Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[O:10][C:6]=2[CH:5]=[C:4]([CH2:19][C:20](O)=[O:21])[CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.FC(F)(F)C(O)=O.[CH3:54][O:55][C:56](=[O:71])[CH2:57][C:58]1([C:64]2[CH:69]=[CH:68][C:67]([NH2:70])=[CH:66][CH:65]=2)[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1>CN(C)C=O.C(N(C(C)C)CC)(C)C>[CH3:54][O:55][C:56](=[O:71])[CH2:57][C:58]1([C:64]2[CH:65]=[CH:66][C:67]([NH:70][C:20](=[O:21])[CH2:19][C:4]3[CH:3]=[C:2]([CH3:1])[C:7]4[N:8]=[C:9]([NH:11][C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=5[CH3:18])[O:10][C:6]=4[CH:5]=3)=[CH:68][CH:69]=2)[CH2:59][CH2:60][O:61][CH2:62][CH2:63]1
Reactant: Cc1ccccc1Nc1nc2c(C)cc(CC(=O)O)cc2o1
Reactant: COC(=O)CC1(c2ccc(N)cc2)CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CC1(c2ccc(NC(=O)Cc3cc(C)c4nc(Nc5ccccc5C)oc4c3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
A stirred solution of (4-methyl-2-o-tolylamino-benzoxazol-6-yl)-acetic acid [0.44 g, prepared according to the procedure described in International Patent Application No. WO00/61580 for Reference Example 9] in dry dimethylformamide (10 mL), under argon, was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.8477 g) and then with diisopropylethylamine (1.05 mL). After stirring at room temperature for 10 minutes the bright yellow solution was added to a solution of [4-{4-amino-phenyl}-tetrahydro-pyran-4-yl]-acetic acid methyl ester trifluoroacetate (0.444 g, Reference Example 18) in a mixture of dimethylformamide (8 mL) and diisopropylethylamine (1.05 mL). The mixture was stirred at room temperature under argon overnight and then evaporated to low bulk. The residue was dissolved in ethyl acetate and this solution was washed with water, then with aqueous sodium bicarbonate solution, and then with water and then evaporated. The residue was subjected to reverse phase HPLC on a Hypersil Elite C18 column using as the mobile phase a mixture of acetonitrile, water and trifluoroacetic acid (35:65:0.1, v/v/v) followed by a 1% acetonitrile/minute gradient to give the title compound (0.178 g, approximately 90% purity) which was used without further purification. LC-MS: RT=3.71 minutes, MS(ES+): 528(M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]2[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[C:4]([CH2:13][NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH:3]=1.[CH2:19]([N:26]1[CH2:30][CH2:29][CH:28]([C:31]([OH:33])=O)[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.C(N=C=NCCCN(C)C)C.CC1C=CN=C(N)C=1C>ClCCl.O>[CH2:19]([N:26]1[CH2:30][CH2:29][CH:28]([C:31]([N:14]([CH2:13][C:4]2[CH:3]=[CH:2][C:7]3[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=3[CH:5]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:33])[CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)C1CCN(Cc2ccccc2)C1
Reactant: CC(C)CNCc1cc(Cl)c2c(c1)OCCCO2
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccnc(N)c1C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)CN(Cc1ccc2c(c1)OCCCO2)C(=O)C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The above amine product, N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-2-methylpropan-1-amine (807 mg, 3 mmole) was combined with 1-Benzyl-pyrrolidine-3-carboxylic acid (615 mg, 3 mmole) in 50 ml dichloromethane. 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (764 mg, 4 mmole) and dimethyl aminopyridine (562 mg, 4 mmole) were added. The reaction solution was stirred at room temperature overnight. 50 ml of water was added and the mixture was extracted with 50 ml ethyl acetate three times. The organic layer was washed with saturated sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was purified by column chromatography using 50-75% ethyl acetate in hexane. MS (m+1)=457.3; H NMR (500 MHz, CDCl3) 0.95 (m, 6H), 2.00 (m, 1H), 2.05 (m, 1H), 2.15 (m, 1H), 2.25 (m, 1H), 2.55 (m, 1H), 2.65 (m, 1H), 2.90 (m, 1H), 3.00 (m, 1H), 3.10 (d, 1H), 3.15 (m, 1H), 3.25 (d, 1H), 3.40 (m, 1H), 3.75 (m, 2H), 4.30 (m, 4H), 4.45 (s, 1H), 4.55 (d, 1H), 6.6-7.0 (m, 2H), 7.2-7.5 (m, 5H).
Reaction SMILES: [OH-].[Li+].[Si:3]([O:10][C@@H:11]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:28]=[CH:27][C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>C1COCC1.CO.O>[Si:3]([O:10][C@@H:11]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:28]=[CH:27][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)[CH2:16][CH2:17]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: CCOC(=O)c1ccc(N2CCC([C@@H](O[Si](C)(C)C(C)(C)C)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
Lithium hydroxide (1.42 g, 59.29 mmol) was added to a mixture of (R)-ethyl 4-(4-((tert-butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoate (INTERMEDIATE 12, 3.83 g, 6.78 mmol) in THF (27 ml), MeOH (9 ml) and water (1 ml). The resulting mixture was stirred at room temperature overnight and then the volatiles were removed under reduced pressure. The concentrate was purified by column chromatography (ISCO, 80 g silica column, eluting with 0→80% EtOAc/hexanes) to give the title product (3.24 g, yield: 89%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[CH3:41][C:42]1[C:51]2[C:46](=[CH:47][C:48]([C:52]([F:55])([F:54])[F:53])=[CH:49][CH:50]=2)[NH:45][C:44](=[O:56])[C:43]=1[C:57](O)=[O:58]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][NH:6][C:57]([C:43]2[C:44](=[O:56])[NH:45][C:46]3[C:51]([C:42]=2[CH3:41])=[CH:50][CH:49]=[C:48]([C:52]([F:54])([F:55])[F:53])[CH:47]=3)=[O:58])[CH:7]=[CH:8][CH:9]=1
Reactant: NCc1cccc(F)c1
Reactant: Cc1c(C(=O)O)c(=O)[nH]c2cc(C(F)(F)F)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)NCc2cccc(F)c2)c(=O)[nH]c2cc(C(F)(F)F)ccc12
Temperature: 50 °C
Reaction time: 16 h
Yield: 83.6 %

