Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:8]=[C:9]([CH:49]=[CH:50][CH:51]=1)[CH2:10][C@H:11]1[C:36](=[O:37])[N:35]2[NH:38][C@@H:31]([CH2:32][CH2:33][CH2:34]2)[C:30](=[O:39])[O:29][CH2:28][C:27]2=[CH:40][C:23](=[CH:24][CH:25]=[N:26]2)[CH:22]=[CH:21][CH2:20][CH2:19][C@@H:18]([O:41][CH3:42])[C@@H:17]([CH3:43])[C:16](=[O:44])[NH:15][C@@H:14]([CH:45]([CH3:47])[CH3:46])[C:13](=[O:48])[NH:12]1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[OH:6][C:7]1[CH:8]=[C:9]([CH:49]=[CH:50][CH:51]=1)[CH2:10][C@H:11]1[C:36](=[O:37])[N:35]2[NH:38][C@@H:31]([CH2:32][CH2:33][CH2:34]2)[C:30](=[O:39])[O:29][CH2:28][C:27]2[CH:40]=[C:23]([CH:24]=[CH:25][N:26]=2)[CH:22]=[CH:21][CH2:20][CH2:19][C@@H:18]([O:41][CH3:42])[C@@H:17]([CH3:43])[C:16](=[O:44])[NH:15][C@@H:14]([CH:45]([CH3:47])[CH3:46])[C:13](=[O:48])[NH:12]1
Reactant: CO[C@@H]1CCC=Cc2ccnc(c2)COC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](Cc2cccc(O[Si](C)(C)C(C)(C)C)c2)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CO[C@@H]1CC/C=C/c2ccnc(c2)COC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](Cc2cccc(O)c2)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1C
Agent: CO[C@@H]1CC/C=C/c2ccnc(c2)COC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](Cc2cccc(O[Si](C)(C)C(C)(C)C)c2)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1C
Solvent: C1CCOC1
Product: CO[C@@H]1CCC=Cc2ccnc(c2)COC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](Cc2cccc(O)c2)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of (E)-(1S,14R,15R,18S,21S)-21-[3-(tert-butyl-dimethyl-silanyloxy)-benzyl]-18-isopropyl-14-methoxy-15-methyl-3-oxa-6,17,20,23,27-pentaaza-tricyclo[21.3.1.1*5,9*]octacosa-5(28),6,8,10-tetraene-2,16,19,22-tetraone (160 mg, 0.21 mmol) in tetrahydrofuran (10 mL) was stirred at 0° C. under nitrogen. A solution of tetra-N-butylammonium fluoride (1 M in tetrahydrofuran, 0.34 mL, 0.34 mmol) was added and the reaction mixture was stirred at 0° C. for 15 minutes and then at room temperature for 15 minutes. Silica gel was added and the solvent was evaporated. The residue was purified by silica gel chromatography using a gradient of ethyl acetate to ethyl acetate/acetone 9:1 to afford the title compound (88 mg, 65%) as a white solid. 1H NMR (300 MHz, CD3CN) δ 0.97 (d, J=7.1 Hz, 3H), 0.99 (d, J=7.1 Hz, 3H), 1.32 (d, J=7.4 Hz, 3H), 1.60-2.20 (m, 9H), 2.55-2.89 (m, 4H), 3.28-3.34 (m, 1H), 3.46 (s, 3H), 3.62-3.69 (m, 1H), 4.19-4.41 (m, 3H), 5.19 (d, J=14.5 Hz, 1H), 5.35 (d, J=14.5 Hz, 1H), 5.58-5.65 (m, 1H), 5.83 (d, J=15.8 Hz, 1H), 6.30-6.39 (m, 1H), 6.51 (dd, J=7.9, 1.6 Hz, 1H), 6.67 (d, J=7.6 Hz, 1H), 6.75-6.81 (m, 1H), 7.01-7.07 (m, 3H), 7.22-7.28 (m, 2H), 8.02 (s, 1H), 8.39 (d, J=5.1 Hz, 1H).
