Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:9]([NH2:11])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br[C:15]1[N:23]=[CH:22][N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:9]([NH:11][C:15]2[N:23]=[CH:22][N:21]=[C:20]3[C:16]=2[N:17]=[CH:18][N:19]3[CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COc1c(Br)cc(Cl)cc1C(C)N
Reactant: Brc1ncnc2c1ncn2C1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(Br)cc(Cl)cc1C(C)Nc1ncnc2c1ncn2C1CCCCO1
Yield: 98.3 %

Procedure:
A solution of 1-(3-bromo-5-chloro-2-methoxyphenyl)ethanamine (2.2 g, 8.5 mmol) in ethanol (69 mL), was treated with 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (3.6 g, 13 mmol, from Example 108, Step 1) and N,N-diisopropylethylamine (4.4 mL, 25 mmol) and heated at reflux overnight. The reaction mixture was cooled, poured into sodium bicarbonate (150 mL) and extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with water and brine, dried with sodium sulfate, filtered, and concentrated to a crude residue. Purification by flash column chromatography using acetonitrile in dichloromethane (5%-10%) and then ethyl acetate in hexanes (60%-100%) gave the desired product (3.9 g, 98%). LCMS for C19H22BrClN5O2 (M+H)+: m/z=466.1, 468.1. Found: 466.0, 468.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:33])=[CH:23][C:24]([O:31]C)=[C:25]([CH:30]=4)[C:26]([O:28][CH3:29])=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.B(Cl)(Cl)Cl.CO>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:33])=[CH:23][C:24]([OH:31])=[C:25]([CH:30]=4)[C:26]([O:28][CH3:29])=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)OC)c(OC)cc3C)cc12
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)OC)c(O)cc3C)cc12
Yield: 77.9 %

Procedure:
To a 100 mL round-bottomed flask was added methyl 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoate (350.5 mg, 0.783 mmol) in DCM (8 mL). To this solution was then added, under nitrogen, a 1M solution of boron trichloride (3.92 mL, 3.92 mmol) and the mixture was stirred overnight at room temperature. The reaction mixture was cooled in an ice bath and 10 mL of methanol was slowly added. The solvent was removed under vacuum. The flask was again cooled, 25 mL of ice cold methanol was added and the resulting solid was filtered to give 264.5 mgs (78% yield) of methyl 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-hydroxy-4-methylbenzoate as an ivory colored solid. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 μm C18, 2×50 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. 1H NMR (400 MHz, DMF-d7) δ ppm 2.30 (s, 3H), 2.95 (d, J=4.77 Hz, 3H), 3.98 (s, 3H), 7.02 (s, 1H), 7.38-7.48 (m, 3H), 7.68-7.73 (m, 2H), 7.76 (d, J=8.53 Hz, 1H), 8.08-8.15 (m, 2H), 8.33 (br. s., 1H). LCMS Rt=3.636, m/z 434.3 (M+H), 100% purity.
Reaction SMILES: [F:1][C:2]1[C:3]2[C:4]3[N:5]([C:13]([C:16]4[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=4)=[N:14][CH:15]=2)[CH2:6][CH2:7][C:8]=3[NH:9][C:10](=[O:12])[CH:11]=1.S(Cl)([Cl:26])=O.ClCC1C=CC(C2N3CCC4NC(=O)C=CC(C=43)=CN=2)=CC=1>>[Cl:26][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[N:5]3[CH2:6][CH2:7][C:8]4[NH:9][C:10](=[O:12])[CH:11]=[C:2]([F:1])[C:3]([C:4]=43)=[CH:15][N:14]=2)=[CH:17][CH:18]=1
Reactant: O=C1C=C(F)C2=CN=C(c3ccc(CO)cc3)N3CCC(=C23)N1
Reactant: O=S(Cl)Cl
Agent: O=C1C=CC2=CN=C(c3ccc(CCl)cc3)N3CCC(=C23)N1
Product: O=C1C=C(F)C2=CN=C(c3ccc(CCl)cc3)N3CCC(=C23)N1

Procedure:
This compound was prepared from intermediate 97 and thionyl chloride using the procedure described in Example 171 for 171a. HPLC Rt=3.260 min.
