Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[C:22]([F:30])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH3:2].[CH3:31][N:32]1[C:36]([NH2:37])=[CH:35][C:34]([C:38]([CH3:44])([CH3:43])[C:39]([F:42])([F:41])[F:40])=[N:33]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CC(=O)OCC>N1C=CC=CC=1.O.C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:37][C:36]3[N:32]([CH3:31])[N:33]=[C:34]([C:38]([CH3:44])([CH3:43])[C:39]([F:41])([F:40])[F:42])[CH:35]=3)=[O:28])=[C:22]([F:30])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[CH3:2]
Reactant: Cn1nc(C(C)(C)C(F)(F)F)cc1N
Reactant: CCOc1cc(-c2ccc(CC(=O)O)c(F)c2)cnc1OCc1ccc(OC)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(C(C)(C)C(F)(F)F)nn3C)c(F)c2)cnc1OCc1ccc(OC)cc1
Reaction time: 2 h
Yield: 61.6 %

Procedure:
To a mixture of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (150 mg, 0.365 mmol), 1-methyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-amine (83 mg, 0.401 mmol) in pyridine (3 mL) was added T3P® (EA solvate) (0.3 mL, 0.365 mmol) at 25° C. Then the mixture was stirred for 2 h, the mixture was concentrated to give the residue which was distributed between DCM (20 mL) and H2O (10 mL) and extracted with DCM (20 mL×2). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to yield a white solid of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(1-methyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-yl)acetamide (150 mg, 0.225 mmol, 61.7% yield): 1H NMR (400 MHz, CD3OD) δ 8.52 (d, J=4.4 Hz, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.44-7.41 (m, 3H), 7.39 (d, J=8.8 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 6.27 (s, 1H), 5.35 (s, 2H), 4.13 (q, J=7.1 Hz, 2H), 3.83 (s, 2H), 3.78 (s, 3H), 3.72-3.67 (m, 3H), 1.47 (s, 6H), 1.41 (t, J=7.0 Hz, 3H). ES-LCMS m/z 601 (M+H).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:19][CH2:20][CH:21]([OH:23])[CH3:22]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:16][O:15][C:13]([C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:19]([CH2:20][CH:21]([OH:23])[CH3:22])[C:5]=32)=[CH:10][CH:9]=1)=[O:14]
Reactant: COC(=O)c1ccc2c(c1)C(=O)C(CC=O)C2
Reactant: CC(O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)-c1c(ccn1CC(C)O)C2
Reaction time: 0.75 h
Yield: 81.2 %

Procedure:
A solution of 2.32 g of (RS)-2-(2-oxoethyl)-6-methoxycarbonyl-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 2.2 g (81%) of (RS)-1-(7-methoxycarbonyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)[C:3]=1[C:17]#[N:18].C(O[CH:22](OCC)[N:23]([CH3:25])[CH3:24])C>C1(C)C=CC=CC=1>[C:17]([C:3]1[C:4]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH3:16])=[CH:12][CH:13]=2)=[N:5][NH:6][C:2]=1[N:1]=[CH:22][N:23]([CH3:25])[CH3:24])#[N:18]
Reactant: CCOC(OCC)N(C)C
Reactant: CCOc1ccc(Nc2n[nH]c(N)c2C#N)cc1
Solvent: Cc1ccccc1
Product: CCOc1ccc(Nc2n[nH]c(N=CN(C)C)c2C#N)cc1
Temperature: 20 °C

