Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([NH:21][C:22]([C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][N:25]2C(OC(C)(C)C)=O)=[O:23])=[CH:16][CH:15]=3)=[O:11])=[C:4]([F:37])[C:3]=1[O:38][C:39]1[CH:44]=[C:43]([C:45]#[N:46])[CH:42]=[C:41]([Cl:47])[CH:40]=1.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>ClCCl>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([NH:21][C:22]([C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]2)=[O:23])=[CH:16][CH:15]=3)=[O:11])=[C:4]([F:37])[C:3]=1[O:38][C:39]1[CH:44]=[C:43]([C:45]#[N:46])[CH:42]=[C:41]([Cl:47])[CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(NC(=O)[C@@H]5CCCCN5)ccc4[nH]3)c2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To a solution of 1,1-dimethylethyl (2S)-2-{[(2-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-indol-5-yl)amino]carbonyl}-1-piperidinecarboxylate (0.025 g, 0.036 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.5 mL, 6.49 mmol). The mixture was stirred at room temperature for 1 hr. The solvent was evaporated and the residue was purified by reverse phase HPLC (acetonitrile:water with 0.1% TFA) to give the title compound (0.012 g, 47%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.63 (br. s., 1H), 10.29 (s, 1H), 8.94-9.03 (m, 1H), 8.82-8.94 (m, 1H), 8.62-8.79 (m, 1H), 7.90 (s, 1H), 7.78 (s, 1H), 7.41-7.52 (m, 2H), 7.30-7.41 (m, 1H), 7.24 (d, 1H), 7.11 (s, 1H), 4.53 (d, 2H), 3.74-3.88 (m, 1H), 3.16-3.31 (m, 1H), 2.85-3.02 (m, 1H), 2.10-2.24 (m, 1H), 1.74-1.88 (m, 1H), 1.41-1.75 (m, 4H). ES MS: m/z 580 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:2].[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[C:27]#[C:28][C:29](O)=[O:30]>ClCCl.CO>[CH2:14]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:29](=[O:30])[C:28]#[C:27][C:18]2[CH:19]=[CH:20][C:21]([C:23]([F:25])([F:24])[F:26])=[CH:22][C:17]=2[Cl:16])=[CH:11][CH:12]=1)[CH3:15]
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: CCN(CC)CCOc1ccc(N)cc1
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)cc1

Procedure:
Prepared analogously to Example 2.3.f. from 69 mg (0.33 mmol) of 4-(2-diethylaminoethoxy)phenylamine and 75 mg (0.30 mmol) of (2-chloro-4-trifluoromethylphenyl)propynoic acid. Yield: 70 mg (53% of theory); melting point: 194° C.-197° C.; C22H22ClF3N2O2 (M=438.88); calc.: molecular ion peak (M+H)+: 439/441; found: molecular ion peak (M+H)+: 439/441; Rf value: 0.35 (silica gel, dichloromethane/methanol=(9:1)).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:15]=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:18][C:19]=1[F:20].CN([CH:28]=[O:29])C.C(O)(=O)C>C1COCC1.C(OCC)(=O)C.O>[Br:13][C:14]1[C:19]([F:20])=[C:18]([CH:17]=[C:16]([C:21]([F:24])([F:22])[F:23])[CH:15]=1)[CH:28]=[O:29]
Reactant: Fc1ccc(C(F)(F)F)cc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)NC(C)C
Product: O=Cc1cc(C(F)(F)F)cc(Br)c1F
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 1.98 mL, 4.94 mmol) was added to a solution of diisopropylamine (0.700 mL, 4.94 mmol) in THF (10 mL) at −30° C. After 15 minutes, the mixture was cooled to −70° C., then 3-bromo-4-fluorobenzotrifluoride (1.00 g, 4.12 mmol) was added. After 30 minutes, anhydrous DMF (0.637 mL, 8.23 mmol) was added dropwise. After 15 minutes, acetic acid (0.50 mL, 8.2 mmol) was added, then the mixture was diluted with ethyl acetate and water. The resulting layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organics were washed with saturated NaCl (aq), dried over Na2SO4, filtered, then concentrated. The resulting light yellow oil was used directly for the following step. 1H NMR (500 MHz, CDCl3) δ 10.38 (s, 1H); 8.10-8.15 (m, 2H). LC1: 3.44 min. Compound does not ionize.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[CH2:15][N:16]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[NH2:16][CH2:15][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=1
