Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])[CH:16]=2)[NH:11][N:10]=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([C:21]([N:46]4[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]4)=[O:22])[CH:24]=[CH:25][CH:26]=3)[CH:16]=2)[NH:11][N:10]=1
Reactant: CN1CCNCC1
Reactant: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(C(=O)O)c3)cc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(C(=O)N4CCN(C)CC4)c3)cc12
Temperature: 60 °C
Reaction time: 16 h
Yield: 5.6 %

Procedure:
To a solution of 3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid (25 mg, 72 μmol) in anhydrous DMF (1.5 mL) was added PS-DCC resin (Argonaut Technologies) (180 mg, 0.22 mmol, 1.21 mmol·g−1) and N-methylpiperazine (9.6 μl, 86 μmol). The resulting mixture was stirred at 60° C. for 16 h. The resin was filtered off, washing with dichloromethane and ether and the filtrate concentrated. The residue was dissolved in dichloromethane and treated with a PS-trisamine resin (Argonaut Technologies) (20 mg). The resin was again removed by filtration and washed with dichloromethane and ether. The filtrate was concentrated and the resulting crude product was purified by reverse phase mass-triggered HPLC using a gradient of acetonitrile in water containing 0.1% of formic acid to afford {3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone (1.7 mg, 4.0 μmol, 6% yield). 1H-NMR (500 MHz, d6-DMSO) δ 8.87 (d, 1H), 8.37 (d, 1H), 8.24 (t, 1H), 8.02 (dt, 1H), 7.98 (dt, 1H), 7.68 (dd, 1H), 7.64 (t, 1H), 7.47 (ddd, 1H), 7.23 (d, 1H), 7.11 (dt, 1H), 3.86 (s, 3H). MS: m/z 346 [MH+].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)[CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH:37]=O>C(Cl)Cl>[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][N:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1ccccn1
Reactant: NC(=O)c1ccc(OC2CCNCC2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)c1ccc(OC2CCN(Cc3ccccn3)CC2)nc1
Reaction time: 3 h
Yield: 59 %

Procedure:
Combine 6-(piperidin-4-yloxy)-nicotinamide (100 mg, 0.45 mmol) with sodium triacetoxy-borohydride (124 mg, 0.59 mmol) and pyridine-2-carbaldehyde (43 μL, 045 mmol) in CH2Cl2 (1.5 mL). Stir the reaction mixture for 3 h. Then, dilute the reaction mixture with CH2Cl2 (5 mL) and washed with NaOH (1M aq, 5 mL). Dry the organic layer over sodium sulfate, filter and concentrate. Purify the residue through an SCX chromatography to provide the title compound (83 mg, 59%). Mass spectrum (ion spray): m/z=313.1 (M+1); 1H NMR (DMSO-d6): 8.67 (ad, J=2.2 Hz, 1H), 8.50 (m, 1H), 8.12 (dd, J=2.6 and 8.8 Hz, 1H), 7.98 (bs, 1H), 7.80–7.76 (m, 1H), 7.47 (d, J=7.9 Hz, 1H), 7.41 (bs, 1H), 7.29–7.26 (m, 1H), 6.84 (d, J=8.8 Hz, 1H), 5.10 (m, 1H), 3.63 (m, 2H), 2.77–2.74 (m, 2H), 2.35–2.30 (m, 2H), 1.99 (bs, 2H), 1.75–1.69 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])/[C:4](/[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=[C:5](/[CH:10]([CH3:12])[CH3:11])\[C:6]([O:8][CH3:9])=[O:7].[C:22]([O:26][C:27]([NH:29][CH2:30][CH2:31]O)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[C:22]([O:26][C:27]([NH:29][CH2:30][CH2:31][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13]/[C:4](=[C:5](\[CH:10]([CH3:11])[CH3:12])/[C:6]([O:8][CH3:9])=[O:7])/[C:3]([O:2][CH3:1])=[O:21])=[CH:19][CH:18]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: COC(=O)/C(Cc1ccc(O)cc1)=C(\C(=O)OC)C(C)C
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: COC(=O)/C(Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)=C(\C(=O)OC)C(C)C
Temperature: 25 °C
Yield: 94.2 %

