Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([F:9])[CH:3]=1.[C:10]([O:14][C:15](=[O:31])[CH2:16][N:17]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[N:18]1)([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:10]([O:14][C:15](=[O:31])[CH2:16][N:17]1[CH:21]=[C:20]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:9])[CH:19]=[N:18]1)([CH3:13])([CH3:11])[CH3:12]
Reactant: Fc1cc(Br)ccc1I
Reactant: CC(C)(C)OC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Cn1cc(-c2ccc(Br)cc2F)cn1
Temperature: 80 °C

Procedure:
To a solution of 4-bromo-2-fluoro-1-iodobenzene (380 mg, 1.3 mmol) in THF (10 mL) was added tert-butyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]acetate (390 mg, 1.3 mmol), 2M sodium carbonate in water (2.5 mL) and tetrakis(triphenylphosphine)palladium (40 mg, 0.04 mmol). The solution was degassed with N2, and heated at 80° C. overnight. The mixture was cooled to RT, poured into water, extracted with EtOAc, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatograph on a silica gel column with EtOAc in Hexanes (30%) to afford the desired compound. LCMS: (M+57)=299.0.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:27])([CH3:26])[C@@H:11]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])(=[O:7])=[O:6].[N-:28]=[N+:29]=[N-:30].[Na+]>CS(C)=O>[N:28]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:27])([CH3:26])[C@@H:11]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])(=[O:7])=[O:6])=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)OC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)OC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-]

Procedure:
Following the general procedure for the preparation of azides of Description 16, isopropyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (25a) (0.61 g, 1.4 mmol) dissolved in 5 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 0.21 g (2.9 mmol) of sodium azide (NaN3). After work-up, the crude material (25b) was used in the next step without further purification or isolation. MS (ESI) m/z 450.13 (M+Na)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:16]([CH3:20])[CH:17]=[CH:18][N:19]=2)[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:36]=[CH:35][C:26]2[NH:27][C:28](=[O:34])[CH2:29][CH2:30][C:31]([CH3:33])([CH3:32])[C:25]=2[CH:24]=1.Cl>O1CCOCC1.COCCO>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:16]([CH3:20])[CH:17]=[CH:18][N:19]=2)=[N:7][C:2]([NH:22][C:23]2[CH:36]=[CH:35][C:26]3[NH:27][C:28](=[O:34])[CH2:29][CH2:30][C:31]([CH3:33])([CH3:32])[C:25]=3[CH:24]=2)=[N:3][CH:4]=1
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Reactant: Cn1ccnc1-c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: Cn1ccnc1-c1ccccc1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl
Yield: 82.5 %

Procedure:
Combined (2,5-Dichloro-pyrimidin-4-yl)-[2-(1-methyl-1H-imidazol-2-yl)-phenyl]-amine (82 mg, 0.256 mmol), 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (63 mg, 0.308 mmol), 4 N HCl in dioxane (80 ul) and 2-methoxyethanol (4 mL). Heated reaction to 120° C. for 6 hours. Evaporated off solvent and purified with normal phase chromatography to yield a light brown solid, 7-{5-Chloro-4-[2-(1-methyl-1H-imidazol-2-yl)-phenylamino]-pyrimidin-2-ylamino}-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (103 mg, 82%). mp 227° C.; LCMS: m/z=488.23 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.20 (m, 1H), 7.95 (s, 1H), 7.54 (dd, 1H, J=8.5, 2.4 Hz), 7.39 (m, 4H), 7.24 (m, 2H), 7.01 (d, 1H, J=1.3 Hz), 6.81 (d, 1H, J=8.6 Hz), 6.71 (m, 1H), 6.53 (dd, 1H, J=8.2, 2.7 Hz), 3.67 (s, 3H), 2.30 (m, 2H), 2.03 (m, 2H), 1.29 (s, 6H).
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[NH4+].[C:11]([NH:14]C1C=NC=C(C=1)C([O-])=O)(=[O:13])[CH3:12]>>[C:11]([NH:14][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([CH:7]=1)[C:1]([NH2:9])=[O:8])(=[O:13])[CH3:12]
Reactant: NC(=O)c1cccnc1
Reactant: CC(=O)Nc1cncc(C(=O)[O-])c1
Agent: [NH4+]
Product: CC(=O)Nc1cncc(C(N)=O)c1

