Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5]1.[CH:14]1([C:21](Cl)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>N1C=CC=CC=1>[O:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:12][CH2:13][CH:4]1[CH2:3][NH:2][C:21]([CH:14]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:22]
Reactant: NCC1CCc2ccccc2O1
Reactant: O=C(Cl)C1CCCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(NCC1CCc2ccccc2O1)C1CCCCCC1
Reaction time: 1 h

Procedure:
5.0 g (25 mmol) of 2-aminomethylchroman hydrochloride are dissolved in 50 ml of pyridine; 5.6 g (35 mmol) of cycloheptanecarbonyl chloride are added dropwise to this solution. After 1 hour at 50° C., the mixture is concentrated and the residue is partitioned between water and toluene/ethyl acetate 1:1. The organic phase is filtered over silica gel. The desired product is eluted with toluene/ethyl acetate 5:1. The amide obtained after concentration is further reacted directly.
Reaction SMILES: C[O:2][C:3]1[C:4](=O)[CH:5]([C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:6][C:7]([CH3:10])([CH3:9])[CH:8]=1.[CH3:19][NH:20][NH2:21].[C:22](O)(=[O:24])C>O>[OH:24][CH:22]=[C:8]1[C:3](=[O:2])[C:4]2[N:20]([CH3:19])[N:21]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]=2[CH2:6][C:7]1([CH3:10])[CH3:9]
Reactant: CCOC(=O)C(=O)C1CC(C)(C)C=C(OC)C1=O
Reactant: CNN
Reactant: CC(=O)O
Solvent: O
Product: CCOC(=O)c1nn(C)c2c1CC(C)(C)C(=CO)C2=O
Reaction time: 24 h
Yield: 67.6 %

Procedure:
A solution of ethyl (3-methoxy-5,5-dimethyl-2-oxocyclohex-3-en-1-yl)(oxo)acetate (15.50 g, 0.061 mol) in acetic acid (100 mL) was treated dropwise with a solution of methyl hydrazine (3.49 mL, 0.066 mol) dissolved in acetic acid (50 mL). After 24 hours at room temperature, the reaction mixture was diluted with water (2 L) under vigorous stirring. The resulting precipitate was filtered and washed with water to obtain the title compound (10.30 g, 67.6% yield) as a yellow solid.
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[C:7]1([N:13]2[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=3[N:15]=[C:14]2SC)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:24](Cl)(Cl)Cl>>[C:7]1([N:13]2[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=3[N:15]=[C:14]2[S:3]([CH3:24])(=[O:5])=[O:2])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CSc1nc2c(n1-c1ccccc1)CCCC2
Reactant: ClC(Cl)Cl
Reactant: O=S([O-])OO
Agent: [K+]
Product: CS(=O)(=O)c1nc2c(n1-c1ccccc1)CCCC2
Temperature: 0 °C
Yield: 62 %

