Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[S:13])[NH:8]3.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].C(N(CC)CC)C>CN(C)C=O>[CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7]([S:13][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[C:21](=[O:30])[C:22]2=[CH:29][CH:28]=[CH:27][CH:26]=[C:23]2[C:24]1=[O:25])=[N:8]3
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Reactant: Cc1nc2cccc3[nH]c(=S)c1n23
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc2cccc3nc(SCCCCCN4C(=O)c5ccccc5C4=O)c1n23
Temperature: 100 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
To a suspension of 2.03 g (10.7 mmol) of 1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-thione in 50 ml of N,N-dimethylformamide were added 3.18 g (10.7 mmol) of N-(5-bromopentyl)phthalimide and 2.24 ml (16.1 mmol) of triethylamine. The mixture was stirred for two hours at 100° C. After cooling, the resulting precipitates were collected by filtration, washed with N,N-dimethylformamide, ethanol, and diethylether, successively, dried to afford 3.44 g of the desired compound (79.3%, a pale brown solid).
Reaction SMILES: C([CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])#N.[NH3:13]>C(O)C.[Ni]>[NH2:13][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12]
Reactant: COc1ccccc1OCC#N
Reactant: N
Agent: [Ni]
Solvent: CCO
Product: COc1ccccc1OCN
Yield: 35 %

Procedure:
A solution of the 2-cyanomethoxyanisole (5.6 g, 0.034 mol) in anhydrous ammonia (25 ml) and ethanol (50 ml) was heated to 120° C. at 500 psi for 12 h in the presence of raney nickel (1.4 g). The reaction mixture was filtered, concentrated under reduced pressure, the residue taken up in ether, and washed with 1.2 M HCl. The acidic phase was then rendered basic (pH=12) with careful addition of solid KOH and the alkaline solution extracted with ether. The organic phase was dried (MgSO4) and concentrated under reduced pressure to give the product (1.99 g, 35%) as an oil. IR. NMR. MS.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][N:26]=[CH:25]3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:38])=[O:37])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH:28]=[CH:27][N:26]=[CH:25]3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3ccnc3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-n3ccnc3)cc2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step B was prepared from {3-[(4-imidazol-1-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester of Step A and benzenesulfonyl chloride following the method described in Example 3, Step B. 1H NMR (400 MHz, CDCl3) δ7.86 (m, 3H), 7.62 -7.52 (m, 3H), 7.22 (m, 6H), 7.15 (t, b 1H), 6.71 (d, 1H), 6.61 (d, 1H), 6.56 (s, 1); MS 534 (M+1).
Reaction SMILES: C1(C)C(C)=CC=CC=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:17]([N:24]=[CH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)C2C=CC=CC=2)[CH:14]=[CH:15][CH:16]=1.[C:32]1(=[O:38])[O:37][C:35](=[O:36])[CH2:34][CH2:33]1>CCOCC>[CH2:25]([N:24]1[C:35](=[O:36])[CH2:34][CH:33]([C:32]([OH:37])=[O:38])[CH:17]1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH3:9])[CH:12]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C1CCC(=O)O1
Reactant: COc1cccc(C(N=Cc2ccccc2)c2ccccc2)c1
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: COc1cccc(C2C(C(=O)O)CC(=O)N2Cc2ccccc2)c1

Procedure:
To 450 ml. of xylene was added 143.3 gm of 3-methoxyphenylbenzylidenebenzylamine and 63.9 gm. of succinic anhydride. The solution was refluxed for 15 hours, cooled and extracted with saturated sodium bicarbonate solution. After washing the basic solution with ether, the aqueous phase was acidified with concentrated hydrochloric acid to provide a white gum. The gum was dissolved in ether, dried (Na2SO4), filtered and concentrated in vacuo to a semi-solid which was titurated with anhydrous ethyl ether and the resultant solid removed by filtration and discarded. Concentration in vacuo provided 18.5 g of the desired product as a gum.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1>>[CH3:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:17]1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: CC1CCCNC1
Product: CC1CCCN(c2nnc(N)nc2-c2ccccc2)C1
Yield: 13.9 %