Procedure:
A suspension of 4.86 g (19.98 mmol) of 5-amino-4-cyano-3-(4-ethoxy-phenylamino)-pyrazole in 3.94 ml (23 mmol) of N,N-dimethylformamide diethyl acetal and 60 ml of toluene is heated under reflux for 2 hours. The reaction mixture is then cooled to 20° C. and filtered and the filter residue is washed with toluene, yielding the title compound; m.p. 246-247° C. (decomp.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:29]([CH3:32])([CH3:31])[OH:30])[CH:5]=[C:6]([O:27][CH3:28])[C:7]=1[O:8][C:9]1[C:14]([N+:15]([O-])=O)=[C:13]([NH:18][CH:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])[N:12]=[C:11]([CH3:26])[N:10]=1>C(O)C.[Pt]>[Br:1][C:2]1[CH:3]=[C:4]([C:29]([CH3:32])([CH3:31])[OH:30])[CH:5]=[C:6]([O:27][CH3:28])[C:7]=1[O:8][C:9]1[C:14]([NH2:15])=[C:13]([NH:18][CH:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])[N:12]=[C:11]([CH3:26])[N:10]=1
Reactant: CCCC(CCC)Nc1nc(C)nc(Oc2c(Br)cc(C(C)(C)O)cc2OC)c1[N+](=O)[O-]
Agent: [Pt]
Solvent: CCO
Product: CCCC(CCC)Nc1nc(C)nc(Oc2c(Br)cc(C(C)(C)O)cc2OC)c1N
Reaction time: 18 h

Procedure:
Platinum black, (5%,0.25 g) was added to a solution of 3-bromo-5-methoxy-α,α-dimethyl-4-[[2-methyl-5-nitro-6-[(1-propyl-butyl)amino]-4-pyrimidinyl]oxy]benzenemethanol (0.80 g) in 50 mL of ethanol. The mixture was hydrogenated at a pressure of 41 psi for 18 hours. The mixture was filtered through celite and the filtrate was stripped under reduced pressure. The residue was taken up in 1N NaOH and extracted with methylene chloride. The combined methylene chloride extracts were dried over MgSO4 and the filtrate was stripped under reduced pressure to yield the title compound, mp 114-116° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:11]([CH3:12])=[C:10]([CH3:13])[S:9][C:4]=2[NH:5][C:6](=[S:8])[N:7]=1.CCN(CC)CC.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C.CCOC(C)=O>[CH3:12][C:11]1[C:3]2[C:2]([NH:1][C:22](=[O:23])[O:24][CH2:25][CH3:26])=[N:7][C:6](=[S:8])[NH:5][C:4]=2[S:9][C:10]=1[CH3:13]
Reactant: Cc1sc2[nH]c(=S)nc(N)c2c1C
Reactant: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)Nc1nc(=S)[nH]c2sc(C)c(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
To a suspension of 4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-thione (211 mg, 1 mmol) in DMF (5 mL) was added Et3N (0.21 mL, 1.5 mmol) and ethyl chloroformate (0.143 mL, 1.5 mmol). The reaction mixture was stirred at room temperature overnight, then diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered and evaporated. The residue was purified on Biotage SP-1 eluting with EtOAc/hexane to give the title compound (154 mg, 54%). 1H NMR (400 MHz, DMSO-d6) δ 1.22 (t, J=7.2 Hz, 3H), 2.38 (s, 3H), 2.39 (s, 3H), 4.25 (q, J=7.2 Hz, 2H), 7.25-7.21 (m, 2H). MS 284 (MH+).
Reaction SMILES: C([Li])CCC.[CH2:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:7].[CH:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[C:15]1([CH:14]([OH:21])[CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH3:7])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCc1ccccn1
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(c1ccccn1)C(O)c1ccccc1
Temperature: -60 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
n-Butyllithium (2.5 M, 15.0 mL, 36.0 mmol) is added drop wise to a solution of 2-ethylpyridine (4.1 mL, 36.0 mmol) in THF (56 mL) at −40° C. The resulting dark red solution is kept at −30° C. to −20° C. for 1 hour and then cooled to −60° C. A solution of benzaldehyde (3.7 mL, 36.0 mmol) in THF (10 mL) is added drop wise. The reaction mixture is allowed to warm up to 0° C. for 1 hour and then quenched with aqueous NH4Cl solution. The mixture is separated and the aqueous phase is extracted with ethyl acetate (2×50 mL). The extracts are combined, dried, concentrated and purified by column chromatography (hexane/ethyl acetate 10:1 to 1:1) to give 2 (7.0 g, 91%) as a yellow oil. This mixture contained two diastereoisomers (3:1). 1H NMR (300 MHz, CDCl3) for the major isomer: δ 1.14 (d, J=7.2 Hz, 3H), 2.98 (q, J=6.9 Hz, 1H), 4.70-4.75 (m, 1H), 5.13-5.16 (m, 1H), 6.80-7.39 (m, 8H), 8.34 (d, J=4.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20](I)=[CH:19][C:18]=2[F:24])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].C([O-])([O-])=O.[K+].[K+].O.N[C:33]1C=CC=C[CH:34]=1>C(COC)OC.[Cl-].[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>[CH:33]([C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:3]2[C:2]([F:1])=[C:14]([F:15])[CH:13]=[CH:12][C:4]=2[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6])=[C:18]([F:24])[CH:19]=1)=[CH2:34]
Reactant: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: Nc1ccccc1
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: [Cl-]
Solvent: O
Solvent: COCCOC
Product: C=Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75.8 %

