Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5](=[O:13])[C:6]1[CH:11]=[C:10](Cl)[CH:9]=[CH:8][N:7]=1)([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:22]2[CH:23]=[C:24]3[NH:30][CH:29]=[CH:28][C:25]3=[N:26][CH:27]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[NH:30]1[C:24]2[C:25](=[N:26][CH:27]=[C:22]([C:10]3[CH:9]=[CH:8][N:7]=[C:6]([C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:13])[CH:11]=3)[CH:23]=2)[CH:28]=[CH:29]1
Reactant: CC(C)OC(=O)c1cc(Cl)ccn1
Reactant: CC1(C)OB(c2cnc3cc[nH]c3c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)c1cc(-c2cnc3cc[nH]c3c2)ccn1
Temperature: 65 °C
Yield: 56.9 %

Procedure:
A mixture of 4-chloropicolinic acid isopropyl ester (1.5 g, 7.5 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine (1.83 g, 7.5 mmol), dppf(Pd)Cl2 (270 mg, 5 mol %), and potassium carbonate (2.0 g, 15 mmol) in degassed toluene (8 mL), degassed water (4 mL) and degassed isopropanol (4 mL) was heated at 65° C. for 2 hours. The aqueous phase was discarded and the solvent removed under reduced pressure. The residue was purified by flash chromatography (rf: 0.41 in 20:1 ethyl acetate:methanol) to provide isopropyl 4-(1H-pyrrolo[3,2-b]pyridin-6-yl)picolinate (1.20 g, 57%) as a yellow powder. 282.1 (M+1).
Reaction SMILES: [C@@H]1(OC2C=CC=CC=2[C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([O:23]C)=[O:22])O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]1O.O.[OH-].[Li+].Cl>C(#N)C>[C:21]([OH:23])(=[O:22])[C:20]1[CH:25]=[CH:26][CH:27]=[CH:18][CH:19]=1
Reactant: COC(=O)c1cccc(-c2ccccc2O[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 120.7 %

Procedure:
Methyl 3-(2-(α-L-fucopyranosyloxy)phenyl)benzoate (0.44 g, 1.18 mmol) was dissolved in acetonitrile (8 ml) and treated with a solution of lithium hydroxide hydrate (60 mg, 1.41 mM, in 0.5 ml water) and the mixture was stirred overnight at room temperature. The mixture was then treated with 2N HCl to pH 3 to 4 and the volatiles were removed under reduced pressure. The residue was purified by HPLC (reverse-phase, gradient elution 5-50% acetonitrile in water, 0.1% trifluoroacetic acid, monitored at 254 nm) which gave 3-(2-α-L-fucopyranosyloxy)phenyl)benzoic acid (174 mg, 40%) as a white solid, m.p.: 92°-93° C.; 1H NMR (300 MHz, DMSO-d6): 8.07 (s, 1H), 7.88 (t, J=8.7, 2H),7.51 (t, J=7.7, 1H), 7.29-7.43 (comp, 2H), 7.27 (d, J=8, 1H), 7.09 (t, J=7.2, 1H), 5.49 (d, J=3, 1H), 3.05-3.90 (comp, 7H), 0.97 (d, J=6, 3H); IR (KBr): 3402, 2932, 1695, 1498, 1457, 1219, 1076, 960, 838, 750; analysis: calculated for C19H20O7.0.3[CF3CO2H].0.2[H2O]: 59.1% C; 5.2% H. found: 59.1% C; 5.5% H.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([O:16][CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][NH:19]2)[CH:4]=1)#[N:2].Cl.[N:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][CH:33]([C:36](O)=[O:37])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([O:16][CH:17]([C:36]([CH:33]2[CH2:32][CH2:31][N:30]([C:27]3[CH:26]=[CH:25][N:24]=[CH:29][CH:28]=3)[CH2:35][CH2:34]2)=[O:37])[C@H:18]2[CH2:22][CH2:21][CH2:20][NH:19]2)[CH:4]=1)#[N:2]
Reactant: CCOC(=O)CCc1ccc(C#N)cc1OC[C@H]1CCCN1
Reactant: O=C(O)C1CCN(c2ccncc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(C#N)cc1OC(C(=O)C1CCN(c2ccncc2)CC1)[C@H]1CCCN1
Reaction time: 8 h

