Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:17])=[C:6]([CH2:8]NC(=O)OC(C)(C)C)[CH:7]=1.Cl.CC[N:21](CC)CC.[CH2:26]([N:28]1[C:32]2=[N:33][C:34]([CH2:57][CH3:58])=[C:35]([CH2:44][NH:45][C:46]([C:48]3[CH:49]=[C:50]([CH:54]=[CH:55][CH:56]=3)[C:51](O)=[O:52])=[O:47])[C:36]([NH:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[C:31]2[CH:30]=[N:29]1)[CH3:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:17])=[C:6]([CH2:8][N:45]([CH2:44][C:35]2[C:36]([NH:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[C:31]3[CH:30]=[N:29][N:28]([CH2:26][CH3:27])[C:32]3=[N:33][C:34]=2[CH2:57][CH3:58])[C:46]([C:48]2[CH:56]=[CH:55][CH:54]=[C:50]([C:51]([NH2:21])=[O:52])[CH:49]=2)=[O:47])[CH:7]=1
Reactant: Cc1ccc(Br)cc1CNC(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1cc(Br)ccc1C)C(=O)c1cccc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.8 %

Procedure:
To a clear solution of 1,1-dimethylethyl [(5-bromo-2-methylphenyl)methyl]carbamate (923 mg, 3.01 mmol) in DCM (10 mL) was added 4N HCl in dioxane (3 mL). Solid precipitated out from the solution after 30 min. The mixture was stirred at RT for another 1 h. It was then concentrated under vacuum to get rid of solvent. The resulting residue was re-dissolved in DCM. Et3N (1.5 mL, 10.3 mmol) was added followed by 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-carbonyl]benzoic acid (1000 mg, 2.05 mmol) and HBTU (933 mg, 2.46 mmol). The mixture was stirred at RT overnight. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were then washed with water followed by the brine wash. The organic layer was then concentrated under vacuum to give a crude residue. It was then purified with CombiFlash chromatography, eluting with 0 to 10% methanol in DCM to obtain N-[(5-bromo-2-methylphenyl)methyl]-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide as a solid (1.4 g, 98%). LC-MS m/z 634 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[CH:6]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:7]3[N:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][N:10]([CH3:11])[C:4]=2[CH:3]=1.[N+:24]1([O-])[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N([OH:56])N=NC=2C=1.CN1CCOCC1>CN(C=O)C.O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[CH:6]([N:16]3[CH2:21][CH2:20][N+:19]([O-:56])([C:31](=[O:32])[CH2:30][C:27]4[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=4)[CH2:18][CH2:17]3)[C:7]3[N:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][N:10]([CH3:11])[C:4]=2[CH:3]=1
Reactant: CN1Cc2cccnc2C(N2CCNCC2)c2ccc(Cl)cc21
Reactant: On1nnc2ccccc21
Reactant: O=C(O)Cc1cc[n+]([O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN1Cc2cccnc2C(N2CC[N+]([O-])(C(=O)Cc3ccncc3)CC2)c2ccc(Cl)cc21
Temperature: 20 °C
Reaction time: 18 h
Yield: 75.6 %

Procedure:
(8-Chloro-6,11-dihydro-6-methyl-5H-pyrido[3,2-c][1]benzazepin-11-yl)-piperazine (100 mg, 0.305 mmol), 4-pyridine-acetic acid 1-oxide (93.3 mg, 0.61 mmol), EDCl (0.116 g, 0.61 mmol) and HOBT (82.4 mg, 0.61 mmol) were dissolved in DMF (2 ml), and NMM (1 ml) was added. The reaction mixture was stirred at 20° C. for 18 hours and then diluted with water (50 ml), and the aqueous phase was then extracted with EtOAc (about 8 times) until no product was visible in the aqueous layer. The EtOAc phase was then washed with aqueous Na2CO3 and chromatographed on silica gel to afford the title compound (107 mg), m.p. 115-118° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=[C:6]([CH3:12])[C:5]=1[N:13]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15].S(=O)(=O)([OH:35])N.Cl([O-])=O.[Na+]>O.C1COCC1.CCOCC>[CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([CH:7]=[C:6]([CH3:12])[C:5]=1[N:13]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=[O:15])=[O:16])[C:10]([OH:35])=[O:11]
Reactant: NS(=O)(=O)O
Reactant: COC(=O)c1cc(C=O)cc(C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: COC(=O)c1cc(C(=O)O)cc(C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 2 h
Yield: 98.9 %