Procedure:
3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide (1.00 g, 2.21 mmol) was dissolved in dry dimethoxyethane (DME, 18 ml) under a nitrogen atmosphere, Pd(Ph3P)4 (0.13 g, 0.11 mmol) was added and the resulting yellow solution was stirred at ambient temperature for 20 min. K2CO3 (−325 mesh, 0.31 g, 2.21 mmol), water (5.3 ml) and boron complex 2 (0.54 g, 2.21 mmol) were added and the contents of the flask were refluxed for 1 h. 1 Water (50 ml) and brine (50 ml) were added and the aqueous phase was extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with brine (20 ml) and dried over MgSO4. The solvent was removed under vacuum and the residual dark orange oil was chromatographed (ethyl acetate as eluent) to give 0.59 g (76% yield) of 2-[(4-vinyl-2-fluorophenyl)amino]-3,4-difluoro-N-(2-hydroxy-ethoxy)benzamide as a light yellow solid, mp 134-137° C. 1H NMR (d6-DMSO) δ 3.53-3.54 (m, 2H), 3.82 (s, 2H), 4.69-4.72 (m, 1H), 5.14 (d, 1H, J=11 Hz), 5.69-5.77 (m, 1H), 6.57-6.64 (m, 1H), 6.77-6.83 (m, 1H), 7.09-7.18 (m, 2H), 7.33-7.40 (m, 2H), 8.74 (bs, 1H), 11.86 (bs, 1H).
Reaction SMILES: [NH2:1][C@H:2]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[C:3]([OH:5])=[O:4].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:20][S:21]([OH:24])(=[O:23])=[O:22].O>C1(C)C=CC=CC=1.C(OC)(C)(C)C>[CH3:20][S:21]([OH:24])(=[O:23])=[O:22].[NH2:1][C@H:2]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[C:3]([O:5][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4]
Reactant: OCc1ccccc1
Reactant: N[C@@H](C(=O)O)C1CCCCC1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: N[C@@H](C(=O)OCc1ccccc1)C1CCCCC1
Reaction time: 6 h
Yield: 92 %

Procedure:
To a suspension of (2R)-2-amino-2-cyclohexylethanoic acid (200 g, 1.27 mol) and benzyl alcohol (276 g, 2.54 mol) in toluene (1600 mL) was added methanesulphonic acid at a rate which did not allow the temperature to reach 100° C. The reaction was stirred for an additional six hours at between 110 and 115° C. The water that was produced was distilled off using a Dean-Stark trap. An additional portion of benzyl alcohol (276 g, 2.54 mol) was added and the mixture was refluxed for a further twelve hours with water distillation. The reaction mixture was then cooled and methyl tert-butyl ether was added to initiate crystallisation. The product was filtered and dried to yield 404 g (92%) of the sub-title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][C:8](=[O:12])[NH:9][C:10]=2[N:11]=1.[C:13]1(/[CH:19]=[CH:20]/B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>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>[CH:20](/[C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][C:8](=[O:12])[NH:9][C:10]=2[N:11]=1)=[CH:19]\[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1COc2ccc(Br)nc2N1
Reactant: OB(O)/C=C/c1ccccc1
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: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C1COc2ccc(/C=C/c3ccccc3)nc2N1
Temperature: 25 °C
Yield: 37.7 %

