Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]=2CNC2C=CC=CC=2)O1.Br[C:29]1[N:34]=[C:33]([C:35]([NH:38][C:39]2[C:44]([CH:45]([CH3:47])[CH3:46])=[CH:43][CH:42]=[CH:41][C:40]=2[CH:48]([CH3:50])[CH3:49])([CH3:37])[CH3:36])[CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].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.C1(C)C=CC=CC=1.CO>[NH:38]([CH2:35][C:10]1[CH:11]=[CH:12][C:17]2[C:18](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:9]=1[C:29]1[N:34]=[C:33]([C:35]([NH:38][C:39]2[C:44]([CH:45]([CH3:47])[CH3:46])=[CH:43][CH:42]=[CH:41][C:40]=2[CH:48]([CH3:50])[CH3:49])([CH3:37])[CH3:36])[CH:32]=[CH:31][CH:30]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC1(C)OB(c2c(CNc3ccccc3)ccc3ccccc23)OC1(C)C
Reactant: CC(C)c1cccc(C(C)C)c1NC(C)(C)c1cccc(Br)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: Cc1ccccc1
Solvent: CO
Product: CC(C)c1cccc(C(C)C)c1NC(C)(C)c1cccc(-c2c(CNc3ccccc3)ccc3ccccc23)n1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 2.02 g (5.64 mmol) of N-{[1-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthyl]methyl}-aniline, 2.11 g (5.64 mmol) of N-[1-(6-bromopyridin-2-yl)-1-methylethyl]-2,6-diisopropylaniline, 4.03 g (14.10 mmol) of Na2CO3×10H2O, 63 ml of water, 18 ml of methanol, and 76 ml of toluene was purged with argon for 30 min. To the obtained solution 0.32 g (0.28 mmol) of Pd(PPh3)4 was added. In argon atmosphere, this mixture was stirred for 12 h at 80° C. Then, it was cooled to room temperature, the organic layer was separated, the aqueous layer was extracted with 3×200 ml of ethyl acetate. The combined organic extract was washed with brine, dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel 60 (40-63 um, eluent: dichloromethane-ethyl acetate=20:1, vol.). Yield 1.56 g (52%) of yellow oil. Anal. calc. for C37H41N3: C, 84.21; H, 7.83; N, 7.96. Found: C, 84.37; H, 7.95; N, 7.84. 1H NMR (CDCl3): δ 7.89 (d, J=8.4 Hz, 1H, 4-H in naphtalene), 7.88 (m, 1H, 8-H in naphthalene), 7.82 (t, J=7.8 Hz, 1H, 4-H in pyridine), 7.67 (d, J=8.4 Hz, 1H, 3-H in naphtalene), 7.63 (dd, J=7.8 Hz, J=0.8 Hz, 1H, 5-H in pyridine), 7.44-7.49 (m, 2H, 5, 7-H in naphtalene), 7.37-7.41 (m, 1H, 6-H in naphtalene), 7.31 (dd, J=7.8 Hz, J=0.8 Hz, 1H, 3-H in pyridine), 7.11 (m, 2H, 3, 5-H in Ph), 7.02-7.06 (m, 3H, 3, 4, 5-H in 2, 6-iPr2C6H3), 6.65 (m, 1H, 4-H in Ph), 6.60 (m, 2H, 2.6-H in Ph), 4.17-4.27 (m, 4H, CH2NH and NHCMe2), 3.20 (sep, J=6.8 Hz, 2H, CHMe2), 1.54 (s, 3H, CMeMe′), 1.40 (s, 3H, CMeMe′), 1.02 (t, J=6.8 Hz, 12H, CHMe2).
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:19]([C:21]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:23][CH:22]=3)=[O:20])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:31]=[C:30]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=[C:21]1[C:19]([NH:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH2:9][NH:8]2)=[CH:13][CH:14]=1)=[O:20]
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(NC(=O)c3c[nH]c4ccccc4c3=O)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2c(c1)NCCC2)c1c[nH]c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
A mixture of 7-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1,2,3,4-tetrahydroquinoline-1-carboxylic acid tert-butyl ester (183) (23 mg, 0.05 mmol), TFA (1 mL) and CH2Cl2 (1 mL) was stirred at room temperature overnight. The solution was concentrated and the residue was dissolved in DMSO (1 mL) and purified by HPLC (10-99% CH3CN—H2O) to yield the product, 4-oxo-N-(1,2,3,4-tetrahydroquinolin-7-yl)-1H-quinoline-3-carboxamide (299) (7 mg, 32%). HPLC ret. time 2.18 min, 10-99% CH3CN, 5 min run; ESI-MS 320.3 m/z (MH+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@@H:21]1[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Cu]I>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@@H:21]1[CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([O:12][C:9]2[CH:10]=[CH:11][C:6]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[CH:7][CH:8]=2)=[CH:31][CH:32]=1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(I)cc1
Reactant: Oc1ccc(-c2nccs2)cc1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2ccc(-c3nccs3)cc2)cc1
Yield: 51.3 %

