Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1
Reactant: Oc1cccc(F)c1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(Oc3cccc(F)c3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from 3-fluoro-phenol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(3-Fluoro-phenoxy)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 365(MH+).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C[Li:15]>O1CCCC1>[C:1]1([Li:15])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: [Li]C
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Solvent: C1CCOC1
Product: [Li]c1cccc2c1Cc1ccccc1-2

Procedure:
In a 500-cm3 four-necked flask in which the atmosphere was replaced with nitrogen, 16.6 g of fluorene were dissolved in 150 cm3 of tetrahydrofuran, followed by treating the solution with methyllithium, thereby obtaining a tetrahydrofuran solution of fluorenyllithium. Next, 200 cm3 of a tetrahydrofuran solution containing 10.4 g of previously synthesized 1,4-biscyclopentadienylidenecyclohexane were added dropwise to the tetrahydrofuran solution at -10° C. over 30 minutes. After completion of the addition, the reaction temperature was elevated up to room temperature, followed by stirring for 15 hours. Then, 200 cm3 of a 3.6% hydrochloric acid solution were poured thereinto to bring the reaction to an end. The resultant solid was collected by filtration, washed with ether, and then dried to obtain 18.5 g of white powdery 1,4-dicyclopentadienyl-1,4-difluorenylcyclohexane.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[N:6][CH:7]=1.[NH3:16]>O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[C:10]1([CH2:9][O:8][C:4]2[CH:3]=[C:2]([NH2:16])[CH:7]=[N:6][CH:5]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N
Reactant: Brc1cncc(OCc2ccccc2)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: Nc1cncc(OCc2ccccc2)c1
Temperature: 180 °C

Procedure:
A thick-walled glass pressure tube was charged with copper(II) sulfate pentahydrate (1.96 g, 7.85 mmol), 5-bromo-3-(phenylmethoxy)pyridine (4.00 g, 15.15 mmol) and concentrated aqueous ammonia (29.7%, 14.8 M, 37 mL). The tube was sealed and the dark blue suspension was stirred and heated at ˜180° C. (oil bath temperature) for 24 h. The mixture was allowed to cool to ambient temperature. After further cooling in an ice-water bath, the mixture was concentrated on a rotary evaporator to a small volume (˜20 mL) of a dark-blue solution. The solution was diluted with water (40 mL) and saturated K2CO3 solution (40 mL) and extracted with CHCl3 (4×40 mL). The combined, turbid-brown CHCl3 extracts were washed with saturated NaCl solution (2×100 ml), dried (Na2SO4), filtered and concentrated (rotary evaporator). The resulting dark-brown oil, was briefly dried on the vacuum pump to give a dark-brown solid (2.06 g). The product was purified by column chromatography on silica gel (100 g) eluting with CHCl3—MeOH (3:1,v/v). Selected fractions, based on TLC (Rf 0.65) analysis, were combined and concentrated to give a 1.64 g(54.1%) of a tan-brown solid.
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([C:8]1[CH:18]=[CH:17][C:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:10]=2[CH:9]=1)([O-:7])=[O:6].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:25](Br)[C:26]#[CH:27]>CC(C)=O>[N+:5]([C:8]1[CH:18]=[CH:17][C:11]2[CH2:12][CH2:13][N:14]([CH2:27][C:26]#[CH:25])[CH2:15][CH2:16][C:10]=2[CH:9]=1)([O-:7])=[O:6]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=[N+]([O-])O
Solvent: CC(C)=O
Product: C#CCN1CCc2ccc([N+](=O)[O-])cc2CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.3 %

