Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1([C:10]([OH:12])=O)[CH2:9][CH2:8]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.Cl.[NH2:48][C:49]1[CH:50]=[CH:51][C:52]([N:56]2[CH2:61][CH2:60][CH2:59][C@@H:58]([C:62]([N:64]3[CH2:68][CH2:67][CH2:66][CH2:65]3)=[O:63])[CH2:57]2)=[N:53][C:54]=1[NH2:55]>ClCCl>[NH2:55][C:54]1[C:49]([NH:48][C:10]([C:7]2([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)[CH2:8][CH2:9]2)=[O:12])=[CH:50][CH:51]=[C:52]([N:56]2[CH2:61][CH2:60][CH2:59][C@@H:58]([C:62]([N:64]3[CH2:68][CH2:67][CH2:66][CH2:65]3)=[O:63])[CH2:57]2)[N:53]=1
Reactant: O=C(O)C1(c2cnccn2)CC1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1NC(=O)C1(c2cnccn2)CC1
Reaction time: 0.17 h
Yield: 34.3 %

Procedure:
To a solution of 1-(pyrazin-2-yl)cyclopropanecarboxylic acid (0.11 g, 0.669 mmol) in anhydrous dichloromethane (15 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (HATU) (0.3 g, 0.803 mmol) and diisopropylethylamine (0.35 mL, 2 mmol) at room temperature. The mixture was stirred for 10 min and then (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (0.29 g, 0.803 mmol) was added. The reaction mixture was stirred for 30 min. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via column chromatography (100-200 mesh silica gel, 0-5% methanol in dichloromethane) to afford (R)—N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-1-(pyrazin-2-yl)cyclopropanecarboxamide (100 mg). MS (ES+APCI) (M+H) 436.1.
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH2:14][OH:15])[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].[O-:18][Mn](=O)(=O)=O.[K+]>CO>[C:1]([NH:8][C@H:9]([C:14]([OH:18])=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 0.25 h
Yield: 94 %

Procedure:
BOC-leucinol (130 mg, 0.598 mmol) was treated with 3.1 ml of 0.25 N NaOH followed by KMnO4 (125 mg, 0.796 mmol) at room temperature and stirred 15 min. The reaction was treated with methanol, stirred 15 min, and the brown precipitate removed by filtration through Celite. The filtrate was acidified with solid citric acid and extracted with ether (3×). The combined ethereal extracts were washed with saturated NaCl (aq) (2×), dried over MgSO4 and filtered. Evaporation of the filtrate in vacuo gave 130 mg of BOC-leucine as an oil homogeneous by TLC (Rf, 0.34; silica GF in 5% MeOH/95% CH2Cl2).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32](O)=[O:33])(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:39][CH2:40][C@H:41]([OH:43])[CH3:42]>>[OH:43][C@H:41]([CH3:42])[CH2:40][NH:39][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=1[S:27]([CH2:26][C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=2[CH:23]=[CH:24][C:15]=1[O:14][C@@H:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)(=[O:29])=[O:28]
Reactant: O=C(O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reactant: C[C@@H](O)CN
Product: C[C@@H](O)CNC(=O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 54.5 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and (R)-1-amino-2-propanol (23 mg, 0.30 mmol, 0.6M in DMF) were combined to give 32 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 588 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31]>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Reactant: CC(C)CCBr
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCCCN3CCC(C)C)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(2-piperidinyl)propyl]-9H-purin-6-amine and 1-bromo-3-methylbutane.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[N:12]=[C:11]([N:13]=[CH:14][N:15]([CH3:17])[CH3:16])[NH:10][C:9](=[O:18])[C:8]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([O:34][CH3:35])=[O:33])=[CH:22][CH:21]=1)[CH2:4][CH2:5][CH3:6]>C1COCC1>[CH2:3]([C:7]1[N:12]=[C:11]([N:13]=[CH:14][N:15]([CH3:17])[CH3:16])[N:10]([CH2:27][C:32]([O:34][CH3:35])=[O:33])[C:9](=[O:18])[C:8]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([O:34][CH3:35])=[O:33])=[CH:24][CH:25]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nc(N=CN(C)C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCc1nc(N=CN(C)C)n(CC(=O)OC)c(=O)c1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Yield: 158.4 %