Reaction SMILES: [CH:1]([N:4]([CH:18]([CH3:20])[CH3:19])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=O)[C:8]1=[O:9])([CH3:3])[CH3:2].Cl.[CH:22]1([NH:28][C:29](=[O:32])[NH:30][NH2:31])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(O)C.C([O-])(=O)C.[Na+]>O>[CH:22]1([NH:28][C:29](=[O:32])[NH:30]/[N:31]=[C:10]2/[C:8](=[O:9])[N:7]([CH2:6][CH2:5][N:4]([CH:18]([CH3:20])[CH3:19])[CH:1]([CH3:3])[CH3:2])[C:17]3[C:12]/2=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: NNC(=O)NC1CCCCC1
Reactant: CC(C)N(CCN1C(=O)C(=O)c2ccccc21)C(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)N(CCN1C(=O)/C(=N/NC(=O)NC2CCCCC2)c2ccccc21)C(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 72.2 %

Procedure:
To a suspension of 0.91 g of 1-(2-diisopropylaminoethyl)isatin and 1.00 g of 4-cyclohexylsemicarbazide hydrochloride in 17 ml of a mixture of ethanol and water (2:1) was added 0.42 g of sodium acetate, and the mixture was stirred for 17 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and an aqueous sodium bicarbonate solution was added to the residue. The precipitates were collected by filtration, washed with water, and recrystallized from aqueous ethanol to obtain 0.99 g of (E)-1-(2-diisopropylaminoethyl)isatin 3-(4-cyclohexylsemicarbazone) having a melting point of 164°-166° C.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[S:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14])(=[O:9])=[O:8]>ClCCl>[CH2:1]([N:3]([CH2:4][CH3:5])[S:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14])(=[O:9])=[O:8])[CH3:2]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CCNCC
Solvent: ClCCl
Product: CCN(CC)S(=O)(=O)c1cccc(C(=O)O)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Diethylamine (Aldrich, 2.5 mL, 24 mmol) was added to a solution of 3-(chlorosulfonyl)benzoic acid (Aldrich, 2.0 g, 9.1 mmol) in anhydrous dichloromethane (20 mL) at 0° C. The mixture was then stirred at 0° C. for 2 hours. The volatiles were removed under reduced pressure. The residue was treated with aqueous potassium hydrogensulfate (1 M, 10 mL) and then extracted with ethyl acetate (3×50 mL). The combined extracts were dried over magnesium sulfate filtered and then concentrated to give the title compound. 1H NMR (300 MHz, CD3OD) δ 1.13 (t, J=7.1 Hz, 6H), 3.22-3.30 (m, 4H), 7.69 (t, J=7.8 Hz, 1H), 8.03 (ddd, J=7.9, 1.9, 1.4 Hz, 1H), 8.25 (dt, J=7.8, 1.4 Hz, 1H), 8.40 (t, J=1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 275 (M+NH4)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH:8]([CH2:11][OH:12])[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:16][C:17](=[O:21])[CH:18]=[N+]=[N-])[CH3:15]>ClCCCl>[CH2:14]([O:16][C:17](=[O:21])[CH2:18][O:12][CH2:11][CH:8]([NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:13])[CH2:9][CH3:10])[CH3:15]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CCC(CO)NC(=O)OC(C)(C)C
Solvent: ClCCCl
Product: CCOC(=O)COCC(CC)NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 40 %

Procedure:
To a solution of (1-(hydroxymethyl)propyl)carbamic acid tert-butylester (7.2 g, 39 mmol) in 1,2-dichloroethane (500 ml) rhodium(II)acetate (180 mg) was added and the mixture was heated to 80° C. Ethyldiazoacetate (6.0 ml, 57 mmol) in 1,2-dichloroethane (180 ml) was added over a period of 60 min and the mixture was heated at 80° C. for 6 hours. Then another portion of ethyldiazoacetate (2.0 ml, 19 mmol) in 1,2-dichloroethane (40 ml) was added and the mixture was refluxed for 7 hours. The mixture was cooled to room temperature and washed with sodium bicarbonate (2×100 ml) and brine (100 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (300 g) is with pentane/ethyl acetate 7:3 as eluent to give 4.3 g of (2-(tert-butoxycarbonylamino)butoxy)acetic acid ethylester. The product was dissolved in of 1 M lithium hydroxide in water/methanol 1:3 (40 ml) and stirred at room temperature for 4 hours. The mixture was concentrated in vacuo and water (100 mL) was added and the solution was washed with ether (20 mL). The aqueous phase was acidified to pH 4 with 1 M aqueous hydrogen chloride and extracted with ethyl acetate (200 ml), dried over magnesium sulfate and concentrated in vacuo to give 2.46 g of (2-(tert butoxycarbonylamino)butoxy)acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].CN(C=O)C.[Br:18][CH2:19][C:20](Br)=[O:21]>O1CCOCC1>[CH3:1][O:2][C:3]1[C:4]([NH:12][C:20](=[O:21])[CH2:19][Br:18])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C(Br)CBr
Reactant: COc1cccc(C(=O)O)c1N
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)O)c1NC(=O)CBr
Temperature: -5 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
A solution of 3-methoxy-2-aminobenzoic acid (5.0 g, 30 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL-3-necked round-bottomed flask equipped with a constant addition funnel (60 mL) was cooled with an ice-bath to -5° C. Bromoacetyl bromide (6.66 g, 2.90 mL, 30 mmol) was added dropwise, keeping the internal temperature between -5° to 0° C. over a 1/2 h period. After the addition of bromoacetyl bromide was completed, the solution was warmed to room temperature and then stirred overnight. To the solution was slowly added 150 mL of ice-water, causing a pale white solid to precipitate. The precipitate was filtered, washed with water, and then dried in a vacuum oven overnight to afford 6.26 g (72%) of the title compound as a pale-white solid, mp 178°--180° C. (decomp): 1H NMR (DMSO-d6) δ12.80 (bs, 1H), 9.80 (s, 1H), 7.30-7.25 (m, 3H), 4.05 (s, 2H), 3.81 (s, 3H); 13C NMR (DMSO-d6) δ167.37, 164.54, 153.67, 129.76, 126.56, 124.39, 121.18, 114.66, 56.03, 29.63; MS (EI, m/z) 287 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)=[O:4].[NH2:16][CH2:17][C@H:18]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].F[B-](F)(F)F.C(C(=NOC(N(C)C)=[N+](C)C)C(OCC)=O)#N.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:30]([O:29][C:27]([NH:26][C@@H:18]([CH2:17][NH:16][C:11](=[O:13])[C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[CH:15][CH:14]=1)[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[O:28])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COC(=O)CCc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCc1ccc(C(=O)NC[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
354 mg (1.7 mmol) of 4-(2-methoxycarbonylethyl)benzoic acid and 500 mg (1.7 mmol) of tert-butyl (2S)-3-amino-2-benzyloxycarbonylaminopropionate were dissolved in 3 ml of dimethylformamide and treated with 557 mg (1.7 mmol) of O-((cyano-(ethoxycarbonyl)-methylidene)amino)-1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU) and 204 mg (1.7 mmol) of diisopropylethylamine and the mixture was stirred at room temperature for 7 h at pH 7-8. The solvent was removed in vacuo, the residue was dissolved in ethyl acetate and the solution was washed three times each with KHSO4 solution and NaHCO3 solution until neutral. The organic phase was separated off and dried and the solvent was removed by distillation in vacuo. Yield: 770 mg (93%).
