Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][NH:4][C:5]1[C:10]([C:11]#[C:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:9][N:8]=[C:7]([C:20]#[N:21])[N:6]=1.[Cl:24][CH2:25][CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29].C(N(CC)CC)C.[Cl-].[NH4+]>C(Cl)Cl>[Cl:24][CH2:25][CH2:26][CH2:27][S:28]([N:17]1[CH2:18][CH2:19][N:14]([CH2:13][C:12]#[C:11][C:10]2[C:5]([NH:4][CH2:3][C:2]([CH3:23])([CH3:22])[CH3:1])=[N:6][C:7]([C:20]#[N:21])=[N:8][CH:9]=2)[CH2:15][CH2:16]1)(=[O:30])=[O:29]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CC(C)(C)CNc1nc(C#N)ncc1C#CCN1CCNCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CNc1nc(C#N)ncc1C#CCN1CCN(S(=O)(=O)CCCCl)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 51 %

Procedure:
To a solution of 4-(2,2-dimethyl-propylamino)-5-(3-piperazin-1-yl-prop-1-ynyl)-pyrimidine-2-carbonitrile (0.16 mmol) in CH2Cl2 (5 ml), 3-chloropropanesulfonyl chloride (0.192 mmol) and triethylamine (0.192 mmol) are added at 0° C. The reaction mixture is stirred at room temperature for 14 h and then saturated aqueous solution of ammonium chloride is added to the reaction mixture. The mixture is extracted with two 50 ml portions of AcOEt. The combined extracts are washed with brine, dried over sodium sulfate and concentrated under vacuum. The purification of the residue by silica gel column chromatography affords 37 mg of title compound in 51% yield. Rf=0.33 (AcOEt only)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][NH2:10])[CH:5]=[CH:6][C:7]=1[F:8].[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21](OCC)=[O:22])[N:20]=2)[CH:17]=1>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21]([NH:10][CH2:9][C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=3)=[O:22])[N:20]=2)[CH:17]=1
Reactant: NCc1ccc(F)c(Cl)c1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: O=C(NCc1ccc(F)c(Cl)c1)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (3-chloro-4-fluorophenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[O:12][C:11](=[O:21])[NH:10]2)[C:5]([F:8])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:41]([Si:43]([CH3:46])([CH3:45])[CH3:44])#[CH:42]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[F:8][C:5]1[C:4]([C@@H:9]2[C@@H:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[O:12][C:11](=[O:21])[NH:10]2)=[CH:3][C:2]([C:42]#[C:41][Si:43]([CH3:46])([CH3:45])[CH3:44])=[CH:7][N:6]=1
Reactant: O=C1N[C@H](c2cc(Br)cnc2F)[C@@H](c2cccc(F)c2)O1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnc(F)c([C@H]2NC(=O)O[C@@H]2c2cccc(F)c2)c1
Temperature: 90 °C
Yield: 69.9 %

Procedure:
To a sealable microwave vial was added (4R,5R)-4-(5-bromo-2-fluoropyridin-3-yl)-5-(3-fluorophenyl)oxazolidin-2-one (105 mg, 0.296 mmol), copper(I) iodide (1.689 mg, 8.87 μmol), triphenylphosphine (23.26 mg, 0.089 mmol) and triethylamine (4 mL). The solution was stirred and ethynyltrimethylsilane (43.6 mg, 0.443 mmol) was added and the reaction mixture was degassed with nitrogen for 10 min. To this mixture was added bis(triphenylphosphine)palladium(II) chloride (4.15 mg, 5.91 μmol) in one portion and the reaction vessel was sealed and heated to 90° C. overnight. The reaction was cooled to room temperature, the solvent was evaporated in vacuo and the crude solid was added to a silica gel column and eluted with 20% EtOAc/80% Hexanes affording (4R,5R)-4-(2-fluoro-5-((trimethylsilyl)ethynyl)pyridin-3-yl)-5-(3-fluorophenyl)oxazolidin-2-one (77 mg, 0.207 mmol, 69.9% yield) as an off white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.35 (s, 1H), 8.04 (dd, J=8.0, 4.0, 1H), 7.47-7.41 (m, 1H), 7.18-7.12 (m, 3H), 5.44 (brs, 1H), 5.36 (d, J=4.0, 1H) 5.00 (d, J=5.0, 1H), 0.30 (s, 9H), LC/Mass spec. (Analytical HPLC method 2): RT=2.23 min. Mass=373.19 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6](B(O)O)[CH:7]=1.[NH2:13][C:14]1[CH:21]=[CH:20][C:19](Br)=[C:18]([Cl:23])[C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.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>[NH2:13][C:14]1[CH:21]=[CH:20][C:19]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:11][CH3:12])=[C:18]([Cl:23])[C:15]=1[C:16]#[N:17]
Reactant: N#Cc1c(N)ccc(Br)c1Cl
Reactant: COc1ccc(Cl)cc1B(O)O
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: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)cc1-c1ccc(N)c(C#N)c1Cl
Yield: 92.6 %