Procedure:
6-(3-Methylpiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine (30 mg, 14%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80 mmol) and 3-methylpiperidine (0.21 g, 1.92 mmol) according to the general procedure of Example 2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=1[N:16]1[C:20](CN2C(=O)C3=CC=CC=C3C2=O)=NN=[C:17]1[CH2:33][N:34]1CCN(C)CC1.O.[NH2:43][NH2:44]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:16]2[CH:20]=[N:43][N:44]=[C:17]2[CH2:33][N:34]=1
Reactant: NN
Reactant: CN1CCN(Cc2nnc(CN3C(=O)c4ccccc4C3=O)n2-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)CC1
Solvent: O
Solvent: CCO
Product: Clc1ccccc1C1=NCc2nncn2-c2ccccc21

Procedure:
In the manner given in Example 27, 2',5-dichloro-2-[3-[(4-methylpiperazino)methyl]-5-(phthalimidomethyl)- 4H-1,2,4-triazol-4-yl]benzophenone is heated in ethanol with hydrazine hydrate to give 8-chloro-1-[4-methylpiperazino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine.
Reaction SMILES: [NH2:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-].[Na+].[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](Cl)=[O:19].C(OCC)(=O)C>O>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([NH:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:19]
Reactant: O=C(Cl)c1ccco1
Reactant: NC1(C(=O)O)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC1(C(=O)O)CCCCC1)c1ccco1
Temperature: 80 °C
Reaction time: 2 h
Yield: 237.3 %

Procedure:
71.6 g (0.5 mol) of 1-aminocyclohexanecarboxylic acid was added to a solution of 20 g (0.5 mol) of sodium hydroxide in 250 ml of water, and the mixture was stirred at 80° C. for 2 hours. The mixture solution was cooled by ice-water, 71.8 g (0.2 mol) of 2-furancarbonyl chloride and a solution of 24 g (0.6 mol) of sodium hydroxide in 100 ml of water were simultaneously added thereto over approximately 1 hour. The reaction solution was slowly returned to room temperature and stirred overnight. After 80 ml of ethyl acetate was added to the reaction solution and the mixture was stirred for 1 hour, the insolubles were removed by filtration. The aqueous layer was separately collected, 49 ml of concentrated hydrochloric acid was added thereto under ice-cooling. The precipitated crystal was collected by filtration and dried-under reduced pressure to obtain 112.6 g (95%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:22]3[CH2:24][CH2:23]3)[C:10](=[O:21])[N:11]([S:13]([C:16]3[NH:20][N:19]=[CH:18][N:17]=3)(=[O:15])=[O:14])[N:12]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Cl:34][C:35]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:36]=1[CH2:37]Br>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH:22]3[CH2:24][CH2:23]3)[C:10](=[O:21])[N:11]([S:13]([C:16]3[N:20]([CH2:37][C:36]4[C:35]([Cl:34])=[CH:42][CH:41]=[CH:40][C:39]=4[Cl:43])[N:19]=[CH:18][N:17]=3)(=[O:15])=[O:14])[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=c1n(S(=O)(=O)c2ncn[nH]2)nc(-c2ccc(Cl)cc2)n1C1CC1
Reactant: Clc1cccc(Cl)c1CBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=c1n(S(=O)(=O)c2ncnn2Cc2c(Cl)cccc2Cl)nc(-c2ccc(Cl)cc2)n1C1CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
37 mg (0.10 mmol) of the compound from Example 93A were dissolved in 3 ml of dichloromethane, and 21 μl (0.13 mmol) of N,N-diisopropylethylamine were added. 30 mg (0.13 mmol) of 2,6-dichlorobenzyl bromide dissolved in 1 ml of dichloromethane were then added, and the mixture was stirred at RT for 20 h. For work-up, the mixture was concentrated under reduced pressure and the crude product was purified chromatographically [Method 19]. This gave 39 mg (74% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29]1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][CH:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29]1
Reactant: NC1Cc2ccccc2C1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: O=C(N1CCc2ccc(Cl)c(NC3Cc4ccccc4C3)c2CC1)C(F)(F)F