Procedure:
To a solution of 317 mg (0.7 mmol) of the product of Example 268 and 102 mg (1.05 mmol) of sulfamic acid in 40 ml of water:THF (3:1) was added 98 mg (1.08 mmol) of sodium chlorite. The resulting mixture stirred for 2 hr, diluted with ether, washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to provide 325 mg (99%) of the desired carboxylic acid as a white solid. Electrospray Mass Spec 468 (M-H).
Reaction SMILES: CS([Cl:5])(=O)=O.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH:20](O)[C:21]2[O:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][C:24]=3[N:29]=2)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>N1C=CC=CC=1>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH:20]([Cl:5])[C:21]2[O:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][C:24]=3[N:29]=2)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(CC(O)c2nc3cnccc3o2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(CC(Cl)c2nc3cnccc3o2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
MsCl (29 μL, 0.38 mmol) was added to a stirred solution of 4-(2-hydroxy-2-oxazolo[4,5-c]pyridin-2-yl-ethyl)piperidine-1-carboxylic acid tert-butyl ester (Preparation 7, 110 mg, 0.32 mmol) in anhydrous pyridine (5 mL) at 0° C. After 1 h, more MsCl (29 μL, 0.38 mmol) was added, then the mixture was stirred at 0° C. for an additional 1 h, before being heated under reflux for 1 h. The reaction was concentrated under reduced pressure, then the residue was purified by flash chromatography (EtOAc-IH, 7:3) to furnish the title compound: RT=3.57 min; m/z (ES+)=310.0 [M+2H-t-Bu]+.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:46]([O:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:60])[CH2:58][NH2:59])[CH2:53][CH2:52]1)=[O:50])[CH3:47]>CN(C=O)C>[CH2:46]([O:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:60])[CH2:58][NH:59][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[S:8][CH:9]=2)=[O:14])[CH2:53][CH2:52]1)=[O:50])[CH3:47]
Reactant: O=C(O)c1csc(-c2ccccc2)n1
Reactant: CCOC(=O)N1CCN(C(=O)CN)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)CNC(=O)c2csc(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of 2-phenyl-1,3-thiazole-4-carboxylic acid (5.1 mg) and DIPEA (3 eq) in DMF (0.4 mL) was added TBTU (1.2 eq) in DMF (0.2 mL). Then, a solution of 4-(2-amino-acetyl)-piperazine-1-carboxylic acid ethyl ester (5.4 mg, prepared as described in WO2006114774) in DMF (0.2 mL) was added. After stirring overnight at RT, the reaction mixture was directly purified by preparative HPLC (IV) to give 4.9 mg of the desired product.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(O)(C(F)(F)F)=O.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[B:20]([OH:22])[OH:21]>>[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([N+:1]([O-:4])=[O:2])=[CH:15][C:14]=1[B:20]([OH:21])[OH:22]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(B(O)O)c(C)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c([N+](=O)[O-])cc1B(O)O
Temperature: -35 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To fuming nitric acid (1 ml) cooled to −40° C. was added TFA (1 ml). The resulting mixture was allowed to warm slightly to −35° C. and 2,4-dimethyl phenyl boronic acid (150 mg, 1 mmol) was added in one portion. After 1 h, ice was added and the heterogenous mixture was filtered. The resulting solid was suspended in Et2O and extracted with 3N NaOH, (aq) (1 ml) then water (2 ml). The aqueous phase was acidified with 3N HCl (aq) (1 ml) and back extracted with EtOAc (3×5 ml). The pooled organics were washed with brine, dried with Na2SO4 decanted and concentrated to give 2,4-dimethyl-5-nitro-phenyl boronic acid (93 mg, 47%). LCMS (ESI+) [M+H]/z Calc'd 196, found 196.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]2)=[C:4]([F:19])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].F[C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:16])[F:17])[C:11]([CH3:18])=[N:10]2)=[C:4]([F:19])[CH:3]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: Cc1nn(-c2cc(O)c(Cl)cc2F)c(=O)n1C(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2cc(Oc3ccc(C#N)cc3)c(Cl)cc2F)c(=O)n1C(F)F
Temperature: 120 °C
Yield: 65.6 %

