Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([NH2:10])[N:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[C:6]=2[CH:17]=1.N1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>CN(C1C=CN=CC=1)C.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([NH:10][C:24](=[O:26])[CH3:25])[N:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[C:6]=2[CH:17]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc2ccc(Br)cc2n1-c1ccccn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(Br)cc2n1-c1ccccn1
Temperature: 25 °C
Reaction time: 60 h
Yield: 58.7 %

Procedure:
To a 250 mL round-bottomed flask was added 6-bromo-1-(pyridin-2-yl)-1H-benzo[d]imidazol-2-amine (1.00 g, 3.46 mmol), dichloromethane (35 mL), pyridine (0.419 mL, 5.19 mmol), acetic anhydride (0.343 mL, 3.63 mmol) and DMAP (0.0042 g, 0.035 mmol). The mixture was stirred at 25° C. for 2.5 days. The mixture was concentrated and taken up in MeOH/CH2Cl2 and then concentrated onto silica. Purification by silica gel chromatography (0.5 to 4.0% MeOH (2 M in NH3)/CH2Cl2) afforded the title compound as a pink solid (0.673 g, 58%). MS (ESI, positive ion) m/z: 331 (M(79Br)+1).
Reaction SMILES: [K:1].[S:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH2:15])=[O:14])=[CH:8][CH:7]=1)([OH:5])(=[O:4])=[O:3].[C:16](O)(=[O:21])[CH2:17][C:18](O)=[O:19].C(OC(=O)C)(=O)C>C(O)(=O)C>[S:2]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:16](=[O:21])[CH2:17][C:18](=[O:19])[NH:15][C:13]2=[O:14])=[CH:10][CH:11]=1)([OH:5])(=[O:4])=[O:3].[K:1]
Reactant: NC(=O)Nc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CC(=O)O
Agent: [K]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C1CC(=O)N(c2ccc(S(=O)(=O)O)cc2)C(=O)N1
Temperature: 95 °C
Yield: 91.1 %

Procedure:
A mixture of 29.9 g of N-(4-sulfophenyl)urea potassium salt, 15 g of malonic acid and 200 ml of glacial acetic acid was heated to 60° to 70° C with stirring and 300 ml of acetic anhydride was added dropwise to the mixture. After about 50 ml of the acetic anhydride had been added, the mixture dissolved. After all of the acetic anhydride (300 ml) was added, the temperature of the reaction solution increased to 95° C. The reaction solution was stirred for 4 hours and then condensed under reduced pressure so as to precipitate crystals. 700 ml of ethanol was added to the condensed solution and the crystals were completely precipitated. The precipitated crystals were collected by filtration, washed thoroughly with ethanol and dried by heating under reduced pressure to obtain 34.5 g of crystals. The obtained crystals were recrystallized using a 90% methanol aqueous solution and, thereby, 29.3 g of white crystals was obtained. Melting point: above 300° C. Elemental Analysis:
Reaction SMILES: [NH2:1][NH2:2].[CH3:3][N:4]1[C:8](Cl)=[C:7]([N+:10]([O-:12])=[O:11])[C:6]([CH3:13])=[N:5]1>C(O)CC>[NH:1]([C:8]1[N:4]([CH3:3])[N:5]=[C:6]([CH3:13])[C:7]=1[N+:10]([O-:12])=[O:11])[NH2:2]
Reactant: NN
Reactant: Cc1nn(C)c(Cl)c1[N+](=O)[O-]
Solvent: CCCO
Product: Cc1nn(C)c(NN)c1[N+](=O)[O-]