Reaction SMILES: [O:1]=[S:2]1(=[O:38])[N:7]([CH:8]([CH3:10])[CH3:9])[CH2:6][C:5]2[CH:11]=[C:12]([C:15]([O:17]CC)=[O:16])[CH:13]=[CH:14][C:4]=2[N:3]1[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][C:25]([C:28]2[C:36]3[C:31](=[CH:32][C:33]([F:37])=[CH:34][CH:35]=3)[NH:30][CH:29]=2)=[CH:24][CH2:23]1.[OH-].[Li+]>O1CCCC1>[O:38]=[S:2]1(=[O:1])[N:7]([CH:8]([CH3:10])[CH3:9])[CH2:6][C:5]2[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[CH:13]=[CH:14][C:4]=2[N:3]1[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][C:25]([C:28]2[C:36]3[C:31](=[CH:32][C:33]([F:37])=[CH:34][CH:35]=3)[NH:30][CH:29]=2)=[CH:24][CH2:23]1
Reactant: CCOC(=O)c1ccc2c(c1)CN(C(C)C)S(=O)(=O)N2CCN1CC=C(c2c[nH]c3cc(F)ccc23)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)N1Cc2cc(C(=O)O)ccc2N(CCN2CC=C(c3c[nH]c4cc(F)ccc34)CC2)S1(=O)=O

Procedure:
Prepared from ethyl 3,4-dihydro-2,2-dioxo-1-{2-[4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl]-1-ethyl}-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-6-carboxylate by lithium hydroxide hydrolysis in aqueous tetrahydrofuran, m.p. 192.8-194.4° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])[N:3]=1.[CH:30]([O:33][C:34]1[CH:40]=[C:39]([CH:41]2[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][O:49][CH3:50])[CH2:43][CH2:42]2)[C:38]([CH3:51])=[CH:37][C:35]=1[NH2:36])([CH3:32])[CH3:31]>CCN(C(C)C)C(C)C.CC(O)C>[Cl:8][C:6]1[C:5]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])[N:3]=[C:2]([NH:36][C:35]2[CH:37]=[C:38]([CH3:51])[C:39]([CH:41]3[CH2:42][CH2:43][N:44]([CH2:47][CH2:48][O:49][CH3:50])[CH2:45][CH2:46]3)=[CH:40][C:34]=2[O:33][CH:30]([CH3:32])[CH3:31])[N:7]=1
Reactant: COCCN1CCC(c2cc(OC(C)C)c(N)cc2C)CC1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nc(Cl)c1C(=O)c1ccccc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COCCN1CCC(c2cc(OC(C)C)c(Nc3nc(Cl)c(C(=O)c4ccccc4)c(Nc4ccccc4S(=O)(=O)C(C)C)n3)cc2C)CC1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
To a 10 mL microwave reaction tube, (2,4-dichloro-6-(2-(isopropylsulfonyl)phenylamino)pyrimidin-5-yl)(phenyl)methanone (24.1 mg, 0.0548 mmol), 2-isopropoxy-4-(1-(2-methoxyethyl)piperidin-4-yl)-5-methylaniline (16.8 mg, 0.0548 mmol), 2-propanol (4 mL) and Hunig's Base (3 drops) were added successively. The resulting mixture was stirred at 150° C. for 2 hours by using a microwave machine. The reaction solution concentrated in vacuo to afford crude (4-chloro-2-(2-isopropoxy-4-(1-(2-methoxyethyl)piperidin-4-yl)-5-methylphenylamino)-6-(2-(isopropylsulfonyl)phenylamino)pyrimidin-5-yl)(phenyl)methanone as a slightly yellow sticky oil. MS (ES+): 720.30 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH:5]([NH:19]C(OCC1C=CC=CC=1)=O)[CH2:6][CH2:7][C:8](=[O:18])[NH:9][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][OH:12])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:30])[CH:5]([NH2:19])[CH2:6][CH2:7][C:8](=[O:18])[NH:9][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][OH:12])[CH3:2]
Reactant: CCOC(=O)C(CO)NC(=O)CCC(NC(=O)OCc1ccccc1)C(=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(N)CCC(=O)NC(CO)C(=O)OCC
Reaction time: 3 h
Yield: 75.1 %

Procedure:
A solution of (4) (11.4 g, 26.86 mmol) in ethanol (225 ml) containing 1.2 g 20% palladium on activated carbon (50% wet) was hydrogenated at 30 psi for 3 hrs. The catalyst was removed by filtration and the solution was washed with ethanol. The solvent was removed in a rotary evaporator. The residue was dried in a vacuum oven (50° C.) to produce (5) (5.86 g, 75%).
