Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[CH:14]3)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:33]2[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=2)[C:15]([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[CH:14]3)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCOCC4)cc3c2)CC1
Product: COc1ccc(-n2c(C(=O)N3CCOCC3)cc3cc(OC4CCN(C(C)C)CC4)ccc32)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from [5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-morpholin-4-yl-methanone (intermediate 2) and 4-methoxyphenylboronic acid. The title compound was obtained in 56% yield as yellow foam. MS (m/e): 478.2 (MH+, 100%).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:14]O>>[CH3:14][O:8][C:7](=[O:9])[C@@H:2]1[CH2:3][CH2:4][C:5](=[O:6])[NH:1]1
Reactant: CO
Reactant: O=C1CC[C@@H](C(=O)O)N1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1CCC(=O)N1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
L-Pyroglutamic acid (15.17 g, 0.1175 mol) was dissolved in CH3OH (100 mL), cooled to 0° C. under Ar and treated dropwise with thionyl chloride (18.9 mL, 0.259 mol) with stirring. The bath was removed and stirring was continued at ambient temperature for 3.5 h. Water (150 mL) and solid NaHCO3 (60 g) were added, the CH3OH was removed on a rotary evaporator, and the residue extracted with CH2Cl2 (3×150 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated to dryness to give the title compound.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]([CH3:15])[CH3:14])=[CH:8][C:7]=2[CH3:16])[CH2:2]1.[C:17]1([C:23]2[O:27][C:26]([C:28](OCC)=[O:29])=[N:25][N:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCO>[CH3:14][N:13]([CH3:15])[CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH:3]2[CH2:2][N:1]([C:28]([C:26]3[O:27][C:23]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[N:24][N:25]=3)=[O:29])[CH2:4]2)=[C:7]([CH3:16])[CH:8]=1
Reactant: Cc1cc(CN(C)C)ccc1OC1CNC1
Reactant: CCOC(=O)c1nnc(-c2ccccc2)o1
Solvent: CCO
Product: Cc1cc(CN(C)C)ccc1OC1CN(C(=O)c2nnc(-c3ccccc3)o2)C1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 58.6 %

Procedure:
Intermediate 16B (0.25 g, 1.13 mmol) was mixed with ethyl 5-phenyl-1,3,4-oxadiazole-2-carboxylate (0.27 g, 1.25 mmol) in a microwave vial, which then was sealed. The mixture was melted in a preheated oil bath and then stirred at 120° C. for 15 min using the oil bath. EtOH (0.2 mL) was added to the reaction mixture via a syringe and the mixture was stirred at 120° C. for another 3 h. To the mixture was added EtOH (5 mL) and the precipitate was stirred at rt for 20 min. The precipitate was filtered, washed with EtOH (20 mL) and then with Et2O (3 mL). The product was dried in vacuo. There was obtained 0.26 g (57%) of 16 as a solid. 1H NMR (500 MHz, CDCl3): δ 2.23 (s, 6H), 2.35 (s, 3H), 3.32 (s, 2H), 4.29-4.37 (m, 1H), 4.60-4.69 (m, 1H), 4.71-4.79 (m, 1H), 5.02-5.17 (m, 2H), 6.52-6.57 (m, 1H), 6.61 (s, 1H), 7.17 (d, 1H), 7.50-7.62 (m, 3H), 8.17 (d, 2H), MS (APCI+) m/z 393 [M+H]+, LC purity: 98%.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH:6]([P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])P(=O)(OCC)OCC)[CH3:5].[Cl:23][C:24]1[S:28][C:27]([CH:29]=O)=[CH:26][CH:25]=1>C1COCC1>[CH2:20]([O:19][P:15]([C:6]([N:4]([CH3:3])[CH3:5])=[CH:29][C:27]1[S:28][C:24]([Cl:23])=[CH:25][CH:26]=1)(=[O:22])[O:16][CH2:17][CH3:18])[CH3:21]
Reactant: CCOP(=O)(OCC)C(N(C)C)P(=O)(OCC)OCC
Reactant: O=Cc1ccc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(=Cc1ccc(Cl)s1)N(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (0.25 g, 6.25 mmol, 60% mineral oil dispersion) in 10 mL of THF is added slowly a solution of tetraethyl dimethylaminomethylenediphosphonate (2.03 g, 6.14 mmol, prepared according to the procedure described in Psaume, Montury, and Cosmetic Comm. 1982, 12, 415) in 10 mL of THF. After stirring 1 h, a solution of 5-chloro-2-thiophene carboxaldehyde (0.90 g, 6.14 mmol) in 10 mL of THF is added. The resulting mixture is heated at reflux for 1 h, then cooled to room temperature. The reaction mixture is partitioned between Et2O and water. The organic layer is washed sequentially with 1N HCl, water and saturated NaCl, then dried over MgSO4, filtered and concentrated. The crude product is purified via flash column chromatography eluting with a gradient of 40% EtOAc/hexanes to 50% EtOAc/hexanes to afford the title compound (1.52 g, 4.69 mmol) as an oil. 1H NMR (CDCl3, 300 MHz) δ7.20 (d, 1H), 6.95 (d, 1H), 6.82 (d, 1H), 4.15 (m, 4H), 2.62 (s, 6H), 1.60 (t, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[OH:27][CH2:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:33]4[CH:32]=[CH:31][CH:30]=[C:29]([CH2:28][OH:27])[CH:34]=4)=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: OCc1cccc(B(O)O)c1
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Product: CN(C(=O)c1cc2c(s1)-c1ccc(-c3cccc(CO)c3)cc1OCC2)c1ccccc1Cl

