Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[O:9][C:8]([C:10](=O)[CH2:11][CH3:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][C:15]([S@:18]([NH2:20])=[O:19])([CH3:17])[CH3:16]>C1COCC1.C(OCC)C.O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:1][S:2]([C:5]1[O:9][C:8](/[C:10](=[N:20]/[S@@:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19])/[CH2:11][CH3:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CCC(=O)c1ccc(S(C)(=O)=O)o1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC/C(=N\[S@](=O)C(C)(C)C)c1ccc(S(C)(=O)=O)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(5-methanesulfonyl-furan-2-yl)-propan-1-one (1.1 g, 5.5 mmol) in THF (30 mL) was added (R)-(+)-2-methyl-2-propanesulfinamide (0.750 g, 6.06 mmol) and titanium (IV) isopropoxide (6 mL, 25 mmol) and the mixture was warmed at reflux. After 18 hours, the mixture was cooled to room temperature, and diluted with diethyl ether (100 mL) and water (6 mL). The mixture was stirred for 10 minutes, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography, eluting with a gradient of 0-80% EtOAc-hexanes to afford (R)-2-methyl-propane-2-sulfinic acid[1-(5-methanesulfonyl-furan-2-yl)-prop-(E)-ylidene]-amide.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH2:13](B(O)O)[CH:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.C(OCC)C>[CH2:13]([C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5])[CH:14]([CH3:16])[CH3:15]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Br
Reactant: CC(C)CB(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: CC(C)Cc1ccc([N+](=O)[O-])cc1C#N
Temperature: 100 °C
Reaction time: 18 h
Yield: 58.9 %

Procedure:
Under an argon gas atmosphere, 2-bromo-5-nitrobenzonitrile (2.0 g), isobutylboronic acid (988 mg), cesium carbonate (5.7 g), and PdCl2 (dppf)-CH2Cl2 (720 mg) were dissolved in toluene (25 ml) and water (1 ml). The mixture was stirred at 100° C. for 18 hours. After the mixture was cooled to room temperature, the mixture was diluted with diethyl ether and water followed by the step of extraction/separation. The organic layer was washed with 1 N-hydrochloric acid, 5 N-sodium hydroxide aqueous solution and saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resulting residue was purified on column chromatography (EtOAc:hexane=1:3) to obtain the title compound (1.06 g) as a pale yellow oily substance.
Reaction SMILES: [F:1][C:2]([F:18])([CH:7]([O:12]C(=O)C(C)=C)[CH2:8][CH:9]([CH3:11])[CH3:10])[C:3]([O:5][CH3:6])=[O:4].[CH2:19](O)C.C1C=CC=CC=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[F:1][C:2]([F:18])([CH:7]([OH:12])[CH2:8][CH:9]([CH3:11])[CH3:10])[C:3]([O:5][CH2:6][CH3:19])=[O:4]
Reactant: CCO
Reactant: C=C(C)C(=O)OC(CC(C)C)C(F)(F)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C(F)(F)C(O)CC(C)C
Yield: 123.2 %

Procedure:
To a mixture of 25.0 g of Intermediate 1 (Example 1), 20 g of ethanol and 200 g of benzene was added 0.15 g of p-toluenesulfonic acid monohydrate. With stirring in a nitrogen atmosphere, the mixture was heated for 20 hours while water of reaction was sequentially removed out of the system. After cooling, the reaction mixture was poured into a saturated sodium hydrogen carbonate aqueous solution and extracted with ethyl acetate. The ethyl acetate solution was washed, dried, and concentrated, obtaining 24.5 g (yield 85%) of crude ethyl 2,2-difluoro-3-hydroxy-5-methylhexanoate. This crude product had a sufficient purity as an intermediate and was ready for use in the subsequent step.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][CH:8]2[CH2:13][CH2:12][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18]([C:20]3[C:21]([CH3:27])=[N:22][CH:23]=[N:24][C:25]=3[CH3:26])=[O:19])[CH2:10][CH2:9]2)=[CH:2]1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([CH2:42][C:43](O)=[O:44])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([CH2:42][C:43](=[O:44])[N:7]([CH:8]2[CH2:9][CH2:10][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18]([C:20]3[C:25]([CH3:26])=[N:24][CH:23]=[N:22][C:21]=3[CH3:27])=[O:19])[CH2:12][CH2:13]2)[CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Reactant: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(NCc2ccsc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2ccsc2)C(=O)CC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Yield: 79.8 %

