Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:7]([C:10]([C:13]2[CH:18]=[C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]3[CH3:25])[N:16]=[C:15]([C:26]3[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=3)[N:14]=2)([CH3:12])[CH3:11])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].Cl[C:39]([O:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:40]>O1CCOCC1>[CH:1]1([S:7]([C:10]([C:13]2[CH:18]=[C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]3[CH3:25])[N:16]=[C:15]([C:26]3[CH:32]=[CH:31][C:29]([NH:30][C:39](=[O:40])[O:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[CH:28][CH:27]=3)[N:14]=2)([CH3:11])[CH3:12])(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)C2CCCCC2)nc(-c2ccc(N)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)C2CCCCC2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
To a solution of 4-[4-(2-cyclohexylsulfonylpropan-2-yl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (1.1 g, 2.40 mmol) in 1,4-dioxane (12 mL) was added sodium bicarbonate (0.302 g, 3.60 mmol). Phenyl chloroformate (0.316 mL, 2.52 mmol) was then added dropwise and the resulting mixture was stirred at RT for 3 hours. The resulting mixture was evaporated to dryness and the residue partitioned between water (10 mL) and DCM (10 mL). The organic layer was separated and evaporated to dryness. The residue was triturated with diethyl ether to give the desired material as a solid (1.328 g).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].[CH3:31][N:32]([CH3:47])[C:33]([CH3:46])([CH3:45])[CH2:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][C:37]=1[F:44]>>[CH3:47][N:32]([CH3:31])[C:33]([CH3:45])([CH3:46])[CH2:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=2[C@@H:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:38][C:37]=1[F:44]
Reactant: CN(C)C(C)(C)COc1ccc(C=O)cc1F
Reactant: CCNc1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1cc(NCCCc2ccc(OCC(C)(C)N(C)C)c(F)c2)c([C@@H]2CCc3cc(O)ccc3C2)cc1OC
Yield: 37.4 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 4-(2-dimethylamino-2-methylpropoxy)-3-fluorobenzaldehyde (55 mg) according to an analogous synthetic method to Example 264 and purified by LC-MS, the title compound (10 mg) was obtained.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([N:13]([CH2:17][CH3:18])[C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)=O.[NH2:20][C:21]1[C:25]([C:26]#[N:27])=[CH:24][NH:23][N:22]=1>O.Cl>[C:26]([C:25]1[CH:24]=[N:23][N:22]2[CH:3]=[CH:4][C:5]([C:7]3[CH:8]=[C:9]([N:13]([CH2:17][CH3:18])[C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=3)=[N:20][C:21]=12)#[N:27]
Reactant: N#Cc1c[nH]nc1N
Reactant: CCN(C(C)=O)c1cccc(C(=O)C=CN(C)C)c1
Agent: Cl
Solvent: O
Product: CCN(C(C)=O)c1cccc(-c2ccn3ncc(C#N)c3n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 1.6 %

Procedure:
N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylacetamide (5.2 g, 0.02 mol) and 3-amino-4-cyanopyrazole (2.16 g, 0.02 mol) were dissolved in the mixture of water (50 ml) and concentrated hydrochloric acid (40 ml) and the mixture was stirred at room temperature for 8 h. The reaction mixture was then cooled to 5° C. and the precipitate was removed by filtration. The filtrate was neutralized by concentrated aqueous ammonia solution to precipitate 380 mg of the mixture of zaleplon and its regioisomer 4 which was collected by filtration. The filtrate was extracted with 100 ml of ethylacetate to give 100 mg of the mixture of the above two compounds upon evaporation. The two crops combined were put to a silica gel column (100 g) and the elution was performed by the solvent mixture of chloroform and acetone 3:1 (v/v) to yield as a second crop 240 mg (4%) of 4; mp 194-196° C.; 1H-NMR (CDCl3) δ (ppm) 1.143 (t, 3H), 1.876 (s, 3H), 3.804 (q, 2H), 7.361 (d, 1H), 7.532 (d, 1H), 7.613 (t, 1H), 8.018 (s, 1H), 8.159 ( d, 1H), 8.375 (s, 1H), 8.805 ((d, 1H); 13C-NMR (CDCl3) δ (ppm) 12.89, 22.68, 43.84, 83.17, 107.71, 112.84, 127.17, 127.48, 130.62, 131.63, 136.67, 137.46, 144.10, 148.31, 149.99, 158.60, 169.90; MS (EI, 70 EV) m/z (%) 305 (M+, 18), 248 (59).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[CH:29]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2cccc(F)c2)cc1
Yield: 85.3 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-fluorobiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 3-fluorophenylboronic acid (0.026 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.059 g (85%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-fluorobiphenyl-4-carboxamide as a white solid.
Reaction SMILES: [N:1]#[C:2]Br.[C:4]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][C@H:14]([NH:18][CH2:19][C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)[C:13]2[CH:34]=[C:35]([CH2:42][CH3:43])[C:36]([C:38]([F:41])([F:40])[F:39])=[CH:37][C:12]1=2)=[O:10])([CH3:7])([CH3:6])[CH3:5].C(N(C(C)C)CC)(C)C>O1CCCC1>[C:4]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][C@H:14]([N:18]([CH2:19][C:20]2[CH:21]=[C:22]([C:30]([F:31])([F:33])[F:32])[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=2)[C:2]#[N:1])[C:13]2[CH:34]=[C:35]([CH2:42][CH3:43])[C:36]([C:38]([F:41])([F:39])[F:40])=[CH:37][C:12]1=2)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: N#CBr
Reactant: CCc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N(C#N)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 67.5 °C
Yield: 76.4 %

