Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[N:5][N:6]=1.[C:12]([C:19](OCC)=[O:20])#[C:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[N:7]1([C:4]2[S:3][C:2]3=[N:1][C:19](=[O:20])[CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:6]3[N:5]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: Nc1nnc(N2CCCC2)s1
Solvent: CCO
Product: CCOC(=O)c1cc(=O)nc2sc(N3CCCC3)nn12
Reaction time: 8 h

Procedure:
8.5 g of 2-amino-5-pyrrolidino-1,3,4-thiadiazole were added to 300 ml of ethanol and mixed with 8.5 g of diethyl acetylenedicarboxylate. On heating for 10 to 20 minutes to about 50° to 60° C. a clear solution was obtained which after standing overnight at room temperature was evaporated in vacuo to dryness. The residue was triturated with a small amount of cold ethyl acetate, filtered off, washed with ether and then dried. 8.4 g (57.1% of the theoretical yield) of ethyl 2-pyrrolidino-7H-1,3,4-thiadiazolo-[3,2-a]pyrimidin-7-one-5-carboxylate were thus obtained.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)[CH3:9])(=O)=O.[C-:23]#[N:24].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([N:13]2[CH2:14][CH2:15][N:10]([CH:8]([CH3:9])[CH2:7][CH2:6][C:23]#[N:24])[CH2:11][CH2:12]2)=[CH:17][CH:18]=1
Reactant: [C-]#N
Reactant: CC(CCOS(C)(=O)=O)N1CCN(c2ccc(F)cc2)CC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(CCC#N)N1CCN(c2ccc(F)cc2)CC1
Temperature: 50 °C
Reaction time: 15 h
Yield: 73 %

Procedure:
To a stirred solution of 3-(4-(4-fluorophenyl) piperazin-1-yl)butyl methanesulfonate (4.5 g, 13.62 mmol) in N,N-dimethylformamide (30 ml) was added potassium cyanide (2.66 g, 40.9 mmol) at 25° C. under nitrogen atmosphere. The reaction mixture was stirred at 50° C. for 15 h. Progress of reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate (150 ml) and washed with water (4×50 ml). The organic layer was dried over sodium sulphate and concentrated under reduced pressure to get oily compound. The resulting crude compound was purified over silica gel (100-200 mesh) by flash chromatography using 30% ethyl acetate in hexane as an eluent to obtain title compound (2.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[S:16][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[CH3:28][N:29]([CH3:34])[CH2:30][C:31](O)=[O:32].O.[C:36]1([CH3:46])[CH:41]=[CH:40][C:39]([S:42]([OH:45])(=[O:44])=[O:43])=[CH:38][CH:37]=1>C1(C)C=CC=CC=1>[C:36]1([CH3:46])[CH:37]=[CH:38][C:39]([S:42]([OH:45])(=[O:43])=[O:44])=[CH:40][CH:41]=1.[CH3:28][N:29]([CH2:30][C:31]([O:26][CH:23]1[CH2:22][CH2:21][N:20]([C:17]2[S:16][C:15](/[CH:14]=[C:11](\[C:12]#[N:13])/[C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:19][CH:18]=2)[CH2:25][CH2:24]1)=[O:32])[CH3:34]
Reactant: COc1ccc(/C(C#N)=C/c2ccc(N3CCC(O)CC3)s2)cc1OC
Reactant: CN(C)CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(/C(C#N)=C/c2ccc(N3CCC(OC(=O)CN(C)C)CC3)s2)cc1OC
Yield: 6.1 %

