Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[C:6]([NH:12][C:13]3[N:18]=[C:17]([NH:19][CH:20]4[CH2:30][CH2:29][C:23]5([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[CH2:22][CH2:21]4)[C:16]([CH3:31])=[CH:15][N:14]=3)[CH:7]=[CH:8]2)=[N:3]1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.[C:60]([CH2:62][C:63](O)=[O:64])#[N:61]>C(Cl)Cl.CN(C=O)C>[CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[C:6]([NH:12][C:13]3[N:18]=[C:17]([NH:19][CH:20]4[CH2:30][CH2:29][C:23]5([CH2:28][CH2:27][N:26]([C:63](=[O:64])[CH2:62][C:60]#[N:61])[CH2:25][CH2:24]5)[CH2:22][CH2:21]4)[C:16]([CH3:31])=[CH:15][N:14]=3)[CH:7]=[CH:8]2)=[N:3]1
Reactant: N#CCC(=O)O
Reactant: Cc1cnc(Nc2ccc3c(C)n(C)nc3c2)nc1NC1CCC2(CCNCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cnc(Nc2ccc3c(C)n(C)nc3c2)nc1NC1CCC2(CC1)CCN(C(=O)CC#N)CC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 20.5 %

Procedure:
To a solution of N2-(2,3-dimethyl-2H-indazol-6-yl)-5-methyl-N4-(3-azaspiro[5.5]undecan-9-yl)pyrimidine-2,4-diamine (203.2 mg, 0.4843 mmol), HOAT (105.8 mg, 0.7773 mmol) and EDCI (144.5 mg, 0.7538 mmol) in DCM/DMF (4 mL/1 mL) were added N,N-diethylethanamine (209.1 mg, 2.066 mmol) and 2-cyanoacetic acid (48.1 mg, 0.565 mmol). The reaction was stirred at rt for 2.5 h and then concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to give the title compound as a light pink solid (48.4 mg, 20.4%).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[OH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](O)[CH:21]=1>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:1]([NH:11][C@H:12]([C:16]([O:18][C:22]1[CH:21]=[C:20]([OH:19])[CH:25]=[CH:24][CH:23]=1)=[O:17])[CH:13]([CH3:14])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Oc1cccc(O)c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1cccc(O)c1
Reaction time: 8 h
Yield: 79.4 %

Procedure:
CBz-L-valine (10 g, 40 mmol), 1,3-dihydroxybenzene (8.7 g, 79 mmol) N,N′dicychlohexylcarbodiimide (10.2 g, 44 mmol) and 4-dimethylaminopyridine (2.4 g, 20 mmol) were dissolved in DMF (50 ml) and left at ambient temperature overnight. The reaction mixture was filtered, the solvent removed under reduced pressure and the crude product was taken up in dichloromethane and filtered. Removal of the solvent followed by purification by chromatography (chloroform-methanol, 10:1) yielded pure title product (10.9 g, 79%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:15])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:26][CH:27]=1>>[ClH:1].[CH2:13]([O:12][C:9]1[CH:10]=[C:11]2[C:6](=[N:7][C:8]=1[CH3:15])[N:5]=[CH:4][C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:2]2[NH:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:26][CH:27]=1)[CH3:14]
Reactant: CCOC(=O)c1cnc2nc(C)c(OCC)cc2c1Cl
Reactant: Nc1ccc(Oc2ccccc2)nc1
Product: CCOC(=O)c1cnc2nc(C)c(OCC)cc2c1Nc1ccc(Oc2ccccc2)nc1
Product: Cl

Procedure:
A mixture of ethyl 4-chloro-6-ethoxy-7-methyl-1,8-naphthyridine-3-carboxylate (2.3 g), 5-amino-2-phenoxypyridine (1.52 g) and IMS (50 ml) was boiled under reflux for 2 hours. The mixture was cooled in ice and filtered to give ethyl 6-ethoxy-7-methyl-4-(2-phenoxy-5-pyridylamino)-1,8-naphthyridine-3-carboxylate hydrochloride, m.p. 220°-221° C.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH2:27][CH2:28][CH:29]4[CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]4)[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[NH:31]1[CH2:30][CH:29]([CH2:28][CH2:27][N:19]2[C:20]3[C:25](=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[C:17]([C:14]3[N:15]=[C:16]4[C:8]([C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:9][NH:10][C:11]4=[N:12][CH:13]=3)=[N:18]2)[CH2:32]1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCC4CN(C(=O)OC(C)(C)C)C4)c4cc(F)ccc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(CCC4CNC4)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.7 %