Procedure:
A suspension of 7 mg of 80% NaH in 1 ml of anhydrous THF is added with a solution of 0.1 g of 6-butyl-2-dimethylaminomethylenamino-5-[(2'-methoxycarbonylbiphenyl-4-yl)methyl]pyrimidin-4-one under nitrogen atmosphere and with magnetic stirring. When bubbling is over, the yellow clear solution is added with 21 μl of methyl bromoacetate and, after 30', the solvent is evaporated off under reduced pressure. The residue is purified by FC (eluent CH2Cl2 --CH3OH 99:1), to obtain 92 mg of a yellow oil (84% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][NH:12][C:13]([C:15]2[N:16]=[CH:17][N:18]([CH3:30])[C:19](=[O:29])[C:20]=2[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:14])=O)=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)Cl.[CH:36]1[CH:41]=[CH:40][C:39]([P:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:38][CH:37]=1.CCN(CC)CC>CC#N.CCOC(C)=O>[CH2:22]([O:21][C:20]1[C:19](=[O:29])[N:18]([CH3:30])[CH:17]=[N:16][C:15]=1[C:13]1[O:14][C:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:11][N:12]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH:52]1[CH:51]=[CH:50][C:49]([P:42]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:39]2[CH:40]=[CH:41][CH:36]=[CH:37][CH:38]=2)=[CH:54][CH:53]=1
Reactant: Cn1cnc(C(=O)NNC(=O)Cc2ccc(F)cc2)c(OCc2ccccc2)c1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1cnc(-c2nnc(Cc3ccc(F)cc3)o2)c(OCc2ccccc2)c1=O

Procedure:
Following the procedure described in European Patent No. 1698628, 5-benzyloxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid N′-[2-(4-fluoro-phenyl)-acetyl]-hydrazide was treated with CCl4 (7 equiv.), Ph3P (3 equiv.) and Et3N (3 equiv.) in CH3CN (10 vol) at room temperature for 1.5 h. TLC showed only one product formed. The reaction mixture was diluted with EtOAc, washed with aqueous NaHCO3 and brine, dried and concentrated to give a crude solid. For the 1.8 g scale reaction, chromatography (4 columns) plus recrystallization twice was needed to isolate the desired product without Ph3P═O contamination. NMR and MS confirmed the structure.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]3[CH2:24][NH:25][CH2:26][CH2:27][C:21]3=[N:20][C:19]=2[NH:28][CH:29]([CH3:31])[CH3:30])[CH2:14][CH2:13]1.C(N(CC)CC)C.[C:44](Cl)(=[O:47])[O:45][CH3:46]>C(Cl)Cl>[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:23]=[C:22]3[CH2:24][N:25]([C:44]([O:45][CH3:46])=[O:47])[CH2:26][CH2:27][C:21]3=[N:20][C:19]=2[NH:28][CH:29]([CH3:31])[CH3:30])[CH2:16][CH2:17]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CNCC2
Reactant: COC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CCc2nc(NC(C)C)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (50 mg, 0.080 mmol) and triethylamine (0.026 mL, 0.185 mmol) in DCM (0.75 mL) was added methyl carbonochloridate (9.3 μL, 0.121 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hr, warmed to 23° C., and concentrated via rotary evaporation. The resulting crude material was reconstituted in DMSO, rinsed with DMSO, and purified by HPLC Method B using a 30% to 70% ACN gradient to give the title compound as a TFA salt (11.0 mg, 23.8%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.18 (d, J=6.8 Hz, 6H), 1.82-1.94 (m, 2H), 2.02-2.12 (m, 2H), 2.65 (t, J=5.9 Hz, 2H), 2.83-2.93 (m, 2H), 3.21-3.33 (m, 2H), 3.63 (s, 3H), 3.64-3.68 (m, 2H), 4.06-4.17 (m, 1H), 4.34 (br s, 2H), 4.51 (tt, J=8.1, 3.9 Hz, 1H), 5.51-5.65 (m, 1H), 6.99-7.05 (m, 1H), 7.25-7.35 (m, 2H); ESI-MS m/z [M+H]+ 462.4.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:23]1[CH:28]=[C:27]([CH:29]([OH:34])[C:30]([F:33])([F:32])[F:31])[CH:26]=[CH:25][C:24]=1[O:35][CH3:36])[C:8](=[O:11])[O:9][CH3:10].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(OCC)C>[F:1][C:2]([F:44])([F:45])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:23]1[CH:28]=[C:27]([C:29](=[O:34])[C:30]([F:31])([F:32])[F:33])[CH:26]=[CH:25][C:24]=1[O:35][CH3:36])[C:8](=[O:11])[O:9][CH3:10]
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(O)C(F)(F)F)ccc1OC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(=O)C(F)(F)F)ccc1OC

