Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](O)=[O:6].C([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[O:23])[CH2:17][CH2:16]1)(=O)C(C)C>>[F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][CH:26]=2)=[O:23])[CH2:17][CH2:16]1)=[O:6]
Reactant: CC(C)C(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Reactant: O=C(O)CCC(F)(F)F
Product: O=C(Nc1ccc(C(F)(F)F)cc1)NC1CCN(C(=O)CCC(F)(F)F)CC1
Yield: 70 %

Procedure:
4,4,4-Trifluorobutanoic acid (59 mg, 0.418 mmol) was reacted with PTU (80 mg, 0.278 mmol) as the same manner as the synthesis of 1-(1-isobutyrylpiperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea yielding the final product (80 mg, 0.194 mmol, 70% yield). 1H NMR (d6-DMSO, 300 Mhz): δ 8.80 (s, 1H), 7.58 (s, 4H), 6.38 (d, J=7.8 Hz, 1H), 4.19 (d, J=13.8 Hz, 1H), 3.79 (d, J=13.8 Hz, 1H), 3.77 (m, 1H), 3.16 (t, J=12.3 Hz, 1H), 2.84 (m, J=11.4 Hz, 1H), 2.60 (d, J=6.3 Hz, 2H), 2.59 (m, 2H), 1.85 (br, 2H), 1.30 (m, 2H).
Reaction SMILES: CO[C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([Br:18])[CH:13]=1.[NH2:20][C:21]1[N:22]=[CH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[C:26]([O:31][CH3:32])[CH:25]=2>>[Br:18][C:14]1[CH:13]=[C:12]([CH2:11][NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:20][C:21]2[N:22]=[CH:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[C:26]([O:31][CH3:32])[CH:25]=3)=[O:19])[CH:17]=[CH:16][N:15]=1
Reactant: COc1ccc2cc(N)ncc2c1
Reactant: COC(=O)c1ccccc1NCc1ccnc(Br)c1
Product: COc1ccc2cc(NC(=O)c3ccccc3NCc3ccnc(Br)c3)ncc2c1

Procedure:
2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(7-methoxy-isoquinolin-3-yl)benzamide was prepared from 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoic acid methyl ester and 3-amino-7-methoxyisoquinoline in analogy to the procedures detailed in WO2004/013102, particularly Example 6A; supra; 1H-NMR (300 MHz, d6-DMSO) 10.62 (1H, s), 9.10 (1H, s), 8.51 (1H, s), 8.32 (1H, d), 8.11 (1H, t), 7.83-7.90 (2H, m), 7.60 (1H, s), 7.50 (1H, m), 7.38-7.41 (2H, m), 7.27 (1H, t), 6.66 (1H, t), 6.55 (1H, d), 4.54 (2H, d), 3.91 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH2:18][NH:19]C(=O)OC(C)(C)C)=[CH:16][C:15]3[C:10](=[C:11]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O.Cl[C:39]1[N:47]=[CH:46][N:45]=[C:44]2[C:40]=1[NH:41][CH:42]=[N:43]2.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH2:18][NH:19][C:39]3[N:47]=[CH:46][N:45]=[C:44]4[C:40]=3[N:41]=[CH:42][NH:43]4)=[CH:16][C:15]3[C:10](=[C:11]([S:27]([CH3:30])(=[O:28])=[O:29])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: CC(C)(C)OC(=O)NCc1cc2cccc(S(C)(=O)=O)c2nc1-c1cccc(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1cccc2cc(CNc3ncnc4[nH]cnc34)c(-c3cccc(F)c3)nc12