Procedure:
570 mg (1.89 mmol) of ethyl 3-[4-cyano-(2R)-2-(pyrrolidine-2-ylmethoxy)phenyl]propionate was dissolved in 10 ml of DMF. 504 mg (2.1 mmol) of 1-(4-pyridyl)-4-piperidinecarboxylic acid hydrochloride, 479 mg (2.8 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.78 ml (5.7 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH2:6].[Br:7][CH:8]([CH3:16])[C:9](=O)[CH2:10][C:11](OC)=[O:12]>>[Br:7][CH:8]([C:9]1[N:6]=[C:2]2[S:1][CH:5]=[CH:4][N:3]2[C:11](=[O:12])[CH:10]=1)[CH3:16]
Reactant: Nc1nccs1
Reactant: COC(=O)CC(=O)C(C)Br
Product: CC(Br)c1cc(=O)n2ccsc2n1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A mixture of polyphosphoric acid (73.8 g, 677 mmol), 1,3-thiazol-2-amine (12.3 g, 123 mmol), and methyl 4-bromo-3-oxopentanoate (34.8 g, 166 mmol) was stirred at 110° C. overnight. After cooling, an ice-cold 10% aq. NaOH solution was slowly added to adjust the pH to 7. The mixture was filtered, and the collected precipitate was air-dried to give crude product which was directly used in next step. LCMS calculated for C8H8BrN2OS (M+H)+: m/z=259.0. Found: 259.0.
Reaction SMILES: C([O:8][C:9](=O)[CH2:10][C@H:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]I)C1C=CC=CC=1.[BH4-].[Li+].C1COCC1>C(OCC)C>[C:18]([O:17][C:15](=[O:16])[NH:14][C@H:11]([CH3:12])[CH2:10][CH2:9][OH:8])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@H](CI)CC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@H](CCO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of (S)-3-tert-butoxycarbonylamino-4-iodo-butyric acid benzyl ester (0.2 g, 0.477 mmol) in dry diethylether (3 ml) cooled to 0° C. under argon, is treated with a 2.0 M solution of lithium borohydride in THF (0.95 ml, 1.9 mmol). The reaction mixture is allowed to warm to ambient temperature with stirring for 18 hours. The reaction is quenched by addition of water and partitioned between ethylacetate and 10% citric acid solution. The organic phase is washed with brine, dried over magnesium sulphate and evaporated. The crude product is purified by flash silica chromatography using 1% methanol in DCM as eluent to afford ((R)-3-hydroxy-1-methyl-propyl)-carbamic acid tert-butyl ester.
Reaction SMILES: Br[C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C@@H:17]([C:29]([OH:31])=[O:30])[C:18]([S:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)([CH3:20])[CH3:19])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[O:34]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35]1>C1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].CCO.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>[O:34]1[CH:38]=[CH:37][C:36]([C:2]2[CH:3]=[CH:4][C:5]([O:6][C:7]3[CH:8]=[CH:9][C:10]([S:13]([NH:16][C@@H:17]([C:29]([OH:31])=[O:30])[C:18]([S:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)([CH3:20])[CH3:19])(=[O:14])=[O:15])=[CH:11][CH:12]=3)=[CH:32][CH:33]=2)=[CH:35]1
Reactant: CC(C)(SCc1ccccn1)[C@@H](NS(=O)(=O)c1ccc(Oc2ccc(Br)cc2)cc1)C(=O)O
Reactant: OB(O)c1ccoc1
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: CCO
Solvent: c1ccccc1
Product: CC(C)(SCc1ccccn1)[C@@H](NS(=O)(=O)c1ccc(Oc2ccc(-c3ccoc3)cc2)cc1)C(=O)O
Temperature: 80 °C
Reaction time: 72 h
Yield: 77.1 %

