Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH:19]([CH3:21])[CH3:20])[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[Cl:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl>[Cl:22][CH2:23][C:24]([NH:2][C@H:3]([CH:19]([CH3:21])[CH3:20])[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)=[O:5])=[O:25]
Reactant: CC(C)[C@@H](N)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)CCl)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Reaction time: 4 h
Yield: 91.3 %

Procedure:
To a solution of (R)-2-amino-1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methylbutan-1-one hydrochloride (340 mg, 1.03 mmol) in DCM (10 mL) cooled to 0° C. was added TEA (144 μL, 1.03 mmol) followed by chloroacetylchloride (82 μL, 1.03 mmol). Upon completion of addition, the reaction mixture was held at 0° C. for 4 h. After this time, an additional aliquot of chloroacetyl chloride (60 μL) was added followed by additional TEA (150 μL). The resulting solution was diluted with dichloromethane (40 mL) and quenched by the addition of aqueous NaHCO3 (25 mL). The layers were separated. The organic layer was dried over Na2SO4, filtered, and concentrated to yield a residue. The residue was purified via SiO2 chromatography (20% to 50% EtOac/heptane) to give (R)-2-chloro-N-(1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methyl-1-oxobutan-2-yl)acetamide as a clear glassy solid (349 mg, 92% yield). MS found: 371.3 (M+), 373.3 (M+2).
Reaction SMILES: COC(C1N(CC=O)C=C(C(=O)NCC2C=CC(F)=CC=2)C(=O)C=1OCC1C=CC=CC=1)=O.Cl.Cl.N[C@@H](C)CCNCC(C)C.[F:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][NH:54][C:55]([C:57]2[C:58](=[O:85])[C:59]([O:77]CC3C=CC=CC=3)=[C:60]3[C:74](=[O:75])[N:64]4[C@@H:65]([CH3:73])[CH2:66][CH2:67][N:68]([CH2:69][CH:70]([CH3:72])[CH3:71])[C@@H:63]4[CH2:62][N:61]3[CH:76]=2)=[O:56])=[CH:49][CH:48]=1>>[F:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][NH:54][C:55]([C:57]2[C:58](=[O:85])[C:59]([OH:77])=[C:60]3[C:74](=[O:75])[N:64]4[C@@H:65]([CH3:73])[CH2:66][CH2:67][N:68]([CH2:69][CH:70]([CH3:71])[CH3:72])[C@@H:63]4[CH2:62][N:61]3[CH:76]=2)=[O:56])=[CH:49][CH:48]=1
Reactant: CC(C)CN1CC[C@H](C)N2C(=O)c3c(OCc4ccccc4)c(=O)c(C(=O)NCc4ccc(F)cc4)cn3C[C@@H]12
Agent: CC(C)CNCC[C@H](C)N
Agent: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Agent: Cl
Product: CC(C)CN1CC[C@H](C)N2C(=O)c3c(O)c(=O)c(C(=O)NCc4ccc(F)cc4)cn3C[C@@H]12
Yield: 68 %

Procedure:
In a similar manner to that described in example Z-35, from 16 (16 mg, 0.035 mmol) and [(3S)-3-Aminobutyl](2-methylpropyl)amine bis-hydrochloride (20 mg, 0.0925 mmol), (4S,12aS)-N-[(4-fluorophenyl)methyl]-4-methyl-1-(2-methylpropyl)-6,8-dioxo-7-[(phenylmethyl)oxy]1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide was prepared as a white solid. This material was deprotected in a second step similar to that described in example Z-37 to give the title compound as a tan solid (13 mg, 68% 2 steps). 1H NMR (CDCl3) δ 12.57 (s, 1H), 10.46 (a, 1H), 8.27 (s, 1H), 7.32 (m, 2H), 6.99 (m, 2H), 4.98 (m, 1H), 4.63-4.54 (m, 2H), 4.45 (m, 1H), 4.26-4.16 (m, 2H), 2.91 (m, 1H), 2.77 (m, 1H), 2.24 (m, 1H), 2.14-2.03 (m, 2H), 1.68 (m, 1H), 1.48 (m, 1H), 1.33 (m, 3H), 1.09 (m, 1H), 0.850 (m, 8H), 0.789 (m, 8H); ES+MS: 457 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]([O:25]C(OC)=O)=[CH:16][C:15]=2[NH:30][C:31]([CH:33]2[O:38][C:37]3[CH:39]=[CH:40][C:41]([C:43]#[N:44])=[CH:42][C:36]=3[N:35](C(OCC)=O)[CH2:34]2)=[O:32])[CH2:10][CH2:9]1)=O)(C)(C)C.[OH-].[Na+].Cl>CO.O>[C:43]([C:41]1[CH:40]=[CH:39][C:37]2[O:38][CH:33]([C:31]([NH:30][C:15]3[CH:16]=[C:17]([OH:25])[C:18]([CH:20]4[CH2:21][CH2:22][CH2:23][CH2:24]4)=[CH:19][C:14]=3[C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)=[O:32])[CH2:34][NH:35][C:36]=2[CH:42]=1)#[N:44]
Reactant: CCOC(=O)N1CC(C(=O)Nc2cc(OC(=O)OC)c(C3CCCC3)cc2C2=CCN(C(=O)OC(C)(C)C)CC2)Oc2ccc(C#N)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1ccc2c(c1)NCC(C(=O)Nc1cc(O)c(C3CCCC3)cc1C1=CCNCC1)O2
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 19.7 %