Procedure:
3.8 g of previously moistened alumina, 7.07 g (11.5 mmol) of oxone and 10 ml of chloroform are vigorously stirred. A solution of 0.9 g (3.7 mmol) of 1-phenyl-2-methylthio-4,5,6,7-tetrahydro-1H-benzimidazole, solubilized in 10 ml of chloroform, is added to this medium and then the stirring is continued while heating under reflux for 2 hours. The mixture is cooled to 0° C. and then filtered, the solid is rinsed with 10 ml of chloroform and 10 ml of a 9/1 THF/CH3OH mixture. The filtrate is concentrated under reduced pressure and then purified on a silica column with the aid of a 99/1 then 98/2 dichloromethane/methanol mixture. 0.65 g of product is obtained. Yield=62%.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]=[C:10]([Cl:16])[C:11]([C:14]#[N:15])=[N:12][CH:13]=2)[CH2:3]1.[N:17]1[CH:18]=[CH:19][N:20]2[CH:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[CH:22][C:21]=12.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Cl:16][C:10]1[N:9]=[C:8]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:2]([NH:1][C:26]([C:24]3[CH:23]=[CH:22][C:21]4[N:20]([CH:19]=[CH:18][N:17]=4)[CH:25]=3)=[O:27])[CH2:3]2)[CH:13]=[N:12][C:11]=1[C:14]#[N:15]
Reactant: N#Cc1ncc(N2CCC[C@@H](N)C2)nc1Cl
Reactant: O=C(O)c1ccc2nccn2c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1ncc(N2CCC[C@@H](NC(=O)c3ccc4nccn4c3)C2)nc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-5-(3-Aminopiperidin-1-yl)-3-chloropyrazine-2-carbonitrile (221, HCl salt, 350 mg, 1.28 mmol) was dissolved in 10 mL DMF. To it were added imidazo[1,2-a]pyridine-6-carboxylic acid (310 mg, 1.92 mmol), DIEA (890 μL, 5.12 mmol) and then PyBOP (1.00 g, 1.92 mmol). The mixture was stirred at RT for 1 hour, diluted with 100 mL EtOAc, washed with water ×3, dried, concentrated, and subjected to silica flash column using 0 to 7% MeOH in DCM to isolate (R)—N-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide (473). Compound 473 (75 mg, 0.20 mmol) was mixed with 4-(tetrahydro-2H-pyran-4-yl)aniline (106 mg, 0.60 mmol), fine-powder cesium carbonate (326 mg, 1.00 mmol), palladium acetate (22 mg, 0.10 mmol), BINAP (62 mg, 0.10 mmol) in 15 mL dioxane. The mixture was degassed using nitrogen stream for 3 min, and stirred in nitrogen atmosphere at 115° C. for 1 hour. It was cooled to RT, diluted with 50 mL EtOAc, stirred and filtered. The filtrate was concentrated and subjected to silica flash column using 0 to 11% MeOH in DCM to isolate (R)—N-(1-(5-cyano-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)pyrazin-2-yl)piperidin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide (474). It was dissolved in 10 mL MeOH and 3 mL DMSO. To it were added one NaOH solid bead (about 100 mg) and 1 mL 30% H2O2. The mixture was stirred at RT for 1.5 hour, quenched with 5 mL MeCN, stirred, concentrated, acidified with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate the title compound, (R)—N—O-(5-carbamoyl-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)pyrazin-2-yl)piperidin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide (475) (24 mg) as HCl salt, and also the by-product, (R)—N—O-(5-carbamoyl-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)pyrazin-2-yl)piperidin-3-yl)-5-hydroxyimidazo[1,2-a]pyridine-6-carboxamide (476) (15 mg) as HCl salt. For compound 475, LC-MS (ESI): m/z (M+1) 541.3. UV: λ=304, 336, 373 nm. Proton NMR (CD3OD): δ 9.26 (1H, s), 8.30 (2H, m), 8.14 (1H, d, J=2.0 Hz), 7.99 (1H, d, J=9.5 Hz), 7.66 (1H, s), 7.51 (2H, d, J=9.0 Hz), 7.11 (2H, d, J=9.0 Hz), 4.41 (1H, m), 4.21 (1H, m), 4.10 (1H, m), 3.92 (2H, m), 3.44 (4H, m), 2.66 (1H, m), 2.16 (1H, m), 1.97 (1H, m), 1.84 (1H, m), 1.76 (1H, m), 1.62 (3H, m), 1.56 (1H, m) ppm.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:12][C:13]([CH3:18])([CH3:17])[CH2:14][CH2:15][NH2:16]>C(O)C>[CH2:10]([O:9][C:7]([C:3]1[CH2:4][CH2:5][CH2:6][C:2]=1[NH:16][CH2:15][CH2:14][C:13]([CH3:18])([CH3:17])[CH3:12])=[O:8])[CH3:11]
Reactant: CC(C)(C)CCN
Reactant: CCOC(=O)C1CCCC1=O
Solvent: CCO
Product: CCOC(=O)C1=C(NCCC(C)(C)C)CCC1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of ethyl 2-oxocyclopentanecarboxylate (4.10 mL, 26.3 mmol) in ethanol (50 mL) was added 3,3-dimethylbutylamine (2.80 g, 26.8 mmol) at 25° C. The mixture was heated at reflux for 12 h. The reaction mixture was allowed to cool to 25° C. and concentrated in vacuo. The crude material was purified by flash column chromatography (Teledyne Isco RediSep Flash Column; 0-20% ethyl acetate in hexanes) to afford the desired product, 2-(3,3-dimethylbutylamino)-cyclopent-1-enecarboxylic acid ethyl ester (5.59 g, 23.4 mmol, 89%), as a yellowish oil. 1H NMR (400 MHz, CDCl3) δ 0.94 (9H, s), 1.28 (3H, t, J=7.0 Hz), 1.46-1.50 (2H, m), 1.80-1.88 (2H, m), 2.51-2.58 (4H, m), 3.16-3.21 (2H, m), 4.14 (2H, q, J=7.0 Hz).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:13]([CH3:32])[O:12]C1O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([Si](C)(C)C)[CH:34]=[CH2:35].[CH3:40][Si](OS(C(F)(F)F)(=O)=O)(C)C>C(#N)C>[CH2:34]([C@@H:35]1[O:12][C@@H:13]([CH3:32])[C@@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:9]1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:33]=[CH2:40]
Reactant: C=CC[Si](C)(C)C
Reactant: C[C@@H]1OC(O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: C=CC[C@@H]1O[C@@H](C)[C@@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 79 %