Procedure:
tert-Butyl (2-(3-fluorophenyl)-8-(methyl sulfonyl)quinolin-3-yl)methylcarbamate (18 mg, 0.042 mmol) was treated with 50% TFA in DCM (1 mL) for 30 min at rt and the reaction mixture was concentrated to driness. The resulted solid was treated with 6-chloropurine (7.1 mg, 1.1 eq) and hunig's base (0.04 mL, 4 eq) in BunOH (1 mL) at 90° C. HPLC on reverse phase gave a white solid. 1H-NMR (400 Hz, CD3OD) δ 8.47 (s, 1H), 8.38 (dd, J=8.0, 4.0 Hz, 1H), 8.24 (s, 1H), 8.18 (dd, J=8.0, 4.0 Hz, 1H), 7.68 (t, J=8.0 Hz, 1H), 7.50-7.39 (m, 3H), 7.11 (t, J=8.0 Hz, 1H), 5.24 (s, 2H), 3.45 (s, 3H). Mass Spectrum (ESI) m/e=449 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]([C@@H:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:25])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:26][C:27]1[C:32](B(O)O)=[CH:31][C:30]([F:36])=[CH:29][N:28]=1.[F-].[Cs+].COC>C(O)CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Cl:25][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:32]1[C:27]([Cl:26])=[N:28][CH:29]=[C:30]([F:36])[CH:31]=1)[C:11]([C@@H:12]([N:14]1[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]1=[O:24])[CH3:13])=[CH:10]2
Reactant: C[C@@H](c1cc2cccc(Cl)c2nc1Cl)N1C(=O)c2ccccc2C1=O
Reactant: OB(O)c1cc(F)cnc1Cl
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COC
Solvent: OCCO
Product: C[C@@H](c1cc2cccc(Cl)c2nc1-c1cc(F)cnc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-2-(1-(2,8-dichloroquinolin-3-yl)ethyl)isoindoline-1,3-dione (120.0 mg, 323 μmol), 2-chloro-5-fluoropyridin-3-ylboronic acid (57 mg, 323 μmol), tetrakis(triphenylphosphine)palladium (37 mg, 32 μmol), cesium fluoride (147 mg, 970 μmol) and copper(I) iodide (12 mg, 65 μmol) in 1,2-ethanediol, dimethyl ether (3.0 mL, 323 μmol) was subjected to microwave at 100° C. for 1 h, cooled to room temperature. Filtration of the resultant mixture and rinsed with EtOAc, the filtrates were collected and concentrated. Purification of the residue by flash chromatography over silica gel, gradient elution, 0-100% EtOAc in hexane, gave 2-((S)-1-(8-chloro-2-(2-chloro-5-fluoropyridin-3-yl)quinolin-3-yl)-ethyl)isoindoline-1,3-dione, Mass Spectrum (ESI) m/e=466.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:23][CH:22]([CH2:24]O)[CH2:21][C:20]2=[O:26])=[CH:15][CH:14]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N(CC)CC)C.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:24][CH:22]2[CH2:21][C:20](=[O:26])[N:19]([C:16]3[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=3)[CH2:23]2)=[CH:6][CH:5]=1
Reactant: O=C1CC(CO)CN1c1ccc(F)cc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(OCC2CC(=O)N(c3ccc(F)cc3)C2)cc1
Temperature: 0 °C
Yield: 73.1 %

Procedure:
4-Hydroxybenzoic acid methyl ester (0.20 g, 1.314 mmol), 1-(4-fluoro-phenyl)-4-hydroxymethyl-pyrrolidin-2-one (0.33 g, 1.577 mmol), Ph3P (0.345 g, 1.314 mmol) and triethyl amine (0.20 ml, 1.577 mmol) were mixed under argon atmosphere followed by the addition of the dry toluene (10 mL). The reaction mixture was cooled to 0° C. followed by addition of DIAD (0.3 mL, 0.788 mmol) drop wise. The reaction mixture was allowed to warm to room temperature and heated at 80° C. for 24 h. The reaction was quenched with 5% HCl (10 mL), extracted with DCM. The organic layer was dried over Na2SO4 and concentrated to afford the crude product which was purified by flash column chromatography to obtain 4-[1-(4-fluorophenyl)-5-oxo-pyrrolidin-3-ylmethoxy]-benzoic acid methyl ester (0.33 g, 73%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]([F:17])([F:16])[F:15])=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][C:4]=1[NH2:18].[C:19](OC(=O)C)(=[O:21])[CH3:20].C1(C)C=CC=CC=1.CC(C)=O.C1(C)C=CC=CC=1>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]([F:15])([F:16])[F:17])=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][C:4]=1[NH:18][C:19](=[O:21])[CH3:20]
Reactant: COc1cc2[nH]c(=O)cc(C(F)(F)F)c2cc1N
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc2[nH]c(=O)cc(C(F)(F)F)c2cc1NC(C)=O

