Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([C:14]1[CH:23]=[CH:22][C:21]([O:24]CC2C=CC=CC=2)=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18](=[O:32])[NH:19]2)[O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[N+]=[N-].C1CC=CCC=1>[Pd].C(O)C>[NH2:1][CH2:4][C@@H:5]([C:14]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18](=[O:32])[NH:19]2)[O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCC=CC1
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
To an ice-cooled suspension of (R)-5-(2-azido-1-(tert-butyldimethylsilyloxy)-ethyl)-8-(benzyloxy)quinolin-2(1H)-one (5.77 g, 12.8 mmol) and palladium on activated charcoal (5.8 g, 10% w/w wet) in ethanol (50 mL), 1,4-cyclohexadiene (12.0 mL, 126 mmol) was added dropwise. After stirring at this temperature for 30 minutes, the coolant was removed and replaced with a water bath at 30° C. The reaction was stirred at this temperature for 1 hour. The suspension was filtered and the filter cake washed with further ethanol. The filtrate was evaporated under reduced pressure to dryness. The resulting solid was suspended in acetonitrile and stirred for 1 hour. The suspension was filtered and the resulting solid air-dried under vacuum to afford the title compound (2.90 g, 87%).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7](I)[CH:6]=[C:5]([NH:10][CH2:11][CH3:12])[N:4]=1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=[CH2:15].[CH2:20](N(CC)CC)C.CN(C=O)C>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.CC(C)=O>[NH2:2][C:3]1[N:4]=[C:5]([NH:10][CH2:11][CH3:12])[C:6](/[CH:15]=[CH:14]/[C:13]([O:17][CH2:18][CH3:19])=[O:16])=[C:7]([CH3:20])[N:8]=1
Reactant: C=CC(=O)OCC
Reactant: CCN(CC)CC
Reactant: CCNc1cc(I)nc(N)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCNc1nc(N)nc(C)c1/C=C/C(=O)OCC
Temperature: 95 °C
Reaction time: 3 h
Yield: 66.6 %

Procedure:
To a three-neck round bottom flask equipped with over-head mechanic stirrer were added 2-amino-6-ethylamino-4-iodopyrimidine hydrochloride (188.5 g, 0.60 mol), ethyl acrylate (221 mL, 2.0 mol), triethylamine (285 mL, 2.0 mol), DMF (1.3 L), and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 31.3 g, 0.027 mol). The reaction mixture was heated to 95° C. and stirred for 3 h (monitored by LC/MC). After reaction completion, the reaction mixture was evaporated about to 1/10 of original volume and partitioned with 500 mL of ethyl acetate and 1000 mL of water. The aqueous layer was extracted with ethyl acetate 5 times. (E)-Ethyl 3-(2-amino-4-(ethylamino)-6-methylpyrimidin-5-yl)acrylate (100 g, 67% yield) was obtained by recrystallization from acetone after evaporation of ethyl acetate. 1H NMR (400 MHz, CD3OD) δ 7.48 (dd, J1=16.0 Hz, J2=4.0 Hz, 1H), 6.20 (dd, J1=16 Hz, J2=4 Hz, 1H), 4.25 (q, J=7.2 Hz, 2H), 3.51 (q, J=7.6 Hz, 2H), 2.39 (s, 3H), 1.3 (t, J=7.2 Hz, 3H), 1.2 (t, J=7.6 Hz, 3H). MS (EI) for C12H18N4O2: 251.3 (MH+).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Na].[Cl-].[CH3:12][O:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:34]([N:39]1[CH2:44][CH2:43][C:42](=O)[CH2:41][CH2:40]1)([O:36][CH2:37][CH3:38])=[O:35].O>C1COCC1.CCOCC>[CH3:12][O:13][CH:14]=[C:42]1[CH2:43][CH2:44][N:39]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:40][CH2:41]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)N1CCC(=COC)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 89.4 %