Procedure:
Following general procedure E: a solution of 4,6-dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide (41 mg, 0.1 mmol), 4-carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.22 mmol), EDCI (39 mg, 0.20 mmol), HOBT (27 mg, 0.20 mmol), and DIPEA (0.05 ml, 0.3 mmol) in CH2Cl2 (2 ml) was stirred overnight. Purification of the crude product by column chromatography on silica gel (CH2Cl2/MeOH, 9:1) afforded 4-{[(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-thiophen-3-ylmethyl-carbamoyl]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (50 mg, 80%).
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:6]=1.[ClH:22].[CH3:23]O>O=[Pt]=O>[ClH:22].[CH3:23][CH:4]([CH:5]1[CH2:10][CH2:9][NH:8][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH2:6]1)[C:3]([OH:2])=[O:21]
Reactant: COC(=O)Cc1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CO
Agent: O=[Pt]=O
Agent: Cl
Product: CC(C(=O)O)C1CCNC(c2ccc(C(F)(F)F)cc2)C1
Reaction time: 5 h

Procedure:
A mixture of methyl{2-[4-(trifluoromethyl)phenyl]pyridin-4-yl}acetate (6.2 g, 21 mmol), PtO2 (200 mg, 0.9 mmol) and HCl solution (4N in dioxane, 5.8 ml, 23 mmol) in MeOH (100 ml) was hydrogenated at 20 psi on a Parr® apparatus for 5 hours. The catalyst was removed by filtration and the filtrate evaporated in vacuo to give the desired piperidine as white solid (7.1 g, quant). 1H NMR (400 MHz, CD3OD) δ: 1.58-1.72 (1H, m), 1.75-1.85 (1H, m), 2.08 (1H, d, J 14.2), 2.19 (1H, t, J 14.2), 2.28-2.38 (1H, m), 2.45 (2H, d, J 6.9), 3.24-3.32 (1H, m), 3.51-3.57 (1H, m), 3.67 (3H, s), 4.46 (1H, d, J 10.2), 7.72 (2H, d, J 8.3), 7.79 (2H, d, J 8.4).
Reaction SMILES: [C:1]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].CI.[C:17](OCC)(=O)C>O1CCCC1>[CH3:17][CH:2]([C:3]([O:5][CH3:6])=[O:4])[C:1]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: COC(=O)CC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
9.91 Gram (95%, 56.9 mmol) of tert-butyl methyl malonate was dissolved in 120 mL of tetrahydrofuran (THF), and the resulting solution was added dropwise to a suspension containing 2.28 g (60 wt %, 56.9 mmol) of sodium hydride (NaH) and 120 mL of THF at 0° C. over 0.5 hours, followed by stirring for 0.5 hours. Thereafter, a solution containing 8.08 g (56.9 mmol) of methyl iodide (MeI) and 20 mL of TI-IF was added dropwise over 0.5 hours, and the resulting mixture was stirred at 0° C. for 0.5 hours and further stirred at 25° C. for 5 hours. After adding 200 of ethyl acetate, the organic layer was washed, in order, twice with saturated brine and twice with water, and dried over sodium sulfate, and the solvent was concentrated to obtain 13.0 g of 1-tert-butyl 3-methyl 2-methylmalonate as a colorless transparent oil. Subsequently, 45.9 g of an aqueous formalin solution was added to 13.0 g of the oil, and resulting mixture was cooled to 0° C. Furthermore, 7.81 g of potassium carbonate was added, and the mixture was stirred at 0° C. for 1 hour and further stirred at 25° C. for 3 hours. After adding 200 mL of ethyl acetate, the organic layer was washed, in order, three times with an aqueous saturated sodium hydrogensulfite solution and twice with water, and dried over sodium sulfate. The solvent was concentrated, and the residue was dissolved in 50 mL of pyridine. The resulting solution was cooled to 0° C., and 21.7 g of p-toluenesulfonyl chloride was added thereto. The obtained mixture was stirred at 0° C. for 2 hours and then stirred at 60° C. for 4 hours. After adding 200 mL of ethyl acetate, the organic layer was washed, in order, three times with an aqueous saturated ammonium chloride solution and twice with water, and dried over sodium sulfate. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate=4/1) to obtain 15.8 g of the objective Compound (I-31) as a colorless transparent oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1B(O)O.Cl[C:14]1[CH:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=1.[IH:21]>>[I:21][C:14]1[CH:19]=[C:18]([C:3]2[C:4]([O:8][CH3:9])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:17]=[CH:16][N:15]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: I
Reactant: COc1cccc(F)c1B(O)O
Product: COc1cccc(F)c1-c1cc(I)ncn1