Procedure:
27,85 mg of 7-methoxy-6-amino-4-trifluoromethyl-2-(1H)-quinolone are dissolved in 0,5 ml of glacial acetic acid, mixed with 0.15 ml acetic acid anhydride and made to react for 2 hours at 20° C. After subtracting the solvent, the remainder is cleaned with Flash chromatography (silica gel, toluene/acetone 1:1). Yield: 30.7 mg (99%). Melting point 280° C. (toluene, dec), UV λ max 368 nm, emission max 448 nm, IR 1680 (CO).
Reaction SMILES: [CH3:1][N:2](C)CCN(C)C.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:52]1[C:53]([O:73][CH2:74][CH3:75])=[C:54]([CH:60]([N:62]2[C:66]3=[N:67][CH:68]=[N:69][C:70]([NH2:71])=[C:65]3[C:64]([CH3:72])=[N:63]2)[CH3:61])[CH:55]=[C:56]([Cl:59])[C:57]=1[CH3:58]>CN(C)C=O.[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:71][C:70]1[N:69]=[CH:68][N:67]=[C:66]2[N:62]([CH:60]([C:54]3[C:53]([O:73][CH2:74][CH3:75])=[C:52]([C:57]([CH3:58])=[C:56]([Cl:59])[CH:55]=3)[C:1]#[N:2])[CH3:61])[N:63]=[C:64]([CH3:72])[C:65]=12
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1Br
Reactant: CN(C)CCN(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C#N
Temperature: 160 °C
Yield: 19.6 %

Procedure:
N,N,N′,N′-Tetramethylethylenediamine (10 μL, 0.07 mmol), zinc cyanide (3 mg, 0.03 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.9 mg, 0.001 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2 mg, 0.003 mmol) was added successively to a solution of 1-[1-(3-bromo-5-chloro-2-ethoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (14 mg, 0.033 mmol, Peak 1 from Example 195, step 4) in N,N-dimethylformamide (0.5 mL) in a microwave tube. The tube was sealed and degassed and refilled with N2 three times, and then heated at 160° C. under microwave irradiation for 400 seconds. The mixture was cooled, filtered and the crude filtrate was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (2.4 mg, 20%). The product was isolated as a single enantiomer. LCMS calculated for C18H20ClN6O (M+H)+: m/z=371.1; Found: 371.2.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[C:18]1([C:24]2[N:25]=[C:26]([C:30]([O:32][CH2:33][CH3:34])=[O:31])N=N[CH:29]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.COCCOCCOC>>[N:12]1([C:10]([C:7]2[CH:8]=[C:9]3[C:4]([C:3]4[CH:29]=[C:24]([C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=5)[N:25]=[C:26]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:2]=4[NH:1]3)=[CH:5][CH:6]=2)=[O:11])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=C(c1ccc2cc[nH]c2c1)N1CCOCC1
Reactant: CCOC(=O)c1nncc(-c2ccccc2)n1
Solvent: COCCOCCOC
Product: CCOC(=O)c1nc(-c2ccccc2)cc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Temperature: 185 °C

Procedure:
(1H-Indol-6-yl)(morpholino)methanone (200 mg, 0.869 mmol), ethyl 5-phenyl-1,2,4-triazine-3-carboxylate (299 mg, 1.303 mmol) and 1-methoxy-2-(2-methoxyethoxy)ethane (556 μL, 3.91 mmol) were mixed in a sealed microwave vial. The mixture was heated in microwave at 185° C. for 8 hrs. The mixture was purified using preparative HPLC to give titled product. MS (ESI) m/z 430.09 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.82 (s, 1H), 9.13 (s, 1H), 8.47 (d, 1H, J=7.9), 8.27 (d, 2H, J=7.7), 7.81 (s, 1H), 7.56(t, 2H, J=7.6), 7.44 (t, 1H, J=7.3), 7.36 (d, 1H, J=7.9), 4.57 (q, 2H, J=7.1), 3.67-3.45 (bm, 8H), 1.47 (t, 3H, J=7.1). NOE and ghmbc were used to confirm the structure.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)[CH:25]=[C:24](I)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:2].[N:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1>>[CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)[CH:25]=[C:24]([C:45]3[CH:46]=[CH:47][N:42]=[CH:43][CH:44]=3)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:2]
Reactant: OB(O)c1ccncc1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccncc3)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Yield: 62.1 %

