Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]=[CH:10][C:9]3[CH:12]=[N:13][N:14]([C:15]4[N:20]=[C:19]([N:21]5[CH2:27][C:26]([O:29][CH3:30])([CH3:28])[CH2:25][N:24]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:23][CH2:22]5)[CH:18]=[CH:17][CH:16]=4)[C:8]=3[CH:7]=2)[CH:3]=[N:2]1.FC(F)(F)S(O[CH2:44][C:45]([F:48])([F:47])[F:46])(=O)=O>CN(C=O)C>[CH3:30][O:29][C:26]1([CH3:28])[CH2:25][N:24]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:23][CH2:22][N:21]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([N:14]3[C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][N:2]([CH2:44][C:45]([F:48])([F:47])[F:46])[CH:3]=5)[N:11]=[CH:10][C:9]=4[CH:12]=[N:13]3)[N:20]=2)[CH2:27]1
Reactant: COC1(C)CN(C(=O)OC(C)(C)C)CCN(c2cccc(-n3ncc4cnc(-c5cn[nH]c5)cc43)n2)C1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Product: COC1(C)CN(C(=O)OC(C)(C)C)CCN(c2cccc(-n3ncc4cnc(-c5cnn(CC(F)(F)F)c5)cc43)n2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.9 %

Procedure:
To a solution of tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-methoxy-6-methyl-1,4-diazepane-1-carboxylate (265 mg, 0.53 mmol) in DMF (15 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (610 mg, 2.63 mmol). The mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with brine, extracted with DCM (100 mL×3), and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford tert-butyl(±)-6-methoxy-6-methyl-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate as a white solid (264 mg, 85%). MS (ESI) m/z: 587 [M+H]+.
Reaction SMILES: [Si:1]([N:8]1[CH:11]([CH2:12][CH2:13][O:14]C(=O)C)[CH2:10][C:9]1=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[O-].[Na+].C(O)(=O)C>CO>[Si:1]([N:8]1[CH:11]([CH2:12][CH2:13][OH:14])[CH2:10][C:9]1=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)OCCC1CC(=O)N1[Si](C)(C)C(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)N1C(=O)CC1CCO
Yield: 54916.6 %

Procedure:
A solution of N-(t-butyldimethylsilyl)-4-(2-acetoxyethyl)-azetidin-2-one (41.7 g, 0.154 mmol) in anhydrous methanol (415 ml) is stirred under a N2 atmosphere with ice-bath cooling. A solution of sodium methoxide (415 mg, 7.7 mmol) in anhydrous methanol (15 ml) is added and the resulting solution is stirred in the cold for 2 more hrs. Acetic acid (2.2 ml) is then added and the solvents are evaporated in vacuo (i.v.). The residue is taken up in EtOAc (300 ml), washed with H2O (4×75 ml), 5% NaHCO3 (75 ml) and brine, dried with MgSO4 and evaporated i.v. to a clear oil (21.3 g). This material is purified by chromatography on a Baker silica gel column (425 g, packed under EtOAc). After a 100 ml forefraction, 25 ml EtOAc fractions are collected every 2.5 mins. Fractions 41-49 yield starting material and fractions 51-90 afford N-(t-butyldimethylsilyl)-4-(2 hydroxyethyl)-azetidin-2-one (19.4 g) as a clear oil: ir (neat) 2.88, 5.73, 5.80, 7.52, 7.67, 7.99, 8.40, 11.95, and 12.18 cm-1 ; nmr (CDCl3) δ0.25 (s, 6), 0.98 (s, 9), 1.82 (m, 2), 2.67 (dd, 1), 3.17 (dd, 1), 3.67 (t, 2), and 3.67 (m, 1); mass spectrum m/e 172.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].FC1C=CC([NH:19][C@H:20]([CH2:24][CH3:25])[C:21]([OH:23])=[O:22])=C([N+]([O-])=O)C=1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:19][C@H:20]([CH2:24][CH3:25])[C:21]([OH:23])=[O:22])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CC[C@@H](Nc1ccc(F)cc1[N+](=O)[O-])C(=O)O
Product: CC[C@@H](Nc1cc(F)ccc1[N+](=O)[O-])C(=O)O
Yield: 83 %