Procedure:
7-Nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine nitric acid salt (1.0 g, 3.94 mmol) was dissolved in acetone (100 mL) followed by addition of Cs2CO3 (3.84 g, 11.82 mmol, 3.0 eq) and propargyl bromide (80% in toluene) (463 μL, 4.33 mmol, 1.1 eq). The reaction was stirred at room temperature for 24 hours. The solution was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (100 mL) and washed with water (100 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-10% MeOH/CH2Cl2 as the eluting solvent to obtain 7-nitro-3-prop-2-ynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow solid (756 mg, 83%). m.p.=122-125° C.; LCMS (m/e) 231 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.05-7.98 (m, 2H), 7.30-7.23 (m, 1H), 3.49-3.43 (m, 2H), 3.13-3.02 (m, 4H), 2.84-2.71 (m, 4H), 2.26-2.22 (m, 1H).
Reaction SMILES: [CH3:1][O-:2].[Na+].[NH2:4][C:5]1[N:6]=[C:7](Cl)[C:8]([C:11]#[N:12])=[N:9][CH:10]=1>O1CCOCC1>[NH2:4][C:5]1[N:6]=[C:7]([O:2][CH3:1])[C:8]([C:11]#[N:12])=[N:9][CH:10]=1
Reactant: C[O-]
Reactant: N#Cc1ncc(N)nc1Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1nc(N)cnc1C#N
Temperature: 90 °C
Yield: 32.9 %

Procedure:
Sodium methoxide (70 mg, 1.29 mmol) was added to a stirred solution of 5-amino-3-chloropyrazine-2-carbonitrile (100 mg, 0.647 mmol) in dioxane (1 mL). The reaction mixture was heated in a sealed tube at 90° C. overnight. The solvent was removed in vacuo, and the residue was partitioned between water and ethyl acetate. The aqueous layer was re-extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to give the title compound (32 mg, 0.213 mmol, 33%). LC-MS (3) Rt=0.96 min; m/z (ESI+) 151 (M+H+).
Reaction SMILES: [C:1]1([O:7][C:8]2[C:13]3[CH:14]=[N:15][C:16]4[NH:20][N:19]=[CH:18][C:17]=4[C:12]=3[N:11]3[N:21]=[CH:22][N:23]=[C:10]3[N:9]=2)[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:13]3[C:8]([O:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:9][C:10]4[N:11]([N:21]=[CH:22][N:23]=4)[C:12]=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=C(Cl)c1ccccc1
Reactant: c1ccc(Oc2nc3ncnn3c3c2cnc2[nH]ncc23)cc1
Solvent: c1ccncc1
Product: O=C(c1ccccc1)n1ncc2c1ncc1c(Oc3ccccc3)nc3ncnn3c12

Procedure:
0.01 mol. of 5-phenyloxy-8H-pyrazolo[4',3':5,6]pyrido-[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine 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-5-phenyloxy-8H-pyrazolo[4',3':5,6]pyrido-[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine is filtered off.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].[OH:10]O>ClCCl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:10])[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: OO
Reactant: Clc1cncc(Cl)c1Cl
Solvent: ClCCl
Product: [O-][n+]1cc(Cl)c(Cl)c(Cl)c1
Reaction time: 15 h
Yield: 74 %

Procedure:
To a stirred solution of 3,4,5-trichloropyridine (1 g, 5.45 mmol) in dichloromethane (20 mL) at 0° C., was added dropwise a 30% hydrogen peroxide solution (1.2 mL, 10.9 mmol). Following the addition, the temperature was allowed to rise to room temperature and was stirred for 15 hours. The reaction mixture was diluted with dichloromethane (50 mL) and was washed with water (10 mL) and then by brine (25 mL×2). The organic phase was dried (Na2SO4), concentrated under vacuum to afford the title product as a white solid (0.8 g, 74% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.78 (2H, s). MS m/z: 197.90 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([NH:15]C(=O)OC(C)(C)C)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1.ClS([N:27]=[C:28]=[O:29])(=O)=O.O.C(=O)([O-])O.[Na+]>C(#N)C>[C:28](=[O:29])([O:1][CH2:2][CH2:3][CH:4]([NH2:15])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:12])([F:13])[F:14])[CH:6]=1)[NH2:27]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC(CCO)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NC(=O)OCCC(N)c1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
Of the compound from Example 128A, 827 mg (2.59 mmol) were introduced in 100 ml of acetonitrile. A solution of 676 μl (7.77 mmol) of chlorosulphonyl isocyanate in 10 ml of acetonitrile was added dropwise at −15° C. After 5 min, 50 ml of water were added and the mixture was then stirred at 60° C. overnight. The reaction mixture was admixed with saturated aqueous sodium hydrogen carbonate solution and then extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate and freed from the solvent on a rotary evaporator. Drying of the residue in an HV gave 678 mg (quant.) of the title compound.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:8][CH2:7][C@@H:6]2[CH2:9][C@H:3]1[C:4](=[O:10])[O:5]2.[CH3:11][CH2:12][O-:13].[Na+]>C(O)C>[OH:13][C@H:12]1[CH2:9][C@@H:3]([C:4]([O:5][CH2:6][CH3:7])=[O:10])[C@H:2]([CH3:8])[CH2:1][CH2:11]1
Reactant: CC[O-]
Reactant: C[C@@H]1CC[C@@H]2C[C@H]1C(=O)O2
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)[C@@H]1C[C@H](O)CC[C@H]1C