Procedure:
To a solution of 2-(4-hydroxybenzyl)-3-isopropylmaleic acid dimethyl ester (204.5 mg, 0.6996 mmol) in benzene (6 mL) were added N-(t-butoxycarbonyl)ethanolamine (343 mg, 2.13 mol), tributylphosphine (853 mg, 4.20 mmol) and 1,1′-(azodicarbonyl)dipiperidine (1.05 g, 4.20 mmol) with stirring at room temperature. After stirring at room temperature for 1 h, the reaction mixture was filtered, and the residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography (hexane-ethyl acetate 2:1) to give 287 mg of dimethyl 2-{4-[2-(t-butoxycarbonylamino)ethoxy]benzyl}-3-isopropylmaleate as oil (yield: 98%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:14]=3)=[CH:11][N:10]([C:25]3[CH:30]=[CH:29][C:28](=[O:31])[NH:27][N:26]=3)[N:9]=2)=[CH:4][CH:3]=1.NC1C=C(C2C(C3C=CC=CC=3)=NN(C3C=CC(=O)NN=3)C=2)C=CN=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:20][C:21]([F:23])([F:22])[F:24])[CH:14]=3)=[CH:11][N:10]([C:25]3[CH2:30][CH2:29][C:28](=[O:31])[NH:27][N:26]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=c1ccc(-n2cc(-c3ccnc(NCC(F)(F)F)c3)c(-c3ccc(F)cc3)n2)n[nH]1
Agent: Nc1cc(-c2cn(-c3ccc(=O)[nH]n3)nc2-c2ccccc2)ccn1
Product: O=C1CCC(n2cc(-c3ccnc(NCC(F)(F)F)c3)c(-c3ccc(F)cc3)n2)=NN1
Yield: 64 %

Procedure:
The reaction was carried out in the same manner as in Example 49 except for using 200 mg (0.47 mmol) of 3-(4-fluorophenyl)-1-(1,6-dihydro-6-oxopyridazin-3-yl)-4-[2-(2,2,2-trifluoroethyl)aminopyridin-4-yl]-1H-pyrazole obtained in Example 28-2) in place of 4-(2-aminopyridin-4-yl)-1(1,6-dihydro-6-oxopyridazin-3-yl)-3-phenyl-1H-pyrazole to obtain 130 mg of the title compound as a white powder. (Yield: 65%)
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]2)=[C:4]([F:19])[CH:3]=1.[CH3:20][C:21]1([CH3:39])[CH2:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:29]([S:30]([NH:33][C:34](=[O:38])[CH:35](Br)[CH3:36])(=[O:32])=[O:31])[C:23]=2[O:22]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:39][C:21]1([CH3:20])[CH2:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:29]([S:30]([NH:33][C:34](=[O:38])[CH:35]([O:8][C:7]3[CH:6]=[C:5]([N:9]4[C:13](=[O:14])[N:12]([CH:15]([F:16])[F:17])[C:11]([CH3:18])=[N:10]4)[C:4]([F:19])=[CH:3][C:2]=3[Cl:1])[CH3:36])(=[O:32])=[O:31])[C:23]=2[O:22]1
Reactant: Cc1nn(-c2cc(O)c(Cl)cc2F)c(=O)n1C(F)F
Reactant: CC(Br)C(=O)NS(=O)(=O)c1cccc2c1OC(C)(C)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1nn(-c2cc(OC(C)C(=O)NS(=O)(=O)c3cccc4c3OC(C)(C)C4)c(Cl)cc2F)c(=O)n1C(F)F