Procedure:
To a stirred solution of 5.0 g (0.017 mole) of 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one in 150 mL of N,N-dimethylformamide was added 2.8 g (0.020 mole) of potassium carbonate. The resultant mixture was stirred for ten minutes, and 2.1 g (0.017 mole) of 4-fluorobenzonitrile was added. The mixture was stirred and heated at 120° C. for approximately 18 hours. The solvent was removed from the mixture by distillation under reduced pressure leaving a residue which was partitioned between diethyl ether and water. The organic phase was separated, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure to give 4.4 g of 1-[4-chloro-5-(4-cyanophenoxy)-2-fluorophenyl]-4-difluoromethyl -4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[C:5]([N+:12]([O-])=O)=[CH:4][N:3]=1.[C:15]([OH:20])(=O)[CH2:16][CH2:17][CH3:18]>>[CH3:11][C:6]1[C:5]([NH:12][C:15](=[O:20])[CH2:16][CH2:17][CH3:18])=[CH:4][N:3]=[C:2]2[NH:1][C:4]([CH2:5][CH2:6][CH3:7])=[N:8][C:7]=12
Reactant: CCCC(=O)O
Reactant: Cc1c([N+](=O)[O-])cnc(N)c1[N+](=O)[O-]
Product: CCCC(=O)Nc1cnc2[nH]c(CCC)nc2c1C

Procedure:
The title compound was prepared from 2-amino-4-methyl-3,5-dinitropyridine according to method described in Example 1, Step 2 using butyric acid in the place of valeric acid.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-]#N.[Na+].[F:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21](=[O:23])[CH3:22])=[CH:15][CH:14]=1.O>CN(C=O)C>[F:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]([CH2:20][C:21](=[O:23])[CH3:22])[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])=[CH:17][CH:18]=1
Reactant: CC(=O)/C=C/c1ccc(F)cc1
Reactant: O=Cc1ccccc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)CC(C(=O)c1ccccc1)c1ccc(F)cc1
Reaction time: 1.5 h
Yield: 45.6 %

Procedure:
A solution of benzaldehyde (1.650 ml, 16.32 mmol) in DMF (5 ml) was added dropwise over the course of ½ hour to a mixture of sodium cyanide (0.401 g, 8.17 mmol) in DMF (20 ml) at 35° C. Stirring was then continued for 1.5 hours at 35° C. A solution of (E)-4-(4-fluorophenyl)but-3-en-2-one (2.0 g, 12.18 mmol) and DMF (10 ml) was then slowly added dropwise over the course of 3.5 hours at 35° C. Stirring was then continued for 3.5 hours at the same temperature. The reaction mixture was treated with twice its volume of water and extracted with DCM. The combined extracts were washed with water and brine, dried with Na2SO4, filtered and concentrated to give a liquid, which was further purified by chromatography on silica gel using an automated Biotage system and EtOAc/Hex (0-50%) to give 2-(4-fluorophenyl)-1-phenylpentane-1,4-dione (1.5 g, 5.55 mmol, 45.6% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.95-7.93 (m, 2H), 7.50-7.46 (m, 1H), 7.40-7.32 (m, 3H), 7.26-7.21 (m, 3H), 5.11 (dd, 1H), 3.59 (dd, 1H), 2.76 (dd, 1H), 2.19 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:14]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]2[N:6]([C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=2)[N:7]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:51][C:52]1[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=1>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([N:14]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:5]2[N:6]([C:8]([C:11]([NH:51][C:52]3[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=3)=[O:13])=[CH:9][N:10]=2)[N:7]=1
Reactant: Nc1ccncc1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(C(=O)O)cnc23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(C(=O)Nc4ccncc4)cnc23)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a 2 dram vial was added 6-chloro-8-((4-methoxybenzyl)(phenyl)amino)-imidazo[1,2-b]pyridazine-3-carboxylic acid (0.025 g, 0.06 mmol) from (1a), EDCI (0.018 g, 0.09 mmol), HOBT (0.012 g, 0.09 mmol), 4-aminopyridine (8.46 mg, 0.09 mmol), TEA (0.025 ml, 0.18 mmol) and CH3CN (1.0 ml). The reaction was stirred at 25° C. for 48 hours then concentrated to give crude 6-chloro-8-((4-methoxybenzyl)(phenyl)amino)-N-(pyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide. To this residue was added trans-1,4-cyclohexyldiamine (0.5 g, 4.3 mmol) and the resulting mixture was allowed to heat at 165° C. for 5 hrs. Upon cooling, the sample was dissolved in methylene chloride, and washed with water. The organics were separated, then dried over Na2SO4, filtered and concentrated in vacuo. To this residue was added a 1:1 mixture of CH2Cl2/TFA (2 ml). The solution was stirred at 25° C. for 3 hours, concentrated, diluted with MeOH and purified by preparative HPLC to provide the titled compound (0.008 g, 22%) as a TFA salt. 1H NMR (500 MHz, MeOH) δ ppm 8.74 (2H, d, J=7.15 Hz), 8.30 (2H, d, J=7.15 Hz), 8.19 (1H, s), 7.41-7.50 (2H, m), 7.31-7.41 (2H, m), 7.17-7.26 (1H, m), 6.26-6.33 (1H, m), 3.71-3.87 (1H, m), 3.10-3.23 (1H, m), 2.25-2.39 (2H, m), 2.06-2.24 (2H, m), 1.53-1.66 (2H, m), 1.35-1.52 (2H, m). LC/MS, m/z 443 (M+1). HPLC Rt, 2.34 min. Waters Sunfire C18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[C:6]([N:13]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]>CCOCC>[C:9]([O:8][C:6]([N:13]1[CH2:18][CH2:17][C:16]([CH2:1][CH2:2][CH2:3][CH3:4])([OH:19])[CH2:15][CH2:14]1)=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CCOCC
Product: CCCCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
To a solution of n-butyl lithium (16.06 mL, 40.2 mmol, 2.5 M in hexanes) at −78° C., was drop-wise added a solution of N-Boc-4-piperidone (4.0 g, 20.1 mmol) in ether (10 mL). The resulting solution was allowed to warm to room temperature and stirred for one additional hour. The solution was cooled to 0° C. before being quenched by the drop-wise addition of saturated aqueous ammonium chloride (30 mL), and extracted with ethyl acetate (2×30 mL). The combined organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product as a yellow oil, which was then purified by silica chromatography on a Biotage (0-50% of EtOAc/Hexanes) to give the title compound as a colorless oil (1.66 g, still contaminated with the starting material ketone). This mixture was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4](Cl)[N:3]=1.[Na].[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1
Reactant: OCc1ccccc1
Reactant: Nc1nc(N)c([N+](=O)[O-])c(Cl)n1
Agent: [Na]
Product: Nc1nc(N)c([N+](=O)[O-])c(OCc2ccccc2)n1
Temperature: 160 °C