Procedure:
926 mg (7.4 mmol) 3-Fluorobenzylamine, 2.55 g (6.7 mol) HATU and 2.7 ml (19.5 mmol) NEt3 were added to a solution of 1.82 g (6.7 mmol) 4-methyl-2-oxo-7-(trifluoromethyl)-1H-quinoline-3-carboxylic acid in THF (50 ml). The RS was stirred at 50° C. for 16 h and was then diluted with EtOAc (50 ml) at RT. The resulting precipitate was filtered off and dried in vacuo to give 2.10 g (5.6 mmol, 83%) N-[(3-Fluorophenyl)-methyl]-4-methyl-2-oxo-7-(trifluoromethyl)-1H-quinoline-3-carboxylic acid amide, which was used in the next step without further purification.
Reaction SMILES: CCN(C(C)C)C(C)C.CCCCCC.C([Li])CCC.[Br:21][C:22]1[CH:23]=[C:24]([F:30])[C:25]([O:28][CH3:29])=[N:26][CH:27]=1.[CH:31]1([CH:36]=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1.[Cl-].[NH4+]>C1COCC1>[Br:21][C:22]1[C:23]([CH:36]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[OH:37])=[C:24]([F:30])[C:25]([O:28][CH3:29])=[N:26][CH:27]=1
Reactant: O=CC1CCCC1
Reactant: COc1ncc(Br)cc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ncc(Br)c(C(O)C2CCCC2)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 29.1 %