Reactant: Cn1c(CN2C(=O)c3ccccc3C2=O)nc(-c2ccncn2)cc1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: Cn1c(CN)nc(-c2ccncn2)cc1=O
Yield: 54.3 %

Procedure:
To a solution of 5.3 g (15.26 mmol) of 2-(1-Methyl-6-oxo-1,6-dihydro-[4,4]bipyrimidinyl-2-ylmethyl)-isoindole-1,3-dione in 40 ml of ethanol was added 2.37 mL (76.30 mmol) of hydrazine hydrate and the resulting mixture was heated under reflux for 3 h. The mixture was filtered and the solid obtained was triturated with dichloromethane for 24 h, filtered, and the resulting filtrates were evaporated to dryness, the residue was triturated with diethyl ether and filtered to give 1.8 g of pure compound as a solid.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH:10]=[O:11]>C1COCC1>[CH2:1]([CH:10]([C:6]1[S:5][CH:9]=[CH:8][CH:7]=1)[OH:11])[CH3:2]
Reactant: CC[Mg]Br
Reactant: O=Cc1cccs1
Solvent: C1CCOC1
Product: CCC(O)c1cccs1
Temperature: 23 °C

Procedure:
A 1.0M solution of ethylmagnesium bromide in THF (100 mL) is cooled to -78° C. and 2-thiophene carboxaldehyde (9.35 mL) is added. The reaction is allowed to warm to 23° C. for 1 h, then recooled to -78° C. and quenched with saturated ammonium chloride. After allowing to warm to 23° C., the reaction is extracted with ether (800 mL) and the ethereal layer is washed with water (2×150 mL) and brine. The organic phase is dried over MgSO4, filtered and concentrated in vacuo. The product is purified by chromatography over silica gel(2 kg), eluting with 30% ether in pentane to give 13.4 g of the title product as a colorless oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH2:16][CH2:17][C:18](O)=[O:19])=[CH:15][C:10]=2[O:9][CH2:8]1.Cl>C1COCC1>[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH2:16][CH2:17][CH2:18][OH:19])=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: O=C(O)CCc1ccc2c(c1)OCO2
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
Lithium aluminum hydride (1M in THF, 30 mL, 30 mmol) was added slowly to a solution of 3-benzo[1,3]dioxol-5-yl-propionic acid (5.83 g, 30 mmol) in THF (60 mL) at 0° C. The reaction was warmed to room temperature and was stirred for 2 h. The solution was added in portions to a mixture of ice (200 g) and concentrated HCl (2 mL). The product was extracted into EtOAc. The organic solution was dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (hexanes:EtOAc 6:4) provided the title alcohol (4.51 g). 1H NMR (400 MHz, CDCl3) δ 6.73-6.62 (m, 3H), 5.91 (s, 2H), 3.66 (t, 2H), 2.63 (t, 2H), 1.84 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:5]2[CH:14]=[CH:15][C:16]([C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[C:20]#[N:21])=[CH:17][C:4]=2[S:3]1.Br[C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1.CN1C(=O)CCC1.CCN(C(C)C)C(C)C>CO>[O:1]=[C:2]1[N:6]([CH2:7][CH:8]2[CH2:9][CH2:10][N:11]([C:27]3[N:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH2:12][CH2:13]2)[C:5]2[CH:14]=[CH:15][C:16]([C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[C:20]#[N:21])=[CH:17][C:4]=2[S:3]1
Reactant: N#Cc1ccccc1-c1ccc2c(c1)sc(=O)n2CC1CCNCC1
Reactant: Brc1ncccn1