Procedure:
Following the procedure of Example 93, 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 and 3-hydroxymethylphenylboronic acid were reacted to give 201. MS: (ESI+) 476.16
Reaction SMILES: [CH3:1][CH:2]([C:4]([C:6]1[C:11]([OH:12])=[CH:10][C:9]([OH:13])=[CH:8][C:7]=1[OH:14])=[O:5])[CH3:3].Br[CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19].Cl>CS(C)=O>[CH3:3][CH:2]([C:4]([C:6]1[C:7]([OH:14])=[C:8]([CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[C:9]([OH:13])=[C:10]([CH2:6][CH:4]=[C:2]([CH3:3])[CH3:1])[C:11]=1[OH:12])=[O:5])[CH3:1]
Reactant: CC(C)C(=O)c1c(O)cc(O)cc1O
Reactant: CC(C)=CCBr
Agent: Cl
Solvent: CS(C)=O
Product: CC(C)=CCc1c(O)c(CC=C(C)C)c(O)c(C(=O)C(C)C)c1O
Temperature: 25 °C
Yield: 7 %

Procedure:
Under an atmosphere of nitrogen, 600 mg (15.0 mmol, 3.00 equivalents) of an oily 60% sodium hydride was washed with dry hexane to remove paraffin. In this solution, 20 ml of dimethyl sulfoxide was placed and stirred at room temperature. To the resultant mixture, a dimethyl sulfoxide (5.0 ml) solution of 981 mg (5.00 mmol) of (2-propyl) (2,4,6-trihydroxyphenyl) ketone (4) was added over a period of 15 minutes and stirred for 30 minutes. Then, a dimethyl sulfoxide (5.0 ml) solution of 1.43 g (10.0 mmol, 2.00 equivalents) of 1-bromo-3-methyl-2-butene was added dropwise over a period of 30 minutes. The resultant mixture was stirred at room temperature for 14 hours. The mixture was poured into 50 ml of a cold 2 M hydrochloric acid solution and extracted from ether. The ether layer was washed with saturated brine, dried over sodium sulfate, and distilled to remove the solvent and obtain 1.580 g of a crude product in the form of red oily substance. The crude product was separated by silica gel column chromatography (65 g of Wako Gel C-200, benzene:ethyl acetate=9:1) into (a) 239 mg of a brown viscous oily substance, (b) 342 mg of an orange color viscous oily substance, and (c) 206 mg of a yellow crystalline substance sequentially in the order of elution as indexed by the thin layer chromatography. The fraction (a) was further purified by column chromatography (15 g of Wako Gel C-300, petroleum ether:ether=9:1) to obtain 58 mg of {3,5-bis(3-methyl-2-butenyl)-2,4,6-trihydroxyphenyl} (2-propyl) ketone (12) in the form of yellow crystals.
Reaction SMILES: CN([CH2:4][C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)C.CI.[CH2:22]=[CH:23][CH:24]=[CH2:25]>C(OCC)(=O)C>[C:16]([C:7]1[C:8](=[O:15])[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]2([CH2:25][CH2:24][CH:23]=[CH:22][CH2:4]2)[CH:6]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: C=CC=C
Reactant: CN(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CI
Solvent: CCOC(C)=O
Product: CC(C)(C)C1=CC2(C=C(C(C)(C)C)C1=O)CC=CCC2
Temperature: 100 °C
Yield: 98.4 %