Procedure:
Ethyl 2-(2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-cyclopentyl-5-(methoxycarbonyloxy)phenylcarbamoyl)-6-cyano-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (50 mg, 0.08 mmol) and NaOH (162 mg, 4.05 mmol) were dissolved in 5:1 methanol/water (3.6 mL) and heated at 60° C. for 2 h. The mixture was added to 1 N HCl (25 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. Removal of the Boc protecting group was achieved by dissolving the compound in dichloromethane (3.0 mL) and TFA (3.0 mL) and stirring for 10 min before being concentrated in vacuo. HPLC purification (10-99% CH3CN/0.05% TFA) provided 6-cyano-N-(4-cyclopentyl-5-hydroxy-2-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide (7 mg, 19% yield). LC/MS m/z 562.2 [M+H]+. 1H NMR (400.0 MHz, MeOD) δ 9.56 (s, 1H), 9.15 (s, 1H), 7.16 (s, 1H), 7.01 (m, 3H), 6.90 (s, 1H), 6.45 (s, 1H), 5.56 (s, 1H), 4.89 (q, J=3.0 Hz, 1H), 3.61 (s, 2H), 3.56-3.53 (m, 1H), 3.44-3.39 (m, 1H), 3.33 (m, obscured by H2O peak, 1H), 3.23-3.16 (m, 3H), 2.44 (s, 2H), 1.93 (m, 1.97-1.90, 2H), 1.78-1.71 (m, 2H), 1.65-1.62 (m, 2H), 1.56-1.45 (m, 2H).
Reaction SMILES: C[O:2][C:3]1[C:13]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[BrH:14]>C(#N)C>[BrH:14].[OH:2][C:3]1[C:13]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1CCNCC2
Agent: Br
Solvent: CC#N
Product: Oc1cccc2c1CCNCC2

Procedure:
The 6-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (1.00 g; 0.0056 mol) was heated at reflux in 15 ml of 48% hydrobromic acid, overnight, under argon. It was concentrated to obtain a brown solid which was dispersed in acetonitrile; the mixture was filtered and the solid dried to give 0.94 g of 6-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, m.p. 220°-224°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[C:20]([C:22]4[CH:23]=[N:24][NH:25][CH:26]=4)[N:19](S(C4C=CC=CC=4)(=O)=O)[C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[H-].[Na+].CS(O[CH:43]1[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]1)(=O)=O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[C:20]([C:22]4[CH:23]=[N:24][N:25]([CH:43]5[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]5)[CH:26]=4)[NH:19][C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CN1CCC(OS(C)(=O)=O)CC1
Reactant: COc1cc(CCc2cnc3c(cc(-c4cn[nH]c4)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(CCc2cnc3[nH]c(-c4cnn(C5CCN(C)CC5)c4)cc3n2)cc(OC)c1
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 4.8 %