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccccc1-c1ccc2c(c1)sc(=O)n2CC1CCN(c2ncccn2)CC1
Temperature: 100 °C

Procedure:
To a microwave vial was added 2-[2-oxo-3-(piperidin-4-ylmethyl)-2,3-dihydro-1,3-benzothiazol-6-yl]benzonitrile (11-3) (0.029 g, 0.075 mmol), 2-bromopyrimidine (0.0143 g, 0.090 mmol), NMP (0.7 mL), and DIPEA (0.033 mL, 0.188 mmol). The reaction mixture was then heated under microwave irradiation at 100° C. for 10 minutes. The crude reaction mixture was then allowed to cool to room temperature, diluted with methanol, filtered and concentrated. Purification of crude reaction mixture by reverse phase chromatography (Waters Sunfire MSC18, 10% acetonitrile/0.1% trifluoroacetic acid/water→100% acetonitrile/0.1% trifluoroacetic acid/water) gave 2-{2-oxo-3-[(1-pyrimidin-2-ylpiperidin-4-yl)methyl]-2,3-dihydro-1,3-benzothiazol-6-yl}benzonitrile (11-4) as a brown solid. HRMS (M+H)+: observed=428.1544, calculated=428.1540.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([NH2:27])=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19].CN(C(ON1N=NC2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>ClCCl.CN(C1C=CN=CC=1)C>[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([NH:27][CH:39]3[CH2:40][CH2:41][CH2:42][CH2:37]3)=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: NC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Nc1nc(-n2cc(C(=O)NC3CCCC3)cn2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The trisilyl derivative acid 20 (0.14 g, 0.2 mmol) was then dissolved in 5 mL dichloromethane. To the solution was added HBTU (0.19 g, 0.4 mmol), HOBt (.076 g, 4 mmol), N-methylmorpholine (0.04 g, 0.4 mmol) and cat. DMAP. The mixture was allowed to stir at RT for 24 h. The mixture was then washed with 10% citric acid, saturated NaHCO3, brine and dried over MgSO4. The solvent was removed and the residue was treated with 5 mL 0.5N NH4F/MeOH. The solution was heated at reflux for 24 h. The solvent was evaporated and the residue was purified by preparative TLC to afford compound 21, MS 445.26 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH2:8][NH:9][C:10]2[N:11]=[C:12]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH:5]=[CH:6][CH:7]=1.[O:25]([CH2:32][C:33](Cl)=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH2:8][N:9]2[C:10]3[N:11]=[C:12]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[S:13][C:14]=3[C:15](=[O:16])[N:17]=[C:33]2[CH2:32][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: Cc1c(Cl)cccc1CNc1nc(N2CCOCC2)sc1C(N)=O
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1Cn1c(COc2ccccc2)nc(=O)c2sc(N3CCOCC3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-{[(3-chloro-2-methylphenyl)methyl]amino}-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide (100 mg, 0.273 mmol) in Tetrahydrofuran (THF) (1363 μl) at 0° C. was added phenoxyacetyl chloride (75 μl, 0.545 mmol). The mixture was stirred at room temperature overnight, then quenched with methanol and concentrated. The residue was purified by reversed-phase HPLC to provide 4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)-5-[(phenyloxy)methyl][1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one. (19 mg, 14%); LC/MS: MS (ES+) m/e 483 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.29 (s, 3H), 3.52 (t, J=4.7 Hz, 4H), 3.67 (t, J=4.7 Hz, 4H), 5.07 (s, 2H), 5.55 (s, 2H), 6.55 (m, 1H), 6.69 (d, J=7.8 Hz, 2H), 6.94 (m, 1H), 7.12 (m, 1H), 7.22 (m, 2H), 7.36 (d, J=7.8 Hz, 1H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.B.CC(=C(C)C)C.C=C1C[C@@H:17]2[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][C@@H:16]2C1.[OH-].[Na+].OO>O1CCCC1>[OH:1][CH2:5][CH:4]1[CH2:16][C@@H:17]2[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][C@@H:2]2[CH2:3]1