Reaction SMILES: N1C=CC=CC=1.[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH2:16].CO>CC1C=CC(C)=CC=1>[C:7]([OH:14])(=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O
Reactant: O=C(Cl)c1ccccc1
Solvent: Cc1ccc(C)cc1
Solvent: c1ccncc1
Solvent: CO
Product: O=C(O)c1ccccc1
Reaction time: 1 h

Procedure:
In a reaction vessel having a capacity of 20 l, 1100 g of the so-obtained block copolymer-containing composition was dissolved in 11 l of p-xylene in a nitrogen atmosphere at 100° C. After the composition had been completely dissolved in p-xylene, 400 ml of pyridine was added into the reaction vessel, and 800 g of benzoyl chloride was continuously supplied in the reaction system over a period of 1 hour. Then, reaction was conducted at 100° C. for 1.5 hours after completion of the addition of benzoyl chloride, and the reaction was stopped by adding 2 l of distilled water into the reaction mixture. After termination of the reaction, the temperature was lowered close to room temperature and the liquid reaction mixture was thrown into a great excess of methanol (in a mixer) to precipitate a benzoic acid-esterified polymer composition. The precipitate was recovered by filtration. After filtration, the benzoic acid-esterified polymer composition was washed with methanol repeatedly and dried under reduced pressure at 50° C. for 24 hours to obtain an intended benzoic acid-esterified polymer composition.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:3]=1[C:18]#[N:19].[Li+].CC([N-]C(C)C)C.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:30]>C1COCC1>[N+:38]([C:35]1[CH:34]=[CH:33][C:32]([O:31][C:29]([N:5]2[CH:4]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=3)[C:3]([C:18]#[N:19])=[C:2]([CH3:1])[NH:7][C:6]2=[O:8])=[O:30])=[CH:37][CH:36]=1)([O-:40])=[O:39]
Reactant: CC1=C(C#N)C(c2cccc([N+](=O)[O-])c2)NC(=O)N1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1=C(C#N)C(c2cccc([N+](=O)[O-])c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
To a suspension of 6-Methyl-4-(3-nitrophenyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carbonitrile (0.43 g, 1.7 mmol, prepared by the method described in Example 26, Step 1, in 77% yield) in THF (15 mL) at −78° C. was added LDA (1.25 mL, 2.5 mmol, 2.0 M in hexanes). The resulting mixture was stirred at −78° C. for 15 min, warmed to −25° C. for 15 min, recooled to −78° C. and 4-nitrophenyl chloroformate (0.50 g, 2.5 mmol) was added in one portion. The reaction mixture was stirred at −78° C. for 15 min, gradually warmed to room temperature, quenched with water and extracted with ethyl acetate. The organic extract was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using 50% to 70% ethyl acetate-hexane as eluant to give the title compound as a light yellow solid (0.38 g, 53%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]Cl)=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1.[H-].[Na+].Cl>C1COCC1>[CH3:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]=[CH2:20])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:6][CH2:7]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=COc1ccc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)cc1OC

Procedure:
1.9 g of N-(trans-4-methylcyclohexyl)-4-(2-chloroethoxy )- 3-methoxycinnamamide (Example 138 ) was added to a solution of 0.5 g of sodium hydride in 50 ml of THF. The solution was reacted for 72 hours, while it was refluxed. After reaction, 2 N hydrochloric acid was added to the reaction solution, acidifying the solution, and the solution was extracted with 100 ml of methylene chloride. The organic layer obtained was dried over magnesium sulfate, and the solvent was removed in vacuo. The product obtained was recrystallized from methylene chloride/ether, yielding 0.54 g of N-(trans-4-methylcyclohexyl)-4-vinyloxy-3-methoxycinnamamide (a compound of the present invention ) as white crystal, which had the following physiochemical properties:
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([C:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12][C:11]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]>CO.O1CCCC1>[OH:3][CH:4]([C:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12][C:11]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(=O)c1c(-c2ccccc2)sc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)C(O)c1c(-c2ccccc2)sc2ccccc12
Reaction time: 1 h
Yield: 43.5 %

Procedure:
Sodium borohydride (53 mg, 1.40 mmol) was added to a solution of ethyl 2-oxo-2-(2-phenyl-1-benzothiophen-3-yl)acetate (2b) (430 mg, 1.38 mmol) in a mixture of methanol (10 mL) and tetrahydrofuran (5 mL) under a nitrogen atmosphere. The reaction mixture was stirred for 1 hour, quenched with water (2 mL) and concentrated in vacuo. The residue was diluted with dichloromethane (20 mL), washed with water (2×10 mL), brine (10 mL), dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel (dichloromethane/ethanol 99/1) to afford the desired alcohol (2c) as a white solid (190 mg, 0.60 mmol, 44%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:7][C:8]([Cl:12])=[N:9]2)=[CH:4][CH:3]=1.[N:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[N:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>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.O>[Cl:12][C:8]1[N:7]=[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([C:23]3[CH:24]=[N:19][CH:20]=[N:21][CH:22]=3)=[CH:3][CH:4]=2)[N:9]=1
Reactant: OB(O)c1cncnc1
Reactant: Clc1nc(N2CCOCC2)c2ccc(Br)cc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1nc(N2CCOCC2)c2ccc(-c3cncnc3)cc2n1
Temperature: 95 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
To a 50 mL round bottom flask, 7-bromo-2-chloro-4-morpholin-4-yl-quinazoline (0.2 g, 0.0006 mol), pyrimidine-5-boronic acid (0.068 g, 0.0005 mol), sodium carbonate (0.129 g, 0.0012 mol), DMF (10 mL) and water (3 mL) were added and degassed the reaction vessel with N2 for 5-10 min. To the same reaction mixture, Pd(PPh3)2Cl2 (0.029 g, 0.00004 mol) was added and again degassed with N2 for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified; using column chromatography (60-120 silica gel, 60% ethyl acetate in hexane) to yield the desired product [150 mg, 75%]. 1H NMR (300 MHz, CDCl3): δ 9.27 (s, 1H), 9.04 (s, 2H), 7.85-8.45 (m, 2H), 7.60-7.64 (m, 1H), 3.82-3.91 (m, 8H); LC-MS (ESI): Calculated mass: 327.09; Observed mass: 328.0 [M+H]+ (RT: 0.98 min).