Procedure:
To a stirred solution of 2-[2-(3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-6-(1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine (from Example 35, Step 1, 50.0 mg, 0.102 mmol) in N,N-dimethylformamide (2.0 mL), sodium hydride (6.13 mg, 0.153 mmol) was added at 0° C. After 15 minutes, a solution of 1-methylpiperidin-4-yl methanesulfonate (23.7 mg, 0.122 mmol) in N,N-dimethylformamide (1 mL) was added. The reaction mixture was then warmed up to 55° C. After 2 hours, the reaction was quenched with water, and extracted with methylene chloride. The combined organic layers were dried over MgSO4, then filtered and concentrated. The crude mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) to give the desired product (2.2 mg) as its TFA salt. LCMS calculated for C25H31N6O2 (M+H)+: m/z=447.3. Found: 447.3.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[CH:3]=1.[H-].[Na+].[F:21][C:22]([F:34])([F:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][C:30](Cl)=[O:31]>CN(C=O)C>[OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:4](=[O:18])[C:3]=1[C:30](=[O:31])[CH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([F:33])([F:21])[F:34]
Reactant: O=C(Cl)Cc1ccccc1C(F)(F)F
Reactant: O=c1cc(O)c2cccnc2n1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1C(F)(F)F)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
In accordance with a process described in JP-61-246183A, 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one was synthesized. To a suspension of the synthesized compound (953 mg, 4.0 mmol) in DMF (32 mL) was added sodium hydride (purity of about 60%, 352 mg, 8.8 mmol, 2.2 eq.), and the mixture was stirred at a room temperature for 45 minutes. Then, 2-trifluoromethylphenylacetyl chloride (4.8 mmol, 1.2 eq.) was added thereto with cooling in an ice bath, and the mixture was stirred at a room temperature for 1.5 hours. Thereafter, the resulting mixture was purified by a flash column chromatography to give 4-hydroxy-1-phenyl-3-(2-trifluoromethylphenylacetyl)-1,8-naphthyridin-2(1H)-one as a form of crystal (972 mg, yield 57%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=2[O:35][CH3:36])[C:8]2[NH:13][N:12]=[C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][C@H:21]([F:24])[CH2:20]3)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].[CH2:37](C1N=C(NCC2C=CC(OC)=CC=2OC)C2NN=C(C#CCCCCl)C=2N=1)CCC.Cl.FC1CCNCC1>>[CH2:1]([C:5]1[N:6]=[C:7]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=2[O:35][CH3:36])[C:8]2[NH:13][N:12]=[C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH:21]([F:24])[CH2:37][CH2:20]3)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(CCCCCN3CC[C@H](F)C3)c2n1
Reactant: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(C#CCCCCl)c2n1
Agent: Cl
Agent: FC1CCNCC1
Product: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(CCCCCN3CCC(F)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 25 from and 5-butyl-3-(5-chloropent-1-yn-1-yl)-N (2,4-dimethoxybenzyl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine and 4-fluoropiperidine hydrochloride
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][CH2:4][C@@H:5]([N:12]1C(=O)C2C(=CC=CC=2)C1=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.NN>CCO>[F:1][CH:2]([F:23])[O:3][CH2:4][C@H:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH2:12]
Reactant: O=C1c2ccccc2C(=O)N1[C@H](COC(F)F)c1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: N[C@H](COC(F)F)c1ccccc1
Temperature: 85 °C

Procedure:
(S)-2-(2-(difluoromethoxy)-1-phenylethyl)isoindoline-1,3-dione (659 mg, 2.077 mmol) was dissolved in EtOH (7 ml), charged with hydrazine hydrate (1.01 ml, 20.77 mmol) and heated to 85° C. for 90 minutes. The reaction was diluted with 10 mL EtOH, filtered, and the solvents were evaporated in vacuo. The residue was purified on silica gel 2-10% MeOH/DCM to provide (S)-2-(difluoromethoxy)-1-phenylethanamine MS: [M+H]+ m/z 188.
Reaction SMILES: S([O-])([O-])(=O)=O.P([O-])([O-])([O-])=O.[O:11]1[CH:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12]1.[CH3:28][NH:29][CH:30]([CH3:32])[CH3:31]>>[CH:30]([N:29]([CH2:12][CH:13]([OH:11])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:28])([CH3:32])[CH3:31]
Reactant: CNC(C)C
Reactant: c1ccc(-c2ccccc2OCC2CO2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Product: CC(C)N(C)CC(O)COc1ccccc1-c1ccccc1