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][N:6]=1.Br[CH2:13][CH2:14][CH2:15][Cl:16].O>CS(C)=O>[NH2:4][C:5]1[C:10]([O:11][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: ClCCCBr
Reactant: Nc1ncccc1O
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ncccc1OCCCCl
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 48.7 ml (200 mmol) of a 4.1M sodium methoxide solution in 100 ml of dimethyl sulfoxide, 22.03 g (200 mmol) of 2-amino-3-hydroxypyridine was added at room temperature, followed by stirring at 80° C. for 10 minutes to dissolve the latter. After the reaction mixture was cooled, the methanol was distilled off. To this mixture, 19.8 ml (200 mmol) of 1-bromo-3-chloropropane was added at 0° C., followed by stirring for 30 minutes. The reaction mixture was poured into water (400 ml), extracted with chloroform, washed with2N aqueous sodium hydroxide and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4→ethyl acetate). The obtained crude crystal was washed with diethyl ether-n-hexane to yield 20.48 g (54.8%, white powder) of the desired product.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC.[CH3:39][O:40][C:41]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[C:47]2[C:42]=1[C:43](=[O:65])[NH:44][C:45]([C:53]1[CH:58]=[CH:57][C:56]([N:59]3[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]3)=[CH:55][CH:54]=1)=[N:46]2>C1COCC1>[CH3:39][O:40][C:41]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[C:47]2[C:42]=1[C:43](=[O:65])[NH:44][C:45]([C:53]1[CH:58]=[CH:57][C:56]([N:59]3[CH2:60][CH2:61][N:62]([C:1](=[O:9])[C:2]4[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=4)[CH2:63][CH2:64]3)=[CH:55][CH:54]=1)=[N:46]2
Reactant: O=C(O)c1cccnc1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C(=O)c5cccnc5)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.6 %

Procedure:
To a solution of nicotinic acid (0.066 g, 0.54 mmol) in THF (20 mL) was added HOBt (0.079 g, 0.59 mmol), EDCl (0.113 g, 0.59 mmol), Et3N (0.08 mL, 0.59 mmol) and 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.200 g, 0.54 mmol). The resulting solution was stirred overnight at room temperature. The solution was concentrated in vacuo and the resulting solid was purified by flash chromatography on silica gel, eluting with 10% to 60% of 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2, to afford the title compound (0.050 g, 19%): 1H NMR (300 MHz, DMSO-d6): δ 11.79 (s, 1H), 8.59-8.78 (m, 2H), 8.12 (d, J=8.8 Hz, 2H), 7.82-7.99 (m, 1H), 7.37-7.60 (m, 1H), 7.04 (d, J=9.1 Hz, 2H), 6.69 (s, 1H), 6.47 (s, 1H), 3.63-3.97 (m, 8H), 3.20-3.63 (m, 6H). APCI MS m/z 472 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.[Cl:8][C:9]1[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[C:11]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[N:10]=1.[C:33]1([C@@H:39]([NH2:43])[CH2:40][CH2:41][NH2:42])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(O)C>[ClH:8].[NH2:43][C@H:39]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:40][CH2:41][NH:42][C:9]1[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[C:11]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[N:10]=1
Reactant: NCC[C@H](N)c1ccccc1
Reactant: Cn1c(Cl)nc(-c2ccncc2)c(-c2cccc(C(F)(F)F)c2)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cn1c(NCC[C@H](N)c2ccccc2)nc(-c2ccncc2)c(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Aqueous sat. sodium carbonate (2 ml) was added to a solution of 2-chloro-3-methyl-6-(4-pyridyl)-5-(3-trifluoromethylphenyl)-4(3H)-pyrimidinone hydrochloride (730 mg, 2 mmol) and (S)-1-phenyl-1,3-propanediamine (360 mg, 2.4 mmol) in ethanol (10 ml). The mixture was stirred for 4 h at room temperature. It was evaporated and the remainder partitioned between dichloromethane and water. The organic solution was dried and evaporated followed by column chromatography on silica gel (dichloromethane:methanol conc. ammonium hydroxide=93 7:0.7). MS (m/z): 480 (M+H)+; C26H24F3N5O requir. 479.5 (free base).