Procedure:
39 gms. of hydrazine are dissolved in 500 ml. of n-propanol and 105 gms. of 1,3-dimethyl-4-nitro-5-chloro-1H-pyrazole dissolved in propanol are added dropwise at 100°. The reaction mixture is then refluxed for 4 hours. On cooling, 5-hydrazino-1,3-dimethyl-4-nitro-1H-pyrazole crystallizes in the form of yellow needles. By concentrating the mother liquor an additional quantity of product is obtained. The combined crude is recrystallized from propanol, yield 98 gms. of yellow needles, m.p. 177°-179°.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C@H:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([N:18]([CH3:25])[CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:17])[CH:14]=2)[CH2:9][CH2:8]1)=[O:5].Cl[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([NH2:37])[N:32]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[NH2:37][C:33]1[N:34]=[C:35]([N:22]2[CH2:21][CH2:20][CH:19]([N:18]([CH3:25])[C:16]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[CH2:9][CH2:8][C@H:7]4[NH:6][C:4](=[O:5])[C:3]3[CH:26]=[CH:27][CH:28]=[CH:29][C:2]=3[Cl:1])=[O:17])[CH2:24][CH2:23]2)[CH:36]=[CH:31][N:32]=1
Reactant: Nc1nccc(Cl)n1
Reactant: CN(C(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CC2)C1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CC2)C1CCN(c2ccnc(N)n2)CC1
Reaction time: 0.15 h
Yield: 45 %

Procedure:
A mixture of (R)-3-(2-chlorobenzamido)-N-methyl-N-(piperidin-4-yl)-2,3-dihydro-1H-indene-5-carboxamide (stage 2H-214) (200 mg, 0.486 mmol, 1.0 eq), 4-chloro-pyrimidin-2-ylamine (94 mg, 0.728 mmol, 1.5 eq) and DIPEA (0.125 ml, 0.728 mmol, 1.5 eq) in dioxane (10 ml) was refluxed for 16 h. When the reaction was complete according to TLC monitoring, concentration under reduced pressure was carried out, and the reside was taken up in dichloromethane (50 ml) and washed with water (30 ml) and saturated sodium chloride solution (30 ml). The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 6% methanol in dichloromethane). Yield: 45% (110 mg, 0.267 mmol) Analytical Data—Single Substances Method 1: Equipment and methods for HPLC-MS analysis: HPLC: Waters Alliance 2795 with PDA Waters 2998; MS: Micromass Quattro Micro™ API; column: Waters Atlantis® T3, 3 μm, 100 Å, 2.1×30 mm; column temperature: 40° C., eluent A: purified water+0.1% formic acid; eluent B: acetonitrile (gradient grade)+0.1% formic acid; gradient: 0% B to 100% B in 8.8 min, 100% B for 0.4 min, 100% B to 0% B in 0.01 min, 0% B for 0.8 min; flow: 1.0 ml/min; ionization: ES+, 25 V; batch: 100 μl/min 70% methanol+0.2% formic acid; UV: 200-400 nm.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([O:11][C:12]1[N:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]([NH2:29])[CH3:28])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)([CH3:10])[CH3:9].Cl[C:31]([O:33][CH3:34])=[O:32]>>[CH:8]([O:11][C:12]1[N:17]=[CH:16][C:15]([O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH:27]([NH:29][C:31](=[O:32])[O:33][CH3:34])[CH3:28])=[CH:23][CH:24]=2)=[CH:14][CH:13]=1)([CH3:10])[CH3:9]
Reactant: COC(=O)Cl
Reactant: CC(N)CCc1ccc(Oc2ccc(OC(C)C)nc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)NC(C)CCc1ccc(Oc2ccc(OC(C)C)nc2)cc1