Procedure:
2,4-Difluoronitrobenzene was treated according to the procedure for the preparation of (R)-2-(4-fluoro-2-nitrophenylamino)-butyric acid (see Example 1) to yield (R)-2-(5-fluoro-2-nitrophenylamino)-butyric acid (83%). MS (ESI) m/z 243 ([M#H]+); MS (ESI) m/z 241 ([M−H]−); HRMS: calcd for C10H11FN2O4, 242.07031; found (ESI+), 243.07712.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@H:6]([NH:13]C(=O)C)[CH2:5][CH2:4]1.[OH-].[K+].C(O)CO>O>[CH3:1][O:2][C@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@H:6]([NH2:13])[CH2:5][CH2:4]1
Reactant: CO[C@@H]1CC[C@@H](NC(C)=O)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: CO[C@@H]1CC[C@@H](N)c2ccccc21

Procedure:
A mixture of 6.9 g. of cis and trans-N-(1,2,3,4-tetrahydro-4-methoxy-1-naphthyl)acetamide, 56.11 g. of potassium hydroxide, 50 ml. of ethylene glycol and 20 ml. of water is stirred and heated at reflux for an overnight period. The mixture is cooled, 100 ml. of water is added and the mixture extracted with methylene chloride (3 × 50 ml.). The combined extract was washed with 125 ml. of 10% sodium hydroxide solution, dried and evaporated in vacuo to afford 5.7 g. of title product - an oil. This oily amine is used without further purification for the preparation of the urea derivative.
Reaction SMILES: C([C:3]1[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:5]2[C:10]([C:11](=[O:16])[C:12]=1[C:13]([OH:15])=[O:14])=[N:9][CH:8]=[CH:7][CH:6]=2)C.O.[OH-].[Li+]>CO.O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH2:17][N:4]2[C:5]3[C:10](=[N:9][CH:8]=[CH:7][CH:6]=3)[C:11](=[O:16])[C:12]([C:13]([OH:15])=[O:14])=[CH:3]2)=[CH:25][CH:26]=1
Reactant: CCc1c(C(=O)O)c(=O)c2ncccc2n1Cc1ccccc1-c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cn(Cc2ccccc2-c2ccc(Cl)cc2)c2cccnc2c1=O
Reaction time: 15 h
Yield: 69.2 %

Procedure:
To a brown solution of ethyl 1-((4′-chlorobiphenyl-2-yl)methyl)-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (28) (257 mg, 0.61 mmol) in methanol (15 mL) was added the solid lithium hydroxide monohydrate (515 mg, 12.3 mmol) at room temperature under a nitrogen atmosphere. It gave a clear solution within 30 minutes and the resulting dark brown solution was stirred for 15 h at which time LCMS analysis indicated the absence of starting material. Then, the mixture was diluted with water and the methanol was removed under vacuum. The basic aqueous layer was diluted with water and the brown solids were filtered off using filter paper. Then, the filtrate was neutralized with 1.0N HCl. The precipitated off-white solids were collected by filtration and washed with water and hexanes. After drying in air, 165 mg of 1-((4′-chlorobiphenyl-2-yl)methyl)-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid (29) (68.8% yield) was isolated as an off-white solid.
Reaction SMILES: Br[CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24]#[N:25])=[CH:19][N:18]=2)=[CH:10][CH:9]=1)[C:3]([O:5]C)=O.[NH2:26][C:27]([NH2:29])=[S:28].C([O-])(=O)C.[Na+]>C(O)C>[C:24]([CH2:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH2:15][O:14][C:11]2[CH:12]=[CH:13][C:8]([CH2:7][CH:2]3[S:28][C:27](=[NH:26])[NH:29][C:3]3=[O:5])=[CH:9][CH:10]=2)=[N:18][CH:19]=1)#[N:25]
Reactant: NC(N)=S
Reactant: COC(=O)C(Br)Cc1ccc(OCCc2ccc(CC#N)cn2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: N#CCc1ccc(CCOc2ccc(CC3SC(=N)NC3=O)cc2)nc1
Reaction time: 0.25 h
Yield: 43.3 %