Procedure:
A mixture of the product of step 2 (0.1 g, 0.56 mmol), the product of Example 130, step 2 (0.30 g, 0.73 mmol), N,N-dimethylglycine HCl salt (0.20 g, 1.46 mmol), copper(I) iodide (0.19 g, 1.01 mmol) and cesium carbonate (0.28 g, 0.85 mmol) in dioxane (2 ml) was heated 100° C. for 60 h under nitrogen. The solids were filtered off, and the filtrate was concentrated in vacuo. The residue was purified by a column chromatography on silica gel eluting with 25% EtOAc/hexanes to yield the title product (130 mg, 69%); 1HNMR (400 MHz, CDCl3) δ 7.88 (d, J=8.4 Hz, 2H), 7.84 (d, J=3.2 Hz, 1H), 7.30 (d, J=3.2 Hz, 1H), 7.24 (d, J=8.4 Hz, 2H), 7.10 (d, J=8 Hz, 2H), 6.86 (br d, J=8 Hz, 2H), 4.10 (br, 2H), 3.96 (s, 2H), 3.40 (br, 2H), 2.03-1.80 (m, 4H), 1.46 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]3[O:17][CH2:16]3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:19][CH:20]1[C:28]2[C:23](=[C:24]([CH3:31])[CH:25]=[C:26]([CH3:30])[C:27]=2[OH:29])[CH2:22][C:21]1([CH3:33])[CH3:32].C(=O)(O)[O-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH:15]([OH:17])[CH2:16][NH:19][CH:20]3[C:28]4[C:23](=[C:24]([CH3:31])[CH:25]=[C:26]([CH3:30])[C:27]=4[OH:29])[CH2:22][C:21]3([CH3:33])[CH3:32])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C)c2c(c1O)C(N)C(C)(C)C2
Reactant: Clc1cccc(N2CCN(CC3CO3)CC2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C)c2c(c1O)C(NCC(O)CN1CCN(c3cccc(Cl)c3)CC1)C(C)(C)C2

Procedure:
0.21 Gram of 4-(3-chlorophenyl)-1-(2,3epoxypropyl)piperazine was added to a solution containing 0.21 g of 1-amino-2,3-dihydro-7-hydroxy-2,2,4,6-tetra- methyl-1H-indene hydrochloride in 10 ml of ethanol solution, and the mixture was refluxed for 5 hours. After the reaction was completed, the reaction mixture was concentrated by removing the solvent under a reduced pressure, the residue thus obtained was alkalified with 10%-sodium bicarbonate aqueous solution, then extracted with 100 ml of methylene chloride. The extract was washed three times with 100 ml of water each time, then dried with anhydrous magnesium sulfate. The methylene chloride extract was concentrated by removing the solvent under a reduced pressure, and the residue was purified by a silica gel column chromatography (eluent: ethyl acetate : n-hexane=1 : 1) to obtain 0.21 g of 1-{3-[4-(3-chlorophenyl)-1-piperazinyl]-2-hydroxypropylamino}-2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-indene.
Reaction SMILES: [CH3:1][CH2:2][CH2:3]Br.[I:5][C:6]1[C:7]([OH:16])=[C:8]([O:14][CH3:15])[CH:9]=[C:10]([CH:13]=1)[CH:11]=[O:12].C(=O)([O-])[O-].[K+].[K+].CCCCCC.C(OCC)(=O)C>CN(C=O)C>[I:5][C:6]1[C:7]([O:16][CH2:1][CH2:2][CH3:3])=[C:8]([O:14][CH3:15])[CH:9]=[C:10]([CH:13]=1)[CH:11]=[O:12]
Reactant: COc1cc(C=O)cc(I)c1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCOc1c(I)cc(C=O)cc1OC