Procedure:
The above salt is converted to the desired nicotinamide derivative by conversion to the methyl ester and then to the corresponding amide.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[S:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CC([O-])(C)C.[K+].CS([C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][N:24]=1)(=O)=O.O>C1COCC1>[CH3:32][S:29]([C:26]1[CH:27]=[CH:28][C:23]([O:10][C:7]2[CH:6]=[CH:5][C:4]([S:3][C:2]([F:11])([F:1])[F:12])=[CH:9][CH:8]=2)=[N:24][CH:25]=1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)c1ccc(S(C)(=O)=O)nc1
Reactant: Oc1ccc(SC(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2ccc(SC(F)(F)F)cc2)nc1
Temperature: 25 °C
Yield: 60 %

Procedure:
To 4.95 g of 4-(trifluoromethylthio)phenol dissolved in a 20 ml THF/20 ml DMSO mixture was added 2.9 g of t-BuOK and then 6.0 g of 2,5-bis(methylsulfonyl)pyridine, and the resulting mixture heated at 58° C. for 11/2 hrs. The reaction mixture was cooled to room temperature and added to approximately 3 to 4 volumes of water. The yellow-brown precipitate that formed was removed by filtration and then recrystallized from CH2Cl2 /ethanol. The purified product, 5-(methylsulfonyl)-2-(4-((trifluoromethyl)thio)phenoxy)pyridine, (60% yield), was recovered as tiny cream-white plates, m.p. 134°-135° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[C:10]([CH3:11])=[CH:9][C:8](Cl)=[N:7][C:6]=1[CH3:13])[CH3:2].[F:15][C:16]([F:27])([F:26])[C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([C:16]([F:27])([F:26])[F:15])[CH:22]=2)=[N:7][C:6]=1[CH3:13])[CH3:2]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1c(C)cc(Cl)nc1C
Product: CCOC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)nc1C

Procedure:
In analogy to the procedures described for example 1, for intermediate 5B and for intermediate 1, the title compound has been prepared by the following reaction sequence: i) 6-chloro-2,4-dimethyl-nicotinic acid ethyl ester [Zhou, Y.; Bridger, G. J.; Skerlj, R. T.; Bogucki, D.; Yang, W.; Bourque, E.; Langille, J.; Li, T.-S.; Metz, M. U.S. Pat. Appl. Publ. (2005), US 2005277668 A1] was reacted with 3-trifluoromethyl-phenyl boronic acid to give 2,4-dimethyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid ethyl ester; ii) 2,4-dimethyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid ethyl ester has been saponified to give 2,4-dimethyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid; iii) 2,4-dimethyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid was converted into its acid chloride and reacted with 4-pyrrolidin-1-yl-piperidine to give the title compound as colorless solid. MS: 432.3 (MH+).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C@@H:14]([OH:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=O)=O)=CC=1.[N:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=1)=[C:23]=[O:24].C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[C:15]1([C@@H:14]2[O:21][C:23](=[O:24])[N:22]([C:25]3[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=3)[CH2:12][CH2:13]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H](O)c2ccccc2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: Cc1cccc(N2CC[C@H](c3ccccc3)OC2=O)c1
Yield: 6.1 %

Procedure:
To a solution of (R)-3-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate (100 mg, 0.327 mmol) and 1-isocyanato-3-methylbenzene (44 mg, 0.327 mmol) in CH2Cl2 (2 mL) was added DBU (149 mg, 0.981 mmol) and the reaction mixture was refluxed overnight. After the solvent was removed under reduced pressure, the residue was separated by preparative HPLC to give (R)-6-phenyl-3-m-tolyl-1,3-oxazinan-2-one (5.34 mg, 6%:). LC-MS (10-80) tR=2.439 min, m/z=268; 1H NMR (CDCl3): 2.30-2.34 (m, 5H), 3.63-3.68 (m, 1H), 3.80-3.86 (m, 1H), 5.49 (dd, 1H), 7.09-7.45 (m, 9H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)=[O:6].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:14]([O:13][C:10]1[CH:9]=[CH:8][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])=[CH:12][CH:11]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(CCCCl)c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CCCCl)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 34.4 %