Procedure:
A stirred mixture of 5.7 grams (0.020 mole) of 5-chloro-2-methoxyphenylboronic acid, 3.3 grams (0.014 mole) of 2-amino-5-bromo-6-chlorobenzonitrile (prepared in Step A of this Example), 21 mL of aqueous 2M sodium carbonate, and 0.15 gram (catalyst) of tetrakis(triphenylphosphine)palladium(0) in 50 mL of toluene was heated at reflux for about 17 hours. After this time, 50 mL of ethyl acetate was added to the reaction mixture. The organic layer was separated and washed with 50 mL of water and then with 50 mL of an aqueous solution saturated with sodium chloride. The organic layer was then dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 3.8 grams of 2-amino-6-chloro-5-(5-chloro-2-methoxyphenyl)benzonitrile. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([C:8]1[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[S:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([N:28](CC)CC)[CH3:27]>CC(C)=O>[CH2:1]([C:8]1[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][C:11]([C:12]([O:14][CH2:27][C:26]#[N:28])=[O:13])=[CH:10][C:9]=1[S:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1Cc1ccccc1
Reactant: CCN(CC)CC
Solvent: CC(C)=O
Product: CCCCSc1cc(C(=O)OCC#N)cc(S(N)(=O)=O)c1Cc1ccccc1

Procedure:
A mixture of 4-benzyl-3-n-butylthio-5-sulfamylbenzoic acid (0.78 g) chloroacetonitrile (0.17 g), triethylamine (0.42 g) and dry acetone (10 ml) is refluxed for 6 hours. After cooling, the separated triethylamine hydrochloride is removed by filtration, and the filtrate is evaporated in vacuo. The residue is crystallized by trituration with aqueous ethanol. After cooling the material is collected by filtration, washed with cold aqueous ethanol and dried. After recrystallization from aqueous ethanol, cyanomethyl 4-benzyl-3-n-butylthio-5-sulfamylbenzoate is obtained with a melting point of 112.5°-114° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:30][C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([CH3:40])[C:38]=1[F:39])[CH2:34]Br>C1COCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@H:15]([CH2:34][C:33]1[CH:36]=[C:37]([CH3:40])[C:38]([F:39])=[C:31]([CH3:30])[CH:32]=1)[CH2:16][CH:17]=[CH2:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(CBr)cc(C)c1F
Reactant: C=CCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@H](Cc1cc(C)c(F)c(C)c1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
To a cooled (−78° C.) solution of (R)-4-benzyl-3-pent-4-enoyl-oxazolidin-2-one (0.500 g, 1.928 mmol) in 15 mL of THF, was added LiHMDS (2.9 mL, 2.9 mmol, 1.0 M in THF). The resulting mixture was stirred at −78° C. under N2 for 1 h and then a solution of 3,5-dimethyl-4-fluorobenzyl bromide (0.460 g, 2.121 mmol) in 5 mL of THF was added. After being stirred at −78° C. for 1 h followed by warming to room temperature over 2 h, the reaction mixture was quenched with 50 mL of aqueous NH4Cl solution and extracted with dichloromethane (50 mL×3). The combined organic extracts were dried, filtered, and concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel) eluting with 0-100% dichloromethane/hexanes to give the title compound as colorless oil (0.221 g, 56% yield). GC-MS: tR=7.0 min; m/z 395 (M+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=O)=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:13][CH2:14]1
Reactant: CN1CCN(C(=O)c2c[nH]c3ccccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN(Cc2c[nH]c3ccccc23)CC1
Temperature: 0 °C