Procedure:
A mixture of methyl 2-bromo-3-[4-[2-(5-cyanomethyl-2-pyridyl)ethoxy]phenyl]propionate (7.2 g), thiourea (1.2 g), sodium acetate (1.3 g) and ethanol (80 ml) was heated under reflux for 5 hours and concentrated under reduced pressure. To the residue was added saturated aqueous sodium bicarbonate solution (100 ml)-ether (50 ml) and the mixture was stirred for 15 minutes. The precipitated crystals were filtered off to obtain 5-[4-[2-(5-cyanomethyl-2-pyridyl)ethoxy]benzyl]-2-imino-4-thiazolidinone (2.5 g, yield: 38%). This compound was recrystallized from chloroform-methanol to obtain colorless prisms, m.p. 211°-212° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[C:9]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([OH:22])=[O:21])[S:15][C:10]3=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][C:4]([C:23]([OH:25])=[O:24])=[CH:3]1.C(=O)(O)[O-].[Na+:30]>O>[O:1]=[C:2]1[C:7]2[CH:8]=[C:9]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([O-:22])=[O:21])[S:15][C:10]3=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][C:4]([C:23]([O-:25])=[O:24])=[CH:3]1.[Na+:30].[Na+:30]
Reactant: CCCc1c2oc(C(=O)O)cc(=O)c2cc2c(=O)cc(C(=O)O)sc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCCc1c2oc(C(=O)[O-])cc(=O)c2cc2c(=O)cc(C(=O)[O-])sc12
Yield: 101.3 %

Procedure:
The product of step (h) (1.935 g) and sodium bicarbonate (0.903 g) in distilled water (50 mls) were shaken until complete dissolution had occurred. The solution was filtered and the filtrate freeze dried to give 2.2 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[C:6]([CH:12]([OH:14])[CH3:13])[CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:3]=1.N12CCCN=C1CCCCC2.[Cl:34][C:35]([Cl:39])([Cl:38])[C:36]#[N:37]>C(Cl)Cl>[Cl:34][C:35]([Cl:39])([Cl:38])[C:36](=[NH:37])[O:14][CH:12]([C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[C:10]2[C:5]=1[N:4]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:21])([CH3:20])[CH3:22])[N:3]=[C:2]2[Br:1])[CH3:13]
Reactant: CC(O)c1cc(Cl)cc2c(Br)nn(COCC[Si](C)(C)C)c12
Reactant: N#CC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(Cl)cc2c(Br)nn(COCC[Si](C)(C)C)c12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(±)-1-(3-Bromo-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)ethanol (1.29 g, 3.18 mmol) was dissolved in methylene chloride (10 mL), cooled to 0° C. and treated with 1,8-diazabicyclo(5.4.0)undec-7-ene (96 μL, 0.64 mmol). The reaction was stirred for 10 min and treated with trichloroacetonitrile (3.19 mL, 31.8 mmol) dropwise over 10 min. The ice bath was removed and the reaction stirred at room temperature for 1 h and concentrated. Flash chromatography on silica gel (5% ethyl acetate/hexanes) gave 1.69 g (77%) as an oil. 1H-NMR (CDCl3, 300 MHz) δ 8.27 (s, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.53 (d, J=1.8 Hz, 1H), 6.58 (q, J=6.6 Hz, 1H), 6.19 (qAB, JAB=11.4 Hz, 2H), 3.50-3.56 (m, 2H), 1.74 (m, 3H), 0.80-0.84 (m, 2H), 0.06 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].[CH3:11][CH:12]([CH3:30])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:22][CH:23]=1)=[O:17]>>[CH:12]1([CH2:13][CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([N:24]3[CH2:29][CH2:28][N:27]([C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])[CH2:26][CH2:25]3)=[CH:22][CH:23]=2)=[O:17])[CH2:30][CH2:11]1
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Product: CC(O)(C(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1)C(F)(F)F