Procedure:
n-Propyl bromide (29.2 mL, 0.32 mol) was added to a solution of 5-iodovanillin (50.0 g, 0.18 mol) in DMF (200 mL) containing potassium carbonate (48 g, 0.35 mol) at 80° C. The mixture was stirred at 80° C. for 1-1.5 hours or until TLC (SiO2, 4:1 [v/v] hexane-ethyl acetate) showed the reaction to be complete. The mixture was cooled and the solvent was decanted into ice-water (1 L). The product was extracted with ether and the ethereal layer was washed with water, dried over sodium sulfate, and evaporated in vacuo to an oil, which was used without further purification. Anal. calc. for C11H15IO3 : C, 41.27; H, 4.09. Found: C, 41.59; H, 4.15.
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Na].Cl[C:20]1[N:25]=[C:24](Cl)[C:23]([F:27])=[CH:22][N:21]=1>CCOCC>[CH2:1]([O:17][C:20]1[N:25]=[C:24]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:23]([F:27])=[CH:22][N:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: Fc1cnc(Cl)nc1Cl
Agent: [Na]
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCOc1ncc(F)c(OCCCCCCCCCCCCCCCC)n1
Yield: 63.1 %

Procedure:
A 36.3 g quantity of n-hexadecanol is dissolved in 200 ml of absolute ether, 3.3 g of metal sodium is added to the solution and the mixture is refluxed until the sodium has been completely dissolved. Subsequently 8.5 g of 2,4-dichloro-5-fluoropyrimidine is added to the solution, and the mixture is refluxed for 3 hours. The resulting reaction mixture is washed with a small amount of water, and the ethereal layer is concentrated to separate out crystals, which are recrystallized from ethanol to give 18.6 g of white crystalline 2,4-di(n-hexadecyloxy)-5-fluoropyrimidine in a yield of 63.1%, m.p. 62°-63° C.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]2[CH2:8][CH:9]3[N:14]([C:15](=O)[C:6]=2[CH:5]=1)[CH2:13][CH2:12][CH2:11][CH2:10]3)([O-:3])=[O:2].B.[ClH:20]>C1COCC1.C(O)C>[ClH:20].[N+:1]([C:4]1[CH:18]=[CH:17][C:7]2[CH2:8][CH:9]3[N:14]([CH2:15][C:6]=2[CH:5]=1)[CH2:13][CH2:12][CH2:11][CH2:10]3)([O-:3])=[O:2]
Reactant: O=C1c2cc([N+](=O)[O-])ccc2CC2CCCCN12
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: O=[N+]([O-])c1ccc2c(c1)CN1CCCCC1C2
Temperature: 25 °C
Yield: 70 %

Procedure:
To a solution of 8-nitro-1,3,4,6,11,11a-hexahydro-2H-benzo[b]quinolizin-6-one (4.18 g, 17.0 mmol) in anhydrous THF (50 ml) was added 1.0M borane i THF (50 ml). The reaction mixture was heated at reflux for 18 h. After cooling to room temperature, the excess borane was quenched by the addition of methanol and 6M hydrochloric acid (6 ml) and the solution was heated for 2 h. The solvent was removed in vacuo and the residue was taken up in water. The resulting solution was basified with sodium hydroxide and extracted twice with dichloromethane. The dried (magnesium sulfate) organic phase was concentrated to give an oil which was immediately taken up in ethanol (60 ml). Hydrochloric acid in ethanol was added until the solution was distinctly acidic and the solution was stirred for several hours at ambient temperature. The precipitate was collected, washed with ethanol, and air-dried to give the title compound as a white solid (3.03 g, 70%), m.p. 245-7° C. (dec.).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]1[C:21]([NH2:22])=[CH:20][CH:19]=[C:18]([O:23][CH3:24])[N:17]=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>ClC(Cl)C>[NH2:15][C:16]1[C:21]([NH:22][CH:35]2[CH2:36][CH2:37][N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:33][CH2:34]2)=[CH:20][CH:19]=[C:18]([O:23][CH3:24])[N:17]=1
Reactant: COc1ccc(N)c(N)n1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)n1
Reaction time: 8 h