Procedure:
A stirred mixture of 0.2 gram (0.0007 mole) of 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one, 0.3 gram (0.0007 mole) of N-(2,3-dihydro-2,2-dimethylbenzofuran-7-yl)sulfonyl-2-bromopropionamide, 0.3 gram (0.002 mole) of potassium carbonate in 20 ml of acetone was heated under reflux for 18 hours. The reaction mixture was cooled and concentrated under reduced pressure to a residue. The residue was dissolved in 100 ml of water and the solution acidified by the dropwise addition of concentrated hydrochloric acid. The resultant precipitate was collected by filtration, washed with water, and dried to yield N-(2,3-dihydro-2,2-dimethylbenzofuran-7-yl)sulfonyl-2-[2-chloro-4-fluoro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]propionamide; m.p. 198°-201° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:39]([CH3:40])=[N:38][N:37]([CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][O:42]4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:24][C:23]=3[F:36])[CH:21]=2)=O)[CH:10]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.CSC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:24][C:23]=3[F:36])[N:19]=[C:18]3[N:37]([CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][O:42]4)[N:38]=[C:39]([CH3:40])[C:17]=23)[CH:10]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3c3ccccc3)c12
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(CN3CCN(C(=O)OC(C)(C)C)CC3c3ccccc3)c12
Yield: 51.3 %

Procedure:
To a solution of 529 mg of 4-[6-(4-benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-3-phenyl-piperazine-1-carboxylic acid tert-butyl ester in 15 ml of dry THF 6 ml of borane-dimethylsulfide complex (1 M in DCM) was added slowly at r.t., and the reaction was heated to reflux for 30 min. The reaction was quenched by the addition of 3.75 ml of methanol, and the solvents were evaporated. The residue was purified by preparative HPLC (C18 column, acetonitrile/water gradient) yielding 266 mg (51%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:36])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=3[O:32][CH:33]([CH3:35])[CH3:34])=[N:9]2)=[CH:4][CH:3]=1.[N:37]1([C:43](=[O:51])[CH2:44][N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:36])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:48]3[CH2:47][CH2:46][N:45]([CH2:44][C:43]([N:37]4[CH2:38][CH2:39][O:40][CH2:41][CH2:42]4)=[O:51])[CH2:50][CH2:49]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=3[O:32][CH:33]([CH3:34])[CH3:35])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Reactant: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(C)(c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Product: COc1ccc(C2=N[C@@](C)(c3ccc(Cl)cc3)[C@@](C)(c3ccc(Cl)cc3)N2C(=O)N2CCN(CC(=O)N3CCOCC3)CC2)c(OC(C)C)c1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) to give the title compound. HR-MS (ES, m/z) calculated for C38H46N5O5Cl2 [(M+H)+] 722.2871, observed 722.2874.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15](OCC)=[O:16])[CH:12]=[N:11]2)=[CH:6][CH:5]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[F:21][C:2]([F:1])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([CH2:15][OH:16])[CH:12]=[N:11]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1cnn(-c2ccc(OC(F)(F)F)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCc1cnn(-c2ccc(OC(F)(F)F)cc2)c1
Temperature: 0 °C
Yield: 82.9 %

Procedure:
A mixture of ester 116 (0.730 g, 2.43 mmol) and LiAlH4 (0.200 g, 5.28 mmol) in Et2O (20 mL) was refluxed for 2 h. The mixture was cooled to 0° C., quenched with ice, diluted with Et2O (100 mL) and filtered through Celite. The organic layer was dried (MgSO4), then column chromatography on silica gel (19:1 CH2Cl2:EtOAc) gave {1-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}methanol (117) (0.520 g, 83%) as a white solid: mp 73-74° C.; 1H NMR (CDCl3) δ 7.91 (s, 1H), 7.67-7.73 (m, 3H), 7.31 (d, J=8.4 Hz, 2H), 4.69 (d, J=5.5 Hz, 2H), 1.57 (t, J=5.5 Hz, 1H). APCI MS m/z 259 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11]O)[C:6]=1[CH3:13])(=[O:4])=[O:3].S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[Cl:16][CH2:11][C:7]1[C:6]([CH3:13])=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:10]=[CH:9][N:8]=1
Reactant: Cc1c(S(C)(=O)=O)ccnc1CO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1c(S(C)(=O)=O)ccnc1CCl
Temperature: 62.5 °C