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][N:6]1[C:10](=[O:11])[CH2:9][CH:8]([C:12](OC)=[O:13])[CH:7]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[OH:13][CH2:12][CH:8]1[CH2:9][C:10](=[O:11])[N:6]([CH3:5])[CH:7]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)C1CC(=O)N(C)C1c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1C(=O)CC(CO)C1c1ccccc1
Reaction time: 2 h

Procedure:
To 82.6 g. of sodium borohydride in 950 ml. of methanol at -5° to 0° C. was slowly added in portions 63 g. of methyl 1-methyl-5-oxo-2-phenylpyrrolidin-3-carboxylate. After the addition, the reaction mixture was then allowed to come to ambient temperature over 2 hours. Concentration in vacuo gave a semisolid which was suspended in water at 50° C. and stirred for 30 minutes. The solid was then dissolved in 3:1 chloroform-ether, dried (Na2SO4) filtered, and concentrated in vacuo to yield 40 g. of an oil.
Reaction SMILES: CN(P(N(C)C)(N(C)C)=O)C.[CH3:12][C:13]1([CH3:21])[O:18][C:17](=[O:19])[CH:16]=[C:15]([CH3:20])[O:14]1.[CH:22]([C:24]([CH3:26])=[O:25])=[CH2:23].Cl>CCOCC>[CH3:12][C:13]1([CH3:21])[O:18][C:17](=[O:19])[CH:16]=[C:15]([CH2:20][CH2:23][CH2:22][C:24](=[O:25])[CH3:26])[O:14]1
Reactant: C=CC(C)=O
Reactant: CC1=CC(=O)OC(C)(C)O1
Agent: Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: CC(=O)CCCC1=CC(=O)OC(C)(C)O1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
In an argon gas stream, 20.6 ml of n-butyl lithium (1.6M solution in hexane) were added to 60 ml of an ether solution containing 3.53 g (0.033 mol) of diisopropylamine at -20° C. to form LDA. After stirring for 30 minutes, the solution was cooled to -78° C., and 10.4 ml (0.06 mol) of HMPA were added thereto, followed by stirring for 15 minutes. Afterward, a mixture of 4.26 g (0.03 mol) of 2,2-dimethyl-6-methyl-1,3-dioxin-4-one and 60 ml of ether as well as 60 ml of an ether solution containing 2.1 g (0.03 mol) of methyl vinyl ketone were added to the solution. After the temperature was gradually returned to room temperature, 10% hydrochloric acid was added thereto to neutralize the solution, and extraction was then carried out with ether. The resultant organic layer was dried over anhydrous magnesium sulfate. Next, the used solvent was distilled off, and the residue was then subjected to column chromatography (an eluent of hexane:ethyl acetate=4:1), thereby obtaining 3.16 g of 2,2-dimethyl-6-(4-oxopentyl)-1,3-dioxin-4-one.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5](C=O)=[CH:4][CH:3]=1.CO.CO[CH:14]([O:17][CH3:18])[O:15][CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>>[CH3:18][O:17][CH:14]([O:15][CH3:16])[C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 4.88 g (40 mmol) of 4-hydroxybenzaldehyde, 6.6 g (206 mmol) of methanol and 5.1 g (48 mmol) of trimethylorthoformate and 28 mg of p-toluene sulfonic acid was stirred at room temperature for 12 h. An excess of NaHCO3 was then added and the mixture stirred for a further 60 h. The mixture was then filtered, the solvent removed in-vacuo and the residue purified by flash chromatography (silica; 20% ethyl acetate in hexanes) to give the title compound as a viscous oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([OH:14])[C:3]=1[C:15](=[O:17])[CH3:16].C([O-])([O-])=O.[K+].[K+].[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=O)#[N:25].O>CC(C)=O>[OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]2[C:3]=1[C:15](=[O:17])[CH:16]=[C:29]([C:28]1[CH:27]=[C:26]([CH:34]=[CH:33][CH:32]=1)[C:24]#[N:25])[O:14]2