Procedure:
Alternatively, the intermediates of the formula ##STR5## are allowed to react at reflux with an appropriate secondary amine to afford the corresponding tertiary amines of the formula R1 ? ##STR6## Those compounds then are allowed to react further with a molecular equivalent of the appropriate alkyl halide, sulphate or phosphate, to produce the instant compounds. For example, 1,2-epoxy-3-(2-phenylphenoxy)propane is allowed to react at reflux with methylisopropyl amine to afford the corresponding 1-(N-isopropyl-N-methylamino)-3-(2-phenylphenoxy)propan-2-ol. This compound then is allowed to react further with a molecular equivalent of methyl chloride to afford [3-(2-phenylphenoxy)-2-hydroxypropyl]isopropyldimethylammonium chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([CH2:12][CH2:13][O:14]S(C3C=CC(C)=CC=3)(=O)=O)[N:9]([CH2:25][CH2:26][CH3:27])[C:8]2=[O:28])=[CH:4][CH:3]=1.[CH2:31]([O:33][C:34](=[O:52])[C:35]([CH3:51])([O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:36][C:37]1[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=1)[CH3:32].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:31]([O:33][C:34](=[O:52])[C:35]([CH3:51])([O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:14][CH2:13][CH2:12][C:10]2[N:9]([CH2:25][CH2:26][CH3:27])[C:8](=[O:28])[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:30][CH:29]=3)[CH:11]=2)=[CH:39][CH:38]=1)[CH3:32]
Reactant: CCCn1c(CCOS(=O)(=O)c2ccc(C)cc2)cn(Cc2ccc(C)cc2)c1=O
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCn1c(CCOc2ccc(CC(C)(Oc3ccccc3)C(=O)OCC)cc2)cn(Cc2ccc(C)cc2)c1=O
Temperature: 55 °C
Yield: 33 %

Procedure:
A mixture of toluene-4-sulfonic acid 2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethyl ester (0.029 g, 0.0677 mmol), 3-(4-Hydroxy-phenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (0.018 g, 0.0599 mmol) and Cs2CO3 (0.024 g, 0.0736 mmol) in DMF (3 mL) was heated at 55° C. under N2 for 16 h. The reaction mixture was cooled to room temperature and quenched with aqueous 1 N HCl (0.3 mL) and then was diluted with water and extracted with Et2O. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using a gradient of 4:1 to hexanes:EtOAc to 2:1 EtOAc:hexanes to afford 0.011 g (32%) 2-methyl-3-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=2[CH3:17])[CH:5]=[CH:6][C:7]=1[CH:8]=O.Cl.[NH2:19][OH:20]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=2[CH3:17])[CH:5]=[CH:6][C:7]=1[CH:8]=[N:19][OH:20]
Reactant: NO
Reactant: Cc1cc(O)ccc1-c1ccc(C=O)c(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(O)ccc1-c1ccc(C=NO)c(Cl)c1

Procedure:
The title compound was prepared by reacting 3-chloro-4′-hydroxy-2′-methyl-1,1′-biphenyl-4-carbaldehyde (500 mg, 2.03 mmol) with hydroxylamine hydrochloride (425 mg, 6.10 mmol) in anhydrous tetrahydrofuran (50 mL) and methanol (20 mL) according to Method C to yield 350 mg (57% over two steps) of white solid: mp 169-171° C.; 1H NMR (DMSO-d6): δ 2.19 (3H, s), 6.65-6.70 (2H, m), 7.06 (1H, d, J=8.14 Hz), 7.31 (1H, d, J=8.05 Hz), 7.41 (1H, d, J=1.40 Hz), 7.83 (1H, d, J=8.08 Hz), 8.38 (1H, s), 9.51 (1H, s), 11.69 (1H, s); MS (ESI) m/z 260/262 (M−H)−, 262/264 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([N:15]=[CH:16][NH:17][NH:18][C:19]([N:21]2[CH:25]=[CH:24]N=C2)=[O:20])=[O:14])=[N:4][C:5]([Cl:12])=[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])[N:7]=1.C(N)C>CN1CCCC1=O>[NH2:1][C:2]1[C:3]([C:13]([N:15]=[CH:16][NH:17][NH:18][C:19]([NH:21][CH2:25][CH3:24])=[O:20])=[O:14])=[N:4][C:5]([Cl:12])=[C:6]([NH:8][CH:9]([CH3:10])[CH3:11])[N:7]=1
Reactant: CC(C)Nc1nc(N)c(C(=O)N=CNNC(=O)n2ccnc2)nc1Cl
Agent: CCN
Solvent: CN1CCCC1=O
Product: CCNC(=O)NNC=NC(=O)c1nc(Cl)c(NC(C)C)nc1N