Procedure:
To a mixture of (4-Methanesulfonyl-3-methyl-pyridin-2-yl)-methanol (13 g) and chloroform (130 ml) was added thionylchloride (7.5 ml) at 25-30° C. The reaction mixture was then heated to 60-65° C. and maintained at the same temperature for about 30 min. The solvent was distilled off completely under vacuum at 50-55° C. Ethylacetate (52 ml) was added to the crude followed by cooling to 0-10° C. and maintaining the same temperature for about 2 hrs. The compound is then filtered and washed the solid with ethylacetate (10 ml). The compound at 50-55° C. to obtain 12.2 gm of the title compound characterized by 1HNMR data (300 MHz): δ 2.75 (s, 3H), 3.38 (s, 3H), 4.95 (s, 2H), 7.82 (d, 1H), 8.70 (d, 1H) and mass [M]+: 220.06.
Reaction SMILES: [C:1]([C:4]1[C:21]([OH:22])=[CH:20][C:7]([O:8][CH2:9][C:10]2[N:15]=[C:14]([C:16]([O:18]C)=[O:17])[CH:13]=[CH:12][CH:11]=2)=[C:6]([CH2:23][CH3:24])[CH:5]=1)(=[O:3])[CH3:2].S(=O)(=O)(O)[O-].[K+]>CO.[OH-].[Na+]>[C:1]([C:4]1[C:21]([OH:22])=[CH:20][C:7]([O:8][CH2:9][C:10]2[N:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12][CH:11]=2)=[C:6]([CH2:23][CH3:24])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCc1cc(C(C)=O)c(O)cc1OCc1cccc(C(=O)OC)n1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: CCc1cc(C(C)=O)c(O)cc1OCc1cccc(C(=O)O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 6-[(4-acetyl-2-ethyl-5-hydroxyphenoxy)methyl]pyridine-2-carboxylate (38 mg, 12 mmol) was dissolved in a methanol solution (2 ml), and one normal sodium hydroxide (1 ml) was added to the above solution at 0° C., and the mixture was stirred at room temperature for 1 hour. One-tenth normal potassium bisulfate was titrated to the above solution until it became pH2. Then, precipitated white crystals were separated by filtration, and washed with water, and dried to give 6-[(4-acetyl-2-ethyl-5-hydroxyphenoxy)methyl]pyridine-2-carboxylic acid.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COCC([N:24]1[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][CH:25]1[NH2:31])C.[ClH:32]>CCOCC>[ClH:32].[CH3:9][O:8][CH2:7][CH:1]([NH:31][C:25]1[N:24]=[CH:29][C:28]([NH:30][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:27][CH:26]=1)[CH3:2]
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: COCC(C)N1C=C(N)C=CC1N
Agent: Cl
Solvent: CCOCC
Product: COCC(C)Nc1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a method similar to example 16 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid-[6-(2-methoxy-1-methyl-ethylamino)pyridin-3-yl]amide hydrogen chloride was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N-(2-methoxy-1-methyl-ethyl)-2,5-diaminopyridine. The purified oily material from column chromatography was dissolved in ether and treated with gaseous hydrogen chloride in ether (3N) to give a white precipitate as a hydrochloride salt. LCMS calcd for the neutral form C20H19F3N4O3 m/e 420.39, obsd 421.02 (ES, M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1.[N:21]1([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31](Cl)=[N:30][N:29]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(O)(C(F)(F)F)=O>CCOC(C)=O>[N:21]1([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([O:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][N:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:15][CH:16]=3)=[N:30][N:29]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: Clc1nnc(N2CCCCCC2)c2ccccc12
Reactant: COc1cnc2c(Oc3ccc(N)cc3)ccnc2c1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc2c(Oc3ccc(Nc4nnc(N5CCCCCC5)c5ccccc45)cc3)ccnc2c1
Temperature: 100 °C

