Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:9][CH:10]([CH3:21])[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[Br:26]Br.CCCCCC>ClCCl>[C:1]([CH:9]([Br:26])[CH:10]([CH3:21])[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: CC(CC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CC(C(=O)N1CCC[C@H]1C(=O)O)C(Br)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 1.25 g. of 1-(3-benzoyl-2-methylpropionyl)-L-proline (isomer A of Example 9) in 30 ml. of acetic acid, is added 0.7 g. of bromine in 10 ml. of acetic acid. The mixture is stirred at room temperature for 18 hours, the solvent is concentrated in vacuo to 1/2 volume and the mixture is poured into ice and water. This mixture is extracted with dichloromethane. The organic extract is washed with water, then sodium chloride solution, dried over magnesium sulfate and the solvent is removed in vacuo giving a gum. This gum is dissolved in dichloromethane, hexane is added and the solvent is removed at room temperature giving a white glass. This glass is chromatographed on a silica gel column with ethyl acetate-hexane-acetic acid (75:25:2) giving 1.25 g. of the desired product as a white glass (3-bromo derivative of isomer A).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:43]([CH3:44])=[CH:42][C:39]([C:40]#[N:41])=[CH:38][C:37]=1[CH3:45].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:40]([C:39]1[CH:42]=[C:43]([CH3:44])[C:36]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:10]3[C:6]=2[CH2:7][CH2:8][C@H:9]3[O:11][C:12]2[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=2)=[C:37]([CH3:45])[CH:38]=1)#[N:41]
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(C#N)cc(C)c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(C#N)cc5C)ccc(F)c43)ccc21
Temperature: 100 °C
Reaction time: 4 h

Procedure:
In a microwave vial, methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (200 mg), 4-bromo-3,5-dimethylbenzonitrile (90 mg), K3PO4 (273 mg), Palladium-(II)-acetate (10 mg) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (S-Phos) (17 mg) are suspended in toluene (10 mL) and water (2 mL) and purged for 10 minutes with argon. The vial is sealed and the mixture is stirred at 100° C. for 4 hours. After cooling to ambient temperature the mixture is partitioned between ethyl acetate and water. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10) to give the title compound. Yield: 85 mg; LC (method 19): tR=1.52 min; Mass spectrum (ESI+): m/z=471 [M+−H]+.
Reaction SMILES: [CH2:1]([O:13][C:14]1[N:15]=[CH:16][S:17][C:18]=1[C:19]1[S:23][CH:22]=[N:21][C:20]=1[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Li]CCCC.[CH3:42][Sn:43](Cl)([CH3:45])[CH3:44]>C1COCC1>[CH2:1]([O:13][C:14]1[N:15]=[C:16]([Sn:43]([CH3:45])([CH3:44])[CH3:42])[S:17][C:18]=1[C:19]1[S:23][C:22]([Sn:43]([CH3:45])([CH3:44])[CH3:42])=[N:21][C:20]=1[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C[Sn](C)(C)Cl
Reactant: CCCCCCCCCCCCOc1ncsc1-c1scnc1OCCCCCCCCCCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOc1nc([Sn](C)(C)C)sc1-c1sc([Sn](C)(C)C)nc1OCCCCCCCCCCCC
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A solution of 0.16 g (0.298 mmol) of compound 13 in 24 mL of THF was cooled to −78° C. The resulting suspension was treated dropwise with 0.29 mL (0.725 mmol) n-BuLi (2.5 M in hexanes) and stirred for 30 minutes. The dry ice bath was removed and the mixture was stirred at ambient temperature for 30 minutes. The mixture was treated with 0.167 g (0.84 mmol) of trimethyltin chloride and heated in an oil bath at 60° C. for 30 minutes. The mixture was concentrated in vacuo. The resulting oily solid was triturated with 15 mL of hexanes and filtered warm. The filtrate was concentrated in vacuo to a yellow oil that solidified on standing to give 252 mg (98% yield) of compound 14. 1H NMR (500 MHz) δ 4.46 (t, 4H, J=6.5 Hz), 1.88-1.22 (m, 40H), 0.88 (t, 6H, J=7.0 Hz), 0.44 (s, 18H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.[C:24]([O:28][C:29]([N:31]1[CH2:34][CH:33]([C:35](O)=[O:36])[CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:35]([CH:33]3[CH2:34][N:31]([C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:32]3)=[O:36])=[C:16]2[N:15]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3Cl)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(C(=O)Nc2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4Cl)nc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
To a mixture of (R)-5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Example 8, Step A; 20 mg, 0.06 mmol), 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (15 mg, 0.072 mmol), and HATU (28 mg, 0.072 mmol) was added 0.6 mL acetonitrile to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.032 mL, 0.18 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred overnight. The reaction mixture was directly purified by reverse-phase column chromatography, eluting with 5 to 70% acetonitrile/water to yield the final product as an off-white solid (19 mg, 61% yield). MS (apci) m/z=515.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[N:3]=1.[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[C:27](O)=[O:28])[CH:20]=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH2:14][N:13]([C:27]([C:25]4[CH:24]=[CH:23][CH:22]=[C:21]5[C:26]=4[N:17]=[CH:18][CH:19]=[CH:20]5)=[O:28])[CH2:12][CH:11]3[CH2:10]2)[N:3]=1
Reactant: O=C(O)c1cccc2cccnc12
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4cccc5cccnc45)CC3C2)n1
Yield: 65 %