Procedure:
3-[4-(6-Isopropoxypyridin-3-yloxy)phenyl]-1-methylpropylamine trifluoroacetate (115 mg, 0.28 mmol) was reacted with methyl chloroformate in analogy to example 44. Yield: 48 mg (48%), M+H+: 359.13.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:5]=[C:4](O)[CH:3]=1.P(Cl)(Cl)([Cl:19])=O.O>ClCCl>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:5]=[C:4]([Cl:19])[CH:3]=1
Reactant: Cc1cc(O)nc(Nc2ccc(F)cc2)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1cc(Cl)nc(Nc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
A reaction mixture of 6-methyl-4-hydroxy-2-(4-fluorophenylamino)pyrimidine (1.74 g, 7.93 mmol) and phosphorus oxychloride was stirred for 1 hour at a room temperature and then dissolved in dichloromethane. Water was added dropwise to the reaction mixture and stirred for 30 minutes. The separated organic layer was washed with 2N NaOH solution, dried over anhydrous magnesium sulfate, and then concentrated under a reduced pressure to give 1.57 g of the titled compound. (Yield 83.5%)
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[NH2:25])[CH2:12][CH2:11]2)=[N:2]1.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[NH:25][C:34]([NH:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[Cl:26])=[O:35])[CH2:12][CH2:11]2)=[N:2]1
Reactant: O=C=Nc1ccccc1Cl
Reactant: Nc1ccc(F)cc1CCN1CCN(c2nsc3ccccc23)CC1
Product: O=C(Nc1ccccc1Cl)Nc1ccc(F)cc1CCN1CCN(c2nsc3ccccc23)CC1
Yield: 58.8 %

Procedure:
Starting from 2-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-4-fluoro-phenylamine (142 mg, 0.4 mmol) and 2-chlorophenyl isocyanate (56 μL, 0.4 mmol) and following the procedure as outlined in Example 60, 120 mg of 1-{2-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-4-fluoro-phenyl}-3-(2-chloro-phenyl)-urea was isolated as an off white powder in 100% purity @ 254 nm; LCMS (APCI): 508 [M-2H]−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:8]=[CH:7]2
Reactant: Fc1cccc2cn[nH]c12
Reactant: CCOC(=O)CBr
Product: CCOC(=O)Cn1ncc2cccc(F)c21

Procedure:
The title compound was prepared according to the method described for Preparation 93 using 7-fluoro-1H-indazole and ethyl bromoacetate to afford the title compound as an off-white solid in 41% yield, 200 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:16])[C:9]#[C:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1.[N+:20](=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N-:21]>C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:16])[C:9]2[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:20][NH:21][C:10]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CCOC(=O)C#CC(O)c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: CCOCC
Product: CCOC(=O)c1n[nH]c(C(=O)OCC)c1C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 58.9 %

Procedure:
A solution of ethyl 4-(4-chloro-2-nitrophenyl)-4-hydroxy-2-butynoate (5.00 g, 17.7 mmol) and ethyl diazoacetate (2.75 g, 26.5 mmol) in diethyl ether (43.3 mL) was refluxed for 5 days. After cooling to room temperature the reaction mixture was chromatographed eluting with ethyl acetate:hexanes (20:80, 30:70, 40:60, and 50:50). All of the fractions containing the desired compound were combined, concentrated on the rotary evaporator, and the product was recrystallized twice from toluene (total volume 225 mL) to give the title compound as a white solid (4.15 g, 59%, mp 60° C.).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:18]=3)[CH2:9]2)[N:5]=[C:4]([NH2:25])[N:3]=1.[F:26][C:27]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[CH:31][C:28]=1[C:29]#[N:30].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[NH2:25][C:4]1[N:3]=[C:2]([C:33]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([F:26])[CH:34]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:18]=3)[CH2:9]2)[N:5]=1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
Reactant: Nc1nc(Cl)cc(N2CCOC(c3nc(-c4ccccc4)c[nH]3)C2)n1
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: O
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cc(N3CCOC(c4nc(-c5ccccc5)c[nH]4)C3)nc(N)n2)cc1F
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A mixture of crude 4-chloro-6-[2-(4-phenyl-1H-imidazol-2-yl)-4-morpholinyl]-2-pyrimidinamine, 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (765 mg, 3.10 mmol), Na2CO3 (631 mg, 5.96 mmol) and Pd(PPh3)4 (275 mg, 0.238 mmol) in 1,4-dioxane (6 mL) and water (2 mL) was heated at 140° C. under microwave conditions with stirring for 1.0 hour. The mixture was filtered, washed by EtOAc (150 mL), and concentrated to afford the crude title compound (1.3 g) as a yellow solid. This material was combined with another batch of crude title compound (100 mg). The combined material was washed by EtOAc (150 mL), and concentrated. The resulting residue was purified by silica gel chromatography using EtOAc in petroleum ether from 50% to 70% to afford the title compound (400 mg) as a light yellow solid. LC-MS (ES) m/z=442 [M+H]+.
Reaction SMILES: O=[C:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[CH2:5][C:4](=[O:15])[CH2:3]1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C1(C)C=CC=CC=1>O>[O:15]=[C:4]1[CH2:5][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[CH2:7][C:2]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:3]1
Reactant: C1CNCCN1
Reactant: O=C1CC(=O)CC(c2ccccc2Cl)C1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C=C(N2CCNCC2)CC(c2ccccc2Cl)C1