Procedure:
Use a method similar to the General Procedure 5-3, using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (426 mg, 1.0 mmol) and 2-aminoindane (400 mg, 3.0 mmol), to give 7-chloro-6-(indan-2-yl-amino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a slightly yellow oil (354 mg, 86%). MS (ES+) m/z: 409 (M+H)+.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][OH:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[C:22](F)=[CH:23][C:24]([F:34])=[C:25]([CH:33]=1)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].CC(C)([O-])C.[K+]>CS(C)=O.CCOC(C)=O>[CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][O:19][C:22]2[C:21]([Cl:20])=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[C:24]([F:34])[CH:23]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Reactant: OCC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To solution of (1-benzhydrylazetidin-3-yl)methanol (368 mg) and tert-butyl 5-chloro-2,4-difluoro-benzoate (397 mg) in DMSO (7.3 mL) at 14° C. (bath) was added potassium tert-butoxide (196 mg). The mixture was stirred at rt for 1 hr. Diluted with EtOAc, the contents were washed with 1:4 mixture of 1M HCl and 1M NaH2PO4 (2×) and brine (1×), dried (Na2SO4). After filtration and concentration, the crude was purified with flash chromatography (0-40% EtOAc/heptane) to give the product (511 mg).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[N:22]([C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:21]=[N:20][N:19]=2)=[CH:8][CH:7]=1)(=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[OH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[N:22]([C:23]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:21]=[N:20][N:19]=2)=[CH:8][CH:7]=1
Reactant: CC(=O)OCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 83 %

Procedure:
3.4 g of 4-(acetoxymethyl)-2'-(1-triphenylmethyltetrazol-5-yl)biphenyl dissolved in 30 ml of anhydrous THF, are dropped during 0.5h into a suspension of 0.5 g of LiAlH4 in 20 ml of anhydrous THF at 0° C. The mixture is stirred for 24h at 0° C., then a stoichiometric amount of water is added to decompose LiAlH4 and the precipitated salts are filtered off. The solution is evaporated and the residue is triturated with an hexane:ethyl acetate mixture (9:1). Upon filtration and drying, 2.6 g of a white powder are obtained (Yield: 83%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:10]=1[Br:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[C:23]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])([CH3:25])[CH3:24].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][O:16][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:29])[CH3:28])=[CH:11][C:10]=1[Br:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccc(OCc2ccccc2)c(Br)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(OCc2ccccc2)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.0 g (10.23 mmol) of [4-(benzyloxy)-3-bromophenyl]methanol (Example I) are initially charged in 30 ml of DMF. At room temperature, 1.39 g (12.28 mmol) of 1H-imidazole (60% pure) and 2.01 g (13.3 mmol) of tert-butyl(chloro)dimethylsilane are added. The reaction mixture is stirred at room temperature overnight. Water is then added, and the mixture is extracted three times with diethyl ether. The combined organic phases are washed three times with water and once with saturated sodium chloride solution. The organic phase is dried with sodium sulphate and the solvent is removed under reduced pressure. This gives 4.02 g (86% of theory) of {[4-(benzyloxy)-3-bromobenzyl]oxy}(tert-butyl)dimethylsilane.
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=1.[CH:16]1([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[H-].[Na+]>C(O)(=O)C>[CH:16]1([O:22][C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(OC2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To 30 ml of N,N-dimethylformamide, 1.00 g (6.4 mmol) of 6-chloronicotinic acid and 2.00 g (20 mmol) of cyclohexanol were dissolved, followed by adding 0.80 g (20 mmol) of 60% sodium hydride, stirring at room temperature for 1 hour and heating under refluxing for 3 hours. The reaction liquid was then poured in 100 ml of ice water, and acetic acid was added to make pH 5. The crystal precipitated was filtered, washed with cold water and hexane, and dried to obtain 1.30 g (yield: 92%) of 6-cyclohexyloxynicotinic acid.
Reaction SMILES: Br[C:2]1[C:18](=[O:19])[N:17]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:5]2[N:6]=[C:7]([NH:11][CH2:12][C:13]([OH:16])([CH3:15])[CH3:14])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.[CH3:25][O:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>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>[CH:20]1([N:17]2[C:5]3[N:6]=[C:7]([NH:11][CH2:12][C:13]([OH:16])([CH3:15])[CH3:14])[N:8]=[C:9]([CH3:10])[C:4]=3[CH:3]=[C:2]([C:30]3[CH:31]=[N:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[C:18]2=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1nc(NCC(C)(C)O)nc2c1cc(Br)c(=O)n2C1CCCC1
Reactant: COc1ccc(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3c(C)nc(NCC(C)(C)O)nc3n(C3CCCC3)c2=O)cn1
Temperature: 110 °C
Yield: 44.2 %

