Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:32])([CH3:31])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[C:24]([N+:27]([O-])=O)[CH:25]=[CH:26][C:19]=2[NH:18][C:17]1=[O:30])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>CO.[Zn]>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:32])([CH3:31])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[C:24]([NH2:27])[CH:25]=[CH:26][C:19]=2[NH:18][C:17]1=[O:30])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2cc([N+](=O)[O-])ccc2NC1=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2cc(N)ccc2NC1=O
Yield: 85.4 %

Procedure:
To a solution of 310 mg (0.73 mmol) 2-benzyloxycarbonylamino-2-methyl-N-[7-nitro-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]propanamide (Step B) in 20 mL of methanol was added 78 mg (1.5 mmol) of ammonium chloride followed by 669 mg (10.2 mmol) of zinc dust. The resulting mixture was heated at reflux for four hours. The solids were removed by filtration through Celite. The filter pad was washed with 30 mL of hot methanol. The filtrate was combined and the solvent was removed under vacuum. The residue was dissolved in 10 mL of 1N aqueous hydrochloric acid and the solids were filtered away. To the resulting solution was added sufficient 5N aqueous sodium hydroxide until the pH was approximately 12. The solution was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water then brine, dried over magnesium sulfate and filtered. The solvent was removed under vacuum to afford 256 mg (85%) of the product as a white solid. 1H NMR (400 MHz, CDCl3): δ 1.48 (s, 3H), 1.50 (s, 3H), 1.78 (m, 1H), 2.47 (m, 1H), 2.71 (m, 1H), 2.82 (m, 1H), 3.67 (s, 2H), 4.44 (m, 1H), 5.05 (s, 2H), 5.39 (s, 1H), 6.50 (m, 2H), 6.74 (d, 8 Hz, 1H), 7.04 (d, 7 Hz, 1H), 7.32 (m, 6H). FAB-MS: calculated for C22H26N4O4 410; found 411 (M+H, 100%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:36][CH2:35][CH2:34][C:10]2([CH2:15][N:14]([C:16]3[CH:17]=[C:18]([CH3:33])[C:19]4[N:23]=[C:22]([C:24]5[C:25](=[O:31])[NH:26][CH:27]=[CH:28][C:29]=5Cl)[NH:21][C:20]=4[CH:32]=3)[CH2:13][CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:37][CH2:38][C@H:39]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[CH:42]=1)[OH:40].CCN(CC)CC>CCO>[CH2:1]([N:8]1[CH2:36][CH2:35][CH2:34][C:10]2([CH2:15][N:14]([C:16]3[CH:17]=[C:18]([CH3:33])[C:19]4[N:23]=[C:22]([C:24]5[C:25](=[O:31])[NH:26][CH:27]=[CH:28][C:29]=5[NH:37][CH2:38][C@H:39]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[CH:42]=5)[OH:40])[NH:21][C:20]=4[CH:32]=3)[CH2:13][CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(N2CCCC3(CCCN(Cc4ccccc4)C3)C2)cc2[nH]c(-c3c(Cl)cc[nH]c3=O)nc12
Reactant: NC[C@@H](O)c1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(N2CCCC3(CCCN(Cc4ccccc4)C3)C2)cc2[nH]c(-c3c(NC[C@@H](O)c4cccc(Cl)c4)cc[nH]c3=O)nc12
Yield: 36.9 %

Procedure:
A solution of 3-[6-(8-benzyl-2,8-diaza-spiro[5.5]undec-2-yl)-4-methyl-1H-benzoimidazol-2-yl]-4-chloro-1H-pyridin-2-one (17 mg, 0.034 mmol), (S)-2-amino-1-(3-chlorophenyl)-ethanol (29 mg, 0.17 mmol) and Et3N (34 mg, 0.34 mmol) in EtOH (0.5 mL) was heated at 80° C. for 16 h and then the reaction mixture was evaporated. The residue was purified by chromatography (25:1 CH2Cl2/MeOH) to afford the title compound (8 mg, 64%). 1H NMR (MeOH-d4) δ 1.28 (m, 2H), 1.50-1.83 (4H), 2.07-2.27 (2H), 2.48-2.61 (2H), 2.54 (s, 3H), 2.82-2.94 (2H), 3.041-3.23 (2H), 3.40-3.55 (2H), 3.59-3.73 (2H), 4.75 (m, 1H), 4.98 (m, 1H), 6.20 (d, J=6 Hz, 1H), 6.75 (s, 1H), 6.84 (s, 1H), 7.19-7.32 (8H), 7.35-7.42 (2H), 7.54 (s, 1H). ESI-MS m/z 637 (MH+).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16]#[N:17])=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][C:3]=1[F:18].[CH3:19][Zn]C.C1(C)C=CC=CC=1>O1CCOCC1>[CH:11]1([N:8]2[C:9]3[C:5](=[CH:4][C:3]([F:18])=[C:2]([CH3:19])[CH:10]=3)[C:6]([C:16]#[N:17])=[CH:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C[Zn]C