Procedure:
6-Bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one (6.0 g, 26.3 mmole) and trans-2-phenylvinylboronic acid (3.9 g, 26.3 mmole) were dissolved in 1,4-dioxane (150 mL) and the solution was degassed with argon. (Ph3P)4Pd (230 mg, 0.2 mmole) was added, followed by a solution of potassium carbonate (6.9 g, 50 mmole) in H2O (20 mL). The reaction was heated at reflux under argon overnight, then was cooled to room temperature and diluted with EtOAc (200 mL). The solution was washed sequentially with H2O and brine, dried (Na2SO4), and concentrated in vacuo. The solid residue was purified by flash chromatography on silica gel (5-10% EtOAc/CHCl3) to afford a solid (2.5 g, 38%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[C:6]=2[N:7]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.O>CS(C)=O>[CH3:13][S:12][C:8]1[C:6]2[N:7]=[C:2]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: C1CNCCN1
Reactant: CSc1ncnc2c(N3CCCCC3)nc(Cl)nc12
Solvent: O
Solvent: CS(C)=O
Product: CSc1ncnc2c(N3CCCCC3)nc(N3CCNCC3)nc12

Procedure:
2.0 g (6.8 mmol) of 2-chloro-8-methylthio-4-piperidino-pyrimido[5,4-d]pyrimidine is dissolved warm in 70 ml of dimethylsulphoxide and stirred with a solution of 6 g of piperazine in 70 ml of dimethylsulphoxide for 1 hour at ambient temperature. Then the solution is poured into 1 liter of water, the precipitate obtained is suction filtered and washed with water. The residue is taken up in 50 ml of methylene chloride and extracted with 50 ml of 0.05N sodium hydroxide solution. The organic phase is separated off, dried over sodium sulphate and concentrated in a rotary evaporator.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]2[C:3]=1[CH2:4][CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6]2=[N:13]O.[H][H].C(=O)(O)[O-].[Na+]>C(O)(=O)C.O.[Pt]=O>[NH2:13][CH:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[C:9]([CH3:11])[C:8]=2[OH:12])[CH2:4][CH:5]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cc(C)c2c(c1O)C(=NO)C(c1ccccc1)C2
Reactant: [H][H]
Agent: O=[Pt]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(C)c2c(c1O)C(N)C(c1ccccc1)C2

Procedure:
3.00 Grams of 2,3-dihydro-4,6-dimethyl-7-hydroxy-2-phenyl-1H-inden-1-one oxime was dissolved in 55 ml of glacial acetic acid, and this solution was subjected to catalytic hydrogenation in the presence of 0.3 g of platinum oxide at room temperature under 4 atmospheric hydrogen gas pressude. The hydrogenation was terminated at the point when the stoichiometric amount of hydrogen was absorbed. The catalyst was removed by filtration and the filtrate thus obtained was concentrated. The residue thus obtained was dissolved in water and the pH of this solution was adjusted to about pH 8 by adding an aqueous solution of sodium bicarbonate, then extracted with 200 ml of chloroform. The chloroform extract was washed with water, dried with anhydrous magnesium sulfate, then concentrated under a reduced pressure. Recrystallized from ethanol to obtain 0.24 g of 1-amino-2,3-dihydro-4,6-dimethyl-7-hydroxy-2-phenyl-1H-indene. Colorless needle-like crystals. Melting point: 135°-136° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[CH2:11]([O:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20]=1Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CO>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>[CH2:11]([O:18][C:19]1[C:20]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)c(Br)c1
Reactant: OB(O)c1ccc(O)cc1
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: [Cs+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(OCc2ccccc2)c(-c2ccc(O)cc2)c1
Temperature: 70 °C
Reaction time: 48 h
Yield: 68.6 %