Procedure:
Compound 6 (370 mg) was dissolved in toluene (80 mL), and N,N-dimethylglycin hydrochloride (140 mg) and p-toluenesulfonic acid monohydrate (380 mg) were added to the solution, followed by stirring under reflux for 5 hours. The solvent was evaporated to dryness, and the residue was purified by silica gel column chromatography (CHCl3-MeOH), to thereby yield the target product (yield: 38 mg, 7.7%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7](/[C:10](/[C:16]([F:19])([F:18])[F:17])=[CH:11]\[C:12](OC)=[O:13])=[CH:6][CH:5]=1)[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.C(O)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7](/[C:10](/[C:16]([F:17])([F:18])[F:19])=[CH:11]\[CH:12]=[O:13])=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(/C(=C\C(=O)OC)C(F)(F)F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CCOc1ccc(/C(=C\C=O)C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a solution of methyl E-3-(4-ethoxyphenyl)-4,4,4-trifluorobut-2-enoate, prepared according to Example 17, stage 1, (1.5 g, 5.5×10-3 moles) in toluene (20 ml) at -78° C. was added dropwise one molar equivalent of diisobutylaluminium hydride (5.5 ml, 5.5×10-3 moles) in toluene. The resulting solution was stirred at -78° C. for two hours before quenching the reaction by the sequential addition of acetic acid (0.40 ml, 7.0×10-3 moles), water (1 ml) and sodium sulphate (10 g). The resulting slurry was allowed to warm to room temperature and after a further twenty minutes stirring the solids were filtered off through silica. After removal of the solvent the crude aldehyde was purified by silica chromatography (eluted with 10%, in petroleum ether to give the title compound (0.87 g, 65%).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:24])=[C:7]([C:16]([CH3:23])=[C:17]([O:19][C:20](=[O:22])[CH3:21])[CH:18]=1)[C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])(=[O:3])[CH3:2].[Br:25]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:20]([O:19][C:17]1[C:16]([CH2:23][Br:25])=[C:7]([C:6]([CH3:24])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:18]=1)[C:8]([O:10][CH2:11][C:12]([Cl:14])([Cl:13])[Cl:15])=[O:9])(=[O:22])[CH3:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1cc(OC(C)=O)c(C)c(C(=O)OCC(Cl)(Cl)Cl)c1C
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1cc(OC(C)=O)c(CBr)c(C(=O)OCC(Cl)(Cl)Cl)c1C

Procedure:
A mixture of 4.76 g 2,2,2-trichloroethyl 3,5-diacetoxy-dimethylbenzoate and 2.24 g N-bromosuccinimide in 36 ml of carbontetrachloride was heated at reflux temperature and with light irradiation for 30 minutes. The mixture was cooled in an ice bath and insoluble material was removed by filtration. The filtrate was diluted with methylene chloride, washed with water, dried over sodium sulphate and evaporated in vacuo to provide crude 2,2,2-trichloroethyl 3,5-diacetoxy-2-bromomethyl-6-methylbenzoate, which was used directly without further purification.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]=[O:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[CH2:18]([Mg]Br)[CH3:19]>O1CCCC1>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]([OH:17])[CH2:18][CH3:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(=O)c2cc(C=O)ccc2[nH]1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCCCc1nc(=O)c2cc(C(O)CC)ccc2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.25 g of 2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxaldehyde in 10 ml of dry tetrahydrofuran, cooled to a0° C., is added 1.63 ml of 2.0M ethyl magnesium bromide in tetrahydrofuran. The reaction mixture is stirred for 30 minutes at 0° C. and quenched with 20 ml of saturated ammonium chloride solution and 20 ml of water. The reaction mixture is extracted with 9:1 chloroform-methanol, dried over magnesium sulfate, filtered and evaporated in vacuo to give 0.26 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:7][CH2:6][C:5]2=[CH:8][C:9]([NH2:11])=[N:10][N:4]2[CH2:3]1.Br[C:14]1[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Br:20])[CH:19]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:20][C:18]1[CH:19]=[C:14]([NH:11][C:9]2[CH:8]=[C:5]3[CH2:6][O:7][C:2]([CH3:12])([CH3:1])[CH2:3][N:4]3[N:10]=2)[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CC1(C)Cn2nc(N)cc2CO1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2cc3n(n2)CC(C)(C)OC3)c1=O
Temperature: 100 °C
Yield: 59.5 %

Procedure:
A 100-mL round-bottomed flask equipped with a reflux condenser was charged with 1,4-dioxane (10 mL), 6,6-dimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-amine 330g (167 mg, 1.0 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (320 mg, 1.2 mmol), Pd2(dba)3 (91 mg, 0.10 mmol), XantPhos (116 mg, 0.20 mmol), and cesium carbonate (652 mg, 2.0 mmol). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 3 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 100:1 dichloromethane/methanol to afford 335a (210 mg, 60%) as a yellow solid. MS-ESI: [M+H]+ 352.9
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]3[CH2:14][CH2:13]3)[C:5]=2[CH:6]=O)[CH2:3][CH2:2]1.[C:15](Br)(Br)([Br:17])[Br:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH:1]1([C:4]2[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]3[CH2:14][CH2:13]3)[C:5]=2[CH:6]=[C:15]([Br:17])[Br:16])[CH2:3][CH2:2]1
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1c(C2CC2)cccc1C1CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: BrC(Br)=Cc1c(C2CC2)cccc1C1CC1