Procedure:
4-Chloro-1-(4-hydroxy-phenyl)-butan-1-one (1.0 g, 5.03 mmol) and benzyl bromide (0.86 g, 5.03 mmol) were combined with potassium carbonate (2 g) in acetone (50 mL). The reaction was stirred over 2 days at room temperature and became a thick slurry. This was partitioned between ethyl acetate and water saturated KH2PO4. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give a semi-solid. The product was purified by FCC on silica gel eluting hexane:ethyl acetate (80:20, v:v) to give 1-(4-benzyloxy-phenyl)-4-chloro-butan-1-one (0.5 g, 35%) as a solid. MS found: (M+H)+=289.
Reaction SMILES: [Br-].[CH3:2][CH:3]([CH2:24][CH3:25])[CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:26]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]([O:44][CH3:45])=[O:43])=O>O1CCCC1>[CH3:2][CH:3]([CH2:24][CH3:25])[CH:4]=[CH:26][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]([O:44][CH3:45])=[O:43]
Reactant: CCC(C)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CCCCCCCCCCCCCCC=O
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC(C)C=CCCCCCCCCCCCCCCC(=O)OC
Reaction time: 0.5 h
Yield: 53 %

Procedure:
13 gm of 2-methylbutyltriphenylphosphonium bromide was pulverized and dispersed into 130 ml of anhydrous tetrahydrofuran. To this was added 23.7 ml of 1.5M butyl lithium-hexane solution under a nitrogen atmosphere and the mixture was stirred for 30 minutes. To the solution was slowly added 8.4 gm of methyl 15-formylpentadecanoate which had been dissolved in 130 ml of anhydrous tetrahydrofuran in advance. After stirring for 3 hours, the solvent was evaporated. The crude crystals thus obtained were purified by flash column chromatography (chloroform:hexane=1:1) to obtain 5.3 gm of methyl 18-methyl-16-eicosenoate (yield: 51%). The product was submitted to the next step without purification.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[F:32][C:33]([F:46])([F:45])[O:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:41]([C:38]1[CH:37]=[CH:36][C:35]([O:34][C:33]([F:32])([F:45])[F:46])=[CH:40][CH:39]=1)(=[O:43])=[O:42]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccc(OC(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 4-(trifluoromethoxy)benzenesulfonyl chloride (18 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 26 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-4-(trifluoromethoxy)benzenesulfonamide (percentage yield: 87%), was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:26][O:27][CH3:28])=[N:7][C:8]2[C:13]([C:14]=1Cl)=[CH:12][CH:11]=[C:10]([C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=1)[N:9]=2)=[O:4].[F:29][C:30]([F:39])([F:38])[C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:26][O:27][CH3:28])=[N:7][C:8]2[C:13]([C:14]=1[NH:35][C:34]1[CH:36]=[CH:37][C:31]([C:30]([F:29])([F:38])[F:39])=[CH:32][CH:33]=1)=[CH:12][CH:11]=[C:10]([C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=1)[N:9]=2)=[O:4]
Reactant: COCc1nc2nc(-c3ncccc3C(F)(F)F)ccc2c(Cl)c1C(=O)OC
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: CC#N
Product: COCc1nc2nc(-c3ncccc3C(F)(F)F)ccc2c(Nc2ccc(C(F)(F)F)cc2)c1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve 4-chloro-2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-[1,8]napthyridine-3-carboxylic acid methyl ester (0.57 g, 1.4 mmol) and 4-trifluoromethyl aniline (234 mg, 1.53 mmol) in acetonitrile (10 mL). Stir overnight at room temperature. Remove the solvent under reduced pressure and dissolve the crude product in EtOAc (25 mL) and saturated NaHCO3 (aq) (25 mL). Remove the organic layer and dry over Na2SO4. Remove the solvent under reduced pressure and chromatograph the crude mixture on silica gel eluting with hexane/acetone (2:1) to yield the title compound. MS 537.18 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][C:21](O)=[O:22].[Cl:24]C1C(Cl)=C2C(CC(C3CCCC3)(C)C2=O)=CC=1CC(O)=O>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][C:21]([Cl:24])=[O:22]
Reactant: CC1(C2CCCC2)Cc2cc(CC(=O)O)c(Cl)c(Cl)c2C1=O
Reactant: CC1(C2CCCC2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Product: CC1(C2CCCC2)Cc2cc(OCC(=O)Cl)c(Cl)c(Cl)c2C1=O