Procedure:
(1H-Indol-3-yl)-(4-methylpiperazin-1-yl)methanone (2.44 g, 0.01 moles) in THF was treated with cooled and stirred suspension of Lithium aluminum hydride (g, 0.011 moles in THF slowly over the period of 2 to 5 hours, the reaction mixture was heated to reflux for 2-4 hours, after the completion of reaction, the reaction mixture was poured on to the ice and the compound was extracted in ethyl acetate. The residue obtained was purified by flash chromatography (silica gel, EtOAc/Hexanes, 2/8) to afford the compound, which was identified by IR, NMR and mass spectral analyses as the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:19])[O:10][CH2:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=1>CN(C=O)C>[N:16]1[CH:17]=[CH:18][C:13]([C:12]2[CH2:11][O:10][C:9](=[O:19])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=C1OCC(c2ccncc2)=C1c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1OCC(c2ccncc2)=C1c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 80 °C
Yield: 17.5 %

Procedure:
To a stirred solution of 3-(4-hydroxyphenyl)-4-(pyridin-4-yl)furan-2(5H)-one (700 mg, 2.76 mmol) in DMF (10 mL) was added K2CO3 (763.6 mg, 5.5 mmol) followed by 2-(chloromethyl)quinoline (711 mg, 3.32 mmol). The reaction mixture was then heated at 80° C. for 2 h, quenched with cold water, and extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl) furan-2(5H)-one (190 mg, 19%) as a solid. 1H NMR (500 MHz, d6-DMSO): δ 8.61 (d, J=7.7 Hz, 2H), 8.42 (d, J=7.1 Hz, 1H), 8.04-7.96 (m, 2H), 7.81-7.76 (m, 1H), 7.65 (d, J=7.4 Hz, 1H), 7.60-7.54 (m, 1H), 7.44-7.36 (m, 4H), 7.11 (d, J=7.2 Hz, 2H), 5.40 (s, 2H), 5.34 (s, 2H). MS: M+H: m/z=395.1 and HPLC: 95%, (Condition-H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH3:13][NH:14][CH3:15]>C1COCC1.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8]([N:14]([CH3:15])[CH3:13])(=[O:10])=[O:9])[CH:7]=1
Reactant: CNC
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(F)cc1S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A mixture of 5-fluoro-2-methylbenzene sulfonylchloride (2.1 mL, 14.3 mmol) in THF (18 mL) and 2 M dimethylamine in methanol (18 mL), was stirred at room temperature for 0.5 h. The resulting mixture was concentrated under reduced pressure to give a crude product as a mixture of white solid and colourless oil. The crude product was purified by column (30% EtOAc in Hexane) to give the titled compound as a colourless oil (3.09 g, 99% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C[Al](C)C.[NH:20](/[C:24](/[CH3:30])=[CH:25]\[C:26](OC)=[O:27])[C:21]([CH3:23])=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[C:26](=[O:27])[CH:25]=[C:24]([CH3:30])[N:20]=[C:21]2[CH3:23])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: COC(=O)/C=C(/C)NC(C)=O
Reactant: CCCCCCNc1ccc(N)cc1F
Agent: C[Al](C)C
Solvent: ClCCl
Product: CCCCCCNc1ccc(-n2c(C)nc(C)cc2=O)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.9 %

Procedure:
To a solution of 2-fluoro-N1-hexylbenzene-1,4-diamine (3.36 g, 16 mmol) in CH2Cl2 (20 mL) was added trimethylaluminium (40 mL, 80 mmol, 2 M in toluene) slowly. The mixture was stirred at rt for 0.5 h, followed by the addition of a solution of methyl 3-acetaminocrotonate (3.02 g, 19.2 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred at rt for 72 h, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (150 mL×3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1) to give the title compound as pale yellow oil (1.57 g, 31%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [N:1]1[C:2]([CH2:10][C:11](OCC)=[O:12])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:12][CH2:11][CH2:10][C:2]1[N:1]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[CH:3]=1
Reactant: CCOC(=O)Cc1cn2ccccc2n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1cn2ccccc2n1

Procedure:
A procedure similar to that described in Preparation 2 was repeated, except that 2.65 g of ethyl imidazo[1,2-a]pyridin-2-ylacetate (prepared as described in Preparation 25), 0.5 g of lithium aluminum hydride and 100 ml of tetrahydrofuran were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and ethanol in ratios ranging from 20:1 to 4:1 by volume as the eluent, to give 1.32 g of the title compound, melting at 120.3-126.9° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:10][CH2:9][C@H:8]([OH:11])[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[H-].[Na+].Cl[C:15]1[CH:24]=[N:23][C:22]2[C:17](=[CH:18][C:19]([O:27][CH3:28])=[C:20]([O:25][CH3:26])[CH:21]=2)[N:16]=1>C1COCC1>[CH3:26][O:25][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:27][CH3:28])[N:16]=[C:15]([O:11][C@@H:8]1[CH2:9][CH2:10][C@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6][CH2:7]1)[CH:24]=[N:23]2
Reactant: COc1cc2ncc(Cl)nc2cc1OC
Reactant: CC(=O)O[C@H]1CC[C@@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2ncc(O[C@H]3CC[C@@H](OC(C)=O)CC3)nc2cc1OC