Reactant: C=C1C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@@H]2C1
Reactant: C1CCOC1
Agent: B
Agent: CC(C)=C(C)C
Agent: OO
Product: CC(C)(C)OC(=O)N1C[C@H]2CC(CO)C[C@H]2C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, borane tetrahydrofuran complex (1M in THF, 42 mL, 41.9 mmol) was diluted with tetrahydrofuran (42 mL) and cooled with an ice bath. Neat 2,3-dimethylbut-2-ene (5.0 mL, 41.9 mmol) was added in portions over 0.25 h and the solution was stirred at 0° C. for 3 h. A solution of 1,1-dimethylethyl (3aR,6aS)-5-methylidenehexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.98 g, 8.88 mmol) in tetrahydrofuran (10 mL) was added slowly, and the solution was warmed to room temperature and stirred 12 h. After cooling to 0° C., 10% aqueous sodium hydroxide (17 mL, 41.7 mmol) was added slowly, followed by 30% aqueous hydrogen peroxide (13 mL, 128 mmol) and the solution was warmed to room temperature. The solvent was removed in vacuo and the solution was partitioned between water and diethyl ether. The layers were separated and the aqueous layer was further extracted (3×50 mL diethyl ether). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide 2.04 (95%) of 1,1-dimethylethyl (3aR,6aS)-5-(hydroxymethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate, which was used without purification. 1H NMR (400 MHz, CDCl3): 8.50 (broad s, 1H), 3.66-3.46 (m, 3H), 3.20-3.00 (m, 2H), 2.70-2.59 (m, 2H), 2.37-2.18 (m, 1H), 2.04 (m, 1H), 1.84 (broad s, 1H), 1.70-1.55 (m, 1H), 1.46 (s, 9H), 1.17 (m, 1H), 0.93 (m, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4][OH:5].[CH2:9](Br)[CH:10]=[CH2:11].[NH4+].[Cl-]>CN(C=O)C>[CH2:11]([O:5][CH2:4][C:3]([O:7][CH3:8])=[O:6])[CH:10]=[CH2:9]
Reactant: C=CCBr
Reactant: COC(=O)CO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C=CCOCC(=O)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
To a suspension of sodium hydride (1.76 g, 60% in oil, 44.0 mmol) in DMF (40 mL) cooled at 0° C. was added dropwise methyl glycolate (3.09 mL, 3.60 g, 40.0 mmol). The mixture was warmed to 25° C., stirred for 1 h and cooled down to 0° C., before allyl bromide (3.81 mL, 5.32 g, 44.0 mmol) was added dropwise. The solution was warmed to 25° C., stirred for 1 h, poured in a saturated solution of NH4Cl (100 mL) and extracted with ethyl acetate (3×50 mL). The organic phases were washed with brine (2×50 mL), dried over sodium sulfate and the concentrated. The residue was distilled in vacuo utilizing a Vigreux column to afford the ester (2.77 g, 53%) as a colorless oil (b.p. 54-55° C./2 mmHg). 1H NMR (CDCl3) δ 3.74 (s, 3H), 4.06-4.08 (m, 4H), 5.21 (d, J=10.2 Hz, 1H), 5.29 (d, J=17.2 Hz, 1H), 5.84-5.94 (m, 1H).
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[H-].[Na+].[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16]Cl>C1(C)C=CC=CC=1>[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9]
Reactant: O=Cc1ccccc1O
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(C)CCCOc1ccccc1C=O
Yield: 76.7 %

Procedure:
The reaction between 100 g (0.82 mole) of salicylaldehyde, 40 g (0.82 mole) of 50% NaH, and 650 ml (1.2 mole) of 1.89 N 3-dimethylaminopropyl chloride in toluene in a procedure described in Example 2, part A, gives 130.4 g (77%) of yellow product, bp 125°-130°/0.5 mm.