Procedure:
2,4-Diamino-6-chloro-5-nitropyrimidine (O'Brien et. al., J. Med. Chem., 9, 573-575 (1966)) (1.0 g, 5.28 mmol) was added to a solution of sodium (0.14 g, 6.08 mmol) in benzyl alcohol (9 mL). The solution was heated in a 160° C. oil bath for 3.5 h and the solvent was evaporated under reduced pressure to provide a yellow solid. This solid was washed with water, and air dried. Crystallization from benzene/ether gave a pale yellow filamentous solid: yield, 0.69 g (50%); mp 194-195° C. (171° C.; Kosary et. al., Acta. Pharm. Hung., 49, 241-247 (1989)); UV (pH 1) 1max 236 nm (sh) (e=1.452×104) 264 (0.522×104) 321 (1.294×104); (pH 6.9) 242 (sh) (0.965×104), 337 (1.493×104); (pH 13) 242 (sh) (0.952×104), 338 (1.479×104); 1H NMR d 5.43 (s, 2 H, ArCH2), 7.26 (br s, 2 H, NH2, exchange with D2O), 7.33-7.51 (m, 5 H, ArH), 7.93 (br s, 2 H, NH2, exchange with D2O); MS (EI) calcd. m/z for C11H11N5O3 261.0861, found 261.0866; Anal. (C11H11N5O3).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][C:15]=1[Cl:21]>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>[Cl:21][C:15]1[CH:16]=[C:17]([NH2:18])[CH:19]=[CH:20][C:14]=1[C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: Nc1ccc(Br)c(Cl)c1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Nc1ccc(-c2cccc([N+](=O)[O-])c2)c(Cl)c1
Yield: 32.2 %