Procedure:
Sodium triacetoxyborohydride (3.39 g, 16.0 mmol) was added to a solution of 2,3-diamino-6-methoxypyridine (2.23 g, 16.0 mmol) and N-(t-butoxycarbonyl)-4-piperidone (7.66 g, 38.4 mmol) in dichloroethane (50 mL) at room temperature. The reaction was quenched with water (50 mL) and stirred overnight, then extracted with chloroform and washed with 5% aqueous sodium hydroxide, water and saturated sodium chloride solution. After drying over sodium sulfate, the solution was filtered and evaporated to give the crude product. This was purified by chromatography, where the more polar product was isolated (silica gel, 50% ethyl acetate hexane, Rf=0.36), to give the title compound. MS 323 (M+1). 1H NMR (500 MHz, CDCl3) δ 7.99 (d, J=8 Hz, 1H), 6.05 (d, J=8 Hz, 1H), 4.45 (br s), 4.03 (br s), 3.83 (s, 3H), 3.15 (m, 1H), 2.86 (m, 2H), 1.91 (d, J=12 Hz, 2H), 1.5 (br s, 11H), 1.26 (br s, 2H).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH:12]([N:14]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:29](=[O:38])[C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[CH:31]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:11][CH2:10][N:9]1[C:29](=[O:38])[C:30]1[CH:31]=[C:32]([Cl:37])[CH:33]=[C:34]([Cl:36])[CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)N1CCC(N(CCc2ccccc2)C(=O)C(F)(F)F)CC1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C(c1cc(Cl)cc(Cl)c1)N1CC[C@H](NCCc2ccccc2)C[C@H]1Cc1ccccc1

Procedure:
0.130 g (0.231 mmol) of (2R*,45*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(2-phenylethyl)-N-trifluoroacetyl-4-piperidinamine is reacted with 0.035 g (0.923 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR81## is obtained (0.101 g, 94%) as oil. TLC:methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.34, FD-MS:M+ =466, 468.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][C:6]=2[CH:7]=1>[Pd].C(O)C>[F:15][C:2]([F:1])([F:14])[CH:3]1[CH2:7][C:6]2[CH:8]=[C:9]([CH2:12][OH:13])[CH:10]=[CH:11][C:5]=2[O:4]1
Reactant: OCc1ccc2oc(C(F)(F)F)cc2c1
Agent: [Pd]
Solvent: CCO
Product: OCc1ccc2c(c1)CC(C(F)(F)F)O2
Yield: 52.4 %

Procedure:
To an ethanol solution (1.0 mL) of [2-(trifluoromethyl)benzofuran-5-yl]methanol (30.0 mg, 0.139 mmol) synthesized in Reference Synthesis Example 96, palladium-activated carbon (15.0 mg) was added and the resultant solution was stirred under hydrogen atmosphere at room temperature for 30 hours. After completion of the reaction, the reaction solution was filtered with Celite and the filtrate was concentrated under reduced pressure to obtain a crude product of the title compound (15.9 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[O:16][CH2:15][CH2:14][O:13][C:5]2=[C:6]2[C:11]=1[NH:10][CH:9]=[CH:8][C:7]2=[O:12].[OH-].[Na+]>O.O1CCOCC1.[Pd]>[O:13]1[C:5]2=[C:6]3[C:11](=[CH:2][CH:3]=[C:4]2[O:16][CH2:15][CH2:14]1)[NH:10][CH:9]=[CH:8][C:7]3=[O:12]
Reactant: O=c1cc[nH]c2c(Br)cc3c(c12)OCCO3
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=c1cc[nH]c2ccc3c(c12)OCCO3
Reaction time: 8 h
Yield: 114.8 %