Procedure:
The compound was prepared according to Example 1 using 2-fluoro-6-methoxyphenylboronic acid and 4,6-dichloropyrimidine. The resultant chloro compound was converted to iodo with hydroiodic acid as described in the general procedure.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1([O:17]C(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.O[C:26]1[CH:27]=[CH:28][C:29]([CH2:58][C:59](O)=[O:60])=[N:30][C:31]=1[C:32]1[CH:33]=[C:34]2[C:40]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[O:47][CH3:48])=[N:39][N:38](CCOCC[Si](C)(C)C)[C:35]2=[N:36][CH:37]=1.[CH3:62][NH:63][CH3:64].C(N(C(C)C)CC)(C)C>O1CCCC1>[OH:17][CH:58]([C:29]1[CH:28]=[CH:27][CH:26]=[C:31]([C:32]2[CH:33]=[C:34]3[C:40]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[O:47][CH3:48])=[N:39][NH:38][C:35]3=[N:36][CH:37]=2)[N:30]=1)[C:59]([N:63]([CH3:64])[CH3:62])=[O:60]
Reactant: COc1ccccc1-c1nn(CCOCC[Si](C)(C)C)c2ncc(-c3nc(CC(=O)O)ccc3O)cc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(C(O)C(=O)N(C)C)n3)cc12
Reaction time: 16 h
Yield: 24.1 %

Procedure:
In a microwave vial O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (53.9 mg, 0.14 mmol) was added to a solution of 5-hydroxy-{6-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxylethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-pyridin-2-yl}-acetic acid (71 mg, 0.14 mmol), dimethyl amine (2 M in THF, 65 μl, 0.14 mmol) and di-iso-propyl ethyl amine (75 μl, 0.43 mmol) in tetrahydrofuran (1 ml). The vial was sealed and the solution irradiated to 70° C. for 10 min in a microwave reactor. The solvent was then removed under reduced pressure and 1 ml of trifluoroacetic acid was added this reaction was stirred for 16 hours and the solvent evaporated under reduced pressure, and purified by preparative mass-triggered reverse-phase HPLC to afford 2-hydroxy-2-{6-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-pyridin-2-yl}-N,N-dimethyl-acetamide (13.6 mg, 24% yield). 1H NMR (500 MHz, Dimethyl sulfoxide-d6) δ 2.85 (s, 3H) 3.30 (s, 3H); 3.85 (s, 3H)); 5.63 (m, 2H); 7.10 (t, J=8 Hz 1H); 7.4 (d, J=8 Hz 1H); 7.44 (m, 2H); 7.63 (d, J=8 Hz 1H); 7.87 (m, 2H) 8.88 (s, 1H); 9.22 (s, 1H); 13.84 (s, br, 1H) MS: m/z 404.3 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][CH2:8][C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=3)[O:11][N:10]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:29]1([O:35][C:36](Cl)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl.CCOC(C)=O>[C:29]1([O:35][C:36]([N:1]2[CH2:6][CH2:5][CH:4]([O:7][CH2:8][C:9]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=4)[O:11][N:10]=3)[CH2:3][CH2:2]2)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N#Cc1cc(-c2nc(COC3CCNCC3)no2)ccn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cc(-c2nc(COC3CCN(C(=O)Oc4ccccc4)CC3)no2)ccn1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-[3-(piperidin-4-yloxymethyl)[1,2,4]oxadiazol-5-yl]pyridine-2-carbonitrile (Preparation 25, 700 mg, 2.5 mmol) in DCM (30 ml) was added triethylamine (0.7 ml, 4.9 mmol). The resulting solution was transferred to a stirred solution of phenylchloroformate (0.62 ml, 4.9 mmol) in DCM (30 ml) and stirring was continued for 30 min at rt. The reaction mixture was diluted with EtOAc (250 ml) then washed successively with water (100 mL), saturated aqueous sodium carbonate (100 ml) and brine (100 ml). The organics were dried (MgSO4) then adsorbed onto silica gel. Purification via chromatography (EtOAc-IH, 1:1 to 3:2) afforded the title compound: RT=3.63 nm in; m/z (ES+)=406.01 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:41][O:42]C(OC)OC.[C:48]([O-])(O)=O.[Na+]>CO.ClCCl>[CH3:48][O:1][C:2]([O:42][CH3:41])([C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: COC(OC)OC
Reactant: O=C([O-])O
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCC(=O)c2ccc(C(F)(F)F)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(CCCCCCOS(=O)(=O)c1ccc(C)cc1)(OC)c1ccc(C(F)(F)F)cc1
Yield: 59 %