Procedure:
A mixture of 24.0 g (0.108 mol) of 1,3-dioxo-5-(o-chlorophenyl)-cyclohexane, 28.4 g (0.33 mol) of anhydrous piperazine and 270 ml of toluene is heated at the boiling point under reflux for 5 hours, using a water separator. The toluene is distilled off, while still warm, in vacuo and the residue is dissolved in chloroform. This solution is extracted three times by shaking with water, to remove the excess piperazine, and dried with sodium sulphate. The concentrated solution is purified by means of column chromatography (corresponding to Example 2). Some of the fractions contain 6.5 g of the base [3-oxo-5-(o-chlorophenyl)-1-cyclohexen-1-yl]-piperazine in pure form, of melting point 159°-160° C., and another portion is still contaminated. The latter is purified by the oxalate: 6.2 g of a white salt of melting point 225°-227° C. (decomposition). After converting back into the base, a further 5.0 g are obtained. Total yield: 11.5 g (=36.7%). RF value: 0.38 (conditions corresponding to Example 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][C:27]([NH2:29])=[NH:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:28]=[C:27]([NH:26][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[Cl:19])[N:29]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: N=C(N)Nc1ccccc1Cl
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Product: O=C1Cc2cnc(Nc3ccccc3Cl)nc2-c2ccc(Cl)cc2N1

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and 1-(2-chlorophenyl)guanidine were converted to I-12 (26%): HRMS Calcd. for C, H12Cl2N4O: 371.0466, Found 371.0467.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]([F:17])([F:16])[CH:13]([OH:15])[CH3:14].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:15][CH:13]([CH3:14])[C:12]([F:17])([F:16])[F:11])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Yield: 95.4 %

Procedure:
To a solution of 1-fluoro-4-nitro-benzene (4.24 g) and (rac)-1,1,1-trifluoro-propan-2-ol (4.563 g) in acetonitile (50 ml) under an argon atmosphere was added at RT Cs2CO3 (13.04 g) and the mixture was refluxed for 10 h. It was then acidified with diluted aqueous HCL and partitioned between ethyl acetate and water. The layers were separated, dried over Na2SO4 and the solvent was then evaporated off to give (rac)-1-nitro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzene as brown oil (6.74 g) that was used without further purification.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C[O:14][C:15](=[O:45])[CH2:16][C:17]1[CH:22]=[C:21]([Br:23])[C:20]([O:24][C:25]2[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[C:28]([OH:34])=[CH:27][C:26]=2[C:35](=[O:43])[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[CH:37]=2)=[C:19]([Br:44])[CH:18]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:65][C:66](=[CH2:70])[CH2:67][CH2:68]O>C(Cl)Cl>[Br:44][C:19]1[CH:18]=[C:17]([CH2:16][C:15]([OH:14])=[O:45])[CH:22]=[C:21]([Br:23])[C:20]=1[O:24][C:25]1[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[C:28]([O:34][CH2:68][CH2:67][C:66]([CH3:70])=[CH2:65])=[CH:27][C:26]=1[C:35](=[O:43])[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[CH:37]=1
Reactant: COC(=O)Cc1cc(Br)c(Oc2cc(C(C)C)c(O)cc2C(=O)c2cccc(C)c2)c(Br)c1
Reactant: C=C(C)CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=C(C)CCOc1cc(C(=O)c2cccc(C)c2)c(Oc2c(Br)cc(CC(=O)O)cc2Br)cc1C(C)C
Temperature: 40 °C