Procedure:
Methyl [3,5-bis(trifluoromethyl)benzyl]{[2′-methoxy-5′-(2,2,2-trifluoro-1-hydroxyethyl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (Example 139, 29 mg, 0.048 mmol) was dissolved in methylene chloride, and Dess-Martin periodinane (31 mg, 0.072 mmol) was added. Once the reaction was complete, the solution was diluted in diethyl ether and washed sequentially with saturated sodium thiosulfate, saturated sodium bicarbonate and water. The aqueous extracts were combined and back extracted with diethyl ether, then recombined with the previous organic layers. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The title compound was obtained by preparative thin layer chromatography using 1:3 acetone:hexane.
Reaction SMILES: [NH2-].[Na+].CC1C=CC=CC=1.[C:10]1([CH2:16][C:17]#[N:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:19]1([CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([C:32](OCC)=[O:33])[CH2:28][CH2:27]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1C=CC=CC=1.C(O)C>[OH:33][C:32]([CH:29]1[CH2:28][CH2:27][N:26]([CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:31][CH2:30]1)=[C:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:17]#[N:18]
Reactant: N#CCc1ccccc1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Agent: [NH2-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: N#CC(=C(O)C1CCN(Cc2ccccc2)CC1)c1ccccc1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a stirred mixture of 7.8 parts of sodium amide 5% in benzene and 135 parts of methylbenzene was added dropwise a solution of 11.7 parts of benzeneacetonitrile in 45 parts of methylbenzene at 25° C (cooling was necessary). After stirring for 30 minutes at 30° C., there was added dropwise a solution of 24.7 parts of ethyl 1-(phenylmethyl)-4-piperidinecarboxylate in 45 parts of methylbenzene at 30° C. Upon completion, stirring was continued overnight at 80° C. The reaction mixture was cooled, 12 parts of ethanol were added and the whole was poured into ice water. The layers were separated and the aqueous phase was neutralized with acetic acid The oily Product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from 4-methyl-2-pentanone, yielding 12 parts (38%) of α-[hydroxy[1-(phenylmethyl)-4-piperidinyl]methylidene]-benzeneacetonitrile: mp. 191.9° C. (intermediate 5).
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8](O)=[O:9])[CH:2]=1.[NH2:21][C@@H:22]1[CH2:28][CH2:27][C@@H:26]([CH3:29])[N:25]([S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)(=[O:32])=[O:31])[CH2:24][C@H:23]1[OH:39].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[CH3:29][C@H:26]1[N:25]([S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)(=[O:32])=[O:31])[CH2:24][C@@H:23]([OH:39])[C@H:22]([NH:21][C:8](=[O:9])[CH:7]([C:3]2[CH:2]=[C:1]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:6]=[CH:5][CH:4]=2)[CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:28][CH2:27]1
Reactant: C[C@@H]1CC[C@@H](N)[C@H](O)CN1S(=O)(=O)c1ccccn1
Reactant: CC(C)CC(C(=O)O)c1cccc(-c2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CC(C(=O)N[C@@H]1CC[C@@H](C)N(S(=O)(=O)c2ccccn2)C[C@H]1O)c1cccc(-c2ccccc2)c1
Yield: 61.6 %