Procedure:
A similar procedure as described in Example 12, step 8 was used, starting from 4-{3-[6-(3-iodo-5-thiophen-3-yl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (207 mg, 0.3 mmol) and pyridin-4-ylboronic acid (123 mg, 1.0 mmol) to obtain 4-{2-(2-ethoxycarbony-ethyl)-3-[6-(3-pyridin-4-yl-5-thiophen-3-yl-phenoxy)-hexyl]-phenoxy}-butyric acid ethyl ester (120 mg, 62%) as an yellow oil: ES(+)-HRMS m/e calculated for C38H45NO6S (M+H)+ 644.3041, found 644.3041.
Reaction SMILES: COC[O:4][C:5]1[CH:45]=[CH:44][C:8]2[CH:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][S:33][CH2:34][CH2:35][CH2:36][C:37]([F:43])([F:42])[C:38]([F:41])([F:40])[F:39])[C:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20]COC)=[CH:16][CH:15]=3)([CH3:13])[CH2:11][O:12][C:7]=2[CH:6]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CO>[OH:4][C:5]1[CH:45]=[CH:44][C:8]2[CH:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][S:33][CH2:34][CH2:35][CH2:36][C:37]([F:43])([F:42])[C:38]([F:39])([F:40])[F:41])[C:10]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)([CH3:13])[CH2:11][O:12][C:7]=2[CH:6]=1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCSCCCC(F)(F)C(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CO
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCSCCCC(F)(F)C(F)(F)F
Temperature: 25 °C
Yield: 66.1 %

Procedure:
(3RS,4RS)-7-Methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentylthio)nonyl]-2,3-dihydro-4H-benzopyran (100 mg, 0.15 mmol) and pyridinium p-toluenesulfonate (380 mg, 1.5 mmol) were dissolved in methanol (5 ml) and refluxed for 4 hours. The reaction solution was cooled to room temperature and, after adding water, extracted with ethyl acetate. The extracted organic layer was dried over magnesium sulfate and concentrated. The residue was subjected to column chromatography (n-hexane:ethyl acetate=4:1) to obtain 57 mg (yield: 66%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[C:9]2[N:10]=[C:11]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=3)[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])[C:8]=2[CH2:7][CH2:6][N:5]1[CH2:33][CH3:34])#[N:2].C(N1CCC2C(N3CCOCC3)=NC(C3C=CC(NC(NCC)=O)=CC=3)=NC=2C1CC#N)(=O)C.Cl.[OH-].[Na+].CC1C=CC(COC(NNC(C2C=NC=CN=2)=O)=O)=CC=1>O1CCCC1>[C:1]([CH2:3][C@@H:4]1[C:9]2[N:10]=[C:11]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=3)[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])[C:8]=2[CH2:7][CH2:6][N:5]1[CH2:33][CH3:34])#[N:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(CC)[C@H]3CC#N)cc1
Agent: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(C)=O)C3CC#N)cc1
Agent: Cc1ccc(COC(=O)NNC(=O)c2cnccn2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(CC)[C@@H]3CC#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
and 1-(4-((S)-8-(cyanomethyl)-7-ethyl-4-((S)-3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)-3-ethylurea (xs2): 1-(4-(7-acetyl-8-(cyanomethyl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)-3-ethylurea (0.051 g, 0.00011 mol) in dry Tetrahydrofuran (1.00 mL, 0.0123 mol) at 0° C. was added 1.0 M of Borane-THF complex in Tetrahydrofuran (0.320 mL) dropwise. The reaction mixture was allowed to warm slowly to room temperature and stirred overnight. The reaction mixture was cooled at 0° C. then about 1 mL 1M HCl dropwise then added 1M NaOH until pH10. The reaction mixture was extracted three times with 10% MeOH in dichloromethane, dried over Magnesium sulfate, filtered, concentrated, purified by HPLC, and the diastereomers were separated by SFC. R Diastereomer (xs1): 1H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 8.19 (t, J=11.3, 2H), 7.48 (d, J=8.7, 2H), 6.15 (t, J=5.3, 1H), 4.19 (d, J=6.6, 1H), 3.90 (d, J=11.6, 1H), 3.75 (d, J=12.2, 2H), 3.60 (dd, J=25.9, 11.5, 3H), 3.51-3.38 (m, 1H), 3.23-3.17 (m, 1H), 3.10 (ddd, J=24.6, 15.3, 9.3, 3H), 2.86 (dt, J=14.5, 7.2, 1H), 2.67 (s, 1H), 2.59 (dd, J=13.2, 6.9, 2H), 2.55-2.39 (m, 2H), 1.18 (d, J=6.6, 3H), 1.08 (dt, J=14.3, 7.1, 6H). LC/MS-m/z+464.2 (M+H)+; S Diastereomer (xs2) 1H NMR (400 MHz, DMSO) δ 8.63 (s, 1H), 8.20 (d, J=8.7, 2H), 7.48 (d, J=8.7, 2H), 6.15 (t, J=5.5, 1H), 4.14 (d, J=6.8, 1H), 3.88 (d, J=10.3, 1H), 3.81-3.70 (m, 2H), 3.70-3.57 (m, 3H), 3.39 (t, J=11.0, 1H), 3.14 (ddd, J=19.9, 12.1, 6.1, 4H), 3.07-2.98 (m, 1H), 2.84 (dq, J=13.9, 7.0, 1H), 2.59 (ddd, J=21.5, 15.3, 8.2, 4H), 1.34 (d, J=6.6, 3H), 1.08 (dt, J=14.3, 7.1, 6H). LC/MS-m/z+464.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH2:19][NH2:20])([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:11][CH:12]=2)[CH2:4][CH2:3]1.[F:21][C:22]([F:38])([F:37])[C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:29]=[N:30][CH:31]=[C:32]([CH:36]=2)[C:33](O)=[O:34])[N:24]=1>>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]([CH2:19][NH:20][C:33](=[O:34])[C:32]2[CH:36]=[C:28]([C:25]3[N:24]=[C:23]([C:22]([F:38])([F:37])[F:21])[O:27][N:26]=3)[CH:29]=[N:30][CH:31]=2)([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:11][CH:12]=2)[CH2:6][CH2:7]1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Reactant: CN1CCC(CN)(c2csc(-c3ccccc3)n2)CC1
Product: CN1CCC(CNC(=O)c2cncc(-c3noc(C(F)(F)F)n3)c2)(c2csc(-c3ccccc3)n2)CC1
Yield: 8 %