Procedure:
To a pale yellow solution of tert-butyl 3-(2-(3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-6-fluoro-1H-indazol-1-yl)ethyl)azetidine-1-carboxylate (43 mg, 64.6 μmol) in dichloromethane (4.00 mL) was added TFA (740 mg, 500 μL, 6.49 mmol00), the reaction mixture turned orange and was stirred at 25° C. for 18 h. The reaction mixture was concentrated and the residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1) and stirred at 25° C. for 1 h, then evaporated to a yellow solid which was dissolved in dichloromethane (added few drops of MeOH) and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 10% over 30 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. The pure product dissolved in dichloromethane with few drops of MeOH and cyclohexane added to allow solid formation, off-white solid separated by decantation and dried under high vacuum to give 2-(1-(2-(azetidin-3-yl)ethyl)-6-fluoro-1H-indazol-3-yl)-N-tert-butyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (23 mg, 52.8 μmol, 81.8%). MS (M+H)+=436; 1H NMR (DMSO-d6) δ: 9.08 (s, 1H), 8.48 (dd, J=8.7, 5.3 Hz, 1H), 8.39 (s, 1H), 7.90 (s, 1H), 7.77 (dd, J=9.8, 1.9 Hz, 1H), 7.16 (td, J=9.1, 1.9 Hz, 1H), 4.49 (t, J=6.6 Hz, 2H), 3.68-3.85 (m, 2H), 3.44-3.56 (m, 2H), 2.75 (dt, J=15.2, 7.7 Hz, 1H), 2.20 (q, J=6.7 Hz, 2H), 1.51 (s, 9H).
Reaction SMILES: CN(C)C=O.[C:6]([C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][C:16]([OH:18])=O)=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7].Cl.[NH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[C:26]([F:35])[CH:25]=1.Cl.C(N=C=NCCCN(C)C)C>C(N(CC)CC)C>[C:6]([C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][C:16]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[C:26]([F:35])[CH:25]=2)=[O:18])=[CH:19][CH:20]=1)([CH3:7])([CH3:8])[CH3:9]
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(OCC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 722.2 %

Procedure:
To a N,N-dimethylformamide (DMF) (10 ml) solution of (4-tert-butylphenoxy)acetic acid (50 mg, 0.2 mmol) and N-[4-(aminomethyl)-2-fluorophenyl]methanesulfonamide hydrochloride (40.4 mg, 0.2 mmol, J. Med. Chem. 2003, 46, 3116–3126), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (112 mg, 0.6 mmol), 1-hydroxybenzotriazole(HOBt) monohydrate (catalytic amount 5 mg) and triethylamine (0.3 ml) were added and the mixture was stirred for 3 hours at ambient temperature. The reaction mixture was then quenched with saturated aqueous solution of sodium bicarbonate and then crude products were extracted with methylene dichloride. The organic layer was then washed with brine and dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with methylene dichloride/methanol=9/1 to furnish 0.59 g (75% yield) of the title compound as a white solid.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[C:37]1([P:43]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C1C=CC=CC=1.CCOCC>[Br-:1].[C:13]1([CH:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:11][C:9]([C:8]2[N:7]3[C:25](=[O:36])[C@@H:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)[C@H:6]3[S:5][CH2:4][C:3]=2[CH2:2][P+:43]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:10])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CBr)CS[C@H]12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Product: [Br-]
Yield: 57.5 %