Reaction SMILES: [C:1]([C:3]1([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]1)#[CH:2].C#CCCCCCC.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34]([N:37]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[CH:40]=2)[CH3:38])(=[O:36])=[O:35])=[CH:30][CH:29]=1.IC1C=C2C(=CC=1)CN(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C2>>[C:14]([O:13][C:12](=[O:18])[NH:11][C:3]1([C:1]#[C:2][C:28]2[CH:29]=[CH:30][C:31]([S:34](=[O:36])(=[O:35])[N:37]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[CH:40]=3)[CH3:38])=[CH:32][CH:33]=2)[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: COc1cccc(N(C)S(=O)(=O)c2ccc(Br)cc2)c1
Reactant: C#CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Agent: C#CCCCCCC
Agent: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Product: COc1cccc(N(C)S(=O)(=O)c2ccc(C#CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)cc2)c1
Yield: 59 %

Procedure:
When tert-butyl 5-ethynyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate was substituted for 1-octyne and the product of Step B was substituted for 5-iodo-2-tritylisoindoline in Example 2, Step D, the similar process afforded the title compound in 59% yield, as a creamy paste. 1H-NMR (CDCl3) 1.45 (s, 3H); 1.46 (s, 9H); 1.49 (5, 3H); 1.58 (s, 2H); 2.63 (s, 2H); 3.13 (s, 3H); 3.75 (s, 3H); 3.96 (d, 2H, J=17.23 Hz), 4.07 (d, 2H, J=17.23 Hz); 6.54 (dd, 1H, J=1.66, 7.92 Hz), 6.69 (tr, 1H, J=2.18 Hz); 6.79 (dd, 1H, J=2.39, 10.68 Hz); 7.16 (tr, 1H, J=8.15 Hz); 7.47 (s, 4H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:36])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:33](O)=[O:34])[CH:32]=2)[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][NH2:45])=[CH:40][CH:39]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:36])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:33](=[O:34])[NH:45][CH2:44][C:41]3[CH:42]=[CH:43][C:38]([F:37])=[CH:39][CH:40]=3)[CH:32]=2)[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C(=O)O)nn2c1-c1cc(F)c2c(c1C)CCCO2
Reactant: NCc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C(=O)NCc3ccc(F)cc3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.6 %

Procedure:
To a mixture of 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid (21 mg, 0.042 mmol) and (4-fluorophenyl)methanamine (10.52 mg, 0.084 mmol) in DMF (1 mL) was added DIEA (0.037 mL, 0.210 mmol), HATU (32.0 mg, 0.084 mmol) and DMAP (1.027 mg, 8.41 μmol) and the resulting mixture was stirred at rt for 16 h. At this point LCMS indicated completion of reaction. The reaction mixture was then filtered and purified by prep HPLC to afford (2S)-ethyl 2-(tert-butoxy)-2-(7-(8-fluoro-5-methylchroman-6-yl)-2-((4-fluorobenzyl)carbamoyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (12 mg, 0.020 mmol, 47.1% yield) as off-white solid. 1H NMR (500 MHz, CDCl3) δ: 7.34-7.30 (m, 2H), 7.23 (t, J=6.4 Hz, 1H), 7.20 (s, 1H), 7.06-6.99 (m, 2H), 6.85 (d, J=10.7 Hz, 1H), 4.96 (s, 1H), 4.67-4.53 (m, 2H), 4.35 (t, J=5.3 Hz, 2H), 4.15 (q, J=7.0 Hz, 2H), 2.79 (s, 3H), 2.76 (t, J=6.6 Hz, 2H), 2.24-2.14 (m, 2H), 1.82 (s, 3H), 1.21 (t, J=7.2 Hz, 3H), 1.17 (s, 9H). LCMS (M+H)=607.4.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:11].Cl[C:27]1[N:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=1>>[Cl:33][C:30]1[CH:29]=[N:28][C:27]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=2[C:20]2[N:21]=[CH:22][CH:23]=[CH:24][N:25]=2)=[O:11])=[N:32][CH:31]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2-c2ncccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2-c2ncccn2)[C@@H]1CNc1ncc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(4,5-difluoro-2-(pyrimidin-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. ESI-MS (m/z): 459 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[CH2:20][N:21]([C:31]([O:33][CH3:34])=[O:32])[C@@H:22]([CH3:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=1)[CH3:2].