Procedure:
A mixture of 2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole (60.0 mg, 0.28 mmol), quinoline-8-carboxylic acid (52.4 mg, 0.30 mmol), HATU (156.8 mg, 0.41 mmol) and DIPEA (106.6 mg, 0.83 mmol) was stirred into DMF (5.0 mL) at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (60.0 mL) and washed with water (2×100 mL). The organic phase was dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified using Agilent HPLC (Basic system) to yield pure title compound (68.0 mg, 66.2%). MS (ESI) mass calcd. for C22H23N5O, 373.46; m/z found 374.2 [M+H]+. 1H NMR (CDCl3): 8.95 (s, 1H), 8.16 (d, J=7.9, 1H), 7.89-7.79 (m, 1H), 7.69 (d, J=6.8, 1H), 7.61-7.49 (m, 1H), 7.41 (s, 1H), 6.26 (d, J=19.1, 1H), 4.29-4.03 (m, 1H), 3.96-3.59 (m, 4H), 3.65-3.29 (m, 2H), 3.21-2.84 (m, 3H), 2.37-2.18 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.[N+:8]([O-])([OH:10])=[O:9]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:6]([N+:8]([O-:10])=[O:9])=[CH:5][N:4]([CH3:7])[N:3]=1
Reactant: Cn1ccc(Cl)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cn1cc([N+](=O)[O-])c(Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-chloro-1-methylpyrazole (Maybridge, Basel, Switzerland, 953 mg, 8.18 mmol) in concentrated sulfuric acid (1.4 ml), cooled with an ice-bath, was added over 30 min fuming nitric acid (1.19 mL, 28.6 mmol). The reaction mixture was stirred at rt for 2 h before being poured on ice/water and extracted with EtOAc (2×). The organic layers were washed with saturated aqueous NaHCO3 (2×) and brine, dried over Na2SO4, filtered, evaporated and dried over vacuum to give the title compound as a white solid (HPLC tR 2.24 min (Method A); M+H=162 MS-ES)
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][C:19]([C@@H:22]([NH:24][C:25](=[O:27])[CH3:26])[CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.Br[CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32]>CN(C=O)C>[CH2:29]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:17]=[CH:18][C:19]([C@@H:22]([NH:24][C:25](=[O:27])[CH3:26])[CH3:23])=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)[CH2:30][CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)CCBr
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3cccc(O)c3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3cccc(OCCC(C)C)c3)CC2)cc1
Temperature: 70 °C
Reaction time: 72 h

Procedure:
8 mg (0.2 mmol) NaH (60% in mineral oil) are added to a mixture of 34 mg (0.10 mmol) (S)—N-{1-(4-[1-(3-hydroxyphenyl)-piperidin-4-yl]-phenyl}-ethyl)-acetamide (compound 1.27) and 23 mg (0.15 mmol) 1-bromo-3-methylbutane in 2 mL DMF at 0° C. The mixture is stirred at 70° C. for 3 d. The reaction mixture is quenched with water, filtered and the solvent is evaporated. The residue is purified using reversed phase HPLC (water/MeOH, 0.1% TFA) to yield the desired product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1>>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[O:29])[CH:24]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C(=O)c3cccnc3)CC1)O2