Procedure:
Add cyanogen bromide (0.352 g, 3.33 mmol) to a solution of (S)-5-(3,5-Bis-trifluoromethyl-benzylamino)-7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (0.647 g, 1.11 mmol) and diisopropylethylamine (0.679 mL, 3.89 mmol) in tetrahydrofuran (3 mL) at room temperature under nitrogen and heat the mixture at 65-70° C. for 16 hours and then for another 90° C. 16 h. Partition the cooled mixture between dichloromethane (40 mL) and brine (40 mL), separated layers. Extract aqueous with more dichloromethane (40 mL). Combine organic layers, dry over anhydrous sodium sulfate, filter and concentrated under reduced pressure. Purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (0-20%), to provide the title compound (0.517 g, 76%), MS (ES+): 627 (M+NH4), 632 (M+Na).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=[O:13])=[CH:6][CH:5]=1.O>CO>[CH3:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][CH:10]2[OH:13])=[CH:6][CH:5]=1
Reactant: Cc1ccc2c(c1)C(=O)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc2c(c1)C(O)CC2
Reaction time: 1 h
Yield: 108.5 %

Procedure:
Sodium borohydride (1.3 g) was added to a solution of 6-methyl-indane-1-one (5.0 g) in methanol (50 ml) at 0° C., and the mixture was stirred for one hour. The reaction mixture was poured into ice-cooled water, and extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain 6-methylindane-1-ol (5.5 g). To a solution of 6-methylindane-1-ol in toluene (50 ml) was added p-toluene sulfonic acid monohydrate (0.2 g), and the mixture was stirred for 20 minutes. The temperature of the reaction mixture was returned to room temperature, and the reaction mixture was washed with water, 5% sodium hydrogencarbonate aqueous solution, and saturated saline solution in order and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain 5-methyl-1H-indene (5.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7]Br.[C:13]([NH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7][N:25]1[CH2:26][CH2:27][CH:22]([NH:21][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:23][CH2:24]1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: COc1ccccc1OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccccc1OCCN1CCC(NC(=O)c2ccccc2)CC1
Yield: 83.3 %

Procedure:
2-(2-Methoxyphenoxy)ethyl bromide (2.31 g.), 4-benzamidopiperidine (2.04 g.) and anhydrous potassium carbonate (1.38 g.) were well mixed and heatedon a steam bath for 4 hr. The resulting mass was crushed and stirred in water (200 ml.) at 60° for 12 hr. Filtration afforded the crude base of the title compound (2.95 g.). Conversion to the hydrochloride by solution in ethanol/HCl and precipitation with ether provided 3.01 g. of the title compound, as the hydrochloride m.p. 193.4°. Analysis : Found C, 64.74; H, 7.08; N, 7.14. C21H26N2O3. HCl requires C, 64.52; H, 6.96; N, 7.17%.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:27])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:26][O:25][C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=2)[OH:4])[CH3:27])=[CH:21][CH:20]=1)=[O:24]
Reactant: Cc1cccc(C(O)CN)c1
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cccc(C)c2)cc1
Yield: 54.1 %