Procedure:
This compound was synthesized from (1-methyl-4-(2-phenylthiazol-4-yl)piperidin-4-yl)methanamine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (15 mg, yield 8%). 1H NMR (400 MHz, CDCl3) δ 9.43 (d, J=1.5 Hz, 1H), 9.22 (d, J=1.8 Hz, 1H), 8.76 (m, 1H), 7.92-7.90 (m, 3H), 7.42-7.41 (m, 3H), 7.19 (s, 1H), 3.92-3.87 (m, 2H), 3.00 (m, 2H), 2.84 (m, 2H), 2.57 (m, 5H), 2.25 (m, 2H). MS (ESI) m/z: Calculated for C25H23F3N6O2S: 528.55. found: 529.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C@H:13]([C:15]2[CH:16]=[C:17]3[C:26](=[CH:27][C:28]=2Br)[O:25][CH2:24][C:23]2[N:18]3[C@H:19]([CH3:31])[C:20](=[O:30])[NH:21][N:22]=2)[CH3:14])([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:32](B1OC(C)(C)C(C)(C)O1)([CH3:34])=[CH2:33].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C@@H:13]([C:15]2[CH:16]=[C:17]3[C:26](=[CH:27][C:28]=2[C:32]([CH3:34])=[CH2:33])[O:25][CH2:24][C:23]2[N:18]3[C@H:19]([CH3:31])[C:20](=[O:30])[NH:21][N:22]=2)[CH3:14])([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(Br)c([C@H](C)C4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: C=C(C)c1cc2c(cc1[C@@H](C)C1(C)CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)[C@H]1C)CO2
Temperature: 90 °C
Reaction time: 4 h
Yield: 92.6 %