Reactant: N#Cc1cn(C2CCCC2)c2cc(Br)c(F)cc12
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1cc2c(cc1F)c(C#N)cn2C1CCCC1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
Into a solution of 6-bromo-1-cyclopentyl-5-fluoro-1H-indole-3-carbonitrile (6.6 g, 21.5 mmol) and PdCl2dppf (0.31 g, 0.43 mmol) in dioxane (45 mL) was added a solution of dimethylzinc in toluene (1.2 M, 35.8 mL, 43 mmol). The atmosphere was replaced with nitrogen. The mixture was stirred at 90° C. for 90 min and then cooled to room temperature. The reaction was quenched by careful addition of methanol. Ethyl acetate (200 mL) was added and the mixture washed with aq. 2 N HCl, water and brine, dried over Na2SO4 and concentrated. The residue was purified on silica gel eluting with a gradient of 5 to 35% ethyl acetate in hexane to provide 1-cyclopentyl-5-fluoro-6-methyl-1H-indole-3-carbonitrile (4.4 g, 85%)
Reaction SMILES: [C:1]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:17](Cl)=[O:18])[CH:11]=[CH:10]2)(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:20][CH:21]([C:29]([F:32])([F:31])[F:30])[C:22]([F:28])([F:27])[S:23]([O-:26])(=[O:25])=[O:24].[C:33]1([S+:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[F:28][C:22]([F:27])([S:23]([O-:26])(=[O:24])=[O:25])[CH:21]([O:20][C:17]([C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[CH:15][CH:16]=[C:7]([O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])[CH:8]=2)[CH:13]=1)=[O:18])[C:29]([F:30])([F:32])[F:31].[C:46]1([S+:39]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: C=C(C)C(=O)Oc1ccc2cc(C(=O)Cl)ccc2c1
Reactant: O=S(=O)([O-])C(F)(F)C(O)C(F)(F)F
Agent: Cl
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)Oc1ccc2cc(C(=O)OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-])ccc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 3.0 g (11 mmol) of the resulting 6-methacryloyloxynaphthalene-2-carboxylic acid chloride were added 4.9 g (10 mmol) of triphenylsulfonium 2-hydroxy-1,1,3,3,3-pentafluoropropane-1-sulfonate in Synthesis Example 1-11 and 20 g of methylene chloride, which was ice cooled. To the solution, a solution of 1.1 g (11 mmol) of triethylamine and 0.2 g (2 mmol) of N,N-dimethylaminopyridine in 5 g of methylene chloride was added such that the temperature might not exceed 5° C., followed by stirring at room temperature for 3 hours. Thereafter, 11 g of 5% dilute hydrochloric acid was added. The organic layer was separated and washed with water whereupon methylene chloride was distilled off under vacuum. The residue was combined with 30 g of methyl isobutyl ketone and washed with dilute aqueous ammonia and then with water, whereupon the methyl isobutyl ketone was distilled off under vacuum. The residue was washed with diisopropyl ether and purified by silica gel chromatography. The target compound, triphenylsulfonium 1,1,3,3,3-pentafluoro-2-(6-methacryloyloxy-naphthalene-2-carbonyloxy)-propane-1-sulfonate was obtained as colorless solid (6.5 g, yield 89%). The compound has the following structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=O)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:64][C:65]1[S:66][CH:67]=[CH:68][N:69]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:18]([CH3:22])([CH3:23])[C:19]([NH:64][C:65]4[S:66][CH:67]=[CH:68][N:69]=4)=[O:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Nc1nccs1