Procedure:
To a suspension of 221 mg (0.40 mmol) of N-[4-(4-bromophenoxy) benzenesulfonyl]--S--[(pyrid-2-yl)methyl]-D-penicillamine (from example 3(d)) in 2 mL of benzene and 2 mL of 2M aqueous Na2CO3 solution was added a solution of 71 mg (0.48 mmol) of 3-furan boronic acid (J. Org. Chem. 1984, 49, 5237-5243) in 2 mL of EtOH. To the resulting mixture was added solid Pd(PPh3)4 (46 mg, 0.04 mmol) under a flow of Ar. The mixture was heated at 80° C. with vigorous stirring for 72 hours, cooled to room temperature, and partitioned between ehtyl acetate and AcOH/H2O buffer (pH 3). The aqueous layer was adjusted to pH of 3 by adding AcOH, then extracted with EtOAc (2×70 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residual yellow solid was chromatographed on silica gel, eluting first with CH2Cl2, then with 10% methanol in dichloromethane to elute the product fractions. After concentration of the product-containing fractions, the residue was triturated with hexane/t-butyl methyl ether, and the solid was collected by filtration. The solid was dried in high vacuum to give 166.1 mg (77%) of N-[4-(4-(furan-3-yl)phenoxy)benzenesulfonyl]--S--[(pyrid-2-yl)methyl]-D-penicillamine as a yellow solid: mp 185-189° C.; 1H--NMR (CDCl3) δ 1.40 (s, 3H) 1.44 (s, 3H), 3.32-4.01 (m, 3H), 6.83 (s, 1H), 7.10-7.13 (m, 4H), 7.22-7.23 (m, 2H), 7.57-7.92 (m, 8H), 8.42 (d, J=4 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CN1CCC(ON)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN1CCC(ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.8 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.150 g, 0.543 mmol, US 2005/20572 A1) in DCM (10 mL) were added 4-(aminooxy)-1-methylpiperidine 50 (0.129 g, 0.99 mmol), 1-hydroxybenzotriazole (0.110 g, 0.814 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.156 g, 0.814 mmol) sequentially at room temperature. The mixture was stirred at room temperature for 16 h, diluted with DCM, washed with water, brine, dried over sodium sulfate and concentrated to provide a residue which was subjected to chromatography to give 51 (0.065 g, 31%) as a yellow oil.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:14])=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])(=[O:3])[CH3:2].S(Cl)([Cl:17])=O.CN(C)C=O>COC(C)(C)C>[C:1]([O:4][C:5]1[C:6]([CH3:14])=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([Cl:17])=[O:9])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1cccc(C(=O)O)c1C
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CC(=O)Oc1cccc(C(=O)Cl)c1C
Reaction time: 3 h
Yield: 100 %

Procedure:
3-Acetoxy-2-methylbenzoic acid was slurried in methyl-t-butyl ether (MTBE) and treated with 1.2 equivalents of thionyl chloride and catalytic dimethylformamide. After three hours at ambient temperatures, the reaction was complete, giving a brown solution. Solvent (MTBE) was removed by vacuum distillation. Residual thionyl chloride was removed by addition of toluene followed by vacuum distillation. The resulting 3-acetoxy-2-methylbenzoyl chloride was isolated either directly as an oil or by crystallization from two volumes of heptane at <10° C. Product was obtained in >100% yield when isolated as an oil and 82-85% yield when crystallized from heptane.
Reaction SMILES: Br[C:2](Br)=[CH:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].O1CCCC1.C([Li])(CC)C>CCOCC>[C:3]([C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])#[CH:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=C(Br)Br
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#C[C@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
In according with Scheme I, N-α-BOC-D-proline 2a is reacted in an ether solvent such as tetrahydrofuran at a temperature ranging from -2° C. to the reflux temperature of the solvent with 10M boran-methyl sulfide complex to produce (R)-2-(hydroxymethyl)-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 3a. Compound 3a in a chlorinated hydrocarbon solvent such as methylene chloride is treated with an oxidizing agent such as pyridinium chlorochromate, 4 Å molecular sieves and glacial acetic acid to give (R)-2-formyl-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester 4a. Compound 4a in methylene chloride is treated with a methylene chloride solution of triphenylphosphine and carbon tetrabromide to produce (R)-2-(2,2-dibromoethenyl)-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 5a. The dibromo compound 5a in an ether solvent such as tetrahydrofuran is reacted at -78° C. with an alkyl lithium reagent such as sec-butyllithium to give (R)-2-ethynyl-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 6a.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]([C:10]#[N:11])[C:8]#[N:9])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][CH2:18][F:19]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]([CH2:17][CH2:18][F:19])([C:8]#[N:9])[C:10]#[N:11])=[CH:12][CH:13]=1
Reactant: FCCBr
Reactant: N#CC(C#N)Cc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCF)Cc1ccc(Br)cc1
Yield: 48.8 %