Procedure:
Following a procedure similar to that described in Example 3, but using 2.5 g of 2-amino-1-(3-methylphenyl)ethanol (prepared as described in Preparation 44), 4.4 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 80 ml of benzene, 60 ml of absolute methanol and 4.5 g of sodium cyanoborohydride, and then purifying the reaction product by column chromatography through silica gel, using ethyl acetate as the eluent, 3.2 g of the title compound were obtained having an Rf=0.24 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][OH:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[CH:8]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].[C:21]1([CH3:30])[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH3:30])[C:11]([CH2:12][OH:13])=[CH:10]2
Reactant: OCc1cc2cc(F)ccc2nc1Cl
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccccc1-c1nc2ccc(F)cc2cc1CO
Temperature: 120 °C
Yield: 22.8 %

Procedure:
A mixture of (2-chloro-6-fluoroquinolin-3-yl)methanol (200 mg, 0.95 mmol), K2CO3 (198 mg, 1.43 mmol) and o-tolylboronic acid (143 mg, 1.05 mmol) in DME (10 mL) and water (1 mL) was degassed by bubbling N2 through it for 5 minutes. Pd(PPh3)4 (55 mg, 0.05 mmol) was added and the mixture heated in the microwave at 120° C. for 1 h. The solvent was removed in vacuo. Purification by column chromatography (SiO2, 0-50% EtOAc in heptane) then by preparative HPLC (Method 1) gave the title compound (58 mg, 23%) as a white solid. δH (CDCl3) 8.32 (s, 1H), 8.10-8.15 (m, 1H), 7.45-7.55 (m, 2H), 7.20-7.35 (m, 4H), 4.58 (s, 2H), 2.09 (s, 3H). LCMS (ES+) 268 (M+H)+, RT 2.89 minutes (Method 3).
Reaction SMILES: Br[CH:2]([C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)[CH:3](Br)[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1.[CH3:23][C:24]1[CH:30]=[CH:29][C:27]([O-:28])=[CH:26][CH:25]=1.[Na+].CC1C=CC(O)=CC=1>C1COCC1>[C:24]1([CH3:23])[CH:30]=[CH:29][C:27]([O:28][C:2]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)=[CH:3][C:4](=[O:12])[C:5]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=2)=[CH:26][CH:25]=1
Reactant: O=C(c1ccc(Br)cc1)C(Br)C(Br)C(=O)c1ccc(Br)cc1
Reactant: Cc1ccc([O-])cc1
Agent: Cc1ccc(O)cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(OC(=CC(=O)c2ccc(Br)cc2)C(=O)c2ccc(Br)cc2)cc1

Procedure:
To a solution of 1,2-dibromo-1,2-di(4-bromobenzoyl)ethane (11.1 g, 0.02 mole) in 35 ml of THF was added a suspension of sodium 4-methyl phenoxide [prepared from 0.92 g (0.04 mole) Na and 4.32 g (0.04 mole) 4-methylphenol in 30 ml THF by refluxing for 4-5 hr]. The yellow mixture was refluxed for 2-3 hr (TLC followed) after which the THF was removed under reduced pressure. The residue was treated with water, and the solid was filtered, washed with water, dried (Na2SO4), and dissolved in chloroform. The chloroform solution was passed through a silica column (elution with 2-5% ether in hexane). The result was an off white crystalline solid, 4.95 g (50%), mp 137°-8° C. IR (KBr) 3087, 3035, 2868, 1687, 1646, 1587, 1572, 1557, 1502, 1399, 1364, 1194, 1068, 1009, 971, 876, 815, 772, 526. 1H NMR (CDCl3 /35° C.) 7.92 (d, 2H, J=8.8), 7.65 (d, 2H, J=8.8), 7.55 (d, 2H, J=8.8), 7.48 (d, 2H, J=8.8), 7.27 (d, 2H, J=8.3), 7.11 (d, 2H, J=8.3), 6.32 (s, 1H), 2.4 (s, 3H). 13C NMR (CDCl3 /35° C.) 189.4, 187.6, 168.4, 150.9, 136.6, 136.0, 133.4, 132.3, 131.8, 130.9, 130.3, 129.6, 129.2, 128.2, 120.6, 101.8, 20.95. MS m/e 500 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].I.[CH:35]([O:38][CH2:39][CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]=[C:42]1[N:50]1[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)([CH3:37])[CH3:36]>>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:53]2[CH2:54][CH2:55][CH2:56][N:50]([C:42]3[N:41]([CH2:40][CH2:39][O:38][CH:35]([CH3:37])[CH3:36])[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:51][CH2:52]2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8]1)=[O:6]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Reactant: CC(C)OCCn1c(N2CCCNCC2)nc2ccccc21
Agent: I
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCN2CCCN(c3nc4ccccc4n3CCOC(C)C)CC2)(c2ccccc2)C1