Procedure:
1,3-Dicyclopropyl-2-(2,2-dibromo-vinyl)-benzene was prepared from 2,6-dicyclopropyl-benzaldehyde, carbon tetrabromide and triphenylphosphine in analogy to Example 1d): colourless oil; MS (EI): 343.9 (14%), 342.0 (24%) and 340.0 (14%) (M+), 182.2 ([M-2Br]+, 66%), 167.2 ([M-2Br—CH3)+, 100%).
Reaction SMILES: [CH2:1]([C@:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[CH:21]=4)[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2].[CH:29](=O)[CH2:30][CH2:31][CH2:32]C>>[CH2:29]([C:21]1[C:20]2[CH:19]=[CH:18][C:17]([F:22])=[CH:16][C:15]=2[N:14]=[C:13]2[C:23]3[N:10]([CH2:11][C:12]=12)[C:9](=[O:26])[C:8]1[CH2:7][O:6][C:5](=[O:27])[CH2:4][C@@:3]([CH2:1][CH3:2])([OH:28])[C:25]=1[CH:24]=3)[CH2:30][CH2:31][CH3:32]
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3ccc(F)cc3nc2-1
Reactant: CCCCC=O
Product: CCCCc1c2c(nc3cc(F)ccc13)-c1cc3c(c(=O)n1C2)COC(=O)C[C@]3(O)CC

Procedure:
The product of Example 84 is treated with valeraldehyde according to a procedure similar to Stage 95e to produce the expected solid (m.p. 235–236° C.).
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-])=O)=[CH:5][C:4]([C:10]#[N:11])=[N:3]1.Cl>O.C(O)C.[Fe]>[NH2:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([C:10]#[N:11])[CH:5]=1
Reactant: Cn1nc(C#N)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cn1nc(C#N)cc1N
Temperature: 50 °C

Procedure:
To a suspension of 1-methyl-5-nitro-1H-pyrazole-3-carbonitrile (2 g; 13.1 mmol) in a mixture of water (14 mL) and ethanol (120 mL) there are added HCl 37% (170 L) and iron filings (5.1 g; 91 mmol). The reaction mixture is heated for 5 hours at 50° C. After cooling to ambient temperature, the reaction mixture is filtered. The filtrate is concentrated to dryness and then purified by chromatography over silica gel using dichloromethane and ethyl acetate as eluants to yield the expected compound in the form of a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].[CH3:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[O:15][CH2:16][C:17](Cl)=[O:18].Cl>[OH-].[Na+]>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH:11][C:17](=[O:18])[CH2:16][O:15][C:14]1[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=1[CH3:12]
Reactant: Cc1ccccc1OCC(=O)Cl
Reactant: Cc1cccc(C(=O)O)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccccc1OCC(=O)Nc1c(C)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.7 %

Procedure:
3-Methylanthranilic acid 1.0 g (6 mmol) was dissolved in 10% aqueous sodium hydroxide solution 27 ml and to this soulution, 2-methylphenoxyacetyl chloride 1.3 g (7.3 mmol) was added dropwise at 0° C. The resulting solution was stirred at room temperature for 5 minutes and acidified with 10% hydrochloric acid solution. Deposited crystals were collected by filtration, washed with hot water and recrystallized from ethanol to obtain 3-methyl-N-(2-methylphenoxyacetyl)anthranilic acid (melting point: 133° to 136° C.) 1.7 g (yield: 83%).
Reaction SMILES: [C:1]1([C@H:7]([NH:26][C:27]([O:29][C@@H:30]2[CH:35]3[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]3)[CH2:31]2)=[O:28])[C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].Cl>C1COCC1>[C:1]1([C@H:7]([NH:26][C:27]([O:29][C@@H:30]2[CH:35]3[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]3)[CH2:31]2)=[O:28])[C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(COc2cccc([C@@H](NC(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(N[C@@H](c1ccccc1)c1cccc(OCc2ccc(C(=O)O)cc2)c1)O[C@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
To a stirred solution of methyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate (2.27 g, 4.50 mmol) in THF (23 mL) was added an aqueous solution of lithium hydroxide (2.0 M, 9.0 ml, 18.0 mmol). The mixture was stirred at RT for 16 hours. The pH of the reaction mixture was adjusted to 6 by the addition of 4M aqueous hydrochloric acid. The mixture was then extracted with 10% methanolic ethyl acetate (×2) and the combined organic extracts evaporated at reduced pressure. The residue was then dissolved in ethanol and re-evaporated at reduced pressure to afford the title compound as a pale yellow solid (1.85 g, 84%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[C:10]2[CH:22]=[C:21]([C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=3)[NH:20][C:11]2=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[OH-:31].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[C:10]2[CH:22]=[C:21]([C:23]3[CH:30]=[CH:29][C:26]([C:27]([NH2:28])=[O:31])=[CH:25][CH:24]=3)[NH:20][C:11]2=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: [OH-]
Reactant: N#Cc1ccc(-c2cc3nc(-c4ccncc4F)c(-c4cccnc4)nc3[nH]2)cc1
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1ccc(-c2cc3nc(-c4ccncc4F)c(-c4cccnc4)nc3[nH]2)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 36.5 %