Procedure:
To a 250 mL glass reaction vessel containing an ethyl acetate (50 mLs) solution of N,N-dimethyl,2,6-di-t-butyl-4-aminomethylphenol (1.32 g; 5 mmols), there was added methyl iodide (0.31 mLs; 5 mmols) to give a colorless slurry. The vessel was sealed and 1,3-butadiene (20 mmols) was introduced into the system. The reaction mixture was heated to 100° C. and the pressure was increased from atmospheric to 45 psig. The reaction mixture was maintained at these conditions for approximately 30 hours. The reaction vessel was then allowed to cool to room temperature. After cooling, the black reaction mixture was filtered to remove ammonium iodide salt by-product. The filtrate was concentrated to afford a viscous oil which was crystallized from ethanol:water (80:20) to give 1.34 g of 2,4-di-t-butylspiro[5.5]undeca-1,4,8-trien-3-one (49% yield based on the N,N-dimethyl,2,6-di-t-butyl-4-aminomethylphenol starting reactant) as colorless crystals.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:31])[C:9]2[CH:14]=[C:13]([O:15][C:16]3[C:24]([CH3:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[C:21]4[C:17]=3[CH2:18][CH2:19][CH2:20]4)[CH:12]=[CH:11][C:10]=2[O:29]C)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Li+]>N1C(C)=CC(C)=CC=1C>[CH:1]1([NH:7][C:8](=[O:31])[C:9]2[CH:14]=[C:13]([O:15][C:16]3[C:24]([CH3:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[C:21]4[C:17]=3[CH2:18][CH2:19][CH2:20]4)[CH:12]=[CH:11][C:10]=2[OH:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)cc1C(=O)NC1CCCCC1
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Product: Cc1cc([N+](=O)[O-])c2c(c1Oc1ccc(O)c(C(=O)NC3CCCCC3)c1)CCC2
Yield: 72.4 %

Procedure:
N-Cyclohexyl-2-methoxy-5-(5-methyl-7-nitroindan-4-yl oxy)benzamide (40 mg) and lithium iodide (38 mg) were dissolved in 2,4,6-collidine (2 mL). The mixture was heated under reflux for 15 hours. Adding water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1) to give the title compound (28 mg).
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[N:9]=[CH:8][N:7]=[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH:5]=1>CCO>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C:6]2[N:7]=[CH:8][N:9]=[C:4]([NH:2][CH3:1])[CH:5]=2)=[CH:12][CH:13]=1
Reactant: Nc1ccc(Cc2cc(Cl)ncn2)cc1
Reactant: CN
Solvent: CCO
Product: CNc1cc(Cc2ccc(N)cc2)ncn1
Temperature: 50 °C