Procedure:
A solution of diphenylmethyl 3-bromomethyl-7β-(2-thienylacetamido)ceph-3-em-4-carboxylate (300 mg.), Rf 0.6 in benzene (5 ml.) was treated with triphenylphosphine (140 mg.) and the total warmed to 50° for 10 minutes. After the mixture had stood at room temperature for a further hour it was diluted with ether and the precipitated solid was collected by filtration. This material was washed thoroughly with ethyl acetate and ether, and on drying in vacuo gave the phosphonium bromide (250 mg.) Rf 0.0 m.p. 135° - 140° C (decomp.) [α]D + 12° (tetrahydrofuran), νmax (CHBr3) 3410 (NH), 1784 (β-lactam), 1710 (CO2R), 1680 and 1515 (CONH) and 1442 (P--C aryl.) cm.-1 τ (CDCl3) 4.38 (C(7) --H, dd, J 4.5 and 9 Hz), 5.19 (C(6) --H, d, J 4.5 Hz), 4.62 and 4.8 (CH2 -- P, two d, JP-H 16 Hz), 6.02 and 6.6 (C(2) -- CH2, two dd, JH-H 18 Hz and JP-H 3-4 Hz).
Reaction SMILES: C[O:2][C:3](OC)([C:5]([C:13]#[N:14])=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:4].CCCCCC.C(OCC)(=O)C>Cl>[C:13]([C:5](=[CH:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:3](=[O:2])[CH3:4])#[N:14]
Reactant: COC(C)(OC)C(C#N)=Cc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)C(C#N)=Cc1ccccc1
Temperature: 25 °C
Yield: 38 %

Procedure:
A sample of 3-cyano-4-phenyl-3-buten-2-one dimethylketal, prepared in accordance with the procedure of Example 5 (5.0 g, 23 mmol) was suspended in 6N HCl (100 mL) and stirred at room temperature for 72 h1. Thin layer chromatographic analysis (SiO2, hexane—ethyl acetate 7:3) indicated nearly complete conversion of the ketal to the lower Rf ketone which had deposited along the bottom of the reaction flask as a yellow solid. The solid was purified by column chromatography (SiO2, hexane—ethyl acetate 9:1) and the desired fractions evaporated to give 1.5 g (38%) of 3-cyano-4-phenyl-3-buten-2-one, as colorless needles, mp 83-84° C. (lit. 80-81° C.2).
Reaction SMILES: [Mg].II.Br[C:5]1[CH:13]=[CH:12][C:8]([N:9]([CH3:11])[CH3:10])=[CH:7][CH:6]=1.[P:14]([O-:21])(OCC)OCC.Cl>C1COCC1.C1(C)C=CC=CC=1.O>[CH3:10][N:9]([CH3:11])[C:8]1[CH:12]=[CH:13][C:5]([PH:14](=[O:21])[C:5]2[CH:13]=[CH:12][C:8]([N:9]([CH3:11])[CH3:10])=[CH:7][CH:6]=2)=[CH:6][CH:7]=1
Reactant: CCOP([O-])OCC
Reactant: CN(C)c1ccc(Br)cc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CN(C)c1ccc([PH](=O)c2ccc(N(C)C)cc2)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
Under an argon atmosphere, a solution of magnesium (3.0 g, 1.0 equivalent) and a small amount of iodine in THF (30 mL) was stirred at room temperature for 1 hr. 4-Bromo-N,N-dimethylaniline (25 g, 0.125 mol) was added at 45° C., and the mixture was stirred at 5° C. for 1 hr. Then, diethyl phosphite (8.63 g, 0.50 equivalent) was added at 5° C., and the mixture was stirred at 5° C. for 1 hr. Water (30 mL) was added at 3° C., and then toluene (60 mL) and 6M—HCl (30 mL) were added. The mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned, and the aqueous layer was neutralized with NaOH and extracted with THF (30 mL). The combined organic layer was dried over anhydrous magnesium sulfate, filtered by gravity, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from diisopropyl ether to give the title compound (9.53 g, slightly brown white crystals). yield 52.9%. melting point: 152.1° C.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:15].[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19]>N1C=CC=CC=1>[CH3:16][C:17]([CH3:22])([CH3:21])[C:18]([NH:15][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]=3[C:9]=2[CH:1]=1)=[O:19]
Reactant: Nc1ccc2oc3c(c2c1)CCCCC3
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 84.1 %