Procedure:
2-Biphenyl-3-yl-4-methyl-pentanoic acid (270 mg, 1.0 mmol, preparation described in J. Am. Chem. Soc. 1997, 120, 9114), and (3R,4R,7R)-4-Amino-7-methyl-1-(pyridine-2-sulfonyl)-azepan-3-ol (320 mg, 1.0 mmol, Example 1k), EDCI (190 mg, 1.0 mmol), HOBT (135 mg, 1.0 mmol) and diisopropylethylamine (1.7 g, 0.23 ml, 1.3 mmol) in DMF (5 ml) were stirred at RT for 4 h. The reaction mixture was diluted with EtOAc (20 ml), washed with H2O, brine, dried with magnesium sulfate, filtered, concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 40% EtOAc/hexanes) to yield the title compound (330 mg, 62%): 1H NMR (400 MHz, CDCl3): δ 8.55-8.60 (m, 1H), 8.00 (t, 1H), 7.80-7.90 (m, 1H), 7.65 (d, 2H), 7.25-7.55 (m, 8H), 5.50-5.60 (m, 1H), 4.00-4.10 (m, 1H), 3.70-3.85 (m, 1H), 3.50-3.70 (m, 2H), 2.90-3.05 (m, 1H), 2.00-2.10 (m, 2H), 1.30-1.85 (m, 5H), 0.90-0.95 (d, 9H); ESMS: 536.4 (M+H+)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1[C:8]([F:13])=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2([CH2:19][CH2:20][OH:21])O.[N:22]([Si](C)(C)C)=[N+:23]=[N-:24].B(F)(F)F.CCOCC>C1COCC1>[N:22]([C:5]1([CH2:19][CH2:20][OH:21])[C:6]2[CH:11]=[C:10]([Cl:12])[N:9]=[C:8]([F:13])[C:7]=2[O:14][C:15]2[C:4]1=[CH:3][C:2]([Br:1])=[CH:17][CH:16]=2)=[N+:23]=[N-:24]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: OCCC1(O)c2cc(Br)ccc2Oc2c1cc(Cl)nc2F
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: [N-]=[N+]=NC1(CCO)c2cc(Br)ccc2Oc2c1cc(Cl)nc2F
Temperature: 60 °C
Reaction time: 3 h
Yield: 80.5 %

Procedure:
To a solution of 7-bromo-3-chloro-1-fluoro-5-(2-hydroxyethyl)-5H-chromeno[2,3-c]pyridin-5-ol (48 g, 128 mmol) in THF (58 mL) were added azidotrimethylsilane (34.0 ml, 256 mmol) and boron trifluoride diethyl etherate (31.6 ml, 256 mmol). The reaction mixture was heated to 60° C. for 15 h. Additional azidotrimethylsilane (34.0 ml, 256 mmol) and boron trifluoride diethyl etherate (31.6 ml, 256 mmol) were added and heating was continued for 3 h. The reaction mixture was quenched with aqueous, saturated NaHCO3 solution and extracted with EtOAc. The organic phase was separated, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography (0-30% EtOAc/hexanes) to afford 2-(5-azido-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)ethanol (41 g, 103 mmol, 80% yield) as a pale yellow solid-foam.
Reaction SMILES: [CH:1]1([CH2:6][C:7]2[C:8]3[CH2:29][NH:28][CH2:27][CH2:26][C:9]=3[N:10]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH:24]=[CH:23][N:22]=[C:21]4[CH3:25])=[CH:16][CH:15]=3)[N:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:30]=O>>[CH:1]1([CH2:6][C:7]2[C:8]3[CH2:29][N:28]([CH3:30])[CH2:27][CH2:26][C:9]=3[N:10]=[C:11]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH:24]=[CH:23][N:22]=[C:21]4[CH3:25])=[CH:18][CH:19]=3)[N:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C=O
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(CC4CCCC4)n2)CNCC3)cc1
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(CC4CCCC4)n2)CN(C)CC3)cc1
Yield: 6 %