Procedure:
A 4 N solution of HCl in dioxane (11.7 mL, 46.9 mmol, 30 equiv) is added to a solution of [4-(6-chloro-pyrimidin-4-ylmethyl)-phenyl]-carbamic acid tert-butyl ester (Example 117) (0.50 g, 1.56 mmol) in CH2Cl2 (6.7 mL), under an argon atmosphere. The resulting white suspension is stirred at rt for 6.5 h. Additional 4 N HCl solution (1.1 mL, 4.6 mmol, 3.0 equiv) is added. The reaction mixture is allowed to stir for 0.5 h and concentrated in vacuo to afford 0.467 g of crude 4-(6-chloro-pyrimidin-4-ylmethyl)-phenylamine as a white solid. An 8 M solution of methylamine in EtOH (5.1 mL, 40.0 mmol, 30 equiv) Is added to a solution of crude 4-(6-chloro-pyrimidin-4-ylmethyl)phenylamine (0.300 g, 1.37 mmol) in EtOH (2.7 mL), under an argon atmosphere. The mixture Is heated to 50° C. (oil bath temperature) for 5 h, allowed to cool to rt and concentrated in vacuo. The residue is purified by silica gel (48 g) column chromatography (CH2Cl2/MeOH, 85/15) to afford the title compound as a light yellow oil: ES-MS: 215.0 [M+H]+; single peak at tR=3.03 min (System 2); Rf=0.49 (CH2Cl2/MeOH, 85/15).
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[C:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34]([N:13]2[C:14]3[C:10](=[CH:9][C:8]([O:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:16][CH:15]=3)[C:11]([C:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH:22]=3)=[CH:12]2)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1CC=C(c2c[nH]c3ccc(OC4CCCCC4)cc23)CC1
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccc(C(C)(C)C)cc3)c3ccc(OC4CCCCC4)cc23)CC1

Procedure:
(34.0 mg, 81%); from 5-cyclohexyloxy-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4c, 25.6 mg, 0.082 mmol) and 4-t-butylphenylsulfonyl chloride (37.2 mg, 0.16 mmol); HRMS-FAB+ for C30H38N2O3S: calculated MH+ : 507.26813; found: 507.27183.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Oc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)Oc1ccccc1N
Temperature: 25 °C
Reaction time: 30 h
Yield: 97.7 %

Procedure:
To a solution of 1-tert-butoxy-2-nitrobenzene (Journal of Organic Chemistry, 1998, 63, 25, 9495-9496.) (15.0 g) in methanol (300 mL) was added 10% palladium on carbon (1.67 g), and the mixture was stirred at room temperature for 30 hr under a hydrogen atmosphere. Palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (12.4 g).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][C:14]#[N:15])[CH2:9]1)(C)(C)C.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]>ClCCl>[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20].[NH2:7][C@@H:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][C:14]#[N:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CC#N)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC[C@H]1CC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a round-bottomed flask, (cis-3-cyanomethyl-cyclopentyl)-carbamic acid tert-butyl ester (188 mg, 0.84 mmol) was dissolved in dichloromethane (5 ml) and trifluoroacetic acid (2.0 ml, 26.0 mmol) was slowly added. The reaction mixture was stirred at room temperature for 2 h then concentrated to afford (cis-3-amino-cyclopentyl)-acetonitrile trifluoroacetate as a yellow oil which was used without further purification.
Reaction SMILES: C([NH:5][C:6](=[O:26])[C:7]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[CH:11][C:10]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[N:9][CH:8]=1)(C)(C)C.CS(O)(=O)=O>>[N:20]1([C:10]2[CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[C:7]([C:6]([NH2:5])=[O:26])=[CH:8][N:9]=2)[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: Cc1ccccc1-c1cc(N2CCOCC2)ncc1C(=O)NC(C)(C)C
Agent: CS(=O)(=O)O
Product: Cc1ccccc1-c1cc(N2CCOCC2)ncc1C(N)=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 96.8 %

Procedure:
A mixture of 6.0 g (16.5 mMol) N-tert.-butyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide and 12 ml (185 mMol) methanesulfonic acid was stirred at 100° C. for 5 hours, then poured on ice. The aqueous phase was extracted with tert.-butyl-methylether, brought to pH=10 with NaOH aq. 28% and extracted further with tert.-butyl-methylether. The second organic extracts were dried (Na2SO4) and concentrated to yield 4.75 g (96%) 6-morpholin-4-yl-4-o-tolyl-nicotinamide as a light beige crystalline foam.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([CH:13]=1)[CH2:7][NH:8][C:9](=[O:12])[O:10][CH3:11].[CH:15]#[C:16][CH:17]([OH:19])[CH3:18].[Cl-].[Na+]>[Cu]I.C(N(CC)CC)C>[F:14][C:5]1[CH:4]=[CH:3][C:2]([C:15]#[C:16][CH:17]([OH:19])[CH3:18])=[CH:13][C:6]=1[CH2:7][NH:8][C:9](=[O:12])[O:10][CH3:11]
Reactant: C#CC(C)O
Reactant: COC(=O)NCc1cc(Br)ccc1F
Agent: [Cu]I
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: COC(=O)NCc1cc(C#CC(C)O)ccc1F
Temperature: 100 °C
Reaction time: 48 h
Yield: 41.1 %