Procedure:
reacting said (1R,2R,5R)-2-methyl-6-oxabicyclo[3.2.1]octan-7-one (9) with with EtONa and ethanol, or with Na and ethanol to produce ethyl (1R,2R,5R)-5-hydroxy-2-methylcyclohexane-1-carboxylate (10),
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[C:8]([NH:14]CC2C=CC=CC=2)=[CH:7][C:6]=1[O:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH3:2]>[Pd].C1COCC1.CO>[CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([NH2:14])=[CH:7][C:6]=1[O:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH3:2]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(NCc2ccccc2)cc1OCCN(C)C
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(N)c(N)cc1OCCN(C)C

Procedure:
Prepared analogously to example 655d by hydrogenation of the product obtained from (687a) using palladium on charcoal in THF and methanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]([O:11][C:12](=[O:26])[CH:13]([C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:14][C:15](=O)[CH3:16])[CH3:10].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.C(Cl)Cl>[CH2:9]([O:11][C:12]([C:13]1[CH:14]=[C:15]([CH3:16])[N:5]([C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([Br:1])[CH:3]=2)[C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:26])[CH3:10]
Reactant: Nc1cccc(Br)c1
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cc(C)n(-c2cccc(Br)c2)c1-c1ccccc1

Procedure:
m-Bromoaniline (5 mmol, 0.9 g), 2-benzoyl-4-oxo-pentanoic acid ethyl ester (5 mmol, 1.2 g), and tosic acid were combined in ethanol, then heated under reflux. The resulting oil was resuspended in methylene chloride, then washed with water, 5% sodium bicarbonate and brine. The organic layer was dried over MgSO4, then the solids were separated and the solvents evaporated under vacuum. The crude product was recrystallized from ethanol to yield the named product (m.p. 117.5° C.-119.2° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:12])([CH3:11])[CH:9]=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)(CO)c1ccc(Br)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2-(4-bromophenyl)-2-methylpropan-1-ol (10 g, 44 mmol) in dichloromethane (80 mL) was added PCC (14 g, 65 mmol) in portions at 0° C. The resulting solution was stirred at ambient temperature for 16 hours, and then filtered and concentrated in vacuo. The crude residue was purified by MPLC on silica gel (eluting with 1-2% EtOAc/hexane) to afford the title compound as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 9.49 (s, 1H), 7.52 (d, J=6.3 Hz, 2H), 7.17 (d, J=6.3 Hz, 2H), 1.43 (s, 6H).
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.[Cl:8][C:9]1[N:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2/[C:23](=[CH:28]\O)/[C:24]([O:26][CH3:27])=[O:25])[CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:8][C:9]1[N:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2/[C:23](=[CH:28]\[O:6][CH3:7])/[C:24]([O:26][CH3:27])=[O:25])[CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)/C(=C/O)c1ccccc1COc1cccc(Cl)n1
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
Dimethyl sulphate (0.4 ml, 4.2 mmol) was added dropwise to a mixture of (E)-methyl 2-[2-(6-chloropyrid-2-yloxymethyl)phenyl]-3-hydroxyacrylate (1.04 g, 2.9 mmol) and anhydrous potassium carbonate (0.78 g, 5.6 mmol) in dry DMF (10 ml). After stirring at room temperature for 3 hours, the mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extracts were washed with water, dried and concentrated to give an oil which was purified by column chromatography (silica eluted with 20% ethyl acetate in hexane) to give (E)-methyl 2-[2-(6-chloropyrid-2-yloxymethyl)phenyl]-3-methoxyacrylate (Compound No.244 in Table I of EP-A-0278595) (0.72 g, 74%) as a cream solid; mp 91-92° C.; 1H NMR (270 MHz)δ: 3.69(3H,s), 3.83(3H,s), 5.26(2H,s), 6.63(1H,d), 6.90(1H,s), 7.15-7.55(5H,m), 7.56(1H,s) ppm.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[S:32]>>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31]([N:17]1[CH2:18][CH2:19][N:14]([C:11]2[N:12]=[CH:13][C:8]3[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=3[N:10]=2)[CH2:15][CH2:16]1)=[S:32]
Reactant: S=C=Nc1ccccc1Cl
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4ccccc4Cl)CC3)nc21