Procedure:
A suspension of 6-bromo-2,3-dihydro-7H-[1,4]dioxino[2,3-f]quinolin-10-one (3.4 g, 12 mmol) in water/dioxane (150 mL/80 mL) was treated with 1M aqueous sodium hydroxide solution then hydrogenated over 10% palladium on charcoal (1.5 g) for 20 hours. The mixture was filtered then acidified with 5M aqueous hydrochloric acid. On concentrating to ca 100 mL, a solid began to crystallise out. The mixture was stored at 5° C. overnight. Filtration and drying afforded a pale yellow solid (2.8 g, 100%). LC/MS (ES) m/z 203 (MH+ 92%); 1H-NMR (400 MHz, d6-DMSO), 11.4 (1H, s, NH), 7.64 (1H, d, J=7.2, CHNHC), 7.15 (1H, d, J=9.2, CHCO), 6.95 (1H, d, J=8.8, CHCN), 5.80 (1H, d, J=7.2, CH═CO), 4.26-4.27 (4H, m, 2×(CH2O)).
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(CN)O.Cl>O>[CH:8](=[C:7]1[NH:1][C:2](=[O:3])[NH:4][C:5]1=[O:6])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CNC(=O)N1
Agent: Cl
Solvent: NCCO
Solvent: O
Product: O=C1NC(=O)C(=Cc2ccccc2)N1
Temperature: 90 °C
Reaction time: 4 h
Yield: 89.8 %

Procedure:
50 g (0.5 mole) of hydantoin, 55 g (52 ml, 0.52 mole) of benzaldehyde and 46 g (45 ml, 0.7 mole of ethanol amine are admixed in 500 ml of water at 70° C. The temperature is raised to 90° C. and the reaction mixture is stirred for 4 hours. The solution is cooled and acidified with concentrated hydrochloric acid (pH 3-4). The mixture is allowed to stand at 10° C. for an hour, the product is filtered off, washed with cold water and dried. Thus 84.5 g of the desired compound are obtained, yield 89%. Mp.: 220°-222° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:11][O:12][C:13]1[CH:34]=[CH:33][C:16]([CH2:17][C:18]2[O:19][C:20]3[C:27]([Cl:28])=[CH:26][C:25]([CH2:29][CH2:30][CH3:31])=[C:24]([OH:32])[C:21]=3[C:22]=2[CH3:23])=[CH:15][CH:14]=1.CC[O:37]CC>>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([C:18]2[O:19][C:20]3[C:27]([Cl:28])=[CH:26][C:25]([CH2:29][CH2:30][CH3:31])=[C:24]([OH:32])[C:21]=3[C:22]=2[CH3:23])=[O:37])=[CH:33][CH:34]=1
Reactant: CCCc1cc(Cl)c2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Reactant: CCOCC
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Product: CCCc1cc(Cl)c2oc(C(=O)c3ccc(OC)cc3)c(C)c2c1O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
To an ice cold suspension of aluminium chloride (467 mg, 3.5 mmoles) in ether (100 mL) was added slowly lithium aluminium hydride (570 mg, 15 mmoles). After stirring for a period of 10 minutes, 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (491 mg, 1 mmole) in ether (10 mL) was added over a period of 2 minutes. The reaction mixture was stirred at room temperature for 10 minutes. It was cooled with an ice bath and ice was added slowly. When the vigorous reaction subsided, the organic layer was separated and the aqueous phase was extracted with ether. The organic phases were combined, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed on silica gel and eluted with 10% ethyl acetate in hexane to yield 0.30 gm (87%) of 2-(p-methoxybenzoyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran, mp. 103°-105° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]([O:23]C)=[O:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]([OH:23])=[O:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Solvent: C1CCOC1
Product: O=C(O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 52.3 %

Procedure:
To a suspension of the methyl 1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine-6-carboxylate (200 mg, 0.624 mmol) in THF (40 ml) cooled to 5° C. with ice bath was added potassium trimethylsilanoate (80.1 mg, 0.62 mmol). After stirring for 20 mins at 5° C., the reaction mixture was concentrated. The resulting residue was dissolved in 7 ml of DMAC and purified via reversed phase column eluted with 5-75% 0.1% TFA H2O and 0.1% TFA ACN to afford the desired product (100 mg, 66%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=2[F:24])=[C:10]([N:25]([CH3:27])[CH3:26])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=2[F:24])=[C:10]([N:25]([CH3:26])[CH3:27])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1-c1cccc(F)c1F
Agent: Cl[Sn]Cl
Solvent: O
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1-c1cccc(F)c1F

Procedure:
The title compound was prepared from (2-dimethylamino-2′,3′-difluoro-5-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example D1) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as an orange solid (2.206 g).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[N:11]=2)=[CH:6][CH:5]=1.C1COCC1.CO.[OH-].[Na+].Cl>O>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][N:12]1[C:13](=[O:16])[CH:14]=[CH:15][C:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:22])=[O:2])=[CH:9][CH:8]=2)=[N:11]1
Reactant: COC(=O)c1ccc(-c2ccc(=O)n(CCN(C)C)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CN(C)CCn1nc(-c2ccc(C(=O)O)cc2)ccc1=O
Reaction time: 1.5 h
Yield: 94.2 %