Procedure:
To a solution of DIEA (0.827 mL) in THF (90 mL) was added 1.6 M n-butyllithium hexane solution (3.64 mL) at −78° C., and the mixture was stirred under argon atmosphere at −78° C. for 30 min. To the reaction mixture was added a solution of 5-bromo-3-fluoro-2-methoxypyridine (1.00 g) in THF (30 mL) at −78° C., and the mixture was stirred under argon atmosphere at −78° C. for 1 hr. To the reaction mixture was added cyclopentanecarbaldehyde (0.572 g) at −78° C., and the mixture was stirred under argon atmosphere at −78° C. for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution at −78° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (430 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[CH:5]=O.[CH3:12][C:13](=[O:18])[CH2:14][C:15](=[O:17])[CH3:16].N1CCCCC1>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:14]([C:13](=[O:18])[CH3:12])[C:15](=[O:17])[CH3:16])[CH:7]=[C:8]([F:11])[C:9]=1[F:10]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: CC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CC(=O)C(=Cc1cc(F)c(F)c(F)c1)C(C)=O

Procedure:
A stirring mixture of 3,4,5-trifluorobenzaldehyde (4.2 g, 26.2 mmol), 2,4-pentanedione (2.62 g, 26.2 mmol), piperidine (0.430 g, 5 mmol) in benzene (150 mL) was heated at reflux temperature (equipped with a Dean-Stark trap) for 8 h. The benzene was evaporated, the yellow oily residue, 2-{(3,4,5-trifluorophenyl)-methylene}-2,4-pentanedione, was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH3:19][C:20]1[CH:33]=[CH:32][C:23]([C:24]([NH:26][N:27]2[NH:31][CH:30]=[CH:29][S:28]2)=[O:25])=[CH:22][C:21]=1B1OC(C)(C)C(C)(C)O1>>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:17]=[CH:18][C:2]([C:21]3[CH:22]=[C:23]([C:24](=[O:25])[NH:26][N:27]4[NH:31][CH:30]=[CH:29][S:28]4)[CH:32]=[CH:33][C:20]=3[CH3:19])=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc(NC(=O)c2ccc(Cl)nc2)cc1
Reactant: Cc1ccc(C(=O)NN2NC=CS2)cc1B1OC(C)(C)C(C)(C)O1
Product: COc1ccc(NC(=O)c2ccc(-c3cc(C(=O)NN4NC=CS4)ccc3C)nc2)cc1

Procedure:
N-(4-Methoxyphenyl)-6-[2-methyl-5-(thiadiazol-2-ylcarbamoyl)-phenyl]-nicotinamide was prepared from 6-chloro-N-(4-methoxyphenyl)nicotinamide (Intermediate 2) and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide (Intermediate 12) using General Method B. LCMS: retention time 3.05 min, MH− 446. NMR: δH [2H6]-DMSO 13.15, (1H, b), 10.41, (1H, s), 9.24, (2H, m), 8.45, (1H, dd), 8.28, (1H, s), 8.11, (1H, d), 7.88, (1H, d), 7.71, (2H, d), 7.56, (1H, d), 6.97, (2H, d), 3.76, (3H, s), 2.48, (3H, s).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:8]=2)[N:3]=1.CC(=CC)C.Cl([O-])=[O:29].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O>[C:19]([O:18][C:16](=[O:17])[CH2:15][O:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([Cl:1])[C:11]([C:12]([OH:29])=[O:13])=[CH:10]2)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)COc1ccc2nc(Cl)c(C=O)cc2c1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)COc1ccc2nc(Cl)c(C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a suspension of tert-butyl 2-(2-chloro-3-formylquinolin-6-yloxy)acetate (3.6 g, 11 mmol) in tert-butanol (150 mL) was added 2-methyl-2-butene (14.9 mL, 133 mmol) and a solution of sodium chlorite (8.27 g, 73.1 mmol) and sodium dihydrogenphosphate (8.10 g, 58.7 mmol) in water (50 mL). The reaction was allowed to stir at room temperature for 1 hour. The tert-butanol was removed in vacuo. The mixture was diluted with water (60 mL) and acidified to pH=4 with 1 N aqueous hydrochloric acid. The resulting precipitate was filtered, washed with water, and dried under vacuum to give the title compound (3.7 g, 100%) as a white solid. +ESI (M+H) 338.1; 1H NMR (400 MHz, CD3OD, δ): 8.69 (s, 1 H), 7.89 (d, J=9.19 Hz, 1 H), 7.56 (dd, J=9.19, 2.74 Hz, 1 H), 7.34 (d, J=2.93 Hz, 1 H), 4.76 (s, 2 H), 1.49 (s, 9 H).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:14]([CH:26]([C:37]([CH3:39])=[CH2:38])[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[C:13]1=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].O(Cl)[Cl:47].O>C(OCCOCC)(=O)C.C(Cl)(Cl)(Cl)Cl>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:14]([CH:26]([C:37]([CH2:39][Cl:47])=[CH2:38])[C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])[C:13]1=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClOCl
Reactant: C=C(C)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCCOC(C)=O
Solvent: O
Product: C=C(CCl)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 94 %