Procedure:
Pipemidic acid (56 mg, 0.184 mmol) and 2-chlorophenylisothiocyanate (20 μL, 0.153 mmol) were used. Purification on silica yielded compound 17 in Table 1, below (72 mg, 99%). 1H NMR (300 MHz, CDCl3) δ 9.34 (s, 1H), 8.68 (s, 1H), 7.75 (d, J=8.10 Hz, 1H), 7.44 (d, J=8.00 Hz, 1H), 7.37-7.27 (m, 2H), 7.15 (t, J=7.67 Hz, 1H), 4.35 (q, J=7.15 Hz, 2H), 4.29-4.01 (m, 8H), 1.50 (t, J=7.20 Hz, 3H) ppm.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C(N(CC)CC)C>ClCCl>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.7 %

Procedure:
Add sodium borohydride (0.82 mol, 31.3 g) in portions to a solution of 1-(tert-butoxycarbonyl)-4-piperidone (0.74 mol, 150 g) and triethylamine (1.5 mol, 151.6 g) in dichloromethane (1 L) at 0° C. Upon complete addition, warm the reaction mixture to room temperature and stir for 4 h. Quench the reaction mixture with saturated ammonium chloride solution and remove the ethanol under reduced pressure. Dissolve the residue in water and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (150 g, 99%) as a viscous solid. 1H NMR (400 MHz, CDCl3) δ 1.45 (s, 9H), 1.53 (d, 2H), 1.83-1.87 (m, 2H), 3.02 (dt, 2H), 3.8-3.85 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[N:23])[CH:20]=3)[N:15]=[CH:14][C:13]=2[C:24]([OH:26])=[O:25])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[F:27][C:28]1[C:33](O)=[C:32]([F:35])[C:31]([F:36])=[C:30]([F:37])[C:29]=1[F:38].C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C.C(OCC)(=O)C>[F:27][C:28]1[C:33]([O:25][C:24]([C:13]2[CH:14]=[N:15][C:16]3[C:21]([C:12]=2[NH:11][CH2:10][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=2)=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=3)=[O:26])=[C:32]([F:35])[C:31]([F:36])=[C:30]([F:37])[C:29]=1[F:38]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: COc1ccc(CNc2c(C(=O)O)cnc3ccc(C#N)cc23)cc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2c(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)cnc3ccc(C#N)cc23)cc1Cl
Reaction time: 18 h
Yield: 41 %

Procedure:
To 275 mg (0.748 mmol) of 4-[[(3-chloro-4-methoxyphenyl)-methyl]amino]-6-cyano-3-quinolinecarboxylic acid was added 276 mg (1.50 mmol, 2.0 eq) pentafluorophenol, and the mixture was dispersed in 5 mL anhydrous DMF under nitrogen. To this dispersion was added a solution of 231 mg (1.12 mmol, 1.5 eq) of dicyclohexylcarbodiimide (Aldrich) in 2 mL anhydrous ethyl acetate at RT. The resulting mixture was stirred for 18 hours. The reaction was then diluted with 10 mL EtAc, and the white precipitate was filtered and discarded. The filtrate was concentrated in vacuo, and the residue was triturated with 5% MeOH/95% CH2Cl2 to give 164 mg (0.307 mmol, 41% yield) of the title compound as a white solid: LC/MS: M/Z 534 (M+H) observed, 100% purity; mp: decomposed 215-217° C. LC: 4.15.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].O.[OH-].[Li+:13].O>CC(O)C>[C:1]([O-:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Li+:13]
Reactant: O=C(O)c1ccccc1O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=C([O-])c1ccccc1O
Yield: 70.3 %