Procedure:
Following the procedure of Example 1, 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (1.0 g, 5.0 mmol) and trimethylacetyl chloride (0.68 mL, 5.5 mmol) in pyridine (10 mL) provided 2,2-dimethyl-N-(6,7,8,9-tetrahydro-5H-10-oxa-benzo[a]azulen-3-yl)-propionamide (1.2 g). Mp 208-209° C.; Anal. Calcd. for C18H23NO2: C, 75.76; H, 8.12; N, 4.91; Found: C, 76.06; H, 8.03; N, 4.94.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:31])[CH:3]=1.[C:32]1([CH2:38][C:39]([N:41]=[C:42]=[O:43])=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1.CCCCCC.C(OCC)(=O)C>[F:31][C:4]1[CH:3]=[C:2]([NH:1][C:42]([NH:41][C:39](=[O:40])[CH2:38][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:43])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4F)ccn3)CC2)CC1
Reactant: O=C=NC(=O)Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)NC(=O)Cc5ccccc5)cc4F)ccn3)CC2)CC1
Reaction time: 5 h
Yield: 61 %

Procedure:
To a solution of 4-(4-amino-2-fluorophenoxy)-2-{[4-(1-methylpiperidin-4-yl)piperazin-1-yl]carbonylamino}pyridine (811 mg) in tetrahydrofuran (50 ml) was added a solution of 2-phenylacetyl isocyanate in hexane (0.25 M, 17 ml) at room temperature, followed by stirring for 5 hours. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, ethyl acetate:methanol=97:3). Fractions containing the target compound were concentrated to give a residue, which was then suspended in ethyl acetate (8 ml) and hexane (16 ml). The crystals were filtered off and dried under aeration to provide the titled compound (629 mg, 61%) as white crystals.
Reaction SMILES: O=[Zn:2].[C:3]([OH:22])(=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[C:3]([O-:22])(=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[Zn+2:2].[C:3]([O-:22])(=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=[Zn]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]
Product: [Zn+2]

Procedure:
Zinc white is reacted with stearic acid to give zinc stearate functioning as a vulcanization auxiliary.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1[N:10]1[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[N:12]([CH3:21])[C:11]1=[O:22].C(N(CC)CC)C.[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1[C:40](Cl)=[O:41].O>O1CCCC1>[Cl:8][C:6]1[CH:5]=[C:4]([F:9])[C:3]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[N:12]([CH3:21])[C:11]2=[O:22])=[C:2]([NH:1][C:40]([C:31]2[CH:32]=[CH:33][C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:30]=2)=[O:41])[CH:7]=1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(N)cc(Cl)cc2F)c1=O
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)cc2NC(=O)c2ccc3ccccc3c2)c1=O
Yield: 71.4 %

Procedure:
A mixture of (2-amino-4-chloro-6-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (0.25 g), triethylamine (0.15 g) and 2-naphthoyl chloride (0.21 g) in anhydrous tetrahydrofuran (30 ml) was heated at refluxtemperature overnight under nitrogen atmosphere. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium acetate. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel using ethyl acetate-hexane (1:4) as the eluent to give the title compound as an white solid (0.26 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5][C:6]=1[C:7]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])=[O:8].[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)C(C)C)C>ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:20][CH2:19]2)[S:5][C:6]=1[C:7]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])=[O:8]
Reactant: Nc1nc(NC2CCNCC2)sc1C(=O)c1c(F)cccc1F
Reactant: CS(=O)(=O)Cl
Agent: CCN(CC)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(Nc2nc(N)c(C(=O)c3c(F)cccc3F)s2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask was charged with [4-amino-2-(piperidin-4-ylamino)thiazol-5-yl]-(2,6-difluorophenyl)methanone (0.25 g, crude product from step D), anhydrous dichloromethane (1.5 mL) and methanesulfonyl chloride (3 eq, 155 uL). Then Diethylisopropyl amine (6 eq, 697 uL) was added to the above mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified through a silica gel column. 0.38 g of [4-amino-2-(1-methanesulfonylpiperidin-4-ylamino)thiazol-5-yl]-(2,6-difluorophenyl)methanone was obtained as a light brown solid. The overall yield for step D and E was 15%. 1H NMR (DMSO−d6, 400 MHz): δ1.45-1.57 (m, 2H, CH2), 1.95-2.05 (m, 2H, CH2), 2.82-2.90 (m, 5H, CH3, CH2,), 3.45-3.55 (m, 2H, CH2), 3.6-4.0 (broad, 1H, CH), 7.14-7.20 (m, 2H, Aromatic), 7.45-7.55 (m, 1H, Aromatic), 8.15-8.25 (broad, 1H, NH2), 8.7-8.9 (broad, 1H, NH). HR-MS (M+H)+: Observed: 417.0865: Calculated for 417.0861. Ki for CDK1 0.003 μM; CDK2 0.005 μM; CDK4 0.006 μM.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([F:43])=[C:14]([CH:42]=2)[C:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=2[N:28]2[CH2:33][CH2:32][CH2:31][C@@H:30]([O:34][Si](C(C)(C)C)(C)C)[CH2:29]2)=[O:16])=[CH:4][N:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>CCOC(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([F:43])=[C:14]([CH:42]=2)[C:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][C:19]=2[N:28]2[CH2:33][CH2:32][CH2:31][C@@H:30]([OH:34])[CH2:29]2)=[O:16])=[CH:6][N:7]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCCN(c2ccc(C(F)(F)F)cc2NC(=O)c2cc(C#Cc3cnc(N)nc3)ccc2F)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ncc(C#Cc2ccc(F)c(C(=O)Nc3cc(C(F)(F)F)ccc3N3CCC[C@@H](O)C3)c2)cn1
Reaction time: 6 h