Procedure:
Using 0.47 g of (4-bromobenzyl)malononitrile, 5 ml of N,N-dimethylformamide, 0.12 g of sodium hydride (60% in oil), and 0.25 g of 1-bromo-2-fluoroethane, and according to the process described in the Production Example 1, there was obtained 0.27 g of 2-(4-bromobenzyl)-2-(2-fluoroethyl)malononitrile (the present compound (51)).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(OP(N)([NH2:24])=O)C=CC=CC=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1[N:7]=[C:6]([NH2:24])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NP(N)(=O)Oc1ccccc1
Reactant: Cc1[nH]c(=O)ccc1-c1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1nc(N)ccc1-c1ccccc1

Procedure:
A mixture of 6-methyl-5-phenyl-2-pyridone (12.0 grams) and phenylphosphorodiamidate (14.4 grams) in 300 ml diphenyl ether was heated for 19-20 hours at approximately 220°-225° [250]° C. After cooling, the reaction mixture was chromatographed over silica gel with ethyl acetate. A total of 0.8 gram, of desired product was collected and recrystallized from dichloromethane/petroleum ether, m.p. 110°-113° C.
Reaction SMILES: [C:1]([C:4]1[C:5]([Cl:23])=[CH:6][C:7]([F:22])=[C:8]([N:10]2[C:15](=[O:16])[CH2:14][CH:13]([C:17]([F:20])([F:19])[F:18])[CH2:12][C:11]2=[O:21])[CH:9]=1)([OH:3])=O.S(Cl)([Cl:26])=O>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:26][C:1]([C:4]1[C:5]([Cl:23])=[CH:6][C:7]([F:22])=[C:8]([N:10]2[C:15](=[O:16])[CH2:14][CH:13]([C:17]([F:18])([F:20])[F:19])[CH2:12][C:11]2=[O:21])[CH:9]=1)=[O:3]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(N2C(=O)CC(C(F)(F)F)CC2=O)c(F)cc1Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cc(N2C(=O)CC(C(F)(F)F)CC2=O)c(F)cc1Cl
Temperature: 90 °C