Reaction SMILES: [Br:1][CH2:2][C:3](=[N:9][OH:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:1][CH2:2][C:3](=[N:9][O:10][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([Cl:11])=[CH:13][CH:14]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(CBr)=NO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(CBr)=NOC(=O)c1ccc(Cl)cc1
Yield: 100.3 %

Procedure:
To the mixture of ethyl 3-bromo-2-(hydorxyimino)propanoate (3 g, 14.3 mmole) and 4-chlorobenzoyl chloride (2.75 g, 15.71 mmole) in dry methylene chloride (100 ml) at 0° to 5° C. with stirring, was slowly added dry pyridine (1.2 g, 15.18 mmole). After addition, the reaction mixture was stirred at room temperature for one hour. The reaction mixture was diluted with 50 ml of methylene chloride and washed with water and brine. The organic layer was dried with magnesium sulfate and the solvent evaporated to afford 5.0 g (99% yield) of ethyl 3-bromo-2-(4-chlorobenzoyloximino)propanoate as a white solid, m.p. 82°-84.5° C.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH2:13]([NH2:15])[CH3:14].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C.C1COCC1.C(N(CC)CC)C>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:15][CH2:13][CH3:14])=[O:10])=[CH:11][CH:12]=1)=[N+:2]=[N-:3]
Reactant: CCN
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC#N
Product: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 4-azidobenzoic acid (0.65 g) in acetonitrile-DMF (2:1, 15 ml) were successively added 2M ethylamine in THF solution (2.4 ml), triethylamine (0.67 ml), HOBt (0.79 g) and WSC (0.92 g), and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a pale-yellow powder (0.73 g, 96%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH2:9])=[O:8].Cl[C:11](Cl)([O:13]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1>[N:1]1[C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([OH:8])=[N:9][C:11]=1[OH:13]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NC(=O)c1sccc1N
Solvent: C1COCCO1
Product: Oc1nc(O)c2sccc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
50 mg (0.35 mmol) 3-amino-thiophene-2-carboxamide is dissolved in 3 mL dioxane. 52 mg (0.175 mmol, 0.5 eq) triphosgene is added and the mixture is heated at 80 C. After 30 min, TLC and LCMS indicate that the reaction is complete. The mixture is cooled down to RT and the resulting white precipitate is collected and washed with diethyl ether. Yield: 46 mg (0.27 mmol, 78%).
Reaction SMILES: [C:1]1([C:14]([OH:16])=[O:15])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.N.[Li]>C(O)C>[CH:1]1([C:14]([OH:16])=[O:15])[CH:13]2[CH:5]([C:6]3[C:11]([CH2:12]2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc2c1Cc1ccccc1-2
Agent: N
Agent: [Li]
Solvent: CCO
Product: O=C(O)C1CCCC2c3ccccc3CC12

Procedure:
A solution of 21.0 g (0.10 mole) of fluorene-1-carboxylic acid in 25 ml of absolute ethanol is added to 500 ml of liquid ammonia and the solution treated portionwise with 4.2 g (0.60 mole) of lithium cut in small pieces. After evaporation of the NH3, the residue is cooled in ice and treated first with water and then with sufficient conc. HCl to render it strongly acidic. The crude partially reduced product is filtered off and dissolved in acetic acid. Reduction of the solution over 1 g of PtO2 under up to 55 psi of H2 is complete after about 1 equivalent of H2 is taken up. The solution is freed of catalyst and taken to dryness. Recrystallization from hexane affords the desired product, mp 138°-139°.