Procedure:
(4-Hydroxyphenyl)boronic acid (5.0 g, 36.3 mmol), methyl 4-benzyloxy-3-bromobenzoate (7.0 g, 21.8 mmol) and cesium carbonate (18.0 g, 55.2 mmol) were added to a mixed solution of methanol (50 mL) and toluene (100 mL), the air was substituted with argon gas, and tetrakis(triphenylphosphine)palladium(0) (0.45 g, 0.39 mmol) was added. The reaction mixture was stirred under an argon atmosphere at 70° C. for 2 days. After cooling the reaction mixture, the insoluble material was filtered off through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:5-2:1), and the obtained crystals were recrystallized from ethyl acetate-hexane to give the title compound (5.0 g, yield 69%) as colorless prism crystals.
Reaction SMILES: O.NN.[N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N+:7]([O-])=[CH:6][C:5]=1[OH:15].[OH-].[Na+]>[Ni]>[N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][C:5]=1[OH:15]
Reactant: [O-][n+]1cc(O)nc2ccccc21
Agent: [Ni]
Agent: NN
Agent: [Na+]
Solvent: O
Product: Oc1cnc2ccccc2n1
Reaction time: 5 h
Yield: 91.8 %

Procedure:
An aqueous Raney nickel paste (containing 0.5 g of metallic nickel) and 5.0 g of a 80% aqueous hydrazine hydrate solution were added dropwise to 200 g of an aqueous solution containing 16.2 g of 2-quinoxalinol-4-oxide and 8 g of sodium hydroxide at a temperature of 40° to 50° C., and the resulting mixture was stirred at 40° to 70° C. for 5 hr, whereby the reducing reaction was terminated. The catalyst was then recovered by filtration, and 35% hydrochloric acid was added dropwise to the filtrate at 50° to 60° C. to adjust the pH to 4. The precipitated crystal was collected by filtration, washed with water and dried to give 13.4 g (yield 92%) of 2-quinoxalinol with melting point of 268° C.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:11][C:12]1[C:16]([CH3:17])=[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:14][N:13]=1>C(#N)C>[CH2:8]([O:7][C:5]([CH2:4][C:3]1[NH:11][C:12]2[N:13]([CH:2]=1)[N:14]=[C:15]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:16]=2[CH3:17])=[O:6])[CH3:9]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Cc1c(N)n[nH]c1-c1ccccc1
Solvent: CC#N
Product: CCOC(=O)Cc1cn2nc(-c3ccccc3)c(C)c2[nH]1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
0.78 ml of ethyl 4-chloroacetoacetate was added to a solution of 1.0 g of 3-amino-4-methyl-5-phenyl-1H-pyrazole in 25 ml of acetonitrile, and then the mixture was stirred at room temperature for 4 days. At the end of this time, the crystals which separated were filtered off and the mother liquor was concentrated by evaporation under reduced pressure. The residue was partitioned between ethyl acetate and water, and the organic phase was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent, to give 80 mg of the title compound in the form of an oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[C:12]([NH2:14])[N:13]=[C:9]3[CH:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[CH:6]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[CH3:25][N:26]([CH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)[CH3:27]>ClCCl>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[C:12]([NH:14][C:33](=[O:34])[C:32]4[CH:36]=[CH:37][C:29]([CH2:28][N:26]([CH3:25])[CH3:27])=[CH:30][CH:31]=4)[N:13]=[C:9]3[CH:8]=[C:7]([C:15]([F:16])([F:17])[F:18])[CH:6]=2)[CH2:2][CH2:3]1
Reactant: Nc1nc2cc(C(F)(F)F)cc(NC3CC3)n2n1
Reactant: CN(C)Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)Cc1ccc(C(=O)Nc2nc3cc(C(F)(F)F)cc(NC4CC4)n3n2)cc1
Yield: 51.9 %