Procedure:
To a mixture of N-(5'-carboxy-4'-chloro-2'-fluorophenyl)-3-(trifluoromethyl)glutarimide (Compound 62) (3.0 g, 8.5 mmol) and 35 ml toluene was added thionyl chloride (0.80 ml, 1.3 g, 1.1 mmol) followed by 2 drops of N,N-dimethylformamide and the suspension was heated to 90° C. for two hours. The resulting clear, orange solution was cooled to room temperature and the solvents were removed in vacuo (1 mm Hg). The resulting N-(5'-chlorocarbonyl-4'-chloro-2'-fluorophenyl)-3-(trifluoromethyl)glutarimide, a dark semisolid, could be used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:13][C:12]([C@@H:25]2[CH2:27][C@H:26]2[NH2:28])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][CH2:30][CH:31]=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=2)=[CH:13][C:12]([C@@H:25]2[CH2:27][C@H:26]2[NH:28][CH2:31][CH2:30][Cl:29])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CCCl
Reactant: N[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)c(-c2ccc(C(F)(F)F)cc2)c1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(-c2cc([C@@H]3C[C@H]3NCCCl)ccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
To a solution of (trans)-2-(6-(benzyloxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopropanamine (520 mg, 2.08 mmol) in DCM (6 mL), 4° A molecular sieves was added followed by chloroacetaldehyde (0.33 mL, 2.5 mmol) and stirred at RT for 1 h. After completion, monitored by TLC, the reaction mixture was cooled at −10° C. and Na(CN)BH3 (157 mg, 2.5 mmol) was added and stirred at RT for 2 h. After completion, the reaction mixture was quenched with NH4Cl (5%) and filtered through a pad of celite. The filtrate was extracted with DCM (2×20 mL), combined extracts were washed with water (20 mL), dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by flash column chromatography by using EtOAc: Pet ether to get (trans)-2-(6-(benzyloxy)-4′-(trifluoromethyl)biphenyl-3-yl)-N-(2-chloroethyl)cyclopropanamine (500 mg, 83.3%) as a liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:13]([OH:15])=O.[CH3:16][N:17]([CH3:35])[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1>>[CH3:16][N:17]([CH3:35])[C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:33])[CH3:34])=[CH:28][CH:27]=2)[C:13]([CH:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[O:9][CH2:8][CH2:7]2)=[O:15])=[CH:22][CH:23]=1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCO2
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Product: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(C(C)C)cc1)CCO2
Yield: 25.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using 6-methoxychroman-4-carboxylic acid (0.54 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.7 g) as starting materials, N-[(4-dimethylaminophenyl) methyl]-N-(4-isopropylphenyl)-6-methoxychroman-4-carboxamide (0.3 g) was obtained. melting point: 82-84° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:28]([NH:32][CH2:33][CH3:34])([CH3:31])([CH3:30])[CH3:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>O1CCOCC1>[C:28]([N:32]([CH2:33][CH3:34])[C:16]([C:13]1[CH:12]=[CH:11][C:10]([C:9]#[C:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[CH:15][N:14]=1)=[O:18])([CH3:31])([CH3:30])[CH3:29]
Reactant: CCNC(C)(C)C
Reactant: O=C(O)c1ccc(C#Cc2cccc(F)c2)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C(=O)c1ccc(C#Cc2cccc(F)c2)cn1)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.7 %

Procedure:
(100 mg, 0.41 mmol) 5-(3-Fluoro-phenylethynyl)-pyridine-2-carboxylic acid (Example 1, step 2) was dissolved in dioxane (1 ml) and Hunig's Base (217 μl, 1.24 mmol, 3 equiv.), tert.-butylethylamine (63 mg, 0.62 mmol, 1.5 equiv.) and TBTU (146 mg, 0.45 mmol, 1.1 equiv.) were added at room temperature. The mixture was stirred for 16 hours at room temperature. The reaction mixture was evaporated and extracted saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 0:100. The desired 5-(3-fluoro-phenylethynyl)-pyridine-2-carboxylic acid tert-butyl-ethyl-amide (102 mg, 76% yield) was obtained as a light yellow oil, MS: m/e=325.3 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[NH:9][CH2:8][C:7]1=[O:18].[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>O1CCOCC1>[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:12](=[O:13])[C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[NH:9][CH2:8][C:7]2=[O:18])[CH2:27][CH2:26]1
Reactant: O=C1CNc2ccccc2C(=O)N1CCCCBr
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: C1COCCO1
Product: O=C1CNc2ccccc2C(=O)N1CCCCN1CCN(c2ncccn2)CC1
Yield: 86.8 %