Reaction SMILES: I[C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14]([NH:17][C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][NH:22]2)[CH2:15][CH3:16].[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[C:32]([F:34])[CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.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>[F:27][C:28]1[CH:29]=[C:30]([C:2]2[C:7](=[O:8])[N:6]3[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]3=[N:4][C:3]=2[CH:14]([NH:17][C:18]2[N:26]=[CH:25][N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][NH:22]3)[CH2:15][CH3:16])[CH:31]=[C:32]([F:34])[CH:33]=1
Reactant: CCC(Nc1ncnc2[nH]cnc12)c1nc2cccc(C)n2c(=O)c1I
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCC(Nc1ncnc2[nH]cnc12)c1nc2cccc(C)n2c(=O)c1-c1cc(F)cc(F)c1
Temperature: 100 °C

Procedure:
To a mixture of 3-iodo-6-methyl-2-[1-(9H-purin-6-ylamino)propyl]-4H-pyrido[1,2-a]pyrimidin-4-one (from example 3, step 2; 0.030 g, 0.065 mmol) and (3,5-difluorophenyl)boronic acid (Aldrich, 12.3 mg, 0.0780 mmol) in 1,4-dioxane (0.5 mL) was added a 1M solution of sodium carbonate (8.27 mg, 0.0780 mmol) in water (0.077 mL) and tetrakis(triphenylphosphine)palladium (0) (3.76 mg, 0.00325 mmol). The reaction mixture was heated at 100° C. overnight. After cooling to rt, the mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified on RP-HPLC at pH 10 conditions (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to provide the desired product. LCMS calculated for C23H20F2N7O (M+H)+: m/z=448.2. Found: 448.3. 1H NMR (DMSO-d6, 300 MHz) δ 8.06 (2H, m), 7.61 (1H, m), 7.38 (1H, m), 7.14 (5H, m), 6.88 (1H, m), 5.08 (1H, m), 2.83 (3H, s), 1.75 (2H, m), 0.70 ((3H, t, J=7.8 Hz) ppm. 19F NMR (DMSO-d6, 282 MHz) δ −111 ppm.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][O:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[C:8](=[O:17])[C:7]=2[CH:18]=1.[C-:19]#[N:20].[Na+]>CN(C)C=O.O>[C:19]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][O:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[C:8](=[O:17])[C:7]=2[CH:18]=1)#[N:20]
Reactant: O=C1c2cc(CBr)ccc2COc2ccccc21
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccc2c(c1)C(=O)c1ccccc1OC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Dissolve 6.4 gm of the bromomethyl compound of Step C in 75 cc of dimethylformamide and add 2.95 gm of sodium cyanide. Stir the mixture at room temperature for 1.5 hours. Dilute with 600 cc of water and extract three times with ether. Wash the combined organics with water, dry and strip to a solid residue. Triturate in hexane and recover the solid by filtration.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[C:9](=[N:22][NH2:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:10]1([C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:22][NH:23][C:7]2[CH:2]=[CH:3][C:4]([CH3:8])=[N:5][CH:6]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cc(Br)ccn1
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Cc1ccc(NN=C(c2ccccc2)c2ccccc2)cn1
Temperature: 85 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a solution of 4-bromo-2-methylpyridine (0.7 ml, 5.81 mmol) in anhydrous toluene, previously degassed with Ar, were added benzophenone hydrazone (1.25 g, 6.4 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (336 mg, 0.58 mmol), palladium (II) acetate (130 mg, 0.581 mmol), and sodium tert-butoxide (838 mg, 8.72 mmol). The reaction mixture was sealed and stirred at 85° C. overnight, then filtered through celite, washed with DCM and concentrated under reduced pressure. The residue was taken in EtOAc, washed with water, extracted, and the organics were combined and dried (MgSO4). The crude was purified by silica gel chromatography (hexane/ethyl acetate 10-100%) to afford 5-(2-(diphenylmethylene)hydrazinyl)-2-methylpyridine (1.6 g, 95%). 1H NMR (300 MHz, CDCl3) δ 2.47 (s, 3H), 6.76 (d, J=2 Hz, 1H), 6.83 (s, 1H), 7.31-7.36 (m, 5H), 7.53-7.63 (m, 6H), 8.20 (d, J=6 Hz, 1H); LC-MS (ESI) m/z 288 (M+H)+.