Reactant: CC(C)(C(=O)O)C(Cc1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
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: CN(C)C=O
Product: CC(C)(C(=O)Nc1nccs1)C(Cc1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40 %

Procedure:
To a stirred solution of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-4-phenylbutanoic acid (10 mg, 0.025 mmol) and diisopropylethylamine (0.05 mL) in anhydrous DMF (0.2 mL) was added HATU (25 mg, 0.066 mmol) at rt under argon. After stirring at rt for 10 min, 2-aminothiazole (15 mg, 0.15 mmol) was added. The reaction mixture was stirred at rt for 2.5 hr, 40° C. for 1 hr, and 80° C. for 30 min. Purification using reverse phase HPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA) gave 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-4-phenyl-N-(thiazol-2-yl)butanamide (Example 138, 7 mg, 0.01 mmol, 40% yield) as a white solid. MS found: (M+H)+=485. 1H-NMR (400 MHz, CDCl3) δ ppm 8.00 (1H, s) 7.53-7.58 (3H, m) 7.44 (1H, d, J=8.65 Hz) 7.35 (1H, d, J=3.56 Hz) 7.23 (1H, d, J=7.63 Hz) 7.11-7.15 (2H, m) 6.89-6.99 (7H, m) 3.63 (1H, dd, J=10.43, 4.32 Hz) 2.97-3.08 (2H, m) 1.37 (3H, s) 1.18 (3H, s).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10](=[O:12])[CH3:11])=[N:2]1.Br[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:21])[O:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[C:10]([C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:1]([CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:21])[O:19][CH3:20])[N:2]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)c1n[nH]c2ncccc12
Reactant: COC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)NCCCn1nc(C(C)=O)c2cccnc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1-(1H-pyrazolo[3,4-b]pyridin-3-yl)ethanone (500 mg) and methyl (3-bromopropyl)carbamate (912 mg) in N,N-dimethylformamide (5 mL) was added potassium carbonate (864 mg), and the mixture was stirred at room temperature for 3 days. To the reaction solution was added ethyl acetate, and the mixture was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=95/5→1/1) to give methyl [3-(3-acetyl-1H-pyrazolo-[3,4-b]pyridin-1-yl)propyl]carbamate) [REx(103-2)] (308 mg) as a red oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([O:12][CH2:13][CH2:14]Br)(=[O:11])[CH3:10].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.CCOC(C)=O>[CH2:13]([O:12][C:9](=[O:11])[CH2:10][O:8][C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:14]