Procedure:
Prepare by the method of Example 102.1.2 using 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) (0.52 g, 1.10 mmol) and 4-(1-(2-(isopropoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (0.60 g, 1.08 mmol) to give the title compound; Rf=0.28 (silica gel, dichloromethane/methanol/concentrated aqueous ammonia 90/10/0.1).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]2[CH2:17][C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([OH:16])[C:10]=3[C:8](=[O:9])[C:4]2=[C:5]([OH:7])[CH:6]=1.N1C=CC=CC=1.[C:24](Cl)(=[O:27])[CH2:25][CH3:26]>C1(C)C=CC=CC=1>[OH:16][C:15]1[C:10]2[C:8](=[O:9])[C:4]3[C:3](=[CH:2][CH:1]=[CH:6][C:5]=3[OH:7])[CH:17]([C:24](=[O:27])[CH2:25][CH3:26])[C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: CCC(=O)Cl
Reactant: O=C1c2c(O)cccc2Cc2cccc(O)c21
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCC(=O)C1c2cccc(O)c2C(=O)c2c(O)cccc21
Temperature: 85 °C

Procedure:
To a suspension of 56.6 g (0.25 mol) of purified anthralin in 1750 m3 of anhydrous toluene at room temperature, 27.3 cm3 (0.34 mol) of anhydrous pyridine was added first and then 26.2 cm3 (0.3 mol) of propionyl chloride was added dropwise in around 20 minutes. The mixture was then heated to around 85° C. for 1 hour. The mixture was recooled to room temperature, 27.3 cm3 of pyridine and 26.2 cm3 of propionyl chloride were again added and the mixture was heated for 1 hour to a temperature of around 85° C.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][Si:10]([CH3:60])([CH3:59])[CH2:11][CH2:12][O:13][CH2:14][N:15]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])[C:16]1[N:21]2[N:22]=[CH:23][C:24]([C:25]3[CH:26]=[N:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:29][CH:30]=3)=[C:20]2[N:19]=[C:18]([O:37][CH:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]2)[CH:17]=1>CC#N>[CH3:58][Si:55]([CH3:57])([CH3:56])[CH2:54][CH2:53][O:52][CH2:51][N:15]([CH2:14][O:13][CH2:12][CH2:11][Si:10]([CH3:9])([CH3:59])[CH3:60])[C:16]1[N:21]2[N:22]=[CH:23][C:24]([C:25]3[CH:26]=[N:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:29][CH:30]=3)=[C:20]2[N:19]=[C:18]([O:37][CH:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]2)[C:17]=1[Br:8]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Oc2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NBS (246 mg, 1.38 mmoL) was added to a solution of tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yloxy)piperidine-1-carboxylate (Int-11b, 1022 mg, 1.38 mmoL) in CH3CN (15 mL). After stirring at room temperature for 30 min, the mixture was concentrated in vacuo. Purification by column chromatography afforded tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yloxy)piperidine-1-carboxylate (Int-11c): LCMS tR=3.59 Min (5 min run, UV254nm). Mass calculated for, M+824.3, observed m/z 825.1 (M+H).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:2][C:3]#[CH:4].Br[C:14]1[N:18]([CH3:19])[N:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21]>CCN(CC)CC.CCOC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:19][N:18]1[C:14]([C:4]#[C:3][CH2:2][CH2:1][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[N:17]1
Reactant: Cn1ncc([N+](=O)[O-])c1Br
Reactant: C#CCCNC(=O)OC(C)(C)C
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cn1ncc([N+](=O)[O-])c1C#CCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.5 %