Procedure:
Compound 59 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, nicotinoyl chloride and conditions outlined in procedure N. M.p.=218-220° C.; 300 MHz 1H NMR (CDCl3) δ 8.71 (brs, 2H), 8.08 (d, J=7.5 Hz, 1H), 7.77 (m, 3H), 7.53 (t, J=7.5 Hz, 1H), 7.40 (m, 1H), 4.62 (m, 1H), 3.78 (m, 1H), 3.42 (m 2H), 2.99 (s, 2H), 2.24 (s, 2H), 1.90 (m, 2H); LCMS: 407 [M+H].
Reaction SMILES: ClC1C=CC=CC=1C([O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=O.[Cl-].[Al+3].[Cl-].[Cl-].Cl.[CH:23]([Cl:26])(Cl)Cl>>[Cl:26][C:23]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:7]([C:12]1[CH:11]=[C:10]([F:13])[CH:9]=[CH:8][C:7]=1[OH:6])=[O:6]
Reactant: O=C(Oc1ccc(F)cc1)c1ccccc1Cl
Reactant: ClC(Cl)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1cc(F)ccc1O)c1ccccc1Cl
Reaction time: 1 h
Yield: 56.3 %

Procedure:
To a stirred solution of 2.5 g of compound A was added in small portions 1.47 g of powdered aluminum chloride at 130° C. and stirring was continued for another 1 hour. After cooling 1N HCl and chloroform was added to the reaction mixture and the organic layer was separated. The aqueous layer was extracted with chloroform. The combined organic layer was dried over magnesium sulfate and distilled to remove the solvent. The crude product thus obtained was crystallized from hexane to obtain 1.41 g of compound B. Yield: 56.3%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](Cl)=[O:5].[OH:12][C:13]1[CH:14]=[C:15]([B:19]([OH:21])[OH:20])[CH:16]=[CH:17][CH:18]=1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([O:12][C:13]1[CH:14]=[C:15]([B:19]([OH:21])[OH:20])[CH:16]=[CH:17][CH:18]=1)=[O:5]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: OB(O)c1cccc(O)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Oc1cccc(B(O)O)c1)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To make compound (6a), a solution of 2,6-dichlorobenzoyl chloride (29 μL, 0.2 mmol) in 5 mL of dried THF was added dropwise to an ice-cold solution of 3-hydroxyphenylboronic acid (21 mg, 0.15 mmol), dried triethyl amine (42 μL, 0.3 mmol) and 10 mL of dried THF. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was dissolved in 25 mL of ethyl acetate and washed with 1N aqueous HCl, 10% aqueous NaHCO3, saturated brine solution, dried (Na2SO4) and then concentrated. The residue was purified by flash chromatography eluting with MeOH-ethyl acetate (1:10) to give 38 mg (81% yield) of desired compound as a white powder, mp: 238° C.(dec). 1H-NMR (400 MHz, 5% D2O in d6-DMSO): δ7.08–7.19 [m, 1H, Ar—H], 7.22–7.30 [m, 1H, Ar—H], 7.22–7.30 [m, 1H, Ar—H], 7.42–7.50 [m, 1H, Ar—H], 7.54–7.60 [m, 1H, Ar—H], 7.60–7.68 [m, 2H, Ar—H], 7.73–7.78 [m, 3H, Ar—H].
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22]N3C4C=CC=CC=4N=N3)=O)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:43]([NH2:47])[CH2:44][CH2:45][CH3:46]>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:17][CH2:16][C:15]([C:20]([NH:47][CH2:43][CH2:44][CH2:45][CH3:46])=[O:22])([CH2:18][CH2:19]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCN
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Product: CCCCNC(=O)C12CCC(N(CC(=O)N3C[C@@H](F)C[C@H]3C#N)C(=O)OCc3ccccc3)(CC1)CC2