Procedure:
The preparation is carried out by following substantially the procedures described in Example 1, Step C except that an equimolar amount of (+)-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo- 1H-inden-5-yl)oxy]acetic acid is substituted for the (+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)acetic acid used in Example 1, Step C. There is thus obtained first the (+)-enantiomers of the diastereomers of [(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]-acetyl chloride and then (+)-enantiomers of the diastereomers of [(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]acetamide.
Reaction SMILES: C(OC([N:8]1[C@@H:17]([C:18]([OH:20])=O)[CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:21])=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.[CH2:22]([C:26]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH2:31][NH:32][CH2:33][CH2:34][C:29]=2[C:28](=[O:35])[O:27]1)[CH:23]([CH3:25])[CH3:24].CCN(C(C)C)C(C)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[OH:21][C:12]1[CH:11]=[C:10]2[C:15]([CH2:16][C@H:17]([C:18]([N:32]3[CH2:33][CH2:34][C:29]4[C:28](=[O:35])[O:27][C:26]([CH2:22][CH:23]([CH3:24])[CH3:25])([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:30]=4[CH2:31]3)=[O:20])[NH:8][CH2:9]2)=[CH:14][CH:13]=1
Reactant: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CNCC2
Reactant: CC(C)(C)OC(=O)N1Cc2cc(O)ccc2C[C@@H]1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)[C@H]1Cc3ccc(O)cc3CN1)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.9 %

Procedure:
To a solution of (R)-2-(tert-butoxycarbonyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (102 mg, 0.369 mmol), 3-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (50 mg, 0.184 mmol), and N,N′-diisopropylethylamine (112 mg, 0.870 mmol) in THF (5 mL) was added BOP reagent (144 mg, 0.326 mmol) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness and the crude reaction mixture was concentrated and purified by column chromatography (12 g, SiO2, 0 to 30% ethyl acetate in hexanes). The purified fractions were re-dissolved in dichloromethane (5 mL), cooled to 0° C. and stirred with TFA (1 mL) for 5 hours at room temperature. The reaction mixture was concentrated to dryness, re-dissolved in dichloromethane (20 mL), washed with sat. NaHCO3 solution (5 mL), brine (5 mL), dried (MgSO4), and concentrated to provide 5-((R)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-3-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (55 mg, 67%) as a mixture of diastereoisomers in form of white solid: 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.81-1.01 (m, 6H), 1.58-1.88 (m, 2H), 2.25-2.54 (m, 5H), 2.65-2.97 (m, 2H), 3.52 (d, J=6.40 Hz, 1H), 3.75-3.95 (m, 2H), 3.98-4.11 (m, 3H), 4.56-4.86 (m, 1H), 6.51 (s, 1H), 6.59-6.73 (m, 1H), 6.95 (t, J=8.48 Hz, 1H), 7.28-7.45 (m, 5H); MS m/z 447 (M+H)+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[N:10]([C:12]1[NH:13][CH2:14][CH2:15][N:16]=1)[OH:11].[Na].[CH2:18](Br)[CH:19]=[CH2:20]>C(O)C>[CH2:20]([O:11][N:10]([C:12]1[NH:16][CH2:15][CH2:14][N:13]=1)[C:4]1[C:5]([F:9])=[CH:6][CH:7]=[CH:8][C:3]=1[Br:2])[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: ON(C1=NCCN1)c1c(F)cccc1Br
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: C=CCON(C1=NCCN1)c1c(F)cccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.0 gm (0.016 mol) of 2-[N-(2-bromo-6-fluoro-phenyl)-N-hydroxy-amino]-2-imidazoline hydrochloride and 0.7 gm of sodium were dissolved in 75 cc of absolute ethanol, and then 1.6 ml (about 115% of the stoichiometrically required amount) of allyl bromide were added to the solution. The resulting mixture was stirred for one hour at room temperature, and was then evaporated. The residue was dissolved in dilute (about 1 N) hydrochloric acid, and the resulting solution was extracted with ether (the ethereal extracts were discarded). The acidic aqueous phase was then fractionally extracted with ether at stepwisely increasing pH-values (addition of 2-N-sodium hydroxide), and these ethereal extracts were also discarded. The aqueous phase was now made alkaline with 5 N sodium hydroxide, whereupon a white, amorphous substance precipitated, which was collected by suction filtration, washed with water and dried. 2.95 gm (58.3% of theory) of the compound of the formula ##STR4## were obtained. It had a melting point of 141° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([NH:31][CH3:32])[CH2:27][CH2:26]2)[C:10]([CH:12]2[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:22][CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][CH:28]([N:31]([S:41]([C:38]3[CH:37]=[CH:36][C:35]([O:34][CH3:33])=[CH:40][CH:39]=3)(=[O:43])=[O:42])[CH3:32])[CH2:29][CH2:30]2)[C:10]([CH:12]2[CH2:13][CH2:14][N:15]([S:18]([CH3:21])(=[O:19])=[O:20])[CH2:16][CH2:17]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CNC1CCN(CCCN(C(=O)C2CCN(S(C)(=O)=O)CC2)c2ccc(Cl)c(Cl)c2)CC1
Product: COc1ccc(S(=O)(=O)N(C)C2CCN(CCCN(C(=O)C3CCN(S(C)(=O)=O)CC3)c3ccc(Cl)c(Cl)c3)CC2)cc1
Yield: 87 %