Procedure:
To a magnetically stirred solution of toluene-4-sulfonic acid 7-oxo-7-[4-(trifluoromethyl)phenyl]heptyl ester (2.77 g, 6.464 mmol) in methanol (75 ml), a catalytic amount of para-toluenesulfonic acid (0.097 g, 0.508 mmol) and excess trimethylorthoformate (16 ml, 142 mmol) were successively added. The resulting mixture was heated at reflux temperature for 20 hours. After allowing the reaction mixture to attain room temperature saturated aqueous NaHCO3 and dichloromethane were successively added. The separated organic layer was washed with saturated aqueous NaHCO3. The organic layer was subsequently dried over Na2SO4, filtered and concentrated in vacuo to give crude toluene-4-sulfonic acid 7,7-dimethoxy-7-[4-(trifluoromethyl)phenyl]heptyl ester which was purified by column chromatography (alumina, ethylacetate/heptane= 1/10 (v/v)) to give pure toluene-4-sulfonic acid 7,7-dimethoxy-7-[4-(trifluoromethyl)phenyl]heptyl ester (1.82 g, 59% yield). 1H-NMR (400 MHz, CDCl3) δ 0.84-0.93 (m, 2H), 1.06-1.26 (m, 4H), 1.51-1.57 (m, 2H), 1.80-1.86 (m, 2H), 2.44 (s, 3H), 3.13 (s, 6H), 3.94 (t, J=7, 2H), 7.32 (d, J˜8, 2H), 7.55 (d, J˜8, 2H), 7.60 (d, J˜8, 2H), 7.75 (d, J˜8, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2C)=[O:9])[CH:3]=1.ClC1N=CN=C(C(NC2C=CC(O)=CC=2)=O)C=1.C(N(C(C)C)C(C)C)C.[NH2:45][C:46]1[C:47]([CH3:52])=[CH:48][CH:49]=[CH:50][CH:51]=1>C(O)C>[OH:17][C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:8]([C:4]2[CH:3]=[C:2]([NH:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[CH3:52])[N:7]=[CH:6][N:5]=2)=[O:9])=[CH:16][CH:15]=1
Reactant: Cc1ccccc1N
Reactant: Cc1cc(O)ccc1NC(=O)c1cc(Cl)ncn1
Agent: O=C(Nc1ccc(O)cc1)c1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccccc1Nc1cc(C(=O)Nc2ccc(O)cc2)ncn1
Temperature: 160 °C