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and butylamine (11.5 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(N-butylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (44.0 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[CH:10]=[N:11][C:12]([C:15]2([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=3)[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[N:13][CH:14]=1)=O)([CH3:5])[CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:21]([N:18]1[CH2:17][CH2:16][C:15]([C:12]2[N:13]=[CH:14][C:9]([C:7]3[O:1][CH2:2][C:3]([CH3:4])([CH3:5])[N:6]=3)=[CH:10][N:11]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=2)[CH2:20][CH2:19]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(C2(c3ncc(C(=O)NC(C)(C)CO)cn3)CCN(Cc3ccccc3)CC2)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cccc(C2(c3ncc(C4=NC(C)(C)CO4)cn3)CCN(Cc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring solution of 2-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-pyrimidine-5-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (350 mg, 0.745 mmol) and triphenylphosphine (290 mg, 1.11 mmol) in tetrahydrofuran (10 mL) at 0° C. was added diethylazodicarboxylate (0.174 mL, 1.11 mmol). The reaction slowly warmed to room temperature and stirred for 3 hours. The crude mixture was concentrated under reduce pressure and purified by flash chromatography with 2% MeOH/CH2Cl2 to afford 175 mg (%) of the desired product. 1HNMR (400 MHz, CDCl3) δ 9.12 (s, 2H), 7.33-7.26 (comp, 5H), 7.15 (t, 1H), 6.95-6.91 (comp, 2H), 6.68-4.65 (comp, 1H), 4.09 (s, 2H), 3.72 (s, 3H), 3.42 (br s, 2), 3.04 (br s, 2H), 2.83 (br s, 2H), 2.37 (br s, 2H), 2.03 (br s, 2H), 1.36 (s, 6H); MS (M+1) 457.1
Reaction SMILES: [CH3:1][C@H:2]1[O:6][C:5](=[O:7])[CH:4]=[CH:3]1.Cl([O-])(=O)(=O)=O.[Li+].[CH3:14][CH2:15][O:16][CH2:17][CH3:18]>>[O:16]1[C@H:17]2[C@@H:4]3[C@@H:3]([C@@H:15]1[C:14]1[CH2:1][CH2:2][CH2:3][CH2:4][C:18]=12)[C@@H:2]([CH3:1])[O:6][C:5]3=[O:7]
Reactant: CCOCC
Reactant: C[C@@H]1C=CC(=O)O1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: C[C@H]1OC(=O)[C@H]2[C@H]1[C@H]1O[C@@H]2C2=C1CCCC2
Yield: 72 %

Procedure:
Similarly to Example 1, 1.37 g(13.9 mmol) of (R)-5-methyl-2(5H)-furanone and 1.70 g(1 equivalent) of 4,4,6,7-tetrahydroisobenzofuran in 2 ml of dehydrated ether solution were reacted with 1.06 g of lithium perchlorate to obtain 2.20 g of (3R,3aR,4R,9S,9aS)-4,9-epoxy-3-methyl-3a,4,5,6,7,8,9,9a-octahydronaphtho[2,3-c]furan-1(3H)-one(yield 72%).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[C:5]([CH:9]([OH:12])[CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.[CH2:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>C1C=CC=CC=1>[OH:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:10][NH:11][C:13]3([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[O:12]2)[CH:6]=[CH:7][CH:8]=1
Reactant: NCC(O)c1cccc(O)c1
Reactant: C1CCCCC1
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Product: Oc1cccc(C2CNC3(CCCCC3)O2)c1

Procedure:
A suspension of 20 g. of 1-(3'-hydroxyphenyl)-2-amino-ethanol hydrochloride in 100 ml. of cyclohexane is heated, while stirring vigorously, in a three-necked flask equipped with a dropping funnel, water separator, and thermometer. Above a temperature of 80° C., up to 100 ml. of benzene are added dropwise in such a manner so that the water of reaction formed together with the benzene is distilled of azeotropically. The temperature of the flask contents is, at the finish, about 130° C. After cooling, the crystalline reaction product is separated off, digested with benzene, and collected on a frit. There is obtained 20.3 g. (71.5% of theory) of 2-(3'-hydroxyphenyl)-1-oxa-4-azospiro[4,5]decane hydrochloride. After recrystallization from isopropanol/ethyl acetate, the product is obtained in the form of colorless crystals with a melting point of 138° - 139° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([NH:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:8][C:6]1[CH:7]=[CH:2][C:3]2[C:9]3[C:10]([CH:15]([CH3:16])[N:17]([S:18]([C:21]4[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=4)(=[O:19])=[O:20])[C:4]=2[CH:5]=1)=[CH:11][CH:12]=[CH:13][CH:14]=3
Reactant: COc1ccc(S(=O)(=O)NC(C)c2ccccc2-c2ccc(F)cc2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(S(=O)(=O)N2c3cc(F)ccc3-c3ccccc3C2C)cc1
Temperature: 100 °C
Yield: 98.3 %