Procedure:
To a solution of 6-bromo-8-cyclopentyl-2-(2-hydroxy-2-methylpropylamino)-4-methyl-pyrido[2,3-d]pyrimidin-7(8H)-one (50 mg, 0.126 mmol), 6-methoxypyridin-3-ylboronic acid (21 mg, 0.137 mmol), potassium carbonate (3 M, 0.06 mL) in DMF (1.2 mL) was added dichlorobis(triphenylphosphine)palladium(II) (4.5 mg, 0.0064 mmol). The mixture was degassed with N2, sealed and heated for 30 min at 110° C. The solvent was removed under reduced pressure. The crude mixture was purified by chromatography to give the title compound (23.6 mg, 44%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:37]1[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[N:38]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:37]4[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[N:38]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cc1nccc(Br)n1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Product: Cc1nccc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)n1

Procedure:
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-bromo-2-methylpyrimidine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.159, m/z=450; 1H NMR (CDCl3) 1.33 (m, 3H), 1.52 (m, 3H), 1.63 (m, 3H), 1.80-1.95 (m, 2H), 2.15-2.30 (m, 3H), 2.75 (s, 3H), 2.90 (m, 1H), 3.51 (m, 2H), 5.68 (m, 1H), 6.99 (m, 4H), 7.20 (m, 2H), 7.41 (m, 1H), 7.79 (d, 2H), 8.60 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]([OH:15])[CH3:14])[C:9]1=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]([O:15][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][O:17]2)[CH3:14])[C:9]1=[O:16])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C1=COCCC1
Reactant: CC(O)C1CCN(C(=O)OC(C)(C)C)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(OC1CCCCO1)C1CCN(C(=O)OC(C)(C)C)C1=O
Reaction time: 1 h

Procedure:
To a solution of 1-t-butyloxycarbonyl-3-(1-hydroxyethyl)-2-oxopyrrolidine (15 g) in dichlormethane (200 ml) were added 3,4-dihydro-2H-pyran (11.9 ml) and p-toluenesulfonic acid (1.2 g) at 0° C. After stirring for 1 hour at the same temperature, the solution was washed in turn with saturated aqueous bicarbonate and brine. The dried solution was evaporated, and the obtained residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (2:1-3:1, V/V) to give 1-t-butyloxycarbonyl-3-{1-(tetrahydropyran-2-yloxy)ethyl}-2-oxopyrrolidine (18.4 g).
Reaction SMILES: [N+:1]([C:4]1[CH:31]([CH3:32])[CH:8]2[CH2:9][C:10]([CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH:30]=[CH:29][N:28]=[CH:27]5)=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)([CH3:12])[O:11][C:7]2=[C:6]([CH3:33])[C:5]=1[CH3:34])([O-])=O.C(O)C.Cl.[OH-].[Na+]>O>[NH2:1][C:4]1[CH:31]([CH3:32])[CH:8]2[CH2:9][C:10]([CH2:13][N:14]3[CH2:15][CH2:16][N:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH:30]=[CH:29][N:28]=[CH:27]5)=[CH:22][CH:21]=4)[CH2:18][CH2:19]3)([CH3:12])[O:11][C:7]2=[C:6]([CH3:33])[C:5]=1[CH3:34]
Reactant: CC1=C2OC(C)(CN3CCN(c4ccc(-n5ccnc5)cc4)CC3)CC2C(C)C([N+](=O)[O-])=C1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1=C(N)C(C)C2CC(C)(CN3CCN(c4ccc(-n5ccnc5)cc4)CC3)OC2=C1C
Yield: 41.1 %