Procedure:
To a solution of 2,3,4-tri-O-benzyl-L-fucopyranose (11a, 10.0 g) in acetonitrile (100 ml) at 0° C., allyltrimethylsilane (12 ml) was added followed by trimethylsilyltrifluoromethanesulfonate (14.5 ml). The solution was warmed to room temperature and was stirred for 14 hours at room temperature. The mixture was quenched with water (100 ml) in an ice-water bath. The acetonitrile was evaporated in vacuo and the mixture was extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with saturated sodium carbonate solution, followed by saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude mixture was eluted on a silica gel column (150 ml, hexane:ethyl acetate, 10:1) to provide 1-allyl-1-deoxy-2,3,4-tri-O-benzyl-α-L-fucopyranose (11b, 9.2 g, 79%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=3)[N:19]=2)[N:3]=1.N1C=CC=CC=1.[CH3:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>C(Cl)Cl>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([N:44]3[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]3)(=[O:16])=[O:15])[CH:9]=2)[N:5]=[C:4]([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][C:30]([F:31])([F:32])[F:33])=[CH:27][CH:28]=3)[N:19]=2)[N:3]=1
Reactant: CN1CCNCC1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(S(=O)(=O)N2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)benzene-1-sulfonyl chloride (50 mg, 0.1 mmol) in DCM (5 mL) were added pyridine (0.05 ml) and 1-methylpiperazine (20 mg, 0.2 mmol). The mixture was stirred at RT for 1 h, then diluted with DCM and washed with H2O (100 mL). The aqueous layer was separated and extracted with DCM (2×100 mL), the combined organic layers were washed with brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by prep-HPLC (Mobile phase: A=0.1% formic acid/H2O, B=MeCN; Gradient: B=36%-95% in 18 min; Column: XBridge C18, 5 um, 30 mm×150 mm) to give the title compound as a white solid; MS (ES+) C21H19F3N6O4S requires: 508. found: 509 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ ppm 8.28 (d, J=8 Hz, 2H), 7.86 (bs, 1H), 7.84 (m, 1H), 7.64 (m, 2H), 7.50 (d, J=7.5 Hz, 2H), 5.67 (s, 2H), 3.98 (m, 2H), 3.61 (m, 2H), 3.26 (m, 2H), 2.90 (s, 3H), 2.74 (m, 2H), 2.69 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:38](=[O:44])OC(Cl)(Cl)Cl)Cl.[S:46]1[CH:50]=[CH:49][N:48]=[C:47]1[CH:51]([NH2:53])[CH3:52]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38]([NH:53][CH:51]([C:47]2[S:46][CH:50]=[CH:49][N:48]=2)[CH3:52])=[O:44])=[C:18]([C:23]([F:25])([F:26])[F:24])[CH:17]=1
Reactant: CC(N)c1nccs1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C(F)(F)F)c3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC(C)c4nccs4)c(C(F)(F)F)c3)c2cc1OC
Yield: 67.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-(trifluoromethyl)aniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room is temperature for one hr. Next, a solution of 1-(1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (29 mg, yield 68%).
Reaction SMILES: [OH:1]N1C(=O)CCC1=O.[CH2:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10].O=O>C(O)(=O)C.O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:1])[CH3:10]
Reactant: CCc1ccccc1
Reactant: O=C1CCC(=O)N1O
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)c1ccccc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
In this example, a solution of 0.1158 g (1.01 mmol) of N-hydroxysuccinimide, 0.544 g (5.13 mmol) of ethylbenzene and 0.1158 g (0.46 mmol) of cobalt acetate tetrahydrate in 40 ml of acetic acid was heated to 30° C. in a Parr Hastelloy reactor with temperature and pressure transducer. After the temperature reached 30° C., 233 psi of air was slowly introduced to the reactor. The mixture was stirred under pressure for one hour at 30° C., then the pressure was released, and the mixture was cooled to room temperature. A slow temperature rise (due to heat generated by the exothermic oxidation) within roughly 30 minutes following O2 introduction, accompanied by a drop in reactor pressure (due to consumption of O2 in the liquid phase reaction) indicates rapid reaction following induction. These profiles are steep and level off within minutes after induction. The reaction product mixture was extracted by ethyl acetate, then washed by water and saturated NaCl, dried over Na2SO4 to give acetophenone 80% and starting material 20% analysis by GC-MS and HPLC.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:13][CH2:12][O:11][C:10]2=[O:14])=[CH:6][CH:5]=1)([O-])=O.O.O.Cl[Sn]Cl.[OH-].[Na+].C(Cl)Cl>C(O)C>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:13][CH2:12][O:11][C:10]2=[O:14])=[CH:6][CH:5]=1
Reactant: O=C1OCCN1Cc1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: Nc1ccc(CN2CCOC2=O)cc1