Procedure:
A solution of diethyl azodicarboxylate (42 mg, 0.24 mmol) in anhydrous CH2Cl2 (1 mL) was added over 15 min to an ice-cooled, stirred mixture of 3,5-dibromo-4-[4-hydroxy-5-isopropyl-2-(3-methylbenzoyl)phenoxy]phenylacetic acid methyl ester (70 mg, 0.12 mmol), PPh3 (63 mg, 0.24 mmol) and 3-methyl-3-buten-1-ol (24 μL, 0.24 mmol) in anhydrous CH2Cl2 (2 mL). The mixture was stirred at 0° C. for 12 h and 3 d at room temperature, and concentrated. The residue was dissolved in 30% NaOH/MeOH (2 mL) and heated at 40° C. for 12 h. The solution was allowed to cool, acidified with 1M HCl, concentrated and purified by HPLC to give the title compound. 1H NMR (CDCl3): δ 7.9–7.7 (m, 2H), 7.5 (s, 2H), 7.4–7.3 (m, 2H), 7.0(s, 1H), 6.3 (s, 1H), 4.8 (d, 2H), 4.1 (t, 2H), 3.6 (s, 2H), 3.3–3.2 (m, 1H), 2.5 (t, 2H), 2.4 (s, 3H), 1.8 (s, 3H), 1.1 (d, 6H). ESMS: m/z 629 (M−1).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][N:11]([CH:16]1[CH2:18][CH2:17]1)[CH2:10][C:9]2([CH3:20])[CH3:19])=O)C.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[CH:16]1([N:11]2[CH2:10][C:9]([CH3:19])([CH3:20])[C:8]3[C:13](=[CH:14][CH:15]=[C:6]([CH2:4][OH:3])[CH:7]=3)[CH2:12]2)[CH2:18][CH2:17]1
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CN(C1CC1)C2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CC1(C)CN(C2CC2)Cc2ccc(CO)cc21
Temperature: -20 °C
Yield: 87 %

Procedure:
A stirred cooled (−78° C.)solution of ethyl-2-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro isoquinoline-6-carboxylate (Intermediate 23, 1 g, 3.66 mmol) in anhydrous dichloromethane (20 mL) under argon was treated with a 1M solution of di-iso-butyl aluminum hydride in dichloromethane (10 mL) and the reaction mixture was warmed to −20° C. over 1 h. It was then quenched with saturated aqueous ammonium chloride solution and diluted with dichloromethane and filtered over a bed of celite. The phases were separated and the aqueous phase was extracted with dichloromethane (×1). The combined organic extract was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title compound as a viscous oil (0.74 g, 87%).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([CH3:22])[CH:21]=1>>[CH3:15][C:16]1[CH:17]=[C:18]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=[C:20]([CH3:22])[CH:21]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: Cc1cc(C)cc(B(O)O)c1
Product: Cc1cc(C)cc(-c2nnc(N)nc2-c2ccccc2)c1
Yield: 65.4 %

Procedure:
6-(3,5-Dimethylphenyl)-5-phenyl-1,2,4-triazin-3-amine (54 mg, 65%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol) and 3,5-dimethylphenylboronic acid (51.5 mg, 0.344 mmol) according to the general procedure of Example 1.
Reaction SMILES: P(Cl)(Cl)[Cl:2].[CH2:5](O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15]>>[CH2:5]([Cl:2])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: ClP(Cl)Cl
Reactant: CC(C)CCCCCCCCCO
Product: CC(C)CCCCCCCCCCl
Reaction time: 3 h
Yield: 256.7 %