Procedure:
To a reaction vessel containing N5-cyclopropyl-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine ((A18), 77 mg, 0.3 mmol, 1 eq.) and pyridine (0.063 mL, 1.2 mmol, 4 eq.) in dichloromethane (1 mL) was added 4-dimethylaminomethyl-benzoyl chloride (118 mg, 0.6 mmol, 2 eq.) as a solution in dichloromethane (2 mL), dropwise. The vessel was capped and heated to reflux for approximately 16 hours. The reaction mixture was cooled and the solvent removed in vacuo. The residue dissolved in DMSO (1.5 mL) and purified by reverse phase preparatory HPLC to give the title compound as a white solid (65.1 mg, 52%). HPLC, Rt: 2.59 min (purity: 100%). LC/MS M+(ESI): 419.2, M−(ESI) 417.2.
Reaction SMILES: ClC(OC(C)C)=O.FC(F)(F)C(O)=O.N1CCC(N2C3=NC=NC(OC4C=CC=CC=4C#N)=C3C=N2)CC1.[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][CH:49]([N:52]2[C:56]3=[N:57][CH:58]=[N:59][C:60]([O:61][C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=4[C:68]#[N:69])=[C:55]3[CH:54]=[N:53]2)[CH2:48][CH2:47]1)=[O:45])(C)([CH3:41])[CH3:40].FC(F)(F)C(O)=O.C(OC1C=CC(OC2N=CN=C3N(C4CCNCC4)N=CC=23)=C(F)C=1)C.C(N(C(C)C)CC)(C)C>ClCCl.O>[CH:39]([O:43][C:44]([N:46]1[CH2:47][CH2:48][CH:49]([N:52]2[C:56]3=[N:57][CH:58]=[N:59][C:60]([O:61][C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=4[C:68]#[N:69])=[C:55]3[CH:54]=[N:53]2)[CH2:50][CH2:51]1)=[O:45])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccccc4C#N)ncnc32)CC1
Agent: CC(C)OC(=O)Cl
Agent: CCOc1ccc(Oc2ncnc3c2cnn3C2CCNCC2)c(F)c1
Agent: N#Cc1ccccc1Oc1ncnc2c1cnn2C1CCNCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)N1CCC(n2ncc3c(Oc4ccccc4C#N)ncnc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Isopropyl chloroformate (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 1M in toluene; 0.34 mL, 0.34 mmol) was added to a mixture of 2-(1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine-4-yloxy)-benzonitrile trifluoroacetate salt (which was prepared from 4-[4-(2-cyano-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester [Example 45] following the procedure described for the preparation of Intermediate 29; 150 mg, 0.344 mmol), diisopropylethylamine (133 mg, 1.03 mmol) in dichloromethane (6 mL). The reaction was stirred at room temperature overnight. Water was added to quench the reaction and the aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried (sodium sulfate), filtered, evaporated and purified by flash chromatography on silica gel, eluting with 4% methanol/dichloromethane to give 4-[4-(2-cyano-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isopropyl ester (98 mg, 70%) as a white solid. Mass spectrum MH+=407.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([F:10])[CH:3]=1.[C-:11]#[N:12].[K+].C(O)C>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:11]#[N:12])=[C:4]([F:10])[CH:3]=1
Reactant: [C-]#N
Reactant: Fc1cc(Br)ccc1CBr
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccc(Br)cc1F

Procedure:
The solution of 4-bromo-1-(bromomethyl)-2-fluorobenzene (20 g, 74 mmol) and potassium cyanide (10 g, 153 mmol) in the mixed solvent of ethanol (150 mL) and water (30 mL) was stirred at 70° C. for 1 hour. The resulting solution was diluted with water (50 mL), and then extracted with ethyl acetate (3×200 mL). All the organic solution was dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography with 2-5% ethyl acetate in hexane to afford the title compound as a light yellow oil. MS ESI: [M+H]+ m/z 214; 1H NMR (400 MHz, CDCl3) δ 7.38-7.22 (m, 3H), 3.74 (s, 2H).