C.O>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[C:15]([CH:16]=[N:20][OH:21])=[CH:14][NH:13][C:12]1=[S:18]
Reactant: NO
Reactant: O=Cc1c[nH]c(=S)n1C1CCc2ccccc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=Cc1c[nH]c(=S)n1C1CCc2ccccc2C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
A mixture of 3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-4-carbaldehyde (0.25 g, 1.0 mmol), hydroxylamine hydrochloride (0.09 g, 1.3 mmol) and sodium hydroxide (0.064 g, 1.6 mmol) in 2 mL of ethanol and 2 mL of water was stirred at 60° C. for 1 hour. The mixture was cooled giving a crystalline material. The material was isolated by filtration and dried. The filtrate was stirred with ethyl acetate giving more crystalline material. The material was isolated by filtration and dried. Combining the crystalline material gave 1-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-5-carbaldehyde oxime (0.186 g, 0.68 mmol).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].[CH:13]1([N:16]=[C:17]=[O:18])[CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([C:4](=[O:5])[CH2:3][NH:2][C:17]([NH:16][CH:13]2[CH2:15][CH2:14]2)=[O:18])=[CH:7][CH:8]=1
Reactant: O=C=NC1CC1
Reactant: NCC(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)c1ccc(Cl)cc1)NC1CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1000 mg (4.853 mmol) of 2-amino-1-(4-chlorophenyl)ethanone hydrochloride are placed in 20 ml dichloromethane, cooled to 0° C. and treated dropwise with a solution of 363 mg (4.367 mmol) of cyclopropyl isocyanate in 2 ml dichloromethane. It is stirred a further 10 mins at 0° C. and then a solution of 627 mg (4.853 mmol) of N,N-diisopropylethylamine in 4 ml dichloromethane is added dropwise. After two hours' stirring at room temperature the reaction mixture is evaporated and the crude product purified by flash chromatography on silica gel (eluent: dichloromethane/methanol 100:1). 1000 mg (73% of theory) of the target compound are obtained.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.[C:12]1([CH2:18][CH2:19][NH2:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([CH2:18][CH2:19][NH:20][C:2]2[N:10]=[C:9]3[C:5]([NH:6][CH:7]=[N:8]3)=[C:4]([NH2:11])[N:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Reactant: NCCc1ccccc1
Product: Nc1nc(NCCc2ccccc2)nc2nc[nH]c12

Procedure:
The starting material 2-(2-phenylethylamino)-adenine is prepared by reacting 2-chloroadenine with excess 2-phenylethylamine at about 140°.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[CH2:17](Br)[C:18]#[CH:19].C1(C)C=CC=CC=1>C1COCC1>[CH2:19]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]1)[C:18]#[CH:17]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C#CCOC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a RT solution of 1-boc-4-hydroxypiperidine (1.20 g, 5.96 mmol) in THF (20 mL) was added sodium hydride dispersion in mineral oil (0.440 g, 11.00 mmol, 57%), in portions, as a solid. After 30 min propargyl bromide, 80% solution in toluene (1.80 mL, 16.16 mmol) was added dropwise via syringe and the reaction was allowed to stir for 2 h. The reaction was cooled to 0° C., quenched with water and extracted with EtOAc (3×). The combined organic layers were washed with brine, evaporated onto silica gel and purified by flash chromatography (Isco (80 gram)) eluting with (EtOAc):hexanes (0:1→1:1) to give the titled compound as a colorless oil (861 mg, 60%). MS m/z=183.9 [M−tBu]+. Calculated for C9H12NO3: 182
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:8]([C:10]#[N:11])[CH:9]=1)=[O:4].[Li+].[OH-].Cl.C(C1C=C(C(O)=O)SC=1S(C)(=O)=[O:27])#N>C1COCC1.O>[C:10]([C:8]1[CH:9]=[C:5]([C:3]([OH:2])=[O:4])[S:6][C:7]=1[S:12]([CH3:15])(=[O:14])=[O:13])(=[O:27])[NH2:11]
Reactant: COC(=O)c1cc(C#N)c(S(C)(=O)=O)s1
Reactant: CS(=O)(=O)c1sc(C(=O)O)cc1C#N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1sc(C(=O)O)cc1C(N)=O

Procedure:
To 4-cyano-5-methanesulfonyl-thiophene-2-carboxylic acid methyl ester (0.5 g) in THF/H2O (3:1; 16 ml) was added LiOH (0.102 g). Hydrochloric acid (2M) was added and the resulting mixture was extracted with ethyl acetate. The extracts were combined and the solvent evaporated to leave a mixture of 4-cyano-5-methanesulfonyl-thiophene-2-carboxylic acid and the title compound. This mixture was used without further purification. 1H NMR (299.944 MHz, DMSO-D6) δ 3.62 (3H, s), 7.99 (1H, s).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].C(N(CC)C(C)C)(C)C.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>ClCCl>[C:29]1([O:28][C:26](=[O:27])[NH:6][C:5]2[CH:4]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.8 %

Procedure:
3,5-Bis-(trifluoromethyl)aniline (2.0 g, 8.7 mmol) was dissolved in dichloromethane (80 mL) and N,N-diisopropylethylamine (1.6 mL, 9.6 mmol) was added followed by slow addition of phenyl chloroformate (1.1 mL, 8.7 mmol). The resulting mixture was stirred at room temperature for 16 hours. The mixture was successively washed with 1N hydrochloric acid (3×100 mL), water (3×100 mL), a mixture of water and saturated aqueous sodium hydrogen carbonate (1:1, 2×100 mL) and a mixture of water and saturated aqueous sodium chloride (1:1, 3×100 mL), dried (MgSO4) and concentrated in vacuo. The residue was crystallised from heptane containing a little diethyl ether to afford 1.3 g (43%) of (3,5-bis-trifluoromethylphenyl)carbamic acid phenyl ester as a solid.