Procedure:
A 2 g quantity of benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-methyl-3-butenate was dissolved in 12 ml of ethoxyethyl acetate. To the solution was added 6 g of NaHCO3 and the mixture was stirred at room temperature. Thereto was added dropwise over 1 hour 12.1 ml of a 0.285M solution of Cl2O in carbon tetrachloride. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was distilled off at reduced pressure. The resulting residue was separated and purified by silica gel column chromatography, giving 2.0 g of benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-chloromethyl-3-butenate in 94% yield.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][N:12]1[CH2:16][CH2:15][CH2:14][C@@H:13]1[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[CH3:11][N:12]1[CH2:16][CH2:15][CH2:14][C@@H:13]1[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([S:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:35])=[O:34])[CH:19]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC[C@@H]1Cc1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Reaction time: 1 h
Yield: 46.3 %

Procedure:
Sodium bis(trimethylsilyl)amide (0.25 mL, 1M in THF, 0.25 mmol) was added to a solution of (R)-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indole (Example 3e, 25.8 mg, 0.12 mmol) in THF (1.5 mL) at -78° C. and the mixture was stirred for 1 h. Phenylsulfonyl chloride (50 μL, 0.39 mmol) was added and the mixture stirred at room temperature for 1 h. prior to quenching with water (6 drops) and silica gel (~1 g). Purification using solid phase extraction tubes (1000 mg silica) eluting with 2M methanolic ammonia in dichloromethane (0-4%) yielded (R)-3-(1-methyl-2-pyrrolidinylmethyl)-1-phenylsulfonylindole (19.7 mg, 46%, HRMS-FAB+ for C20H22N2O2S: calculated MH+ :355.14801; found MH+ :355.14837).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C@@H:7](O)[CH3:8])=[CH:3][CH:2]=1.C([Li])CCC.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(NC(C)C)(C)C.[CH3:33][C:34]([C:36]12[CH2:45][CH:40]3[CH2:41][CH:42]([CH2:44][CH:38]([CH2:39]3)[CH2:37]1)[CH2:43]2)=[O:35]>C1COCC1.CCCCCC>[C:36]12([C:34](=[O:35])[CH2:33][C@@H:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH3:8])[CH2:43][CH:42]3[CH2:41][CH:40]([CH2:39][CH:38]([CH2:44]3)[CH2:37]1)[CH2:45]2
Reactant: C[C@H](O)c1ccncc1
Reactant: CC(=O)C12CC3CC(CC(C3)C1)C2
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[C@@H](CC(=O)C12CC3CC(CC(C3)C1)C2)c1ccncc1
Yield: 18 %