Reactant: Oc1ccc(Cl)nc1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)COc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a suspension of 6-chloro-pyridin-3-ol (1000 mg, 7.72 mmol) and bromoethyl acetate (1933 mg, 11.57 mmol) in CH3CN was added Cs2CO3 (3772 mg, 11.57 mmol). The mixture was stirred for overnight at room temperature. The reaction mixture was diluted with EtOAc, then washed three times with H2O and brine, and then dried. MgSO4, filtered and concentrated under reduced pressure. The obtained residue was column-chromatographed to yield the (6-chloro-pyridin-3-yloxy)-acetic acid ethyl ester (1.5 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][N:12]=2)[C:5]=1[OH:19].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:25][C@@H:26]1[O:28][CH2:27]1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][N:12]=2)[C:5]=1[O:19][CH2:25][C@H:26]1[CH2:27][O:28]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: COC(=O)c1cccc(Nc2ccc(OC)cn2)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Nc2ccc(OC)cn2)c1OC[C@H]1CO1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.1 %

Procedure:
To a solution of methyl-2-hydroxy-3-(5-methoxypyridin-2-ylamino)benzoate 0.91 g (3.3 mmol) of step 4 in dimethylformamide 10 mL were (R)-glycidyl nosylate 1.0 g (4 mmol) and K2CO3 0.5 g (3.6 mmol), followed by stirring at room temperature for 12 hrs. The reaction mixture was concentrated in a vacuum, diluted with ethylacetate, and washed with distilled water and a saturated NaCl solution. After drying over magnesium sulfate and vacuum concentration, purification by column chromatography (developing solvent: ethylacetate/hexane=1/2) afforded 0.95 g of the title compound (yield 87%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](=[O:26])(=[O:25])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)=[O:4].[NH2:27][CH2:28][C@@H:29]([C:31]1[CH:32]=[CH:33][C:34]([OH:42])=[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=1)[OH:30]>>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:19][CH2:20][CH:21]([NH:27][CH2:28][C@H:29]([OH:30])[C:31]3[CH:32]=[CH:33][C:34]([OH:42])=[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=3)[CH2:22][CH2:23]2)=[CH:16][CH:17]=1)(=[O:25])=[O:26])=[O:4]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: COC(=O)c1sccc1S(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Product: COC(=O)c1sccc1S(=O)(=O)Nc1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from 3-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-thiophene-2-carboxylic acid methyl ester (which was obtained in Example 234) and N-[5-((1 R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 278 as a pale yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 1.20–1.40 (m, 2 H), 1.70–1.90 (m, 2 H), 2.50–2.75 (m, 5 H), 3.40–3.55 (m, 2 H), 3.89 (s, 2 H), 4.46 (dd, J=8.0, 4.2 Hz, 1 H), 6.75–6.85(m, 3 H), 6.90 (d, J=9.0 Hz, 2 H), 7.00 (dd, J=8.3, 2.0 Hz, 1 H), 7.16 (d, J=2.0 Hz, 1 H), 7.32 (d, J=3.3 Hz, 1 H), 7.89 (d, J=3.3 Hz, 1 H); MS (ES) m/z: 624.9 (MH+); HRMS Calcd. for C26H34N4O8S3 (MH+): 625.1455. Found: 625.1441.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][C:10]3[CH:14]=[C:15]([S:18](Cl)(=[O:20])=[O:19])[CH:16]=[CH:17][C:9]2=3)=[C:4]([C:22]#[N:23])[CH:3]=1.[F:24][C:25]1[C:30]([OH:31])=[C:29]([F:32])[C:28]([F:33])=[C:27]([F:34])[C:26]=1[F:35].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][C:10]3[CH:14]=[C:15]([S:18]([O:31][C:30]4[C:29]([F:32])=[C:28]([F:33])[C:27]([F:34])=[C:26]([F:35])[C:25]=4[F:24])(=[O:20])=[O:19])[CH:16]=[CH:17][C:9]2=3)=[C:4]([C:22]#[N:23])[CH:3]=1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: N#Cc1cc(Cl)ccc1N1CCOc2cc(S(=O)(=O)Cl)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cc(Cl)ccc1N1CCOc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