Procedure:
A solution of 6-chloro-N-(4-hydroxy-2-methylphenyl)pyrimidine-4-carboxamide, Intermediate 7 (50.0 mg; 0.20 mmol) in ethanol (3 mL) was treated with N-ethyldiisopropylamine (69 μl; 0.4 mmol) and o-toluidine (Fluka, 21.5 μl; 0.20 mmol). The reaction mixture was heated at 160° C. for 3 hours under microwave irradiation. The solvents were removed in vacuo, EtOAc was added and the organic phase was washed with a citric acid solution, dried over magnesium sulfate then evaporated in vacuo. The crude product was purified by column chromatography (silica), eluting with cyclohexane containing an increasing amount of EtOAc. The title compound was obtained as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1.C(Cl)Cl.C(N(C(C)C)C(C)C)C.[CH2:37]([O:39][CH2:40]Cl)[CH3:38]>CCOCC>[CH2:37]([O:39][CH2:40][O:1][CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:21])([F:20])[F:22])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1)[CH3:38]
Reactant: CCOCCl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CO)c3c2)c1=O
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOCOCc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12

Procedure:
To a mixture of 3-[3-(hydroxymethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (0.800 g, 0.00224 mol) and methylene chloride is added ethyldiisopropylamine (0.780 ml, 0.00448 mol) followed by chloromethyl ethyl ether (0.310 ml, 0.00336 mol). The resultant mixture is stirred 42.5 hours at room temperature, diluted with ether, washed sequentially with 1 M aqueous hydrochloric acid, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to a yellow syrup. The syrup is chromatographed on silica gel with hexanes:ethyl acetate to give the product as a white solid which is identified by NMR spectral analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].Cl[C:14]1[C:23]2[C:18](=[C:19]([C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][CH:34]=3)[N:31]=[C:30]([NH:35][CH3:36])[N:29]=[CH:28]4)[C:20]([CH3:24])=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.O>CN1C(=O)CCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH:7][C:14]1[C:23]2[C:18](=[C:19]([C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][CH:34]=3)[N:31]=[C:30]([NH:35][CH3:36])[N:29]=[CH:28]4)[C:20]([CH3:24])=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: CNc1ncc2cc(-c3c(C)ccc4c(Cl)nccc34)ccc2n1
Solvent: CN1CCCC1=O
Solvent: O
Product: CNc1ncc2cc(-c3c(C)ccc4c(NCc5ccc(OC)c(OC)c5)nccc34)ccc2n1

Procedure:
Dissolved 3,4-dimethoxybenzylamine (3.04 ml, 20.2 mmol) in NMP (15.0 mL) and added 6-(1-chloro-6-methylisoquinolin-5-yl)-N-methylquinazolin-2-amine (2.25 g, 6.72 mmol) as a solid in a sealed vessel and heated the reaction to 220° C. in the microwave 20 minutes. Dripped the reaction mixture into water and isolated the resulting precipitate. Air-dried the solid and redissolved in 2M NH3/MeOH. Concentrated in vacuo, redissolved wet slurry in EtOAc and dried the slurry over Na2SO4. Concentrated and loaded the crude material on a column, and purified the crude eluting with 20-100% EtOAc/hexanes. The pure fractions were combined and concentrated to afford 6-(1-(3,4-dimethoxybenzylamino)-6-methylisoquinolin-5-yl)-N-methylquinazolin-2-amine. MS (M+H)+ 466.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16](Cl)=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[NH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1.C1COCC1>CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16]([NH:23][CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cnc(Cl)c(Br)c2)c(SC)s1
Reactant: NCc1cccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(S(=O)(=O)c2cnc(NCc3cccnc3)c(Br)c2)c(SC)s1