[CH3:36][S:37](Cl)(=[O:39])=[O:38].C(N(CC)CC)C.O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:15][C:14]=2[CH2:20][N:21]([C:31]([O:33][CH3:34])=[O:32])[C@@H:22]([CH3:30])[CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(N)cc2CN(C(=O)OC)[C@@H](C)Cc2ccccc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1cccc(Oc2ccc(NS(C)(=O)=O)cc2CN(C(=O)OC)[C@@H](C)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To [3-(4-amino-2-{[methoxycarbonyl-((S)-1-methyl-2-phenyl-ethyl)-amino]-methyl}-phenoxy)-phenyl]-acetic acid ethyl ester (0.144 g, 0.3 mmol) and methanesulfonyl chloride (0.02 mL, 0.3 mmol) in CH2Cl2 (2 mL) was added triethylamine (0.08 mL, 0.6 mmol), and the reaction was stirred at room temperature for 1 hour. The mixture was worked-up with CH2Cl2 and H2O, and the organic layer was dried and concentrated. The residue was purified by silica gel chromatography (20-40% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[N:20]=[C:19]([CH3:21])[C:18]([CH3:22])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].COCCOC>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.CCOC(C)=O.C(O)C.O>[CH3:22][C:18]1[CH:17]=[CH:16][C:15]([C:6]2[CH:7]=[N:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[N:20][C:19]=1[CH3:21]
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Reactant: Cc1ccc(Br)nc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2ccc(C(F)(F)F)nc2)nc1C
Temperature: 120 °C
Yield: 294.4 %

Procedure:
A 20 mL microwave vial was charged with 6-(trifluoromethyl)pyridin-3-ylboronic acid (564 mg, 2.96 mmol), 6-bromo-2,3-dimethylpyridine (500 mg, 2.69 mmol), bis(triphenylphosphine)palladium(II) chloride (94 mg, 0.134 mmol), and K2CO3 (743 mg, 5.37 mmol), followed by the addition of DME (9.0 mL), water (3.86 mL) and ethanol (2.57 mL). The reaction mixture was heated in a microwave at 120° C. for 10 minutes. To the reaction mixture was added 200 mL EtOAc, and washed with 200 mL water and 200 mL brine. The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on a Grace Reveleris 40 g column, eluted with 0-40% EtOAc in Hexanes (25 mL/min) to provide the title compound (1.997 g, 7.92 mmol, 98% yield) as a white solid. MS (ESI+) m/z 253.2 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 9.40 (d, J=1.9, 1H), 8.68 (dd, J=8.3, 1.7, 1H), 8.00 (d, J=8.3, 1H), 7.92 (d, J=7.9, 1H), 7.71 (d, J=7.9, 1H), 2.54 (s, 3H), 2.33 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].O.C[CH2:15][O:16]C(C)=O>>[Cl:8][C:6]1[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]2[O:12][C:15](=[O:16])[NH:1][C:2]=2[CH:7]=1
Reactant: CCOC(C)=O
Reactant: Nc1cc(Cl)cc([N+](=O)[O-])c1O
Solvent: O
Product: O=c1[nH]c2cc(Cl)cc([N+](=O)[O-])c2o1
Reaction time: 2 h
Yield: 98 %

Procedure:
DCI (36.4 mmol, 5.9 g) was added in one portion to 2-amino-4-chloro-6-nitrophenol 5 (5 g, 26.5 mmol) suspended in AcOEt (150 ml) and the reaction was stirred vigorously for 2 hours. 100 ml of water were added to the reaction and then the organic phase was eliminated by evaporation. HCl 20% was added (20 ml) and the resulting solid material was filtered and washed with HCl 1N, cold water, MeOH and ether obtaining 5.6 g of a beige solid. Yield=98% 1HNMR (DMSO, 200 MHz) δ 7.59 (1H, d, J=2.2 Hz), 7.86 (1H, d, J=2.2 Hz), 12.56 (1H, bs)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10]C)=[O:9])=[N:6][CH:7]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Cl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
Methyl 5-chloropyrazine-2-carboxylate (CAS [33332-25-1], 1 g, 5.79 mmol) was dissolved in a mixture of THF (50 ml) and water (50 ml). Lithium hydroxide monohydrate (243 mg, 5.79 mmol) was added and the reaction mixture was stirred at RT overnight. The pH was adjusted to 1 with 1M HCl and the product was extracted with three portions of EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude material was purified by flash chromatography (SiO2, 50 g, 0 to 20% MeOH in DCM) to yield the title compound as white solid (741 mg, 81%). MS (ISP): m/z=159.0 [M+H]+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:10]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([NH:16][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: N#Cc1ccccc1F
Reactant: NC1CCCCC1
Product: N#Cc1ccccc1NC1CCCCC1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and cyclohexylamine.