Procedure:
To a solution of 4-[1-(2-dimethylamino-ethyl)-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzoic acid methyl ester (542 mg, 1.8 mmol, reference example 62a) in 1:1 THF/methanol (6 mL) is added 10N NaOH (1.8 mL, 18 mmol) followed by H2O (0.5 mL). The resulting solution is stirred for 1.5 hours then cooled to 0°-5° C., adjusted to pH 6 with 2N HCl and concentrated. The residue is purified by reverse phase HPLC (eluting with 15%-40% acetonitrile(0.1%TFA)/H2O(0.1%TFA) over 20 min) to give 487 mg of title compound. 1H NMR (DMSO) δ 2.89 (s, 6H), 3.59 (m, 2H), 4.52 (bt, 2H), 7.14 (d, J=10 Hz, 1H), 8.04 (s, 4H), 8.16 (d, J=10 Hz, 1H), 9.63 (bs, 1H). MS (ion spray) m/z 288 (M+H)+.
Reaction SMILES: BrC1C(NC2C=C(OC(C)C)NN=2)=NC(N[C@H:9]([C:11]2[N:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=2)[CH3:10])=NC=1.C1C[O:31]CC1.C[Mg+].[Br-]>CCOCC>[F:17][C:14]1[CH:13]=[N:12][C:11]([C:9](=[O:31])[CH3:10])=[N:16][CH:15]=1
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ncc2Br)n[nH]1
Reactant: C1CCOC1
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: CC(=O)c1ncc(F)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A round-bottom-flask containing 5-fluoropyrimidine-2-carbonitrile (Method 6, 1.50 g, 12.19 mmol) was charged with anhydrous THF (30 ml) under N2. The solution was cooled to 0° C., and a solution of MeMgBr (4.90 ml of a 3.0 M solution in ether, 14.62 mmol) was added dropwise. After 2 hours at 0° C., the reaction mixture was quenched with ice water and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, and evaporated to dryness to give the title compound as an oil (0.778 g, yield 46%). GC-MS, 140 (M); 1H NMR (CDCl3) δ 8.65 (s, 2H), 2.65 (s, 2H).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][N:15]=1>>[CH3:12][O:13][C:14]1[N:15]=[CH:16][C:17]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH2:11])[N:10]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:19]=1
Reactant: Nc1nc2c(Br)cccn2n1
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2cccn3nc(N)nc23)cn1

Procedure:
8-(6-Methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (1.0 g, 4.7 mmol) and 2-methoxypyridine-5-boronic acid (1.0 g, 6.6 mmol) in a manner analogous to Step 2c. The product of the reaction was isolated as a tan solid (0.58 g, 51%). MP=157-158° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.91 (d, J=2.5 Hz, 1H), 8.54 (dd, J=6.6, 0.9 Hz, 1H), 8.44 (dd, J=8.7, 2.5 Hz, 1H), 7.73 (dd, J=7.6, 1.0 Hz, 1H), 6.97 (t, J=6.9 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 6.12 (s, 2H), 3.92 (s, 3H). MS=242 (MH)+. 8b) [8-(6-Methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-morpholin-4-yl-phenyl)-amine and phenyl-(8-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine were prepared from 8-(6-methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (100.0 mg, 0.4145 mmol) and 4-(4-bromo-phenyl)-morpholine (120.0 mg, 0.4956 mmol) in analogous manner to Example 2d. [8-(6-Methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-morpholin-4-yl-phenyl)-amine was isolated as a yellow solid (0.037 g, 22%). MP=200-202° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.75 (d, J=2.3 Hz, 1H), 8.39 (d, J=6.3 Hz, 1H), 8.29 (dd, J=8.8, 2.6 Hz, 1H), 7.54-7.48 (m, 3H), 7.00-6.87 (m, 4H), 6.67 (s, 1H), 4.01 (s, 3H), 3.90-3.85 (m, 4H), 3.13-3.09 (m, 4H). MS=403 (MH)+.