Procedure:
To a flask were added 10.0 g salicylic acid, 2.9 g lithium hydroxide monohydrate, 20 ml of water and 100 ml 2-propanol. The mixture was heated to 50 C for 1.5 hours and then cooled and the solvent was removed under reduced pressure. The product was slurried in 25 ml diethyl ether, filtered and washed with diethyl ether. After drying, 7.0 g of a white solid was obtained.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:13][C:14]1[C:15]([C:20]([OH:22])=O)=[N:16][CH:17]=[CH:18][N:19]=1.[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1>CN(C)C=O.C(OCC)C>[NH2:13][C:14]1[C:15]([C:20]([NH:23][CH2:24][CH2:25][CH2:26][N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)=[O:22])=[N:16][CH:17]=[CH:18][N:19]=1
Reactant: NCCCn1ccnc1
Reactant: Nc1nccnc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Nc1nccnc1C(=O)NCCCn1ccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
A solution of 19.09 g (0.0776 mol) of 1,1'-carbonyldiimidazole in approximately 200 ml of dimethylformamide was added slowly to a cold (0° C.) solution of 15.78 g (0.1135 mol) of 3-aminopyrazine-2-carboxylic acid in 150 ml of dimethylformamide. The resulting solution was gradually warmed to 25° C. and stirred for about two hours. A solution of 14.75 g (0.118 mol) of N-(3-aminopropyl)imidazole in approximately 40 ml of dimethylformamide was added and the resulting solution was allowed to react for four hours. After four hours, the reaction solution was reduced to dryness under reduced pressure. The resultant semi-solid was suspended in diethyl ether and the portion which did not dissolve was recovered by filtration. The recovered solid was then suspended in diethyl ether containing a small amount of ethyl acetate and the resulting mixture was stirred for about 48 hours. After stirring for 48 hours, the undissolved solid was isolated by filtration. This solid was purified by filtration through silica gel using 4% methanol in dichloromethane. The resultant purified material was recrystallized from a 1:4 dichloromethane/diethyl ether solution to provide 24.4 g of the desired subtitled intermediate (m.p. 118°-120° C.).
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3([C:16]([N:18]4[CH2:22][CH2:21][C@@:20]5([C:30]6[CH:29]=[CH:28][N:27]=[CH:26][C:25]=6[C:24](=[O:31])[O:23]5)[CH2:19]4)=[O:17])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(#N)C.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>>[CH3:42][S:43]([N:1]1[CH2:2][CH:3]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([C:13]3([C:16]([N:18]4[CH2:22][CH2:21][C@@:20]5([C:30]6[CH:29]=[CH:28][N:27]=[CH:26][C:25]=6[C:24](=[O:31])[O:23]5)[CH2:19]4)=[O:17])[CH2:14][CH2:15]3)=[CH:11][CH:12]=2)[CH2:5][CH2:6]1)(=[O:45])=[O:44]
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(C5=CCNCC5)cc4)CC3)C2)c2ccncc21
Reactant: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CC=C(c2ccc(C3(C(=O)N4CC[C@@]5(C4)OC(=O)c4cnccc45)CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R)-1′-({1-[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one (22 mg, 0.000053 mol) in acetonitrile (0.5 mL, 0.01 mol) were added triethylamine (16.8 μL, 0.000120 mol) and methane sulfonyl chloride. The reaction mixture was stirred at room temperature overnight. The crude product was purified by prep-HPLC. LC/MS: 494.2 (M+H+).
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29]1(O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[CH3:20][CH:19]([CH3:21])[C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@H:2]([O:1][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:12]=1)=[O:22]
Reactant: Oc1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3ccccc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 23.7 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), phenol (4.70 mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) in THF (1.0 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (2.7 mg, 23.6% yield) as a thick oil: 1H NMR δ 7.46 (s, 2H), 7.40–7.30 (m, 4H), 7.25 (m, 3H), 7.20 (m, 2H), 6.97 (apparent d, 1H, J=7.4 Hz) 6.89 (apparent tt, 1H, J=0.8, 7.6 Hz), 6.84 (apparent dt, 1H, J=0.8, 8.0 Hz), 5.20 (apparent dd, 1H, J=4.4, 8.5 Hz), 3.35 (m, 2H), 2.91 (m, 2H), 2.60 (m, 2H), 2.30–2.10 (m, 6H), 1.90 (m, 2H), 1.25 (d, 6H, J=7.9 Hz); ESMS m/e: 457.4 (M+H)+.