Procedure:
To a stirred solution of 4-[2-(3-fluoropyridin-4-yl)-3-pyridin-3-yl-5H-pyrrolo[2,3-b]pyrazin-6-yl]benzonitrile (Example 150) (0.050 g, 0.12 mmol) in ethanol (1.5 mL) was added a 2N aqueous solution of sodium hydroxide (0.127 mL, 0.25 mmol) and the mixture was stirred at 80° C. After 18 h, ethanol was evaporated and the aqueous phase was acidified until pH=6 with a 2N aqueous solution of hydrochloric acid. The resulting solid was filtered, washed with water and dried to furnish the titled compound (0.018 g, 36%) as a brown solid.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])=[C:8]([OH:13])[C:9]=1[C:10]([OH:12])=[O:11]>C(O)(=O)C>[Br:1][C:5]1[C:4]([CH3:3])=[C:9]([C:10]([OH:12])=[O:11])[C:8]([OH:13])=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:6]=1
Reactant: Cc1ccc(C(C)(C)C)c(O)c1C(=O)O
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1c(Br)cc(C(C)(C)C)c(O)c1C(=O)O
Temperature: 0 °C

Procedure:
A solution of 16.8 g. of bromine in 105 g. of glacial acetic acid is added during 80 minutes to a stirred solution of 20.8 g. of 6-methyl-3-t-butylsalicylic acid in 190 g. of glacial acetic acid, and the mixture is stirred at laboratory temperature for a further 1 hour and then poured into 500 ml. of an ice-water mixture. The mixture is filtered and there is thus obtained as solid residue 5-bromo-6-methyl-3-t-butylsalicylic acid, m.p. 212°-214° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH:21][CH2:22][C:23]3[C:24]([NH:36][CH:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[C:25]4[CH:33]=[N:32][N:31]([CH2:34][CH3:35])[C:26]4=[N:27][C:28]=3[CH2:29][CH3:30])=[O:20])[CH:14]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:43]([C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][CH:50]=1)=[O:44].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[Cl:8][C:6]1[CH:5]=[C:4]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH:21][CH2:22][C:23]3[C:24]([NH:36][CH:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[C:25]4[CH:33]=[N:32][N:31]([CH2:34][CH3:35])[C:26]4=[N:27][C:28]=3[CH2:29][CH3:30])=[O:20])[CH:14]=2)=[O:12])[CH:3]=[C:2]([C:49]2[CH:48]=[CH:47][CH:46]=[C:45]([CH:43]=[O:44])[CH:50]=2)[CH:7]=1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(Cl)cc(Br)c2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(Cl)cc(-c3cccc(C=O)c3)c2)c1

Procedure:
N-[(3-Bromo-5-chlorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (300 mg, 0.459 mmol), (3-formylphenyl)boronic acid (68.8 mg, 0.459 mmol), potassium carbonate (190 mg, 1.376 mmol), and tetrakis(triphenylphosphine)palladium(0) (26.5 mg, 0.023 mmol) were placed in a 2-5 mL Biotage microwave vial along with a stir bar. Then 1,4-dioxane (3 mL) and water (1 mL) were added. The vial was capped and microwaved for 15 min at normal power in the SmithCreator microwave at 100° C. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (10 mL). The organic phase was washed 3× with water (10 mL), 1× with brine (10 mL), and dried over anhydrous Na2SO4. The crude product was taken up in dichloromethane and absorbed on Isolute® Sorbent and purified using CombiFlash on a 40 g silica column eluted with 0-10% DCM/MeOH to afford the title compound as a pale yellow solid. LC-MS m/z 679.0 (M+H)+, 2.21 min (ret time); mp 123-127° C.; analytical HPLC shows 96.2% purity, (ret time 14.171 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([N:14]2[CH2:19][C@H:18]([CH3:20])[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:16][C@H:15]2[CH3:29])=[O:13])=[C:6]([CH:9]=1)[CH:7]=O.C(=O)([O-])[O-].[K+].[K+].[C:36]([O:39][CH2:40][CH3:41])(=[O:38])[CH3:37]>C(O)C>[CH2:40]([O:39][C:36](=[O:38])[CH:37]=[CH:7][C:6]1[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:10][CH2:11][C:12]([N:14]1[CH2:19][C@H:18]([CH3:20])[N:17]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH2:16][C@H:15]1[CH3:29])=[O:13])[CH3:41]
Reactant: CCOC(C)=O
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C=Cc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzaldehyde (0.50 g, 1.19 mmol) in ethanol (10 mL) at 0° C. was added potassium carbonate (0.4 mL, 2.4 mmol, 6 M solution in water) and triethyl phosphonoacetate (0.47 mL, 2.4 mmol). The reaction was stirred at 0° C. for 2 hours, then at ambient temperature 12 hours. The reaction was diluted with ethyl acetate and filtered through a pad of celite. The filtrate was then washed with saturated aqueous sodium hydrogen carbonate and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel to give the title compound (0.51 g)
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:6]([O:21][CH3:22])[CH2:5]1)(=[O:3])[NH2:2].Br[CH:24]([CH2:34][CH3:35])[C:25](=O)[C:26]([O:28][CH2:29][CH2:30]CC)=[O:27].C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:13]([O:12][C:11]([NH:10][C@H:7]1[CH2:8][CH2:9][N:4]([C:1]2[O:3][C:24]([CH2:34][CH3:35])=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:2]=2)[CH2:5][C@H:6]1[O:21][CH3:22])=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCCCOC(=O)C(=O)C(Br)CC
Reactant: CO[C@@H]1CN(C(N)=O)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)oc1CC
Yield: 108.6 %