Procedure:
Following the procedure of Example 14, making variations only as required to use 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid in place of 4,4,4-trifluoro-2-methylbutyric acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white solid (55% yield). m.p. 181-183° C. 1H NMR (300 MHz, CDCl3) δ 8.07, 7.98, 7.01, 4.86, 3.92-3.81, 3.55, 1.74, 1.51, 0.81-0.68, 0.46, 0.09. 13C NMR (75 MHz, CDCl3) δ 167.2, 163.1, 160.0, 145.4, 127.1, 126.3, 122.5, 112.5. 76.8-75.6 (q, J=117 Hz, C-19F), 44.6, 39.7, 35.3, 20.5, 8.5, 4.8. MS (ES+) m/z 416 (M+1).
Reaction SMILES: [H-].[Na+].COC1C=CC(CCN2CCC[C@H]2C[N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][S:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=CC=1.[CH3:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([N:44]2[CH2:48][CH2:47][CH2:46][C@H:45]2[CH2:49]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:43])=[O:42])=[CH:37][CH:36]=1>CN(C)C=O>[CH3:34][C:35]1[CH:36]=[CH:37][C:38]([S:41]([N:44]2[CH2:48][CH2:47][CH2:46][C@H:45]2[CH2:49][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][S:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)(=[O:42])=[O:43])=[CH:39][CH:40]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2S(=O)(=O)c2ccc(C)cc2)cc1
Reactant: COc1ccc(CCN2CCC[C@H]2CN2c3ccccc3CSc3ccccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2CN2c3ccccc3CSc3ccccc32)cc1
Temperature: 60 °C
Yield: 22.4 %

Procedure:
Sodium hydride (80% dispersion in oil, 40 mg) was added to a solution of 5,11-dihydrodibenzo[b,e][1,4]thiazepine (see Example 1 for source) (213 mg) in dimethylformamide (10 ml) and the mixture heated at 60° C. for 45 minutes, treated with a solution of (S)-1-(4-methylphenylsulphonyl)-2-(4-methylphenylsulphonyloxymethyl)pyrrolidine (see Preparation 15 for source) (440 mg) in dimethylformamide (5 ml), heated at 60° C. for 7 hours and evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water and the organic layer washed with water, dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel, performing a gradient elution initially using hexane as eluant and changing to hexane/ethyl acetate (60:40). Appropriate fractions were combined and evaporated under reduced pressure to give the title compound as a colourless oil, (50 mg, 24%).
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([C:13]2[C:14]([NH2:45])=[N:15][CH:16]=[N:17][C:18]=2[N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[N:26]([CH2:38][CH2:39]OS(C)(=O)=O)[CH:27]=[C:28]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[C:32]([CH3:37])[CH:31]=4)[N:29]=3)[CH2:21][CH2:20]2)[CH:10]=[N:9]1)=O)(C)(C)C.[CH:46]1([NH2:49])[CH2:48][CH2:47]1>C1COCC1>[CH:46]1([NH:49][CH2:39][CH2:38][N:26]2[CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([CH3:37])[CH:31]=3)[N:29]=[C:25]2[CH:22]2[CH2:23][CH2:24][N:19]([C:18]3[N:17]=[CH:16][N:15]=[C:14]([NH2:45])[C:13]=3[C:11]3[CH:10]=[N:9][NH:8][CH:12]=3)[CH2:20][CH2:21]2)[CH2:48][CH2:47]1
Reactant: Cc1cc(-c2cn(CCOS(C)(=O)=O)c(C3CCN(c4ncnc(N)c4-c4cnn(C(=O)OC(C)(C)C)c4)CC3)n2)ccc1F
Reactant: NC1CC1
Solvent: C1CCOC1
Product: Cc1cc(-c2cn(CCNC3CC3)c(C3CCN(c4ncnc(N)c4-c4cn[nH]c4)CC3)n2)ccc1F
Temperature: 50 °C
Reaction time: 8 h