Procedure:
A 1M solution of sodium hexamethyldisilazane (NaHMDS, 350 mL, 0.35 mol) in THF was added slowly to a suspension of (methoxymethyl)triphenyl phosphonium chloride (120 g, 0.35 mol,) in THF (100 mL) at −78° C. under N2. The resulting brown solution was stirred at −78° C. for 20 minutes and then 1-carbethoxy-4-piperidone (50 g, 0.292 mol) in THF (50 mL) was added dropwise. The mixture was stirred at −78° C. for 5 minutes and then for 2 hours at room temperature. Water (200 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic extracts were dried over Na2SO4. The solvent was evaporated to give an orange solid which was suspended in Et2O (200 mL). The solid was removed by filtration and the filtrate was concentrated to give a yellow oil which was triturated with hexane (200 mL). The white solid which precipitated was removed by filtration. The filtrate was concentrated in vacuo and this was procedure repeated twice more to give the title compound (52 g, 89%) as a pale yellow oil. TLC Rf=0.72 (EtOAc:hexane, 1:2); 1H NMR (CDCl3) δ 5.84 (s, 1H), 4.11 (q, J=7 Hz, 2H), 3.54 (s, 3H), 3.37-3.42 (mult, 4H), 2.24 (t, J=5.6 Hz, 2H), 1.99 (t, J=5.6 Hz, 2H), 1.24 (t, J=7 Hz, 3H); 13C NMR (CDCl3) δ 1.55, 140.8, 113.4, 61.3, 59.5, 45.8, 44.6, 29.6, 25.2, 14.8; mass spectrum (API-TIS) m/z 200 (M+H). Anal Calcd for C10H17N1O3: C, 60.28; H, 8.60; 7.03. Found: C, 60.29; H, 8.63; N, 6.81.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:29])=[C:6]([C:8]2(O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[O:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[C:9]2=[O:27])[CH:7]=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C(O)=CC4N(C)C(=O)COC=4C=3)(O)C2=O)C=CC=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:29])=[C:6]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[O:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[C:9]2=[O:27])[CH:7]=1
Reactant: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C1(O)c1cc(Br)ccc1O
Agent: CN1C(=O)COc2cc(C3(O)C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)c(O)cc21
Product: O=C1C(c2cc(Br)ccc2O)c2ccccc2N1Cc1ccc(C(F)(F)F)o1

Procedure:
Following the procedure as described in PREPARATION 17B, and making non-critical variations using 3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1-((5-(trifluoromethyl)furan-2-yl)methyl)indolin-2-one to replace 7-[1-(diphenylmethyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-6-hydroxy-4-methyl-2H-1,4-benzoxazin-3(4H)-one, 3-(5-bromo-2-hydroxyphenyl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one was obtained (89%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.78 (br s, 1H), 7.44-7.36 (m, 1H), 7.36-7.19 (m, 3H), 7.08 (d, J=7.9 Hz, 1H), 6.99 (d, J=2.3 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 6.73-6.68 (m, 1H), 6.37-6.32 (m, 1H), 5.10 (s, 1H), 5.00-4.85 (m, 2H); MS (ES+) m/z 452.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br:18][C:19]1[CH:24]=[C:23](F)[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27].C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[Br:18][C:19]1[CH:24]=[C:23]([N:11]2[CH2:12][CH2:13][C:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)([C:14]([F:17])([F:16])[F:15])[CH2:10]2)[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27]
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CCNC1
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Temperature: 100 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
To the solution of 3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine (1.3 g) and 2-bromo-4-fluoro-1-nitrobenzene (1.0 g) in 1-methyl-2-pyrrolidinone was added potassium carbonate (1.3 g), and the mixture was heated with stirring at 100° C. for 3 hours. The mixture was cooled to room temperature and then poured into water, which was extracted twice with ethyl acetate. The organic layer was combined, which was then washed with water and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled away under the reduced pressure, and the residue was then purified by silica gel chromatography to yield 1-(3-bromo-4-nitrophenyl)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine (1.56 g). 1H-NMR (CDCl3) δ: 2.53-2.66 (1H, m), 2.89-2.97 (1H, m), 3.51-3.71 (2H, m), 3.83 (1H, d), 4.16 (1H, d), 6.53 (1H, dd), 6.84 (1H, d), 7.27 (2H, br s), 7.42 (1H, t), 8.07 (1H, d).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4C)[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][C:22]1[C:23](=[O:28])[NH:24][CH:25]=[CH:26][CH:27]=1.N1NC(=O)C=CC=1>>[CH3:21][C:22]1[C:23](=[O:28])[N:24]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@H:11]([N:13]5[CH2:14][CH2:15][CH2:16][CH2:17]5)[CH2:10]4)[S:8][C:4]=3[CH:3]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: Cc1ccc[nH]c1=O
Agent: O=c1cccn[nH]1
Product: Cc1cccn(-c2ccc3nc([C@H]4C[C@H](N5CCCC5)C4)sc3c2)c1=O