Procedure:
The reaction was conducted following the procedure for Example 162: step a, using 4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (0.100 g, 0.226 mmol), (Example 2: step c), 3-aminomethyl pyridine (0.046 g, 0.430 mmol), THF [4.0 mL]. Chromatography of the residue (25%–50% EtOAc/Hx) yielded the title compound. ESI-MS (m/z): Calcd. for C18H16BrN3O4S3: 515.44 (M+H); found 514.1, 516.0.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[NH2:12][C:13]1[C:14]([C:18]2[N:19]([CH2:34][CH3:35])[C:20]3[C:25]([C:26](N4C=CN=C4)=[O:27])=[CH:24][N:23]=[CH:22][C:21]=3[N:33]=2)=[N:15][O:16][N:17]=1>CN(C=O)C>[NH2:12][C:13]1[C:14]([C:18]2[N:19]([CH2:34][CH3:35])[C:20]3[C:25]([C:26]([N:1]4[CH2:5][CH2:4][CH2:3][C@H:2]4[CH2:6][N:7]4[CH2:11][CH2:10][CH2:9][CH2:8]4)=[O:27])=[CH:24][N:23]=[CH:22][C:21]=3[N:33]=2)=[N:15][O:16][N:17]=1
Reactant: CCn1c(-c2nonc2N)nc2cncc(C(=O)n3ccnc3)c21
Reactant: C1CN[C@H](CN2CCCC2)C1
Solvent: CN(C)C=O
Product: CCn1c(-c2nonc2N)nc2cncc(C(=O)N3CCC[C@H]3CN3CCCC3)c21
Yield: 43.2 %

Procedure:
A mixture of (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (0.142 g; 0.93 mmol) and the product from Step 1 (0.1 g; 0.31 mmol) in DMF (2 ml) was warmed at 60° C. for 18 h. The cooled mixture was partitioned between water (10 ml) and ethyl acetate (3×10 ml). The combined organic extracts were washed with brine (2×20 ml), dried over anhydrous sodium sulphate, filtered and evaporated to give a colourless gum. The crude material was purified by preparative HPLC using Dynamax C18 column, 8 micron particle size; 250 mm×41.4 mm i.d.; 10-90% acetonitrile/water (0.1% TFA); 70 ml/min; UV detection at 254 nm) to afford the title compound, (0.055 g, 28%); MS (ES+) m/e 411 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2Br)=[CH:8][C:7]=1[CH3:20].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:24]=1>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:21])=[C:7]([CH3:20])[CH:8]=2)=[C:25]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:24]=1
Reactant: COC(=O)CCc1ccc(Oc2ccccc2Br)cc1C
Reactant: Oc1ccc(Cl)cc1Oc1ccccc1
Product: Cc1cc(Oc2ccccc2Oc2ccc(Cl)cc2Oc2ccccc2)ccc1CCC(=O)O

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(2-bromo-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with 4-chloro-2-phenoxy-phenol as in Example 18 to afford 0.039 g (8%). 1H NMR (400 MHz, CDCl3); MS (ES−) m/z mass calculated for C28H23O5Cl 474, found 473 and 475 (M−1, and M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:19])([CH3:18])[CH2:14][N:15]([CH3:17])[CH3:16])[C:10](=[O:20])[C@@H:9]([CH2:21][C:22]([O:24]CC)=[O:23])[O:8][C@H:7]([C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][CH:28]=3)[C:6]=2[CH:37]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:18])([CH3:19])[CH2:14][N:15]([CH3:16])[CH3:17])[C:10](=[O:20])[C@@H:9]([CH2:21][C:22]([OH:24])=[O:23])[O:8][C@H:7]([C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][CH:28]=3)[C:6]=2[CH:37]=1
Reactant: CCOC(=O)C[C@H]1O[C@H](c2cccc3ccccc23)c2cc(Cl)ccc2N(CC(C)(C)CN(C)C)C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CN(C)CC(C)(C)CN1C(=O)[C@@H](CC(=O)O)O[C@H](c2cccc3ccccc23)c2cc(Cl)ccc21
Temperature: 25 °C
Yield: 76.9 %

Procedure:
Ethyl trans-7-chloro-5-(1-naphthyl)-1-(2,2-dimethyl-3-dimethylamino-propyl)-2- oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate (212 mg, 0.41 mmol) and potassium carbonate (112 mg, 0.83 mmol) were stirred in a mixture of MeOH (8 ml) and water (2.5 ml) for 18 hours at 60° C. The mixture was cooled to room temperature, acidified to pH 2 with 2N HCl and extracted several times with ethyl acetate. The combined organic layers were dried with MgSO4. The filtrate was concentrated under reduced pressure to give the title compound (156 mg, 76%).