Procedure:
The method followed that described in Example 9 but using (-)-(S)-1-(4-pyridyl)ethanol (1.84 g, 15.0 mmol) in THF (80 ml), butyllithium (1.6M; 9.4 ml, 15.0 mmol) in hexane, p-toluenesulfonyl chloride (2.86 g, 15.0 mmol), diisopropylamine (6.31 ml, 45.0 mmol) in THF (120 ml), butyllithium (1.6M; 28.12 ml, 45.0 mmol) in hexane and 1-adamantyl methyl ketone (8.0 g, 45 mmol). Chromatography, on elution with petrol-ether-triethylamine 100:50:1 gave the title compound (765 mg, 18%), which crystallised from hexane. m.p. 46°-48° C.; [α]D +6.8° (c 1.0, MeOH). IR, NMR and MS data were the same as given in Example 14.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([F:20])=[CH:15][N:14]=1.O>CN(C=O)C>[Cl:12][C:13]1[N:18]=[C:17]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[C:16]([F:20])=[CH:15][N:14]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Fc1cnc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cnc(Cl)nc1-n1ccc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Indole (1.0 g, 8.54 mmol) was added in portions to a suspension of NaH (0.358 g, 8.96 mmol) in DMF (10 mL) at 0° C. under N2 and stirred for 15 minutes at RT. 2,4-Dichloro-5-fluoro-pyrimidine (1.49 g, 8.96 mmol) was then added in portions and allowed to stir at RT overnight. The reaction mixture was poured into cold water, extracted into DCM, washed in brine, dried with Na2SO4, filtered, and dried in vacuo to obtain an oil. The residue was purified using flash chromatography on a silica column eluting with hexane:EtOAc (1000:25) to (1000:50), to yield 1-(2-chloro-5-fluoro-pyrimidin-4-yl)-1H-indole after drying the collected fraction (0.11 g, 5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH3:13])[CH:7]=[CH:6]2.[CH2:14]([O:16][P:17]([CH2:22][CH2:23][CH2:24][Br:25])(=[O:21])[O:18][CH2:19][CH3:20])[CH3:15].C(OCC)(=O)C>CN(C=O)C>[Br-:25].[CH2:19]([O:18][P:17]([CH2:22][CH2:23][CH2:24][N+:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[CH3:13])([O:16][CH2:14][CH3:15])=[O:21])[CH3:20]
Reactant: COc1ccc2nc(C)ccc2c1
Reactant: CCOP(=O)(CCCBr)OCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOP(=O)(CCC[n+]1c(C)ccc2cc(OC)ccc21)OCC
Product: [Br-]
Temperature: 140 °C
Yield: 67.8 %

Procedure:
A mixture of 6-methoxy-2-methylquinoline (1.0 g, 5.8 mmol) and diethyl-(3-bromopropyl)-phosphonate (1.6 g, 6.4 mmol) was heated in a pressure tube at 140° C. for 16 hours. The mixture was allowed to cool to room temperature, and the resulting mass was dissolved in DMF (4 mL). The combined mixture was then added dropwise to ethyl acetate (40 mL). Precipitated purple solid was collected by centrifugation, washed with ethyl acetate (3×40 mL) and dried under vacuum to yield 1.7 g of Compound 13 which was then used without any further purification. The structure of Compound 13 is given below:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][C:28]4[NH:32][N:31]=[N:30][N:29]=4)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1.[N+](C1C=CC(OC(=O)[NH:59][C:60]2[CH:65]=[CH:64][C:63]([O:66][CH:67]([CH3:69])[CH3:68])=[CH:62][CH:61]=2)=CC=1)([O-])=O>N1C=CC=CC=1>[CH:67]([O:66][C:63]1[CH:64]=[CH:65][C:60]([NH:59][C:6]([N:8]2[CH2:9][CH2:10][CH:11]([C:14]3[C:23]4[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][C:28]5[NH:32][N:31]=[N:30][N:29]=5)=[CH:21][CH:22]=4)[N:17]=[CH:16][N:15]=3)[CH2:12][CH2:13]2)=[O:7])=[CH:61][CH:62]=1)([CH3:69])[CH3:68]
Reactant: CC(C)Oc1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCCc4nnn[nH]4)ccc23)CC1
Solvent: c1ccncc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(NC(=O)N2CCC(c3ncnc4cc(OCCCc5nnn[nH]5)ccc34)CC2)cc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 13.8 %