Procedure:
The title compound was prepared according to the procedure described in Example 22, substituting the product of Example 62A for the product of Example 1E and substituting 3-methyl-2-pyridone for 3(2H)-pyridazinone. 1H NMR (300 MHz, CDCl3) δ ppm 8.03 (t, J=8.31 Hz, 1H) 7.89 (d, J=2.03 Hz, 1H) 7.44 (t, 1H) 7.27-7.33 (m, 1H) 6.18 (q, 2H) 3.55-3.75 (m, 1H) 3.03-3.15 (m, 1H) 2.39-2.76 (m, 6H) 2.21 (s, 3H) 1.79-1.99 (m, 4H) 1.50-1.70 (m, 2H). MS: (M+H)+=366.
Reaction SMILES: [C:1]1([CH2:14][N:15]([CH:28]2[C:37]3[N:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH2:31][CH2:30][CH2:29]2)[CH2:16][CH2:17][CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH:4]=[CH:3][N:2]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.S(Cl)([Cl:40])=O>CO>[ClH:40].[ClH:40].[ClH:40].[ClH:40].[C:1]1([CH2:14][N:15]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH:28]2[C:37]3[N:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH2:31][CH2:30][CH2:29]2)[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH:4]=[CH:3][N:2]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: CC(C)(C)OC(=O)NCCCCN(Cc1nccc2c1[nH]c1ccccc12)C1CCCc2cccnc21
Reactant: O=S(Cl)Cl
Solvent: CO
Product: Cl
Product: NCCCCN(Cc1nccc2c1[nH]c1ccccc12)C1CCCc2cccnc21
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A solution of tert-butyl 4-(((9H-pyrido[3,4-b]indol-1-yl)methyl)(5,6,7,8-tetrahydroquinolin-8-yl)amino)-butylcarbamate, 4, (0.12 g, 0.24 mmol) in methanol (5 mL) was treated with thionyl chloride (1 mL) at room temperature. The resulting mixture was stirred for 30 min. The reaction mixture was then concentrated and dried under reduced pressure to afford 0.11 g (80% yield) of the desired product A: 1H NMR (400 MHz, d6-DMSO) δ 13.49 (bs, 1H), 8.80-8.41 (m, 3H), 8.00-7.82 (m, 3H), 7.80 (d, J=8.0 Hz, 1H), 7.78-7.70 (m, 1H), 7.39 (t, J=7.2 Hz, 1H), 4.95-4.85 (m, 1H), 4.68-4.50 (m, 2H), 2.98-2.82 (m, 2H), 2.61-2.50 (m, 2H), 2.47-2.35 (m, 3H), 2.12-1.94 (m, 2H), 1.80-1.30 (m, 5H); ESI+ MS: m/z (rel intensity) 400.2 (100, [M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]3[C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[N:20][N:21]=[C:11]3[CH2:10][N:9]=2)=[CH:4][CH:3]=1.C(O)(=O)C>ClCCl.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]3[C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[N:20][N:21]=[C:11]3[CH2:10][NH:9]2)=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCc1nnc2n1-c1ccccc1C(c1ccc(Cl)cc1)=NC2
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCCCCCCCCc1nnc2n1-c1ccccc1C(c1ccc(Cl)cc1)NC2
Yield: 25.9 %

Procedure:
6-(4-Chlorophenyl)-1-undecyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (1.23 g) was dissolved in dichloromethane (10 ml) and acetic acid (5 ml) and zinc powder (540 mg) were added thereto with stirring. After stirring at room temperature for 6 hours, the mixture was washed with 5% aqueous sodium hydrogencarbonate and water. The reaction mixture was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and the oily substance obtained was crystallized from ethyl acetate to give 320 mg of 6-(4-chlorophenyl)-1-undecyl-4H,5H,6H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine, mp. 94°-95° C.
Reaction SMILES: [C:1]([C:4]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:16][Mg]Cl.O>O1CCCC1>[CH3:2][C:1]([CH3:16])([C:4]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=1)[OH:3]
Reactant: C[Mg]Cl
Reactant: CC(=O)C1=CCCCCCCCCCC1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)C1=CCCCCCCCCCC1
Yield: 96 %

Procedure:
52 g (0.25 mole) of 1-acetyl-1-cyclododecene, prepared as described in Example 2, are added over 30 minutes to 200 ml of a 1.5-molar solution of methyl-magnesium chloride in tetrahydrofuran at from 0° to +10° C. After completion of the addition, the reaction mixture is hydrolyzed with 20 ml of water and the tetrahydrofuran solution is filtered to remove the salt which has precipitated. After destilling off the tetrahydrofuran under reduced pressure (50° C./20 mbars) the product which remains is fractionated. 52 g of dimethyl-cyclododecenyl-carbinol (96% yield) of boiling point=108°-112° C./0.01 mm Hg and refractive index nD25 =1.5000 are obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[N:18][CH:17]=1>CN(C=O)C.O>[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:8][C:9]3[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[N:18][CH:17]=1
Reactant: COc1cc2c(Cl)cnnc2cc1O
Reactant: Cn1ccnc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Cl)cnnc2cc1OCc1nccn1C
Temperature: 40 °C
Reaction time: 8 h
Yield: 2.8 %