Procedure:
4-(Cyclopentylmethyl)-6-methyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (5.7 mg, 6%) was synthesised from 4-(cyclopentylmethyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and formaldehyde according to the general procedure for reductive amination. MS (ES+) m/z 403.4 (M+H)+
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][C:19](F)=[C:20]([F:25])[CH:21]=2)[N:16]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])[C:15]1=[O:35])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][C:19]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:20]([F:25])[CH:21]=2)[N:16]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])[C:15]1=[O:35])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=c1c2cc(F)c(F)cc2n(-c2ccc(F)cc2F)c(=O)n1OCc1ccccc1
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=c1c2cc(F)c(N3CCCC3)cc2n(-c2ccc(F)cc2F)c(=O)n1OCc1ccccc1
Yield: 109.3 %

Procedure:
Pyrrolidine (0.04 mL, 0.52 mmol) was added to a solution of 3-benzyloxy-1-(2,4-difluorophenyl)-6,7-difluoro-1H-quinazoline-2,4-dione (Example J-4, 0.20 g, 0.45 mmol) and triethylamine (0.34 mL, 2.4 mmol) in 20 mL of acetonitrile. The solution was warmed to reflux for 6 hours, cooled, and concentrated to a solid. The solid was dissolved in chloroform, washed with 1N HCl, saturated NaHCO3, brine, and dried over magnesium sulfate. The solution was concentrated to give 0.23 g of the title compound as a solid, mp 212-214° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].O.Cl[C:6]1[N:11]=[C:10]([NH2:12])[CH:9]=[CH:8][N:7]=1>CN(C)C=O>[CH3:1][N:2]([CH3:3])[C:6]1[N:11]=[C:10]([NH2:12])[CH:9]=[CH:8][N:7]=1
Reactant: CNC
Reactant: Nc1ccnc(Cl)n1
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1nccc(N)n1
Temperature: 220 °C
Yield: 91 %

Procedure:
40% Dimethylamine in water (1466 μl, 11.58 mmol) was added into the mixture of 2-chloro-4-pyrimidinamine (300 mg, 2.316 mmol) in N,N-dimethylformamide (DMF) (1.5 ml). The resulting reaction mixture was heated in a microwave reactor at 220° C. for 30 min. The reaction mixture was purified by RP-HPLC to yield N,N-dimethyl-2,4-pyrimidinediamine (290 mg, 2.099 mmol, 91% yield) as a white solid. MS (ES+) m/z 139.2 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH:25]4[CH2:30][CH2:29][N:28]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27][CH2:26]4)=[N:21][NH:22]3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:41](Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH:25]4[CH2:26][CH2:27][N:28]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:30]4)=[N:21][N:22]3[CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN1CCC(c2n[nH]c3cc(/C=C/C4CCN(C(=O)OC(C)(C)C)CC4)ccc23)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCC(c2nn(Cc3ccccc3)c3cc(/C=C/C4CCN(C(=O)OC(C)(C)C)CC4)ccc23)CC1
Reaction time: 0.33 h