Procedure:
N-[1-(2′,4′-Difluoro-1,1′-biphenyl-2-yl)ethyl]4-methoxybenzenesulfonamide (347 mg, 0.86 mmol) was dissolved in anhydrous N,N-dimethylformamide (2 mL) and potassium carbonate (238 mg, 1.72 mmol) was added as a solid in one portion. The mixture was heated at 100° C. with stirring until a single product had formed as gauged by LCMS (5-6 hours). Water (10 mL) was added and a white solid precipitated from the cloudy solution. The mixture was allowed to stand until the solution was clear, and the precipitated solid was filtered and washed with additional water to afford the desired compound (324 mg, 98%) as a white solid, m.p. 137.5-139° C.;
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[CH:4]=1.C(=O)([O-])[OH:13].[Na+].O>CC(C)=O>[CH3:11][O:10][C:5]1[CH:4]=[C:3]([CH2:2][OH:13])[CH:8]=[C:7]([CH3:9])[CH:6]=1
Reactant: COc1cc(C)cc(CBr)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(C)cc(CO)c1
Yield: 80.6 %

Procedure:
To a solution of 1-(bromomethyl)-3-methoxy-5-methylbenzene (2.14 g) in acetone (80 mL) were added sodium hydrogen carbonate (1.05 g) and water (50 mL), and the mixture was heated under reflux for 18 hr. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.22 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([C:19](O)=[O:20])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH:22]1([NH2:25])[CH2:24][CH2:23]1>>[CH:22]1([NH:25][C:19]([C:12]2[C:13]([C:15]([F:18])([F:17])[F:16])=[N:14][C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[N:10][CH:11]=2)=[O:20])[CH2:24][CH2:23]1
Reactant: O=C(O)c1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Reactant: NC1CC1
Product: O=C(NC1CC1)c1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Yield: 81.4 %

Procedure:
In a manner similar to Reference Example 1 (c) 2-(3-chlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (35 mg) and cyclopropylamine (9 mg, ex Lancaster) afforded the title compound (32 mg).
Reaction SMILES: [C:1]([N:3]=[C:4]1[N:19]([CH3:20])[C:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13](B(O)O)=[CH:14][C:15]=3[C:6]=2[N:5]1[C:21]1[CH:22]=[N:23][C:24]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])=[CH:25][CH:26]=1)#[N:2].Br[C:33]1[C:34]([CH3:43])=[CH:35][C:36]([NH:39][C:40](=[O:42])[CH3:41])=[N:37][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[C:1]([N:3]=[C:4]1[N:19]([CH3:20])[C:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([C:33]4[C:34]([CH3:43])=[CH:35][C:36]([NH:39][C:40](=[O:42])[CH3:41])=[N:37][CH:38]=4)=[CH:14][C:15]=3[C:6]=2[N:5]1[C:21]1[CH:22]=[N:23][C:24]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])=[CH:25][CH:26]=1)#[N:2]
Reactant: Cn1c(=NC#N)n(-c2ccc(C(C)(C)C#N)nc2)c2c3cc(B(O)O)ccc3ncc21
Reactant: CC(=O)Nc1cc(C)c(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(C)c(-c2ccc3ncc4c(c3c2)n(-c2ccc(C(C)(C)C#N)nc2)c(=NC#N)n4C)cn1
Temperature: 111 °C

Procedure:
To the stirred solution 2-(cyanoimino)-1-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-3-methyl-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-ylboronic acid (0.390 mmol) in dry DMF (5 mL) was added N-(5-bromo-4-methylpyridin-2-yl)acetamide (0.390 mmol) followed by catalyst palladium dichlorobis triphenylphosphine (0.039 mmol). Saturated solution of sodium carbonate (0.780 mmol) was added to it and the resulting solution was heated to 111° C. for 8 minutes in microwave. Solvent was evaporated and the crude material was extracted in EtOAc, washed with brine several times and dried over anhydrous Na2SO4. The solvent was evaporated and the crude solid was purified (silica gel column, CHCl3/MeOH as eluent) to obtain the title compound. 1H NMR (300 MHz, DMSO-d6): δ 10.46 (s, 1H), 9.26 (s, 1H), 9.02 (d, J=2.4 Hz, 1H), 8.35 (dd, J=2.4, 8.4 Hz, 1H), 8.17 (d, J=8.7 Hz, 1H), 7.91 (m, 3H), 7.70 (dd, J=1.8, 8.7 Hz, 1H), 6.60 (s, 1H), 3.90 (s, 3H), 2.08 (s, 3H), 2.00 (s, 3H), 1.70 (s, 6H); MS (m/z): 516 (M+1)+.