Reactant: CC(=O)c1c(O)cc(N2CCOCC2)cc1O
Reactant: N#Cc1cccc(C(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: N#Cc1cccc(-c2cc(=O)c3c(O)cc(N4CCOCC4)cc3o2)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 6.7 %

Procedure:
To a suspension of 1-(2,6-dihydroxy-4-morpholin-4-yl-phenyl)-ethanone (61 mg, 0.257 mmol) and K2CO3 (178 mg, 1.29 mmol) in acetone (3 mL) was added 3-cyanobenzoyl chloride (43 mg, 0.257 mmol). The reaction vessel was sealed and heated to 60° C. for 2 d. After cooling to room temperature, water (about 2 mL) was added, and the mixture was allowed to stir for about 10 min. The contents were transferred to a separatory funnel containing water (5 mL) and extracted with EtOAc (3×15 mL). The organic layer was dried (MgSO4) and concentrated. The concentrate was purified via Biotage chromatography with gradient elution from 100% hexanes to 30% EtOAc/hexanes to yield 6 mg (7%) of 3-(5-hydroxy-7-morpholin-4-yl-4-oxo-4H-chromen-2-yl)-benzonitrile. Rf=0.33 (50% EtOAc/hexanes).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[CH:14]=[N:15][C:16]4[NH:20][N:19]=[CH:18][C:17]=4[C:10]=3[N:9]3[N:21]=[CH:22][N:23]=[C:8]23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1>[C:24]([N:20]1[C:16]2[N:15]=[CH:14][C:11]3[C:12](=[O:13])[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:8]4[N:9]([N:21]=[CH:22][N:23]=4)[C:10]=3[C:17]=2[CH:18]=[N:19]1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=c1c2cnc3[nH]ncc3c2n2ncnc2n1-c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(c1ccccc1)n1ncc2c1ncc1c(=O)n(-c3ccccc3)c3ncnn3c12

Procedure:
0.01 mol. of 4-phenyl-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one and 0.02 mol. of benzoyl chloride are stirred overnight in 50 ml. of dry pyridine at room temperature. On addition of 50 ml. of water, 8-benzoyl-4-phenyl-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]-triazolo[1,5-a]pyrimidin-5(8H)-one is filtered off.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:25])[CH2:23][NH2:24])[CH3:21])[C:14]=3[Cl:26])[C:5]2=[N:4][C:3]=1[CH3:27].[C:28](O)(=[O:33])[CH2:29][CH2:30][CH:31]=[CH2:32].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:25])[CH2:23][NH:24][C:28](=[O:33])[CH2:29][CH2:30][CH:31]=[CH2:32])[CH3:21])[C:14]=3[Cl:26])[C:5]2=[N:4][C:3]=1[CH3:27]
Reactant: C=CCCC(=O)O
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccn2c1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCC(=O)NCC(=O)N(C)c1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
A mixture of 3-bromo-8-[2,6-dichloro-3-(N-glycyl-N-methylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine (150 mg), 4-pentenoic acid (33 mg), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (77 mg), 1-hydroxybenzotriazole (64 mg) and N,N-dimethylformamide (1.5 ml) was stirred for 2 hours at ambient temperature. Water was added thereto, and the mixture was extracted with methylene chloride three times. The organic layers were combined, washed with water four times and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (methylene chloride:methanol=30:1, V/V) to give 3-bromo-8-[2,6-dichloro-3-[N-(4-pentenoylglycyl)-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (172 mg).