Procedure:
A mixture of 3-amino-5-isopropylamino-6-chloro-N-{[(1-imidazolcarbonyl)amino]aminomethylene}-2-pyrazinecarboxamide (18.25 g., 0.05 mole) and ethylamine (2.7 g., 0.06 m) in 1-methyl-2-pyrrolidinone (150 ml.) is heated at 95° for 1/2 hour, filtered and the filtrate slowly diluted with water (350 ml.) to precipitate 3-amino-5-isopropylamino-6-chloro-N-{[(ethylaminocarbonyl)amino]aminomethylen}-2-pyrazinecarboxamide which melts at 148°-150° C.
Reaction SMILES: N1P(Cl)(Cl)=NP(Cl)(Cl)=NP=1(Cl)Cl.CS(C)=O.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:32]([CH:33]([CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:34][OH:35])=[C:31]3[C:26]([CH2:27][CH2:28][CH2:29][CH2:30]3)=[N:25]2)=[CH:20][CH:19]=1.C(N(CC)CC)C>ClCCl.O>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:32]([CH:33]([CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[CH:34]=[O:35])=[C:31]3[C:26]([CH2:27][CH2:28][CH2:29][CH2:30]3)=[N:25]2)=[CH:20][CH:19]=1
Reactant: OCC(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Agent: ClP1(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=N1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=CC(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Reaction time: 1 h

Procedure:
A turbid solution of 1.245 g (3.58 mmol) phosphonitrilic chloride trimer in 20 ml dichloromethane was cooled to −75° C. To this mixture 1.02 ml (14.32 mmol) DMSO were added, and stirring was continued for 1 h. Then a suspension of 1.28 g (3.58 mmol; 1 eq.; example 37.1) [rac]-2-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-cyclohexyl-ethanol in 50 ml dichloromethane was added dropwise over 10 min to the turbid reaction mixture, keeping the temperature below −60° C. The reaction mixture was then stirred 1 h at −75° C. Then the mixture was stirred in an ice-bath, and at 0° C. 2.50 ml (17.91 mmol) triethylamine were added. The solution was stirred 1.5 h at 0° C. and then at ambient temperature overnight. The reaction mixture was poured onto 120 ml water, extracted 3 times with dichloromethane. The organic layers were washed with water and brine, dried over MgSO4, filtered and evaporated to give the crude product which was purified on a 20 g silica gel column using a gradient from heptane (A) and ethyl acetate (B) to give the title aldehyde.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH:9]([C:29]1[CH:50]=[CH:49][C:32]([C:33]([NH:35][C@H:36]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:34])=[CH:31][CH:30]=1)[CH2:10][CH:11]1[CH2:28][NH:27][C:14]2[N:15]=[C:16]([NH:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[N:17]=[C:18]([OH:19])[C:13]=2[CH2:12]1.C(=O)([O-])[O-].[Na+].[Na+].CO>Cl.O>[OH:7][CH2:8][CH:9]([C:29]1[CH:30]=[CH:31][C:32]([C:33]([NH:35][C@H:36]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:34])=[CH:49][CH:50]=1)[CH2:10][CH:11]1[CH2:28][NH:27][C:14]2[N:15]=[C:16]([NH:20][C:21](=[O:26])[C:22]([CH3:24])([CH3:25])[CH3:23])[N:17]=[C:18]([OH:19])[C:13]=2[CH2:12]1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(C(COC2CCCCO2)CC2CNc3nc(NC(=O)C(C)(C)C)nc(O)c3C2)cc1)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(C(CO)CC2CNc3nc(NC(=O)C(C)(C)C)nc(O)c3C2)cc1)C(=O)OCC
Yield: 97.8 %