To a solution of 4-(4-chloro-2-cyanophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (480 mg, 1.30 mmol) in DCM (5 mL) was added pentafluorophenol (240 mg, 1.30 mmol) at 0° C. Triethylamine (0.27 mL, 1.95 mmol) was added at 0° C. and the reaction mixture was stirred at room temperature for 1 h. After completion, the reaction mixture was diluted with DCM (3 mL) and concentrated under reduced pressure. The crude mass was purified by combi flash column chromatography (12 g column; elution: 7% ethyl acetate in hexane) to provide perfluorophenyl 4-(4-chloro-2-cyanophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate (370 mg, 54.9%) as clear liquid. 1H NMR (400 MHz, DMSO) δ 8.22 (d, J=2.5 Hz, 1H), 7.96 (dd, J=8.7, 2.5 Hz, 1H), 7.70 (d, J=8.7 Hz, 1H), 7.38 (d, J=2.2 Hz, 1H), 7.31 (dd, J=8.7, 2.3 Hz, 1H), 6.59 (d, J=8.7 Hz, 1H), 4.41 (s, 2H), 3.86 (s, 2H); LCMS (ESI) m/z; 516.02 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[N:12][C:11]([C:14](N)=[O:15])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH-].[Na+].C([O-])(O)=[O:20].[Na+]>Cl>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[N:13]=[N:12][C:11]([C:14]([OH:15])=[O:20])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc(C(N)=O)nn2)CC1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN1CCN(c2ccc(C(=O)O)nn2)CC1
Temperature: 25 °C

Procedure:
A suspension of 6-(4-methylpiperazin-1-yl)pyridazine-3-carboxamide (221 mg, 1.00 mmol) in sodium hydroxide (2.0M aqueous) (10.000 mL, 20.00 mmol), was stirred at reflux for 3 h and then allowed to cool to room temperature. The reaction mixture was adjusted to pH7 by addition of 2M HCl (10 mL) and saturated NaHCO3. The crude product was purified by ion exchange chromatography, using a SCX2 column. The desired product was eluted from the column using methanol and the fractions were evaporated to dryness to afford 6-(4-methylpiperazin-1-yl)pyridazine-3-carboxylic acid as a white solid. This material was suspended in methanol (10.00 ml) at 0° C. and treated with thionyl chloride (0.729 ml, 10.00 mmol), over a period of 5 mins. The resulting suspension was stirred at ambient temperature for 18 h. Sodium bicarbonate solution was added until basic and then the mixture was extracted with ethyl acetate (2×75 mL). The solution was further extracted with 1-butanol (100 mL). The organic extracts were combined and evaporated to dryness to give methyl 6-(4-methylpiperazin-1-yl)pyridazine-3-carboxylate a white solid, 212 mg.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[C:25]1([C:31]2[NH:32][CH:33]=[CH:34][N:35]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:32]3[CH:33]=[CH:34][N:35]=[C:31]3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[CH:8][CH:9]=1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Reactant: Cc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1OCCCc1oc(-n2ccnc2-c2ccccc2)nc1-c1ccc(Cl)cc1
Temperature: 125 °C
Reaction time: 1 h

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methylphenoxy)propyl]oxazole (1.00 g), 2-phenylimidazole (432 mg), potassium carbonate (1.38 g) and N,N-dimethylformamide (10 ml) was stirred at 120-130° C. for 1 hour. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (10 ml×2). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and 4-(4-chlorophenyl)-5-[3-(2-methylphenoxy)propyl]-2-(2-phenyl-1-imidazolyl)oxazole was obtained as an oil (512 mg, 39%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction.