Procedure:
A mixture of cis 4-acetoxy-cyclohexanol (632 mg, 4 mmole) and NaH (60%, 220 mg, 5.5 mmole) in 15 mL of anhydrous THF is refluxed for 0.5 hour before addition of 2-chloro-6,7-dimethoxyquinoxaline (674 mg, 3 mmole). The resulting mixture is continued to be refluxed for two hours. The residue after filtration and concentration is chromatographed on silica gel (ether) to provide acetic acid cis-4-(6,7-dimethoxyquinoxalin-2-yloxy)-cyclohexyl ester (m.p. 150-152° C.). Anal. Calcd. for C18H22N2O5: C, 62.42; H, 6.40; N, 8.09; Found: C, 62.39; H, 6.55; N, 7.82 and cis-4-(6,7-dimethoxyquinoxalin-2-yloxy)cyclohexanol (m.p. 148-150° C.). Anal. Calcd. for C16H20N2O4: C, 63.14; H, 6.62; N, 9.20; Found: C, 62.80; H, 6.76; N, 8.67.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:7][CH:8]=1)=[CH2:2]>CCO.[Pd]>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:7][CH:8]=1)[CH3:2]
Reactant: C=Cc1ccc(NC(=O)C(C)(C)C)nc1
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(NC(=O)C(C)(C)C)nc1
Reaction time: 8 h
Yield: 97 %

Procedure:
A catalytic amount of Pd/C was added to a solution of N-(5-vinylpyridin-2-yl)pivalamide (23 g, 0.11 mol) in EtOH (200 mL). The reaction mixture was stirred under hydrogen atmosphere overnight. The catalyst was filtrated off and the solution was concentrated in vacuo to afford N-(5-ethylpyridin-2-yl)pivalamide (22 g, 95%). 1H NMR (CDCl3, 300 MHz) δ 8.15 (d, J=8.4, 1H), 8.09 (d, J=2.4, 1H), 7.96 (br s, 1H), 7.54 (dd, J=8.4 and 2.4, 1H), 2.61 (q, J=7.5, 2H), 1.30 (s, 9 H), 1.23 (t, J=7.5, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH:18][C:19]2[CH:28]=[CH:27][C:26]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:20]=2[C:29]([O:31]C)=[O:30])(=[O:17])=[O:16])[CH2:3][CH2:2]1.[CH2:33]([CH:35]([CH2:38][CH3:39])[CH:36]=O)[CH3:34].C([BH3-])#N.[Li+].[OH-]>CN(C=O)C.C(O)(=O)C>[CH2:33]([CH:35]([CH2:38][CH3:39])[CH2:36][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH:18][C:19]2[CH:28]=[CH:27][C:26]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:20]=2[C:29]([OH:31])=[O:30])(=[O:17])=[O:16])[CH2:3][CH2:2]1)[CH3:34]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2NCC2CCNCC2)ccc2c1CCCC2
Reactant: CCC(C=O)CC
Agent: [BH3-]C#N
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCC(CC)CN1CCC(CNc2ccccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)CCCC3)CC1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 20.5 %