Procedure:
The solution of 942 mg (1.35 mm) of diethyl N-[4-{1-(tetrahydropyr-2-yloxy)-3-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)prop-2-yl}benzoyl]glutamate in 40 ml of 0.1N methanolic hydrogen chloride was stirred at ambient temperatures for 2 hours. The reaction mixture was neutralized with a solution of 205 mg of sodium carbonate in 10 ml of water and most of methanol was removed by evaporation under reduced pressure. One hundred milliliters of methylene chloride were added the solution was washed twice with 20 ml of water, dried over anhydrous magnesium sulfate, and concentrated. The residue was triturated with 1:2 ethyl acetate and ether, filtered, and dried to give 810 mg (98%) of diethyl N-[4-{1-hydroxy-3-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)prop-2-yl}benzoyl]glutamate. mp 133°-135° C. Analysis calculated for C31H43N5O8 : C, 60.67; H, 7.06; N, 11.41. Found: C, 60.42; H, 7.09; N, 11.34. NMR (CDCl3), delta, 1.22 (t, 3H, J=7 Hz), 1.26 (s, 9H), 1.30 (t, 3H, J=7 Hz), 1.78-1.87 (m, 3H), 2.01-2.23 (m, 3H), 2.23-2.36 (m, 1H), 2.38-2.54 (m, 2H), 2.59-2.69) (m, 1H), 2.83-3.12 (m, 2H), 3.14-3.18 and 3.28-3.32 (m, m, 1H), 3.72-3.78 (m, 2H), 4.12 (q, 2H, J=7 Hz), 4.23 (q, 2H, J=7 Hz), 4.74-4.84 (m, 2H, CH, NH), 7.24 (d, NH, J=7 Hz), 7.26-7.30 (m, 1H), 7.72-7.76 (m, 1H), 8.09 (brs, NH), 11.23 (brs, NH).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[CH3:8][C:9]1[CH:14]=[C:13]([C:15]2[NH:24][C:23](=[O:25])[C:22]3[C:17](=[CH:18][C:19](F)=[CH:20][C:21]=3[O:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[N:16]=2)[CH:12]=[C:11]([CH3:35])[N:10]=1.O>CN(C=O)C.C(O)(=O)C>[CH3:8][C:9]1[CH:14]=[C:13]([C:15]2[NH:24][C:23](=[O:25])[C:22]3[C:17](=[CH:18][C:19]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:20][C:21]=3[O:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[N:16]=2)[CH:12]=[C:11]([CH3:35])[N:10]=1
Reactant: Cc1cc(-c2nc3cc(F)cc(OCCN4CCCC4)c3c(=O)[nH]2)cc(C)n1
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COCCOc1cc(OCCN2CCCC2)c2c(=O)[nH]c(-c3cc(C)nc(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methoxy-ethanol (1.35 g, 17.8 mmol) in DMF (10 mL) was added sodium hydride (60% suspension in mineral oil, 0.36 g, 8.89 mmol) in small portions and the reaction mixture was stirred at room temperature for 30 minutes. To this mixture was added 2-(2,6-dimethyl-pyridin-4-yl)-7-fluoro-5-(2-pyrrolidin-1-yl-ethoxy)-3H-quinazolin-4-one (0.34 g, 0.89 mmol) and the reaction mixture was stirred at 70-80° C. for 16 h, then cooled to room temperature. Water (10 mL) was added, and the mixture was neutralized to pH approximately 6 with acetic acid. Solvent was evaporated; the residue was purified by the Simpliflash system (2-5% 7.0M ammonia in methanol and CH2Cl2 as eluent). The compound was further purified by preparative HPLC to give the title compound as a yellow solid. Yield: 72 mg (18%). MP 60.4-62.3° C. 1H NMR (400 MHz, CDCl3): δ 10.23 (br s, 1H), 8.50 (br s, 1H), 7.60 (s, 2H), 6.76 (br s, 1H), 6.43 (br s, 1H), 4.35 (m., 2H), 4.21 (m, 2H), 3.79 (s, 3H), 3.47-3.38 (m, 6H), 2.64 (s, 6H), 1.99 (m, 4H). MS (ES) m/z: 437.09 (M−1) (100%).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:12]([N:16]4[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[N:17]4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:31])=[O:5])[CH2:3][CH2:2]1.[Cl-].[NH4+].O1CCCC1.C(O)C>[Fe].O>[NH2:21][C:19]1[CH:18]=[N:17][N:16]([C:12]2[C:11]([O:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[C:10]3[C:15](=[CH:14][CH:13]=2)[N:6]([C:4]([CH:1]2[CH2:2][CH2:3]2)=[O:5])[C@@H:7]([CH3:31])[CH2:8][CH2:9]3)[CH:20]=1
Reactant: C[C@H]1CCc2c(ccc(-n3cc([N+](=O)[O-])cn3)c2Oc2ccccc2)N1C(=O)C1CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1CCc2c(ccc(-n3cc(N)cn3)c2Oc2ccccc2)N1C(=O)C1CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
A mixture of (S)-cyclopropyl(2-methyl-6-(4-nitro-1H-pyrazol-1-yl)-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)methanone (0.060 g, 0.15 mmol), iron powder (0.040 g, 0.72 mmol), ammonium chloride (0.023 g, 0.43 mmol), tetrahydrofuran (4 mL), ethanol (4 mL), and water (1 mL) stirred overnight at 80° C. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum, and the residue was purified by preparative thin layer chromatography (eluting with 1:1, ethyl acetate/petroleum ether) to afford (S)-(6-(4-amino-1H-pyrazol-1-yl)-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone (0.045 g, 81%) as a brown solid. MS (ESI, pos. ion) m/z 389 [M+H]+.