Procedure:
4-(4-Amino-6-{4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-methanesulfonyloxy-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-yl)-pyrazole-1-carboxylic acid tert-butyl ester (100.00 mg; 0.16 mmol; 1.00 eq.) in seal tube was added THF 2 ml and cyclopropylamine (0.70 ml; 9.81 mmol; 62.84 eq.), stirred at 50° C. for overnight.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH:12]=O)=[C:6]2[CH2:7][CH2:8][CH2:9][O:10][C:5]2=[CH:4][CH:3]=1.[F:14][C:15]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:16]=1[NH2:17].[BH4-].[Na+].Cl>CO.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:11]=1[CH2:12][NH:17][C:16]1[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:15]=1[F:14]
Reactant: O=Cc1c(O)ccc2c1CCCO2
Reactant: Nc1ccc(F)cc1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Oc1ccc2c(c1CNc1ccc(F)cc1F)CCCO2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 34.7 %

Procedure:
A mixture of 6-hydroxy-3,4-dihydrobenzopyran-5-carboxaldehyde (299 mg, 1.68 mmol) and 2,4 -difluoroaniline (219 mg, 1.68 mmol) in methanol (8 mL) was heated to reflux for 20 minutes during which time the intermediate Schiff's base crystallized, and, after cooling to room temperature, was collected by filtration and dried. The isolated Schiff's base (175 mg, 36%) was suspended in methanol (8 mL) and sodium borohydride (25 mg, 0.66 mmol) was added. The mixture was stirred at room temperature for 5 minutes, poured into water (50 mL) and carefully neutralized (pH=7) with 2.5 N HCl. The product was collected by filtration and dried to afford 6-hydroxy-5-(2,4-difluorophenyl)aminomethyl-3, 4-dihydrobenzopyran, (170 mg, 96.6%), m.p. 120°-121° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]#[CH:10].[C:11]([C:13]1[CH:19]=[C:18](I)[C:16]([NH2:17])=[CH:15][CH:14]=1)#[N:12]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[NH:17][C:16]2[C:18]([CH:10]=1)=[CH:19][C:13]([C:11]#[N:12])=[CH:14][CH:15]=2
Reactant: C#Cc1cnccc1OC
Reactant: N#Cc1ccc(N)c(I)c1
Product: COc1ccncc1-c1cc2cc(C#N)ccc2[nH]1

Procedure:
4-Methoxy-3-ethynyl-pyridine and 4-cyano-6-iodoaniline are processed according to the method described in Example 86 to give 2-(4-methoxy-pyridin-3-yl)-1H-indole-5-carbonitrile. 2-(4-Methoxy-pyridin-3-yl)-1H-indole-5-carbonitrile is purified by HPLC using an Xbridge Shield RP18 with a gradient of acetonitrile in 0.1% NH4OH. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.04 (s, 3H), 7.14 (d, J=1.3 Hz, 1H), 7.25 (d, J=5.8 Hz, 1H), 7.47 (dd, J=8.5, 1.6 Hz, 1H), 7.61 (d, J=8.3 Hz, 1H), 8.11 (s, 1H), 8.47 (d, J=5.8 Hz, 1H), 8.91 (s, 1H), 11.91 (br. s., 1H). HRMS (ESI) m/z 250.0968 [(M+H)+ calcd for C16H12N3O: 250.0980].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:5][C:4](=O)[CH:3]=1.S(O)(O)(=O)=O.[NH2:20][OH:21].N1C=CN=C1>>[OH:21][N:20]1[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:7][C:2]([CH3:1])=[CH:3][C:4]1=[O:5]
Reactant: NO
Reactant: Cc1cc(C2CCCCC2)oc(=O)c1
Agent: O=S(=O)(O)O
Agent: c1c[nH]cn1
Product: Cc1cc(C2CCCCC2)n(O)c(=O)c1
Yield: 93.3 %