Procedure:
A solution of 4{-2-[3-(1-tert-butoxycarbonylmethyl-piperidin-4-yl)-1H-indazol-6-yl]-(E)-vinyl}-piperidine-1-carboxylic acid tert-butyl ester (152 mg, 0.29 mmol) in dry DMF (2 ml) under nitrogen was treated with sodium hydride (5 mg of a 60% dispersion in oil, 0.37 mmol) and stirred at +23° for 20 min. The solution was treated with a solution of benzyl bromide in dry DMF (0.1 ml of 3.14M solution, 0.314 mmol; Aldrich). The resulting mixture was stirred at +23° for 24 h and concentrated in vacuo. The residue was dissolved in dichloromethane (100 ml) and the solution washed with water (2×25 ml). The dried (MgSO4) organic layer was concentrated in vacuo onto silica (Merck 9385); purification by flash chromatography eluting with ether--cyclohexane (1:1) gave the title compound as a white foam (102 mg).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:31]=[O:32])[CH:8]=[C:9]2[C:17]=1[CH:16]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[C:15]1([O:24][C:25](=[O:27])[CH3:26])[O:23][N:10]2[CH2:11][CH:12]2[CH:14]1[N:13]2[C:28](=[O:30])[CH3:29])(=O)C.C(OC([O-])=O)([O-])=O.[Na+].[Na+].C(O)(=O)C>CO>[C:25]([O:24][C:15]12[O:23][N:10]([CH2:11][CH:12]3[CH:14]1[N:13]3[C:28](=[O:30])[CH3:29])[C:9]1[C:17](=[C:5]([OH:4])[CH:6]=[C:7]([CH:31]=[O:32])[CH:8]=1)[CH:16]2[CH2:18][O:19][C:20](=[O:22])[NH2:21])(=[O:27])[CH3:26]
Reactant: CC(=O)Oc1cc(C=O)cc2c1C(COC(N)=O)C1(OC(C)=O)ON2CC2C1N2C(C)=O
Agent: O=C([O-])OC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)OC12ON(CC3C1N3C(C)=O)c1cc(C=O)cc(O)c1C2COC(N)=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 55.2 %

Procedure:
To a solution of 11-acetyl-8-carbamoyloxymethyl-4-formyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate (52 mg) in methanol (5 ml) was added sodium dicarbonate (10 mg) in an ice-water bath. The mixture was stirred for 30 minutes in an ice-water bath and for additional 2.5 hours at ambient temperature. To the reaction mixture was added acetic acid to adjust the pH value to about 6 in an ice-water bath and the mixture was evaporated in vacuo. The residue was extracted with a mixture of chloroform and methanol (5:1, v/v) (5 ml×3). The extracts were combined and evaporated in vacuo. The residue was subjected to silica gel column chromatography and elution was carried out with a mixture of chloroform and methanol (50:1, v/v) to afford 11-acetyl-8-carbamoyloxymethyl-4-formyl-6-hydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-9-yl acetate (26 mg).
Reaction SMILES: Cl.FC(F)(F)C1C=CC=CC=1O[CH:7]1[CH2:12]C[NH:10][CH2:9][CH2:8]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[OH:30].C(OC(=O)N[C@@H]1C[C@H]1CO)(C)(C)C.Cl>>[ClH:19].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][C:21]=1[O:30][CH2:12][C@@H:7]1[CH2:8][C@H:9]1[NH2:10]
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Reactant: Oc1cc(C(F)(F)F)ccc1Cl
Agent: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1CO
Agent: Cl
Product: N[C@@H]1C[C@H]1COc1cc(C(F)(F)F)ccc1Cl

Procedure:
The intermediate 1f is synthesised according to the procedure described for the synthesis of 1a from 2-chloro-5-(trifluoromethyl)phenol and trans-(2-hydroxymethyl-cyclopropyl)-carbamic acid tert-butyl ester and, the amine function deprotection step is carried out in an HCl solution (4N in dioxane). 1f is isolated in solid form with a 95% yield.