Procedure:
To a 1-gallon glass-line pressure reactor was charged 715 grams of phosphorus trichloride (PCl3, 5.2 moles). To the reactor was charged 2790 grams of isododecyl alcohol (Exxal 12, 15.0 moles) via an addition pump over a period of one hour while maintaining the reaction temperature below 100° C. After addition, the mixture was stirred at 130°-135° C. for 3 hours and cooled. The top organic layer was collected, yielding 2733 grams (94.5%) of isododecyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.O.O.[Sn](Cl)Cl>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ncc(Br)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
To a solution of 5-bromo-2-(methyloxy)-3-nitropyridine (45 g, 193 mmol) in ethyl acetate (1 L) was added tin(II) chloride dihydrate (174 g, 772 mmol). The reaction mixture was heated at reflux for 4 h. LC/MS indicated some starting material remained, so added 20 mol % tin (II) chloride dihydrate and continued to heat at reflux. After 2 h, the reaction was allowed to cool to ambient temperature and concentrated in vacuo. The residue was treated with 2 N sodium hydroxide and the mixture stirred for 1 h. The mixture was then with methylene chloride (1 L), filtered through Celite, and washed with methylene chloride (500 mL). The layers were separated and the organics dried over magnesium sulfate and concentrated to give 5-bromo-2-(methyloxy)-3-pyridinamine (23 g, 113 mmol, 58.7% yield). The product was used crude in subsequent reactions. MS (ES)+ m/e 201.9, 203.9 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][NH:17][CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.CCN(CC)CC.Br[CH:31]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:32]([O:34][CH2:35][CH3:36])=[O:33].C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([CH:31]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:21][CH:22]=1
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CNCC4)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(c1ccccc1)N1CCc2c(cnc3c2cnn3Cc2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.1 %

Procedure:
To a solution of 3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine (0.506 g, 1.72 mmol) in dichloromethane (10 mL) and Et3N (0.72 mL, 5.16 mmol) was added ethyl 2-bromo-2-phenylacetate (0.41 mL, 1.89 mmol). The reaction mixture was stirred at room temperature for 16 hours followed by addition of aqueous NaHCO3 (30 mL). The reaction was extracted with EtOAc (60 mL) and the organic layer was then washed with brine (30 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified using flash column chromatography (SiO2, 50% EtOAc in hexanes) to give the desired product, ethyl 2-(3-(4-methoxybenzyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7(6H)-yl)-2-phenylacetate as a yellow solid (0.134 g, 86%). 400 MHz 1H NMR (DMSO-d6) δ 8.25 (s, 1H), 8.10 (s, 1H), 7.5-7.34 (m, 5H), 7.19-7.4 (m, 2H), 6.86-6.8 (m, 2H), 5.76 (s, 1H), 5.56 (s, 2H), 4.46 (s, 1H), 4.13 (q, J=7.2 hz, 2H), 3.76 (s, 2H), 3.69 (s, 3H), 3.05 (t, J=6 hz, 2H), 2.88-2.72 (m, 2H), 1.64 (t, J=7.2 Hz, 3H); LCMS [M+H]:457.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[C:15]([O:22][CH3:23])[C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)[N:11]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[C:19]3[C:14](=[C:15]([O:22][CH3:23])[C:16]([O:20][CH3:21])=[CH:17][CH:18]=3)[CH:13]=[C:12]([NH:24][C:25]3[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1OC
Product: COc1ccc2c(Oc3ccc(Cl)cc3)nc(Nc3cc(C)[nH]n3)cc2c1OC

Procedure:
Similar procedure as described in example 10 was used, starting from 4-chloro-phenol and (1-Chloro-5,6-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-chloro-phenoxy)-5,6-dimethoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 411 (MH+).