Procedure:
20 g of 4-methyl-6-cyclohexyl-2-pyrone, 8 g of hydroxylamine sulfate and 50 g of imidazole were heated to 90° C. Further 10 g of hydroxylamine sulfate were added portionwise in the course of 3 hours. After a reaction time of 5 hours, the mixture was worked up. 11.8 g of 1-hydroxy-4-methyl-6-cyclohexyl-2-pyridone melting at 143° C were obtained.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]=[C:13]([NH2:23])[N:14]=[C:15](N3C=NC=N3)[C:16]=2[N:17]=1.[CH3:24][O:25][CH2:26][CH2:27][OH:28]>C(Cl)Cl>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]=[C:13]([NH2:23])[N:14]=[C:15]([O:28][CH2:27][CH2:26][O:25][CH3:24])[C:16]=2[N:17]=1
Reactant: Nc1nc(-n2cncn2)c2nc(Cl)ccc2n1
Reactant: COCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Product: COCCOc1nc(N)nc2ccc(Cl)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.3 %

Procedure:
Potassium t-butoxide (4 mL, 4 mmol; 1 M in THF) was added to a suspension mixture of 6-chloro-4-[1,2,4]triazol-1-yl-pyrido[3,2-d]pyrimidin-2-ylamine (1 g, 4 mmol) and 2-methoxyethanol (0.32 mL, 4 mmol) in DCM (50 mL). After stirring at room temperature for 10 minutes, the mixture was diluted with DCM (100 mL) and washed with brine. The organic layer was dried over Na2SO4 and concentrated to afford the pure title compound as a beige solid (0.91 g, yield 90%) which was characterised as follows: MS (m/z) 225.0 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([O:12][C:13]2[CH:18]=[C:17]([Br:19])[CH:16]=[C:15]([F:20])[C:14]=2[Cl:21])[C:6]=1[F:22])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[Br:19][C:17]1[CH:16]=[C:15]([F:20])[C:14]([Cl:21])=[C:13]([O:12][C:7]2[C:6]([F:22])=[C:5]([CH2:4][NH2:1])[CH:10]=[CH:9][C:8]=2[Cl:11])[CH:18]=1
Reactant: [N-]=[N+]=NCc1ccc(Cl)c(Oc2cc(Br)cc(F)c2Cl)c1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc(Cl)c(Oc2cc(Br)cc(F)c2Cl)c1F
Yield: 73.7 %

Procedure:
1-(azidomethyl)-3-[(5-bromo-2-chloro-3-fluorophenyl)oxy]-4-chloro-2-fluorobenzene (8.3 g, 20.29 mmol) dissolved in THF (100 mL) was treated successively with triphenylphosphine (7.98 g, 30.4 mmol) and water (1.828 g, 101 mmol) at 25° C. for 2 days with stirring. The reaction mixture was concentrated to dryness and purified on 330 g silica gel eluted successively with EtOAc (to remove triphenylphosphine oxide) followed by 0 to 10% CH3OH/DCM to give ({3-[(5-bromo-2-chloro-3-fluorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)amine (5.73 g, 14.96 mmol, 73.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.48-7.63 (m, 3H), 6.71 (s, 1H), 3.77 (s, 2H), 1.90 (s, 2H). LC-MS (ES−) m/z 380.00, 381.97, 384.06 [M−1]. LC-MS (ES+) m/z 381.84, 383.83, 385.87 [M+H].
Reaction SMILES: [Br:1]Br.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])[CH2:4][CH3:5]>ClCCl>[Br:1][CH:4]([CH3:5])[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6]
Reactant: CCC(=O)c1ccccc1
Reactant: BrBr
Solvent: ClCCl
Product: CC(Br)C(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 82 g (0.51 mol) of bromine in 100 ml of dichloromethane is added dropwise to a solution of 72 g (0.5 mol) of propiophenone in 500 ml of dichloromethane, at 20° C. After 30 minutes, the solution is evaporated down. 2-Bromopropiophenone is obtained quantitatively, and is directly reacted further.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:17]([CH2:21][C:22]([C:24]3[C:32]4[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=4)[NH:26][C:25]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:23])[C:18](O)=[O:19])=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1.[Cl:40][C:41]1[CH:49]=[C:48]2[C:44]([CH:45]=[C:46]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[NH:47]2)=[CH:43][CH:42]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]3[C:18](=[O:19])[O:23][C:22]([C:24]4[C:32]5[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=5)[NH:26][C:25]=4[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)([C:45]4[C:44]5[C:48](=[CH:49][C:41]([Cl:40])=[CH:42][CH:43]=5)[NH:47][C:46]=4[C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[CH:21]=3)=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(CC(C(=O)O)c1c(-c2ccccc2)[nH]c2cc(Cl)ccc12)c1c(-c2ccccc2)[nH]c2cc(Cl)ccc12
Reactant: Clc1ccc2cc(-c3ccccc3)[nH]c2c1
Product: O=C1OC(c2c(-c3ccccc3)[nH]c3cc(Cl)ccc23)(c2c(-c3ccccc3)[nH]c3cc(Cl)ccc23)C=C1c1c(-c2ccccc2)[nH]c2cc(Cl)ccc12