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)[N:8]3[CH2:21][CH2:22][N:23]=[C:7]3[C:6]=2[CH:5]=[CH:4][C:3]=1[O:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.Cl[CH2:35][CH2:36][CH2:37][S:38]([N:41]1[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]1)(=[O:40])=[O:39]>>[CH3:47][N:44]1[CH2:43][CH2:42][N:41]([S:38]([CH2:37][CH2:36][CH2:35][O:1][C:2]2[C:11]3[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]4[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=4)[N:8]4[CH2:21][CH2:22][N:23]=[C:7]4[C:6]=3[CH:5]=[CH:4][C:3]=2[O:24][CH2:25][CH2:26][CH2:27][N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)(=[O:40])=[O:39])[CH2:46][CH2:45]1
Reactant: O=C(NC1=Nc2c(ccc(OCCCN3CCOCC3)c2O)C2=NCCN12)c1cccnc1
Reactant: CN1CCN(S(=O)(=O)CCCCl)CC1
Product: CN1CCN(S(=O)(=O)CCCOc2c(OCCCN3CCOCC3)ccc3c2N=C(NC(=O)c2cccnc2)N2CCN=C32)CC1

Procedure:
The procedure used for the preparation of Example 1 was used to prepare the title compound from N-[7-hydroxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide (Intermediate H) and 1-[(3-chloropropyl)sulfonyl]-4-methylpiperazine (Intermediate D). High vacuum drying gave the title compound (29 mg, 27%): HPLC MS RT=0.23 min, MH+=655.6; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.22-2.27 (4H, m), 2.82 (3H, s), 3.09-3.18 (6H, m), 3.29-3.32 (2H, m), 3.45-3.52 (6H, m), 3.64-3.70 (2H, m), 3.77-3.80 (2H, m), 3.99-4.01 (2H, m), 4.24-4.29 (2H, m), 4.32-4.36 (4H, m), 4.55-4.60 (2H, m), 7.49 (1H, d), 7.90 (1H, dd), 8.09 (1H, d), 8.83 (1H, d), 8.98 (1H, dd), 9.47 (1H, d).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:8][CH:7]=1.[C:37](Cl)(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]>>[CH3:39][C:38]([CH3:41])([CH3:40])[C:37]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14][CH:13]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:8][CH:7]=1)=[O:42]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: CC(C)(C)C(=O)Cl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOC(=O)C(C)(C)C)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22(k), by acylating tert-butyl (3RS,4RS)-4-[4-(3-hydroxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with pivaloyl chloride there was obtained tert-butyl (3RS,4RS)-4-[4-[3-(2,2-dimethyl-propionyloxy)-propoxy]-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 576 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[N:10]=2)=[O:7])=[CH:4][C:3]=1[N+:19]([O-])=O.[H][H]>[Pt].C(OCC)(=O)C.C(O)C>[NH2:19][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:2]=1[NH2:1])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[N:10]=1)=[O:7]
Reactant: Cc1ccc(NC(=O)c2ccc(N)c([N+](=O)[O-])c2)nc1C
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)c2ccc(N)c(N)c2)nc1C

Procedure:
A mixture of 4-amino-N-(5,6-dimethylpyridin-2-yl)-3-nitrobenzamide (470 mg, 1.64 mmol) and of 5% platinum on carbon (60 mg) in 50 mL of ethyl acetate/ethanol (1:1) was stirred in under a hydrogen balloon. When the reaction was complete by LC/MS, the mixture was filtered through Celite to remove catalyst, and the filtrate was removed under reduced pressure to afford 3,4-diamino-N-(5,6-dimethylpyridin-2-yl)-benzamide.
Reaction SMILES: [CH2:1]([S:3]/[C:4](/[O:7][Si](C)(C)C)=[CH:5]/[CH3:6])[CH3:2].[C:12]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:15])[CH:13]=[O:14].Cl.CO>C1(C)C=CC=CC=1>[CH2:1]([S:3][C:4](=[O:7])[CH:5]([CH3:6])[CH:13]([OH:14])[C:12]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])[CH3:2]
Reactant: CCCCOC(=O)C=O
Reactant: C/C=C(\O[Si](C)(C)C)SCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCCOC(=O)C(O)C(C)C(=O)SCC
Temperature: 0 °C
Yield: 64 %

Procedure:
0.5 ml (0.1 mmol) of (R)-1 solution prepared in the same manner as in Example 1 were cooled to 0° C., and 190 mg (1 mmol) of (E)-1-ethylthio-1-trimethylsilyloxy-1-propene (77% E) and subsequently 130 mg (1 mmol) of freshly distilled butyl glyoxylate and 0.5 ml of toluene were added thereto, followed by allowing the mixture to react at 0° C. for 0.5 hour. The resulting mixture was poured into 10% hydrochloric acid-methanol cooled at 0° C. The solution was filtered through a pad of Celite, and the filtrate was extracted three times with a 5 ml portion of diethyl ether. The combined organic layer was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate and evaporated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=15/1 by volume) to obtain 158 mg (yield 64%) of n-butyl 4-ethylthio-2-hydroxy-3-methyl-4-oxobutyrate.