Procedure:
A mixture comprising 1.60 g of methyl N-(5-bromo-2-fluorobenzyl)carbamate, 1.40 g of 1-butyn-3-ol, 0.20 g of palladium dichlorobis(triphenylphosphine), 0.10 g of copper(I) iodide and 10 ml of triethylamine, was stirred at 100° C. for 48 hours in an autoclave. The reaction solution was poured into a saturated sodium chloride aqueous solution and extracted with ethyl acetate, followed by washing with water and drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.63 g of methyl N-[2-fluoro-5-(3-hydroxy-1-butynyl)benzyl]carbamate as a brown viscous liquid.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]3[CH:13]=[N:14][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:16][CH:17]=3)=[C:7]2[N:6]=[C:5]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[C:4]=1[C:30](=[O:32])[CH3:31].CCN(C(C)C)C(C)C.[C:42](O)(=[O:46])[C@@H:43]([CH3:45])[OH:44].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[C:30]([C:4]1[C:5]([CH:24]2[CH2:25][CH2:26][N:27]([C:42](=[O:46])[C@H:43]([OH:44])[CH3:45])[CH2:28][CH2:29]2)=[N:6][C:7]2[N:8]([N:9]=[CH:10][C:11]=2[C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:17]=2)[C:3]=1[NH2:2])(=[O:32])[CH3:31]
Reactant: CC(=O)c1c(C2CCNCC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Reactant: C[C@@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1c(C2CCN(C(=O)[C@@H](C)O)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-(7-amino-3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethanone hydrochloride (0.5 mmol), DIEA (350 μL, 2 mmol) in DMF (5 mL) was added a solution of D-lactic acid (45 mg, 0.5 mmol), HOBt (68 mg, 0.5 mmol), EDCI (144 mg, 0.75 mmol) in DMF (1 mL). The reaction was stirred at rt for 20 min. Another solution of solution of D-lactic acid (45 mg, 0.5 mmol), HOBt (68 mg, 0.5 mmol), EDCI (144 mg, 0.75 mmol) in DMF (2 mL) was added and stirred for 5 minutes. LC-MS indicated the reaction was complete and reaction mixture was directly purified by HPLC to furnish the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:10](=[O:22])[CH2:11][CH2:12][N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:7]=[CH:8][CH:9]=1.[CH3:23]I>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([C:10](=[O:22])[CH:11]([CH3:23])[CH2:12][N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: CN(CCC(=O)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(CN(C)C(=O)OC(C)(C)C)C(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.5 %

Procedure:
To NaH (680 mg, 1.7 mmol) in THF (10 mL) was added tert-butyl 3-(3-chlorophenyl)-3-oxopropyl(methyl)carbamate (2.4 g, 8.5 mmol) in THF (5 mL) at 0° C. over 3 min. After a few minutes THF (100 mL) was added. And an additional 10 min, CH3I (1.32 g, 9.3 mmol) was added drop wise. The mixture was stirred for 16 h at room temperature. Then the mixture was quenched with NH4Cl and 1N HCl was added until pH=4 was reached. The mixture was extracted with ethyl acetate. The organic layers was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography to give the product (2.0 g, 79%).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[C:10](#[N:12])[CH3:11].[H-].[Na+]>C1COCC1>[F:9][C:2]([F:1])([F:8])[C:3](=[O:5])[CH2:11][C:10]#[N:12]
Reactant: CC#N
Reactant: CCOC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)C(F)(F)F
Temperature: 25 °C
Yield: 109.4 %