Procedure:
Following a procedure similar to that described above in part A of this example except that 2,4-bis(6-chloro-2-phenyl-3-indolyl)-4-oxobutanoic acid is used in place of 2,4-bis(1-n-propyl-2-methyl-3-indolyl)-4-oxobutanoic acid and 6-chloro-2-phenylindole is used instead of 1-n-propyl-2-methylindole, there is obtained 3,5,5-tris(6-chloro-2-phenyl-3-indolyl)-2(5H)-furanone (Formula III: R=R2 =H; R1 =R3 =C6H5 ; Y=Y1 =6-Cl).
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]#[N:13])[CH:5]=1>[Pd].C(O)C>[N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:12][NH2:13])[CH:5]=1
Reactant: N#Cc1ccccc1-n1cnnc1
Agent: [Pd]
Solvent: CCO
Product: NCc1ccccc1-n1cnnc1
Reaction time: 48 h

Procedure:
2-(1,2,4-Triazol-4-yl)cyanobenzene (0.3 g; 1.76 mmol) was combined with 30% by weight of palladium on carbon, 10% catalyst (100 mg) in ethanol (75 ml) and placed on a PARR Hydrogenation apparatus under a hydrogen atmosphere at 55 psi. for 48 hours. The mixture was filtered through celite and concentrated to give 2-(1,2,4-triazol-4-yl)benzylamine; 1H NMR (CD3OD) δ8.77 (s, 2H), 7.69-7.59 (m, 4H), 3.61 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.O[N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C:13]1=[O:18].C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1>[C:13]1(=[O:18])[N:12]([O:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)[C:16](=[O:17])[CH2:15][CH2:14]1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)c1ccc(Br)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: O=C(ON1C(=O)CCC1=O)c1ccc(Br)cc1
Temperature: 23 °C
Reaction time: 24 h
Yield: 85.4 %

Procedure:
To 4-bromobenzoic acid (5.00 g, 24.9 mmol, 1.00 equiv) and N-hydroxysuccinimide (3.66 g, 31.8 mmol, 1.28 equiv) in a round-bottom flask in dioxane (120 mL) was added an dioxane solution (30 mL) that contained 1,3-dicyclohexylcarbodiimide (DCC) (6.77 g, 32.8 mmol, 1.32 equiv) dropwise over 5 min at 23 ° C. The reaction mixture was stirring at 23 ° C. for 24 h. The reaction mixture was concentrated in vacuo and the crude product was obtained by recrystallization in a cold acetone. The crude product was further purified by chromatography on silica gel eluting with hexanes/EtOAc 2:1 (v/v) to afford 6.34 g of the title compound as a colorless solid (86%).