Procedure:
The title compound was prepared using a similar procedure to that described for example 195 from the title compound of example 323 and 4-methoxybenzenesulfonyl chloride, yield 87%.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=O)[NH:5][N:4]=1)[CH3:2].N#N.P(Cl)(Cl)([Cl:20])=O.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.O>[Cl:20][C:6]1[C:7]2[C:12](=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[C:3]([CH2:1][CH3:2])=[N:4][N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1n[nH]c(=O)c2ccc(OC)cc12
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCc1nnc(Cl)c2ccc(OC)cc12
Yield: 89 %

Procedure:
A suspension of 4-ethyl-6-methoxy-2H-phthalazin-1-one (1.3 g, 6.76 mmoles), prepared as described in example 9, in dry acetonitrile (20 ml), under stirring and dry N2 at room temperature, was added with phosphorous oxychloride (2.07 g, 13.52 mmoles). The mixture was refluxed and after 2 hours cooled, brought to small volume, taken up in water, added with Na2CO3 in excess and extracted three times with CH2Cl2. The organic phases were anhydrified and brought to dryness to give 1.34 g of the title compound (yield: 89%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.CON(C)[C:21](=[O:23])[CH3:22]>>[C:21]([C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:23])[CH3:22]
Reactant: CON(C)C(C)=O
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: [Li]CCCC
Product: COc1ccc(C(C)=O)c(C(=O)O)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with N-methoxy-N-methylacetamide. It is used in crude form in the following reaction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=O)=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.[CH3:16][C:17]([CH3:25])([C:19]1[N:23]=[C:22]([CH3:24])[O:21][N:20]=1)[NH2:18]>>[CH3:16][C:17]([NH:18][C:13]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[C:7]([O:8][CH2:9][CH:10]2[CH2:11][CH2:12]2)[N:6]=1)=[O:15])([C:19]1[N:23]=[C:22]([CH3:24])[O:21][N:20]=1)[CH3:25]
Reactant: O=C(O)c1ccc(Br)c(OCC2CC2)n1
Reactant: Cc1nc(C(C)(C)N)no1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(Br)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 9d) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (Example 33d) as starting materials; MS (EI) 455.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[NH:16][N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:26][C:27]1[CH:28]=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=1>CN(C=O)C.O>[Br:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[N:16]([CH2:26][C:27]3[CH:28]=[N:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)[N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1
Reactant: O=c1[nH]nc2c(Br)c(-c3ccc(Cl)cc3)ccn12
Reactant: FC(F)(F)c1ccc(CCl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(Br)c(-c3ccc(Cl)cc3)ccn12
Temperature: 25 °C
Reaction time: 72 h
Yield: 91 %

Procedure:
To a stirred mixture of 8-bromo-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (3.24 g, 10.0 mmol) in DMF (15 mL) at room temperature under argon was added K2CO3 (2.76 g, 20.0 mmol) and 3-(chloromethyl)-6-(trifluoromethyl)pyridine (2.34 g, 12.0 mmol). After stirring at room temperature for 3 d, HPLC indicated approximately 70% complete reaction. The mixture was then heated to 60° C. for 5 h, after which HPLC indicated complete reaction. The mixture was cooled to room temperature, diluted with water (100 mL), and stirred for 1 h. Solid was collected by filtration and washed with water (10 mL×5), then methanol (5 mL×2), and finally dried under vacuum. The title compound (4.4 g) was obtained as a yellow solid. HPLC/MS: retention time=3.8 min, [M+H]+=485.