Procedure:
The starting material, 4-chloro-6-methoxy-7-[(1-methylimidazol-2-yl)methoxy]-cinnoline was obtained by adding potassium carbonate (531 mg, 3.8 mmol) followed by 2-chloromethyl-1-methylimidazole (232 mg, 1.4 mmol) to a suspension of 4-chloro-7-hydroxy-6-methoxycinnoline (270 mg, 1.28 mmol), (prepared as described for the starting material in Example 10), in DMF (6 ml). After stirring overnight at 40° C. the mixture was diluted with water and adjusted to pH7. After extraction with ethyl acetate, the organic layer was washed with water and then brine, dried (MgSO4) and the solvent evaporated. The residue was purified by flash chromatography using methylene chloride/methanol (98/2) as eluent to give 4-chloro-6-methoxy-7-[(1-methylimidazol-2-yl)methoxy]cinnoline (11 mg, 29%).
Reaction SMILES: [CH:1]1([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([N:14]=[C:15]=[S:16])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[NH2:17][NH2:18].[C:19](=[O:24])(OC)OC>>[CH:1]1([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([N:14]3[C:15]([SH:16])=[N:18][N:17]=[C:19]3[OH:24])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: NN
Reactant: COC(=O)OC
Reactant: S=C=Nc1ccc(C2CC2)c2ccccc12
Product: Oc1nnc(S)n1-c1ccc(C2CC2)c2ccccc12

Procedure:
1-Cyclopropyl-4-isothiocyanatonaphthalene is reacted with hydrazine and then cyclized in the presence of dimethyl carbonate to form 4-(4-cyclopropylnaphthalen-1-yl)-5-mercapto-4H-1,2,4-triazol-3-ol.
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[CH:5]1.[H][H]>FC(F)(F)C(O)=O.[Pt]=O>[CH3:1][CH:2]([CH3:18])[CH2:3][N:4]1[C:16]2[C:15]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[CH:5]1
Reactant: [H][H]
Reactant: CC(C)Cn1cnc2c(N)nc3cnccc3c21
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cn1cnc2c(N)nc3c(c21)CCNC3
Yield: 0.1 %

Procedure:
A catalytic amount of platinum oxide was added to a solution of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine (0.4 g, 1.66 mol)) in trifluoroacetic acid. The reaction mixture was reduced on a Parr apparatus at 50 psi (3.5 Kg/cm2) hydrogen pressure overnight. The reaction mixture was filtered and washed with methanol to remove the catalyst. The filtrate was concentrated under vacuum. The residue was combined with dichloromethane and aqueous sodium bicarbonate was added until the mixture was basic. The dichloromethane layer was separated. The aqueous layer was extracted five times with dichloromethane (100 mL). The dichloromethane extracts were combined, dried over magnesium sulfate and concentrated under vacuum. The resulting residue was recrystallized from toluene to provide 0.34 g of 6,7,8,9-tetrahydro-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine as a solid, m.p. 220-223° C. Analysis: Calculated for C13H19N5+/4H2O: %C, 62.50%H, 7.87; %N, 28.03; Found: %C, 62.50; %H, 7.72; %N, 27.46.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:40])([CH3:39])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([NH:32][CH2:33][C@@H:34]3[CH2:38][CH2:37][CH2:36][NH:35]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.Cl[C:51](Cl)([O:53]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:39])([CH3:40])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:33][C@@H:34]4[CH2:38][CH2:37][CH2:36][N:35]4[C:51]3=[O:53])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(NC[C@@H]2CCCN2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1-c1cc(N2C[C@@H]3CCCN3C2=O)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 37.8 %