Procedure:
A mixture of 3-[(R)-1-((R)-7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-ethyl]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.128 g, 0.26 mmol), 2-isopropenyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.044 g, 0.259 mmol), Na2CO3 (0.055 g, 0.519 mmol) and PdCl2(dppf)-CH2Cl2 adduct (0.042 g, 0.052 mmol) in dioxane (4 mL) and water (1 mL) was stirred at 90° C. for 4 h. The reaction mixture was cooled to ambient temperature. The solvent was removed in vacuo and the residue was purified by prep-TLC (eluting with 50% EtOAc in petroleum ether) to give 3-[(R)-1-((R)-7-isopropenyl-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-ethyl]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.109 g, 59%) as a solid. LC/MS (Table 1, Method 25) Rt=0.925 min.; MS m/z: 455 [M+H]+ and 399 [M+H−56]+. 1H NMR (CDCl3, 400 MHz): δ 8.06 (brs, 1H), 6.79 (s, 1H), 6.65 (s, 1H), 5.25 (s, 1H), 4.86 (s, 1H), 4.70 (q, J=6.8 Hz, 1H), 4.64-4.54 (d, J=13.8 Hz, 2H), 3.96 (d, J=8.0 Hz, 1H), 3.82 (d, J=8.0 Hz, 1H), 3.56 (d, J=8.0 Hz, 1H), 3.42 (d, J=8.0 Hz, 1H), 3.21 (m, 1H), 2.03 (s, 3H), 1.67 (m, 3H), 1.45 (s, 9H), 1.32 (d, J=7.2 Hz, 3H), 1.25 (d, J=15.2 Hz, 3H).
Reaction SMILES: [OH:1][C@:2]([C:32]1[CH:36]=[C:35]([CH3:37])[O:34][N:33]=1)([CH3:31])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]2[O:14][CH2:13][CH2:12][N:11]3[C:15]([C:21]([NH:23][CH:24]4CCOCC4)=[O:22])=[C:16]([C:18]([NH2:20])=[O:19])[N:17]=[C:10]3[C:9]=2[CH:30]=1.CN[CH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>>[OH:1][C@:2]([C:32]1[CH:36]=[C:35]([CH3:37])[O:34][N:33]=1)([CH3:31])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]2[O:14][CH2:13][CH2:12][N:11]3[C:15]([C:21]([NH:23][CH2:24][CH:40]4[CH2:41][CH2:42][O:43][CH2:44][CH2:45]4)=[O:22])=[C:16]([C:18]([NH2:20])=[O:19])[N:17]=[C:10]3[C:9]=2[CH:30]=1
Reactant: CNC1CCOCC1
Reactant: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NC4CCOCC4)n2CCO3)no1
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NCC4CCOCC4)n2CCO3)no1

Procedure:
Prepared as described for (R)-10-(3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-yn-1-yl)-N3-(tetrahydro-2H-pyran-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide replacing 4-aminotetrahydropyran with 4-(methylamino)tetrahydropyran. Off-white solid (19.4 mg, 7%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11]([N:19]=[C:20]=[O:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC(C)=O>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:2]=1[NH:1][C:20]([NH:19][C:11](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:21])#[N:5]
Reactant: N#Cc1ccc(O)cc1N
Reactant: O=C=NC(=O)c1ccccc1
Solvent: CC(C)=O
Product: N#Cc1ccc(O)cc1NC(=O)NC(=O)c1ccccc1

Procedure:
Prepared as in Example 53a, but refluxed in acetone instead of 1,4-dioxane, from 2-amino-4-hydroxybenzonitrile and benzoyl isocyanate as a yellow solid (399 mg, 94%). MS 281 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([O:11][CH3:12])[CH:3]=1.Br[CH2:14][CH2:15][CH2:16]Br.[H-].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:16][CH2:15][CH2:14]2)=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: BrCCCBr
Reactant: COc1cc(Br)ccc1CC#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Br)ccc1C1(C#N)CCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.8 %

Procedure:
To a stirring mixture of (4-bromo-2-methoxyphenyl)acetonitrile (904 mg, 4.00 mmol), 1,3-dibromo-propane (880 mg, 4.40 mmol) in dimethylformamide (10 mL) was added sodium hydride (352 mg, 8.80 mmol) at 0° C. After addition, the mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water and extracted with dichloromethane (50 mL×3). The organic phases were combined, dried over sodium sulfate and concentrated in vacuo to give a brown solid. The solid was purification by combiflash chromatography (Petroleum ether/EtOAc=20:1 to 5:1) to give the title compound (370 mg, 34.8%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.10 (dd, 1H), 7.02 (d, 1H), 7.00 (d, 1H), 3.87 (s, 3H), 2.78 (m, 2H), 2.50 (m, 3H), 1.95 (m, 1H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[CH:12][N:13]=[C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31](O)=[O:32])=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[CH:12][N:13]=[C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:31](=[O:32])[CH2:30][O:29][C:28]5[CH:34]=[CH:35][C:25]([O:24][CH3:23])=[CH:26][CH:27]=5)[CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(OCC(=O)O)cc1
Reactant: Fc1ccc(-c2nc3c(N4CCNCC4)ncnc3s2)cc1
Product: COc1ccc(OCC(=O)N2CCN(c3ncnc4sc(-c5ccc(F)cc5)nc34)CC2)cc1
Yield: 51 %

Procedure:
This compound was prepared from 2-(4-fluorophenyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidine using 4-methoxyphenoxyacetic acid in a yield of 51%, according to the procedure for the synthesis of example 50.