Procedure:
A solution of the compound obtained in Step A (0.244 mol) and SnCl2.2H2O (1.0 mol) in ethanol (300 ml) is stirred at reflux for 20 minutes. The solution is brought to 0° C. and made alkaline at pH=10-12 with aqueous sodium hydroxide solution; 500 ml of DCM are added and the emulsion obtained is filtered over Celite. The filtrate is then extracted with DCM (2×300 ml); the organic phases are combined. The organic phase obtained is washed with water and with saturated aqueous NaCl solution, dried over sodium sulphate and then filtered. The filtrate obtained is evaporated to dryness to yield the title product, which is used directly in the next Step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.Cl[CH2:31][C:32](Cl)=[O:33].C(N(CC)CC)C.[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([C:32](=[O:33])[CH2:31][N:46]4[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]4)[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: CN1CCNCC1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(C(=O)CN5CCN(C)CC5)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (100.0 mg, 0.24 mmol) in 4 mL of DCM was added 2-chloroacetylchloride (23.0 uL, 0.29 mmol) and triethylamine (67.0 uL, 0.48 mmol) sequentially. The reaction was stirred at room temperature for 1 h then washed by brine. The organic extract was dried over Na2SO4, followed by concentration in vacuo to afford a crude product. The crude product was mixed with 1-methylpiperazine (116.0 mg, 1.16 mmol) in 3 mL of DMF and the reaction was stirred overnight at room temperature. The reaction mixture was purified by preparative HPLC to afford 1-(4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidin-1-yl)-2-(4-methylpiperazin-1-yl)ethanone. ESMS m/z 556.3 (M+H+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)=[O:16])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[C].[Pd].CC(O)C>[NH:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]([N:17]2[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]2)=[O:16])[CH2:12][CH2:13]1
Reactant: O=C(CC1CCN(Cc2ccccc2)CC1)N1CCC(O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: O=C(CC1CCNCC1)N1CCC(O)CC1
Temperature: 80 °C
Yield: 89.4 %

Procedure:
14.2 g (0.05 mol) of 1-(1-benzyl-4-piperidylacetyl)-4-hydroxypiperidine [1] and 127.9 g of 2-propanol were mixed with each other. To this mixture, 1.42 g of 5% palladium-carbon (containing water at 50% content) was added. The reaction was allowed to proceed for 14 hours at 50° C. under the flow of hydrogen. The catalyst was removed by filtration therefrom, and the filtrate was concentrated under a reduced pressure. 23.6 g of acetonitrile was added to the concentrated residue, and the temperature of the mixture was increased to a reflux temperature of 80° C. The crystals which precipitated at room temperature were collected by filtration and the resultant wet crystals were dried under a reduced pressure, whereby 9.08 g of the title compound in the state of white powder was obtained (the yield was 89.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([O:12]C(=O)C)[CH:4]=1.[NH2:16][C@H:17]1[CH2:22][C:21]2[C:23]([N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[CH:24][CH:25]=[CH:26][C:20]=2[O:19][CH2:18]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:33][N:30]1[CH2:31][CH2:32][N:27]([C:23]2[C:21]3[CH2:22][C@H:17]([NH:16][C:7](=[O:9])[C:6]4[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[OH:12])[CH2:18][O:19][C:20]=3[CH:26]=[CH:25][CH:24]=2)[CH2:28][CH2:29]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Reactant: COc1ccc(C(=O)O)c(OC(C)=O)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: COc1ccc(C(=O)N[C@@H]2COc3cccc(N4CCN(C)CC4)c3C2)c(O)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 30.2 %

Procedure:
A solution of 4-methoxy-2-acetoxybenzoic acid (232 mg, 1.10 mmol; described in: Schonhofer, F. Ber Deutsch Chem Ges 1951, 84, 13) in thionyl chloride (5 mL) was heated at 55° C. for 30 min. The excess of thionyl chloride was removed in vacuo, and the residue was evaporated with two portions of toluene. The acid chloride was then dissolved in anhydrous methylene chloride (5 mL) and added to a stirred solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (248 mg, 1.00 mmol) and triethylamine (210 μL, 1.50 mmol) in anhydrous methylene chloride (20 mL). The reaction mixture was stirred at room temperature for 2.5 h after which the mixture was washed with a saturated NaHCO3 solution, dried (MgSO4), and the solvent was removed in vacuo. The residue was dissolved in absolute ethanol (20 mL), and conc. NH3 (5 mL) was added. The mixture was stirred overnight. The solvent was removed in vacuo, and the remains was purified by column chromatography on silica (eluent: chloroform/ethanol; 92:8+0.5% conc. NH3) affording 120 mg (33% yield) of the title compound as a white solid: mp sinters>80° C.; [α]21D−92° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 397 (27, M+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[SH:11][C:12]1[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:17][N:13]1[CH:14]=[CH:15][N:16]=[C:12]1[S:11][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cn1ccnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccnc1Sc1ccc([N+](=O)[O-])cc1
Yield: 87.6 %