Procedure:
The same operation as in Example (103c) was performed using cis(±)-benzyl (1-carbamoyl-3-methoxypiperidin-4-yl)carbamate obtained in Example (103b) (0.98 g, 3.2 mmol), butyl 3-bromo-2-oxopentanoate obtained in Example (110a) (5 g, 19.9 mmol), sodium bicarbonate (0.63 g, 7.5 mmol) and THF (20 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 1/2, 1/1, 2/1, 4/1) to obtain 1.5 g of the title compound as a yellow solid (100%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[N:13]=[CH:12][C:11]([S:14][C:15]3[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=3)=[CH:10][C:9]=2[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.CN(C=O)C>O>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[C:9]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:10][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:37][CH2:38][N:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)[CH:16]=3)=[CH:12][N:13]=2)[S:5][CH:6]=1
Reactant: ClCCN1CCCCC1
Reactant: Cc1csc(Nc2ncc(Sc3cccc(O)c3)cc2Oc2ccccc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc(Nc2ncc(Sc3cccc(OCCN4CCCCC4)c3)cc2Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.3 %

Procedure:
A mixture of 3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)phenol (prepared according to Example 57; 70.0 mg, 0.172 mmol), potassium carbonate (71.2 mg, 0.515 mmol), 1-(2-chloroethyl)piperidine hydrochloride (31.6 mg, 0.172 mmol), and DMF (2 mL) was stirred at room temperature for 30 minutes and heated to 50° C. overnight. The reaction was cooled to room temperature and water (15 mL) was added and extracted with ether. A white precipitate formed in the ether layer and was filtered to afford N-(4-methylthiazol-2-yl)-3-phenoxy-5-(3-(2-(piperidin-1-yl)ethoxy)phenylthio)pyridin-2-amine (34.2 mg, 38.4% yield) as a white solid. 1H NMR (d6-DMSO) δ 9.56 (s, 1H), 8.29 (dd, 1H), 7.50 (dd, 1H), 7.28 (m, 2H), 7.11 (t, 1H), 7.00 (t, 1H), 6.82 (m, 2H), 6.65 (m, 1H), 6.58 (m, 1H), 6.54 (m, 1H), 6.35 (m, 1H), 3.79 (t, 2H), 2.23 (s, 3H), 2.17 (m, 4H), 2.12 (t, 2H), 1.38 (m, 4H), 1.31 (m, 2H); Mass spectrum (esi) m/z=519.1 (M+H).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:4][OH:5].[C:12](OCC)(=[O:16])[CH:13]([CH3:15])[OH:14]>>[C:12]([O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])(=[O:16])[CH:13]([CH3:15])[OH:14]
Reactant: CCOC(=O)C(C)O
Reactant: CC(C)CCCC(C)CCO
Product: CC(C)CCCC(C)CCOC(=O)C(C)O
Temperature: 60 °C
Yield: 62.2 %

Procedure:
A mixture of Novozym® 435 (2.81 g), molecular sieves (23.17 g), 3,7-dimethyl-1-octanol (4.64 g), and ethyl lactate (14.78 g) in a 250 mL beaker was maintained at 60° C. in a convection oven for 28 hours. Upon work-up, 4.2 g of 3,7-dimethyl-1-octyl lactate (62% yield) was obtained as an amber-colored liquid. The purity of the product was >96% as assessed by HPLC-RI.