Procedure:
The starting 2-[3,5-bis(trifluoromethyl)phenyl]-N-(4-(4-fluoro-2-methylphenyl)-6-{[(2S)-2-pyrrolidinylmethyl]amino}-3-pyridinyl)-N,2-dimethylpropanamide (D62, 38 mg, 0.064 mmol) was dissolved in 1 mL of anhydrous dichloromethane and treated with triethylamine (20 μL, 0.143 mmol). The solution was brought to 0° C. and triphosgene (10 mg, 0.034 mmol) was added. The reaction was stirred at 0° C. for 15 min, then brought to room temperature. After 24 h, the reaction was diluted with dichloromethane (10 mL) and extracted with brine. The organics were collected and the solvent removed. The product was isolated by flash chromatography (silica, cyclohexane:EtOAc 80:20 to EtOAc). Thus were obtained 8 mg of the target compound.
Reaction SMILES: [H-].[Na+].[F:3][CH:4]([F:7])[CH2:5][OH:6].C(S[C:12]1[N:13]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[CH:26][CH:25]=2)[C:14](=[O:23])[C:15]2[CH:21]=[CH:20][C:19](=[O:22])[NH:18][C:16]=2[N:17]=1)CC.O>O1CCCC1>[F:3][CH:4]([F:7])[CH2:5][O:6][C:12]1[N:13]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[CH:28][CH:29]=2)[C:14](=[O:23])[C:15]2[CH:21]=[CH:20][C:19](=[O:22])[NH:18][C:16]=2[N:17]=1
Reactant: CCCSc1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: OCC(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1ccc2c(=O)n(-c3ccc(OCC(F)(F)F)cc3)c(OCC(F)F)nc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of sodium hydride (60% in oil, 36 mg) in tetrahydrofuran (5 ml) was added 2,2-difluoroethanol (0.095 ml) at room temperature, and the mixture was stirred at room temperature for 10 min. To the reaction mixture was added 2-(propylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (123 mg), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and recrystallized from a mixed solvent of hexane/ethyl acetate to give the title compound (73 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH:23][C:24]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34]CC)=[O:33])[CH2:28][CH2:27]3)=[O:25])=[CH:21][N:22]=2)[N:19]=1.O.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO.O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH:23][C:24]([N:26]3[CH2:27][CH2:28][CH:29]([C:32]([OH:34])=[O:33])[CH2:30][CH2:31]3)=[O:25])=[CH:21][N:22]=2)[N:19]=1
Reactant: CCOC(=O)C1CCN(C(=O)Nc2cnc3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nn23)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCN(C(=O)Nc2cnc3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nn23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-ethyl 1-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-ylcarbamoyl)piperidine-4-carboxylate (Example 31, 9.2 mg, 0.018 mmol) was dissolved in a mixture solvent of THF:MeOH:water (2:2:1 v/v; 0.2 mL), followed by addition of lithium hydroxide monohydrate (2.3 mg, 0.055 mmol). After stirring at ambient temperature overnight, the reaction was diluted with water (1 mL), acidified with 10% citric acid, and extracted with EtOAc (3×1 mL). The combined organic layers were concentrated, and the crude material was purified by reverse-phase column chromatography, eluting with 5 to 55% MeOH/water to yield the final product as a solid. MS (apci) m/z=471.2 (M+H).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[N+]([C:10]1[CH:17]=[CH:16][CH:15]=[C:12]([C:13]#[N:14])[C:11]=1[C:18]#[N:19])([O-])=O.C([O-])([O-])=O.[K+].[K+].C1C=CC=CC=1>CS(C)=O.CC#N>[C:18](#[N:19])[C:11]1[C:12](=[CH:15][CH:16]=[CH:17][CH:10]=1)[C:13]#[N:14].[C:18](#[N:19])[C:11]1[C:12](=[CH:15][CH:16]=[CH:17][CH:10]=1)[C:13]#[N:14].[NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4]
Reactant: N#Cc1cccc([N+](=O)[O-])c1C#N
Agent: NC(CO)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: N#Cc1ccccc1C#N
Temperature: 25 °C
Reaction time: 90 h

Procedure:
A mixture of serinol (45.8 mg, 0.50 mmol, 1 equiv.), 3-nitrophthalonitrile (258.1 mg, 1.5 mmol, 2.5 equiv.) and K2CO3 (277.4 mg, 2.0 mmol, 4 equiv.) in 3 mL DMSO was stirred at room temperature and monitored periodically by TLC (9:1 benzene:CH3CN). The reaction mixture changed from orange to brown as the reaction occurred. After 90 h, the reaction mixture was heated to 70° C. TLC analysis showed the gradual disappearance of 3-nitrophthalonitrile over the next 8.5 h. The reaction mixture was partitioned between EtOAc and water, and the two layers were separated. The aqueous layer was extracted with EtOAc. This organic extract was combined with the phase-separated organic layer from the original separation, and then this mixture was washed twice with saturated NaHCO3, twice with water, and once with saturated NaCl. TLC analysis of the crude material showed no ninhydrin positive spot. The crude material was purified by flash chromatography using benzene:CH3CN (95:5) to extract the major UV-active spot.