Procedure:
1-fluoro-4-nitrobenzene (5.0 g), 2-mercapto-1-methylimidazole (4.04 g) and potassium carbonate (14.7 g) were added to. DMF (100 ml), and the mixture was stirred for 2 hours under argon atmosphere at 130° C. After the mixture was allowed to be at room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water three times, further washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethyl acetate-diisopropyl ether, to give 1-methyl-2-[(4-nitrophenyl)thio]imidazole (7.29 g) as yellow crystals.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:11])=[C:7]([CH:10]=1)[CH:8]=[O:9].Cl.N1C=CC=CC=1>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:11])=[C:7]([CH:10]=1)[CH:8]=[O:9]
Reactant: COc1ccc(C)c(C=O)c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(O)cc1C=O
Temperature: 170 °C
Yield: 47.2 %

Procedure:
A stirred mixture of 5-methoxy-2-methylbenzaldehyde (24.9 g) and pyridine hydrochloride (100 g) is heated at 170° C. for 7 hours. Water (250 mL) is added cautiously to the reaction mixture at 140° C. and the very dark mixture is extracted twice with chloroform (250 mL), filtration through hyflo removes a small amount of insoluble black solid and aids separation. The organic phase is washed with 1 N hydrochloric acid (250 mL), with water (250 mL), with brine (250 mL), dried over magnesium sulphate and evaporated. The residue is washed with pentane to give 5-hydroxy-2-methylbenzaldehyde (10.66 g) as a cream solid, m.p. 116-118° C.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:12][C@H:13]1[CH2:17][CH2:16][CH2:15][C@@:14]1([CH3:19])[OH:18].C(=O)([O-])[O-].[Li+].[Li+]>CS(C)=O.O.CCOC(C)=O>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@:14]2([OH:18])[CH3:19])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(F)ccc(C#N)c1Cl
Reactant: C[C@@]1(O)CCC[C@@H]1N
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(N[C@H]2CCC[C@@]2(C)O)ccc(C#N)c1Cl
Temperature: 130 °C
Yield: 24 %

Procedure:
In a sealed pressure vessel, a mixture of 2-chloro-4-fluoro-3-methyl-benzonitrile (1.2 g, 7.08 mmol), (1R,2S)-2-amino-1-methyl-cyclopentanol (1.63 g, 14.2 mmol) and lithium carbonate (1.10 g, 14.9 mmol) in DMSO (14.4 mL) and water (1.4 mL) is heated at 130° C. overnight. After allowing the reaction to cool to room temperature, the mixture is diluted with EtOAc and washed twice with 1 N hydrochloric acid. The organic phase is concentrated under reduced pressure and purified using radial chromatography eluting with EtOAc/hexanes (20 to 50% EtOAc/hexanes gradient). The resulting residue is repurified using radial chromatography with 1% methanol/dichloromethane. The isolated product is recrystallized with ether/hexanes, collected by filtration, and dried under reduced pressure to yield the title compound as a white solid (450 mg, 24%). A second crop (84 mg) is also isolated. LC-ES/MS m/z (35Cl/37Cl) 265/267 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 1.16 (s, 3H), 1.71-1.73 (m, 5H), 2.12-2.13 (m, 1H), 2.14 (s, 3H), 3.46-3.50 (m, 1H), 4.93 (s, 1H), 5.26-5.30 (m, 1H), 6.63 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.6 Hz, 1H). Chiral HPLC showed the material had an enantiomeric excess of 67%. The enantiomeric excess is determined by SFC on a CHIRALPAK® AS-H (4.6×150 mm, 5 μm) column using 20% ethanol/carbon dioxide. Flow rate: 5 mL/min. Detection: 225 nm. Isomer 1 (title compound): TR=1.39 min; Isomer 2: TR=1.99 min. The absolute stereochemistry of Isomer 1 (1S,2R) is known by correlation of retentions times with Isomer 1 and Isomer 2 as described in Example 3.