Procedure:
A solution of ethyl trifluoroacetate (14.2 g, 0.1 mol) and anhydrous acetonitrile (5.0 g, 0.12 mol) in THF (100 mL) was added dropwise to a suspension of NaH (60%, 6.0 g, 0.15 mol) in THF (100 mL) at 80° C. The resulting mixture was heated to reflux overnight, and then cooled to RT. The reaction mixture was concentrated in vacuo and the residue was diluted with EtOAc and 10% aq HCl. The organic layer was washed with water and brine, dried (MgSO4) and concentrated in vacuo to yield crude 4,4,4-trifluoro-3-oxo-butyronitrile (15 g), which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.O1CCN([C:18]2[CH2:22][CH2:21][CH2:20][CH:19]=2)CC1>C(Cl)(Cl)Cl.S(=O)(=O)(O)O.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:18]3[CH2:22][CH2:21][CH2:20][C:19]=3[C:10](=[O:11])[NH:9][C:5]=2[CH:4]=1
Reactant: C1=C(N2CCOCC2)CCC1
Reactant: COc1cccc(N=C=O)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc2c3c(c(=O)[nH]c2c1)CCC3

Procedure:
A solution of 3-methoxyphenylisocyanate (25.0 g, 168 mmol) in chloroform (110 ml) is mixed with 1-morpholino-1-cyclopentene (25.3 ml, 168 mmol) and refluxed for 15 minutes. The batch is concentrated by evaporation and purified by column chromatography (SiO2) with ethyl acetate-hexane: 34.8 g (87%) of cyclopentanone-2-carboxylic acid-(3-methoxyphenyl)amide: 1H-NMR (CDCl3): δ=1.80-2.55 (m, 6H), 3.18 (t, 1H), 3.81 (s, 3H), 6.68 (dd, 1H), 7.04 (ddd, 1H), 7.22 (t, 1H), 7.33 (t, 1H), 8.76 (br. s, 1H). The amide (11.6 g, 50 mmol) is stirred in concentrated sulfuric acid (40 ml) for 30 minutes at 100° C. The batch is poured onto ice water, diluted with water and extracted with ethyl acetate. The combined extracts are dried (Na2SO4) and concentrated by evaporation in a vacuum: 2.43 g (23%) of product.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([CH:14]=O)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:17][OH:18].N1C=CC=CC=1>CCO>[NH:1]([C:8]1[N:13]=[C:12]([CH:14]=[N:17][OH:18])[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccnc(Nc2ccccc2)n1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=Cc1ccnc(Nc2ccccc2)n1
Yield: 92.1 %

Procedure:
A suspension of 2-anilinopyrimidin-4-carbaldehyde (Method 3; 10 g, 50 mmol) and hydroxylamine hydrochloride (17.4 g, 250 mmol) in EtOH (360 ml) and pyridine (17.4 g, 215 mmol) was stirred and heated at reflux for 1 hour. The reaction mixture was allowed to cool and concentrated to about 150 ml total volume by evaporation. Distilled water (600 ml) was added and the precipitated solid collected by filtration, washed thoroughly with distilled water and dried to give the title compound (9.86 g, 92%) as a white solid. NMR: 6.92 (t, 1H), 7.08 (d, 1H), 7.23 (t, 2H), 7.75 (d, 2H), 7.93 (s, 1H), 8.45 (d, 1H), 9.67 (s, 1H), 12.1 (s, 1H); m/z 215.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH:22]1([NH:25][C:26]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[NH:33][CH:32]=[CH:31]3)=[O:27])[CH2:24][CH2:23]1>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:33]3[C:34]4[C:30](=[CH:29][C:28]([C:26](=[O:27])[NH:25][CH:22]5[CH2:24][CH2:23]5)=[CH:36][CH:35]=4)[CH:31]=[CH:32]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Reactant: O=C(NC1CC1)c1ccc2[nH]ccc2c1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(C(=O)NC5CC5)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-6) and N-cyclopropyl-1H-indole-5-carboxamide (intermediate-11).