Procedure:
To a solution of 70 mg of the compound of Example 14 dissolved in 10 ml of dioxane was added 111 mg (3 equivalents) of 1-(2-pyrimidinyl)piperazine, and the mixture heated under reflux for 8 hours. The reaction treatment and purification were conducted in the same manner as in Example 17 to obtain 77.0 mg of the desired compound (yield 87%). The maleate was obtained by converting the product to maleate, followed by recrystallization from methylene chloride-ether.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C[Si](C)(C)CCOC[N:14]([CH2:54]OCC[Si](C)(C)C)[C:15]1[N:20]2[N:21]=[CH:22][C:23]([C:24]3[CH:25]=[N:26][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:28][CH:29]=3)=[C:19]2[N:18]=[C:17]([CH:36]2[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]2)[C:16]=1[C:49]([O:51]CC)=[CH2:50]>>[C:30]1([C:27]2[N:26]=[CH:25][C:24]([C:23]3[CH:22]=[N:21][N:20]4[C:15]5[NH:14][CH2:54][CH2:50][C:49](=[O:51])[C:16]=5[C:17]([CH:36]5[CH2:37][CH2:38][NH:39][CH2:40][CH2:41]5)=[N:18][C:19]=34)=[CH:29][CH:28]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1.[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2]
Reactant: C=C(OCC)c1c(C2CCN(C(=O)OC(C)(C)C)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCNc2c1c(C1CCNCC1)nc1c(-c3ccc(-c4ccccc4)nc3)cnn21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At 0° C., TFA (5 mL) was added to tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(1-ethoxyvinyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate. The mixture was stirred for 1 h at room temperature. Concentration afforded 3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yl)-8,9-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-6(7H)-one as an TFA salt. LCMS tR=0.99 Min (5 min run, UV254nm). Mass calculated for, M+ 424.2, observed LC/MS m/z 425.2 (M+H).
Reaction SMILES: ClCCl.[CH2:4]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[OH:13])[CH:5]=[CH2:6].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(N(CC)CC)C>[CH3:14][S:15]([O:13][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[CH2:4][CH:5]=[CH2:6])(=[O:17])=[O:16]
Reactant: C=CCC1CCCCC1O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC1CCCCC1OS(C)(=O)=O

Procedure:
To a mixture of 250 ml. of dichloromethane, 25 g. 2-allylcyclohexanol and 16.7 g. of triethylamine cooled in an ice-salt bath to -10° C. is added dropwise, over 15 minutes, 18.9 g. of methanesulfonyl chloride. The mixture is cooled at -10° C. to -15° C. for 30 minutes and then washed with 300 ml. each of cold water, 10% hydrochloric acid, sodium carbonate solution and with saturated sodium chloride solution. The organic layer is dried with magnesium sulfate and concentrated in vacuo to give a pale yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:13]4[S:18][CH:17]=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C1C=C[NH+]=CC=1.Br[Br-]Br.C(O)(=[O:36])C>O>[O:22]1[CH2:21][CH2:20][N:19]([C:12]2[C:13]3[S:18][CH:17]=[CH:16][C:14]=3[N:15]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH2:3][C:2](=[O:36])[NH:1]4)[N:11]=2)[CH2:24][CH2:23]1
Reactant: c1cc(-c2nc(N3CCOCC3)c3sccc3n2)c2cc[nH]c2c1
Reactant: CC(=O)O
Agent: c1cc[nH+]cc1
Solvent: O
Product: O=C1Cc2c(cccc2-c2nc(N3CCOCC3)c3sccc3n2)N1
Temperature: 80 °C

Procedure:
To a solution of 2-(1H-Indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 199 (90 mg) in acetic acid (2 ml) and water (1 ml) was added pyridinium bromide perbromide (103 mg) as a solution in acetic acid (4 ml) and the reaction mixture was heated to 80° C. for 4 hours. The mixture was then basified and extracted into dichloromethane, organic layer was dried (Mg2SO4), filtered and volatiles removed in vacuo. Purification on silica yielded 198 (23 mg). NMR: (CDCl3): 3.39-3.43 (4H, m), 4.03-4.08 (4H, m), 4.10 (2H, s), 6.95 (1H, d, J=7.4), 7.36 (1H, t, J=7.9), 7.49 (2H, m), 7.79 (1H, d, J=5.6), 8.10 (1H, d, J=7.9) MS: (ESI+): MH+ 353 (100%)