Procedure:
To a yellow solution of (R)-5-(2-(2-aminopyrimidin-5-yl)ethynyl)-N-(2-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)-5-(trifluoromethyl)phenyl)-2-fluorobenzamide (0.162 g, 0.264 mmol) was added tetrabutylammonium fluoride, 1.0 M in THF (0.688 ml, 2.38 mmol). The reaction was allowed to stir for 6 h, at which point it was found by TLC analysis to be complete. The reaction was diluted with EtOAc and washed once with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give a yellow oil, which was purified by silica gel chromatography, 0-10% MeOH/MC to give (R)-5-(2-(2-aminopyrimidin-5-yl)ethynyl)-2-fluoro-N-(2-(3-hydroxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)benzamide as an off-white solid. MS m/z=500 [M+H]+. Calc'd for C25H21F4N502: 499.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]([F:20])([F:19])[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[O:11].[B]1OC2C(=CC=CC=2)O1.Cl>O1CCBN1.C(OCC)(=O)C.ClCCl>[F:20][C:9]([F:8])([F:19])[C@@H:10]([C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)[OH:11]
Reactant: O=C(c1ccc(F)cc1)C(F)(F)F
Agent: B1CCON1
Agent: Cl
Agent: [B]1Oc2ccccc2O1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O[C@H](c1ccc(F)cc1)C(F)(F)F
Temperature: 25 °C
Yield: 87.1 %

Procedure:
To a −78° C. toluene (25 mL)/dichloromethane (25 mL) solution of 2,2,2,4′-tetrafluoroacetophenone (2.5 g, 13.01 mmol) and 1M S-methyl CBS oxazaborolidine catalyst (1.3 mL, 1.3 mmol) was added freshly distilled catecholborane (1.66 mL, 15.62 mmol). The reaction mixture was maintained at −78° C. for 16 h at which time 4N HCl (5 mL in dioxane) was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was diluted with ethyl acetate and washed with a saturated brine solution. The organic layer was dried over magnesium sulfate, filtered and concentrated to provide a solid. The solid was suspended in hexanes and filtered off. The hexanes filtrate containing the desired product was concentrated and the residue subjected to flash chromatography (10 hexanes: 1 ethylacetate) to provide the title compound as colorless oil (2.2 g, 87% yield). The ratio of enantiomers was determined to be 95:5 by chiral HPLC (Chiralcel OD column, 95 hexanes: 5 isopropanol mobile phase. Ret. time major product 6.757 min. Ret. time minor isomer 8.274 min.).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][CH:16]2[O:18][CH2:17]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4].[NH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=2)=[CH:27][C:26]=1[CH3:38]>>[CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][CH:16]([OH:18])[CH2:17][NH:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=3)=[CH:27][C:26]=2[CH3:38])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(C2=NNC(=O)CC2)ccc1OCCN
Reactant: CCCCOCCOCc1ccc(OCC2CO2)cc1
Product: CCCCOCCOCc1ccc(OCC(O)CNCCOc2ccc(C3=NNC(=O)CC3)cc2C)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-n-butyloxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-3-methyl-phenyl]-4,5-dihydro-3-(2H)-pyridazinone.