Procedure:
This compound was prepared by General Method 14 (EXAMPLE 191) from 3-nitrobenzeneboronic acid (0.25 g, 1.5 mmol), 4-bromo-3-chloroaniline (0.21 g, 1.0 mmol), and (PPh3)4Pd (35 mg, 0.030 mmol) to afford 0.08 g (32%) of 2-chloro-4-amino-3'-nitrobiphenyl as an orange solid. Data for 2-chloro-4-amino-3'-nitrobiphenyl: 1H NMR (400 MHz, acetone-d6) 8.29 (app t, J=2.0, 1H), 8.18 (dt, J=9.0, 1.2, 1H), 7.76 (dd, J=9.0, 1.2, 1H), 7.56 (t, J=8.0, 1H), 7.14 (d, J=8.2, 1H), 6.82 (d, J=2.2, 1H), 6.65 (dd, J=8.2, 2.2, 1H), 3.86 (br s, 2H).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH2:5][CH2:4]1.[C:14](Cl)(Cl)=[O:15].Cl.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[C:30]([C:32]3[CH:41]=[C:40]4[C:35]([CH2:36][CH2:37][NH:38][CH2:39]4)=[CH:34][CH:33]=3)[N:29]=[C:28]([NH2:42])[N:27]=2)[CH2:22][CH2:21]1>>[NH2:42][C:28]1[N:29]=[C:30]([C:32]2[CH:41]=[C:40]3[C:35]([CH2:36][CH2:37][N:38]([C:14]([NH:2][CH:3]4[CH2:4][CH2:5][CH:6]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH2:7][CH2:8]4)=[O:15])[CH2:39]3)=[CH:34][CH:33]=2)[CH:31]=[C:26]([N:23]2[CH2:22][CH2:21][N:20]([CH3:19])[CH2:25][CH2:24]2)[N:27]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C(Cl)Cl
Reactant: CN(C)C(=O)C1CCC(N)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)NC3CCC(C(=O)N(C)C)CC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 40 starting from 4-amino-N,N-dimethylcyclohexanecarboxamide hydrochloride, phosgene and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=521.3.
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[C:14]([CH3:15])=[CH:13][C:12]2[C:11]([CH3:17])([CH3:16])[CH2:10][CH2:9][C:8]([CH3:19])([CH3:18])[C:7]=2[CH:6]=1.[OH-].[NH4+]>CN1CCCC1>[C:2]([C:5]1[C:14]([CH3:15])=[CH:13][C:12]2[C:11]([CH3:17])([CH3:16])[CH2:10][CH2:9][C:8]([CH3:19])([CH3:18])[C:7]=2[CH:6]=1)#[N:3]
Reactant: Cc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Reactant: N#C[Cu]
Agent: CN1CCCC1
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc2c(cc1C#N)C(C)(C)CCC2(C)C
Temperature: 175 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
28.9 g (322 mmol) of copper(I) cyanide was added to 22.7 g (80.7 mmol) of 2-bromo-3-methyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene in 270 mL of N-methyl pyrrolidine. The reaction mixture was heated at 175° C. After 16 hours, the mixture was cooled to room temperature and treated with 400 mL of 10% aqueous ammonium hydroxide. The reaction mixture was filtered to remove salts and the solids were extracted with hot ethyl acetate. The combined organic fractions were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The product was purified by gradient elution through a pad of silica gel (hexane-5% ethyl acetate/hexane) to give 18 g (95%) of 2-cyano-3-methyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (M+=227).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>O>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: Oc1ccnc2ccccc12
Reactant: O=[N+]([O-])O
Solvent: O
Product: O=[N+]([O-])c1cnc2ccccc2c1O
Temperature: 85 °C
Reaction time: 0.83 h

Procedure:
5 g (34 mmol) 4-hydroxyquinoline are added in small portions to nitric acid (66%) heated at 85° C. The reaction mixture is stirred for 50 min at this temperature. 150 ml water are heated to 100° C. and the reaction mixture is added slowly through a dropping funnel to the boiling water. The yellow precipitate which is formed is filtered off and washed with hot and cold water and acetone to become almost colorless. The title compound is dried at 60° C. under vacuum. mp: 357-358° C.; MS: 191 (M++1); HPLC: tret=8.73 min (Grad 3).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[NH2:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][CH2:17][CH:18]=O.[BH3-]C#N.[Na+].C(O)(=O)C>CO>[Cl:16][CH2:17][CH2:18][NH:10][C:9]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1
Reactant: COc1ccc(N)cc1OC1CCCC1
Reactant: O=CCCl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(NCCCl)cc1OC1CCCC1
Temperature: 15 °C
Yield: 63.4 %

Procedure:
To a solution of 2.15 g (10.4 mmol) 3-cyclopentyloxy-4-methoxyaniline (J. Org. Chem. 2005,70, 1050) in 100 ml methanol were added 2.0 g (14.1 mmol) chloroacetaldehyde solution (55% in water), 3.9 g (62.6 mmol) NaBH3CN and 0.5 ml acetic acid. The reaction was stirred over night at 15° C. and the solvent was subsequently evaporated. The residue was taken up in 120 ml dichloromethane and the organic phase was washed with brine, dried over Na2SO4 and evaporated in vacuo. The crude product was purified by chromatography on silica gel (hexane:ethyl acetate 100:1 then 15:1) to give 1.78 g (63.5%) of the desired product as a yellow oil. 1H-NMR (DMSO): 6.70 (d, 1H), 6.28 (s, 1H), 6.06 (d, 1H), 5.43 (m, 1H), 4.69 (m, 1H), 3.68 (m, 2H), 3.60 (m, 3H), 3.32 (m, 2H), 1.83 (m, 2H), 1.69 (m, 4H), 1.55 (m, 2H).