Procedure:
A solution of tert-butyl 3-butyn-1-ylcarbamate (123 mg, 0.728 mmol) in NEt3 (4 mL) was treated with 5-bromo-1-methyl-4-nitro-1H-pyrazole (100 mg, 0.485 mmol) and copper(I) bromide dimethyl sulfide complex (10 mg, 0.049 mmol). The mixture was degassed four times by evacuating and refilling with nitrogen gas before tetrakis(triphenylphosphine)-palladium(0) (28 mg, 0.024 mmol) was added. Degassing was repeated twice and the reaction mixture was stirred at room temperature for 20 hr. More tert-butyl 3-butyn-1-ylcarbamate (123 mg, 0.728 mmol) and copper(I) bromide dimethyl sulfide complex (10 mg, 0.049 mmol) were added and the mixture was degassed three times. Tetrakis(triphenylphosphine)palladium(0) (28 mg, 0.024 mmol) was added and the reaction mixture was stirred at room temperature for 48 hr. The mixture was diluted with EtOAc (100 mL) and washed with water (20 mL) and brine (20 mL). The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification of the residue via silica gel column chromatography (30-40% EtOAc/isohexane) gave tert-butyl 4-(1-methyl-4-nitro-1H-pyrazol-5-yl)but-3-ynylcarbamate as a yellow oil (112 mg, 78%). 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 5.03 (s, 1H), 3.94 (s, 3H), 3.46 (q, J=6.4 Hz, 2H), 2.79 (t, J=6.4 Hz, 2H), 1.67-1.27 (m, 9H).
Reaction SMILES: C(C1(C(O)=O)CC1)(OCC)=O.ClC(OCC)=O.NC1C=CC=CC=1.C(N(CC)CC)C.Cl[C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40]([C:42]2([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:44][CH2:43]2)=[O:41])=[C:35](CC)[CH:34]=1>>[C:36]1([NH:39][C:40]([C:42]2([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:43][CH2:44]2)=[O:41])[CH:35]=[CH:34][CH:33]=[CH:38][CH:37]=1
Reactant: CCOC(=O)C1(C(=O)Nc2ccc(Cl)cc2CC)CC1
Agent: CCOC(=O)C1(C(=O)O)CC1
Agent: CCOC(=O)Cl
Solvent: Nc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C(=O)Nc2ccccc2)CC1

Procedure:
1-Carboethoxycyclopropanecarboxylic acid (3.95 grams, 0.025 mole), ethyl chloroformate (2.71 grams, 0.025 mole) and aniline (2.33 grams, 0.025 mole) were reacted sequentially in the presence of triethylamine (2.53 grams, 0.025 mole) in a manner similar to that described for ethyl 1-(4-chloro-2-ethylphenylaminocarbonyl)cyclopropanecarboxylate in Example XXXIII to give ethyl 1-(phenylaminocarbonyl)cyclopropanecarboxylate which was then hydrolyzed in a manner similar to that described in Example VII to give 2.42 grams (0.01 mole) of 1-(phenylaminocarbonyl)cyclopropanecarboxylic acid having a melting point of 178° C.-181° C. NMR analysis of the product indicated the following:
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]2[C:14](SC)=[N:15][C:16]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:12]2=[N:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24](OCC)(=[O:27])C=C.C[O-].[Na+].C(O)(=O)C>CO>[CH2:1]([S:8][C:9]1[N:13]=[C:12]2[N:11]([C:14]([O:27][CH3:24])=[N:15][C:16]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=32)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OCC
Reactant: CSc1nc2ncccc2c2nnc(SCc3ccccc3)n12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1nc2ncccc2c2nc(SCc3ccccc3)nn12
Yield: 86.8 %

Procedure:
A mixture of 17.7 g (52 mmol) of 3-benzylthio-5-methylthiopyrido[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine in 200 mL of methanol was prepared and to this was added at ambient temperature with stirring 8.5 mL (7.8 g, 78 mmol) of ethyl acrylate and 2.4 mL of 25 percent sodium methoxide in methanol (10 mmol). Everything dissolved fairly quickly and after 15 min new precipitate formed. After about 1 hour the mixture was acidified with acetic acid and the volatile components were removed by evaporation under reduced pressure. The residue was dissolved in dichloromethane and the resulting solution was washed with water, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure. The residue was diluted with ether, recovered by filtration, and dried to obtain 14.6 g of the title compound as a brown powder melting at 282°-284° C. with decomposition.