Procedure:
To 1.3 g of 4-(±)-(5-nitro-2,4,6,7-tetramethyldihydrobenzofuran-2-ylmethyl)-1-(4-imidazol-1-ylphenyl)piperazine, 30 ml of ethanol was added and 4.4 g of stannous chloride-dihydrate and 15 ml of concentrated hydrochloric acid were added, followed by heating at reflux for 6 hours. The reaction solution was poured into water, neutralized with a 1N sodium hydroxide solution and then extracted with chloroform. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration and concentrating under reduced pressure, the residue was subjected to silica gel column chromatography (chloroform:methanol=30:1) to obtain 0.5 g of the objective product (melting point: 165-167° C.).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[CH:13]([O:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])([CH3:15])[CH3:14]>O1CCOCC1>[CH:13]([O:16][C:17]1[CH:18]=[C:19]([NH:20][C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]3[N:3]=2)[CH:21]=[CH:22][CH:23]=1)([CH3:15])[CH3:14]
Reactant: CC(C)Oc1cccc(N)c1
Reactant: O=Cc1cnn2ccc(Cl)nc12
Solvent: C1COCCO1
Product: CC(C)Oc1cccc(Nc2ccn3ncc(C=O)c3n2)c1
Temperature: 120 °C

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (50 mg, 0.276 mmol) in dioxane was added 3-isopropoxyaniline (125 mg, 0.829 mmol). The mixture was heated in microwave for 20 minutes at 120° C. The solid produced was isolated by filtration and then purified by preparative TLC (2% MeOH/DCM) to yield 5-(3-isopropoxyphenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde. LCMS (M+1=297)
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]([Cl:28])=[CH:25][CH2:26]Cl.CN(C)C=O>O>[C:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:26][CH:25]=[C:24]([Cl:28])[Cl:23])=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Oc1ccc(O)cc1)c1ccccc1
Reactant: ClCC=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Oc1ccc(OCC=C(Cl)Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.8 %

Procedure:
A reaction vessel was charged with 30.5 g of 4-hydroxyphenyl benzoate, 21.6 g of potassium carbonate, 20.8 g of 1,1,3-trichloropropene and 100 ml of N,N-dimethylformamide. After stirring at room temperature for 15 hours, the reaction mixture was poured into water and extracted twice with 150 ml of diethyl ether. The ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 44.1 g of 4-(3,3-dichloro-2-propenyloxy)phenyl benzoate (96% yield).
Reaction SMILES: [ClH:1].[NH:2]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])[N:4]=[CH:3]1.Cl.[CH3:13]O>>[ClH:1].[NH:2]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9]([O:11][CH3:13])=[O:10])[N:4]=[CH:3]1
Reactant: O=C(O)C=Cc1c[nH]cn1
Reactant: CO
Agent: Cl
Product: COC(=O)C=Cc1c[nH]cn1

Procedure:
A solution of 4-imidazoleacrylic acid hydrochloride (20.0 g, 145 mmol) in MeOH (300 mL) was saturated with HCl (g). The resulting solution was refluxed for 90 min., then concentrated to dryness in vacuo to afford the titled ester as a white solid.