Procedure:
A solution of 4-{7-[3-(1H-Tetrazol-5-yl)-propoxy]-quinazolin-4-yl}-piperidine-1-carboxylic acid tert-butyl ester (6.1 mg, 14 μmol), as prepared in the previous step, in 9:1 TFA/anisole (100 μL) was stirred at 100° C. for 10 min. The solution was then concentrated. Pyridine (100 μL) and (4-isopropoxy-phenyl)-carbamic acid 4-nitro-phenyl ester (5.8 mg, 18 μmol), as prepared in Example 1a, were added, and the solution was stirred at 80° C. for 15 min. The reaction was concentrated, taken up in 1M NaH2PO4 (2 mL), and extracted with 95:5 DCM/MeOH (2×2 mL). The combined organic layers were dried (Na2SO4), concentrated, and purified by flash silica cartridge chromatography (EtOAc→acetone eluent) to provide the title compound (1.0 mg, 14%). 1H-NMR (400 MHz, 95:5 CDCl3/CD3OD) δ 9.09 (s, 1H), 8.08 (s, 1H), 7.30-7.21 (m, 4H), 6.85 (m, 2H), 4.49 (septet, 1H), 4.27 (m, 2H), 4.24 (t, 2H), 3.70 (tt, 1H), 3.19 (t, 2H), 3.12 (td, 2H), 2.40 (m, 2H), 2.17-1.92 (m, 4H), 1.32 (d, 6H). LC/MS (ESI) calcd mass 516.3, found 517.2 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:11][C:10]3[CH:22]=[CH:23][CH:24]=[N:25][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35].C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH2:15]([C:12]1[C:13](=[O:14])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH:3]=2)[C:9]2[N:25]=[CH:24][CH:23]=[CH:22][C:10]=2[N:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)OC(=O)Cl
Reactant: Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)OC(=O)Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-(3-aminophenyl)-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (192 mg) and triethylamine (0.12 ml) in 1,4-dioxane (4 ml) was added isopropyl chloroformate (0.10 ml). The mixture was stirred at room temperature for 30 minutes, then poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with methanol to give 2-benzyl-4-(3-isopropoxycarbonylaminophenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (167 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2C=O.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[OH:22][NH3+:23].O>C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:6](=[N:23][OH:22])[CH:7]([Cl:12])[CH:8]=[CH:9][C:10]=2[CH:11]=1
Reactant: [NH3+]O
Reactant: O=Cc1c(Cl)ccc2cc(Cl)cnc12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C1c2ncc(Cl)cc2C=CC1Cl
Yield: 101.1 %

Procedure:
22.6 g of 3,7-dichloroquinoline-8-carbaldehyde were dissolved in 300 parts of ethanol, 10.6 g of sodium carbonate and 6.9 g of hydroxylammonium chloride were added to this solution, and the suspension was refluxed for 1 hour. Thereafter, 1,000 g of water were added, and the precipitated solid was filtered off and dried to give 23 g (96% of theory) of 3,7-dichloro-8-hydroxyliminoquinoline of melting point 202° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[S:3]([O:6][CH2:7][CH:8]=[CH2:9])(=[O:5])=[O:4].[CH3:12][O:13][C:14]1[C:15]([O:24][CH3:25])=[CH:16][C:17]2[Te:21][C:20]([CH3:22])=[N:19][C:18]=2[CH:23]=1>C(Cl)(Cl)(Cl)Cl.ClCCl>[F:1][C:2]([F:11])([F:10])[S:3]([O-:6])(=[O:5])=[O:4].[CH3:12][O:13][C:14]1[C:15]([O:24][CH3:25])=[CH:16][C:17]2[Te:21][C:20]([CH3:22])=[N+:19]([CH2:9][CH:8]=[CH2:7])[C:18]=2[CH:23]=1
Reactant: COc1cc2nc(C)[te]c2cc1OC
Reactant: C=CCOS(=O)(=O)C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: C=CC[n+]1c(C)[te]c2cc(OC)c(OC)cc21
Product: O=S(=O)([O-])C(F)(F)F
Reaction time: 7 h

Procedure:
A dried solution of 2-propen-1-yl tri-fluoromethanesulfonate (0.002 mole) in carbon tetrachloride was added dropwise to a solution of 5,6-dimethoxy-2-methylbenzotellurazole (Example 19) (0.50 g, 0.0016 mole) in dichloromethane (25 ml) under a nitrogen atmosphere at room temperature. After the addition was complete, stirring was continued for 7 hours. The solid was isolated by filtration, washed with diethyl ether, and dried at room temperature under vacuum. Yield 0.38 g. A mass spectrogram of the compound was in agreement with that expected for the structural formula.