Procedure:
A mixture of Example 557B (0.026 g, 0.06 mmol) in DMF (2.5 mL) was treated with acetic acid (0.01 mL) and 2-ethylbutanal (0.025 g, 0.06 mmol). The mixture was shaken at 50° C. for 20 minutes, treated with macroporous polystyrene bound cyanoborohydride resin (85 mg, 0.2 mmol), shaken at 70° C. for 5 hours, and filtered. The filtrate was concentrated, dissolved in 1 mL 2:1 dioxane water, treated with LiOH (25 mg, 0.6 mmol) and heated to 160° C. for 30 minutes in a microwave reactor. The reaction mixture was concentrated and the residues purified by C18 reverse-phase HPLC using acetonitrile/water/0.1% TFA to provide the desired product (6.5 mg). MS (ESI(+)) m/e 528 (M+H)+; (ESI(−)) m/e 526 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 7.51 (dd, 1H), 7.38 (dt, 1H), 6.94 (d, 1H), 6.84 (d, 1H), 6.62 (m, 2H), 6.07 (m, 1H), 3.13 (m, 2H), 2.95-2.80, (m, 4H), 2.66 (m, 4H), 1.83 (m, 3H), 1.66 (m, 5H), 1.34 (m, 6H), 0.85 (t, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:26]2=[CH:27][CH:28]=[N:29][CH:30]=[C:25]2[C:5]2[C:6]([OH:24])=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:11])=[CH:9][C:4]=2[O:3]1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[C:32]([O:24][C:6]1[C:5]2[C:25]3[C:26]([C:2]([CH3:1])([CH3:31])[O:3][C:4]=2[CH:9]=[C:8]([CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:11])[CH:7]=1)=[CH:27][CH:28]=[N:29][CH:30]=3)(=[O:34])[CH3:33]
Reactant: CCCCCCCCCCCCC(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCC(C)c1cc(OC(C)=O)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
10-Acetoxy-5,5-dimethyl-8-(2-tetradecyl)-5H-[1]benzopyrano[3,4-d]pyridine is prepared by reacting 5,5-dimethyl-10-hydroxy-8-(2-tetradecyl)-5H-[1]benzopyrano[3,4-d]pyridine and acetic anhydride in the presence of pyridine according to the method of Example 12.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([C:20]3[CH:21]=[CH:22][C:23]([NH2:26])=[N:24][CH:25]=3)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:27][S:28]([NH2:31])(=[O:30])=[O:29].C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1>[NH2:26][C:23]1[N:24]=[CH:25][C:20]([C:10]2[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:13]=[C:8]([C:7]3[C:2]([NH:31][S:28]([CH3:27])(=[O:30])=[O:29])=[N:3][CH:4]=[CH:5][CH:6]=3)[CH:9]=2)=[CH:21][CH:22]=1
Reactant: CS(N)(=O)=O
Reactant: Nc1ccc(-c2cc(-c3cccnc3F)nc(N3CCOCC3)n2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)Nc1ncccc1-c1cc(-c2ccc(N)nc2)nc(N2CCOCC2)n1
Temperature: 125 °C

Procedure:
To a solution of 5-[6-(2-fluoro-pyridin-3-yl)-2-morpholin-4-yl-pyrimidin-4-yl]-pyridin-2-ylamine (200 mg, 0.57 mmol) and methanesulfonamide (216 mg, 2.3 mmol) in NMP (8 mL) was added Cs2CO3 (372 mg, 1.1 mmol). The solution was heated at 125° C. for 4 hours. The reaction mixture was cooled to room temperature, filtered and purified by reverse phase preparatory HPLC to give the title compound. LC/MS (m/z): 428.3 (MH+), Rt 1.80 minutes.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[N:20]([CH3:28])[N:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=3)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][C:30]1([CH3:42])[O:34][C@H:33]([CH2:35][N:36]2[CH:40]=[CH:39][C:38]([NH2:41])=[N:37]2)[CH2:32][O:31]1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[N:20]([CH3:28])[N:21]=[C:22]([C:24]([F:26])([F:25])[F:27])[CH:23]=3)[CH:13]=[N:12]2)[C:8]([NH:41][C:38]2[CH:39]=[CH:40][N:36]([CH2:35][C@@H:33]3[CH2:32][O:31][C:30]([CH3:42])([CH3:29])[O:34]3)[N:37]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cn1nc(C(F)(F)F)cc1Oc1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Product: Cn1nc(C(F)(F)F)cc1Oc1cnn(C(CC2CCCC2)C(=O)Nc2ccn(C[C@@H]3COC(C)(C)O3)n2)c(=O)c1

Procedure:
Using the method described in Example 49, 3-cyclopentyl-2-[4-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 81) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 3-cyclopentyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-2-[4-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionamide as an off-white solid as a mixture of diastereomers (1.27 g, 88%).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15]C)[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([NH2:22])=[O:21])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([NH2:22])=[O:21])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1nccc2c1c(-c1cccc(C(N)=O)c1)nn2C1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: NC(=O)c1cccc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
To a solution of 3-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzamide (61.2 mg) in acetonitrile (10 mL) were added sodium iodide (54.5 mg) and chloro(trimethyl)silane (0.184 mL), and the mixture was stirred at 60° C. for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate), and the obtained solid was washed with ethyl acetate to give the title compound (50.6 mg).