Procedure:
A pyrex reaction tube was charged with 4-(7-methoxy-1,5-naphthyridin-4-yloxy)benzenamine (128 mg, 0.478 mmol), 1-(azepan-1-yl)-4-chlorophthalazine (125 mg, 0.478 mmol), TFA (0.029 ml, 0.382 mmol) and 2.4 mL of 2-BuOH. The tube was sealed and the reaction mixture was heated at 100° C. for 1.5 h. Upon cooling, EtOAc was added, and the resulting precipitate was filtered and washed with EtOAc. The solid was dissolved in 90/10/1 CH2Cl2/MeOH/NH4OH and purified by silica gel chromatography with 90/10/1 CH2Cl2/MeOH/NH4OH. The material was further purified by reverse phase chromatography (Gilson, 5-95% ACN over 15 min) to provide 4-(azepan-1-yl)-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine as a tan solid. MS m/z=493 [M+H]+. Calc'd for C29H28N6O2: 492.57.
Reaction SMILES: Br[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([O:21]C)=O)[C:11](=[O:23])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[NH3:24]>COCCO>[CH:6]1[C:5]2[N:4]3[C:19](=[O:21])[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[N:12]=[C:3]3[CH2:2][NH:24][C:11](=[O:23])[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccccc1-n1c(CBr)nc2ccccc2c1=O
Reactant: N
Solvent: COCCO
Product: O=C1NCc2nc3ccccc3c(=O)n2-c2ccccc21
Yield: 44 %

Procedure:
14.7 g (0.05 mol) of 2-bromomethyl-3-(2-methoxycarbonylphenyl)-4H-quinazolin-4-one and 25 ml of liquid ammonia in 100 ml of ethylene glycol monomethyl ether are heated to 100° C. for 5 hours in an autoclave. After cooling the mixture, the colourless crystals are filtered off and washed several times with methanol. 6.1 g (44% theory) of 6,7-dihydro-5H,13H-quinazolino[3,2-a][1,4]benzodiazepine-5,13-dione are obtained.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Br:34][C:35]1[CH:36]=[C:37]([OH:41])[CH:38]=[N:39][CH:40]=1.[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][CH2:52][C@H:51](O)[CH2:50]1)=[O:48])([CH3:45])([CH3:44])[CH3:43]>C1COCC1>[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][CH2:52][C@@H:51]([O:41][C:37]2[CH:38]=[N:39][CH:40]=[C:35]([Br:34])[CH:36]=2)[CH2:50]1)=[O:48])([CH3:45])([CH3:43])[CH3:44]
Reactant: Oc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(Br)c2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 66.7 %

Procedure:
To a cooled (0° C.) solution of PPh3 (1.2 g, 4.5 mmol) in THF (50 mL) is added DIAD (0.81 mL, 4.1 mmol), dropwise. After stirring at 0° C. for 15 min, 5-bromo-pyridin-3-ol (441 mg, 2.5 mmol) and (S)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 2.5 mmol) are added and the mixture is warmed and stirred at room temperature for 16 h. The mixture is concentrated and purified by flash column chromatography to give 596 mg of (R)-3-(5-bromo-pyridin-3-yloxy)-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[CH:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=1.[N+]([O-])([O-])=O.[NH2:27][N+:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:10]3[CH:11]=[C:12]([NH:16][C:17](=[O:22])[C:18]([F:19])([F:20])[F:21])[CH:13]=[CH:14][CH:15]=3)=[N:27][N:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][C:33]=23)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Nc1cccc(C=Cc2ccnc(Cl)n2)c1)C(F)(F)F
Reactant: Cc1ccc[n+](N)c1
Agent: O=[N+]([O-])[O-]
Product: Cc1ccc2c(-c3ccnc(Cl)n3)c(-c3cccc(NC(=O)C(F)(F)F)c3)nn2c1
Yield: 21.3 %

Procedure:
N-[3-(2-Chloro-pyrimidin-4-ylethenyl)-phenyl]-2,2,2-trifluoro-acetamide (5.00 g, 18.45 mmol) and 1-amino-3-methylpyridinium nitrate (6.19 g, 36.90 mmol) were combined in a procedure analogous to Example 67, Step A to afford 1.80 g of crude material, which was purified via HPLC separation to give N-{3-[3-(2-chloro-4-pyrimidinyl)-6-methylpyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide (1.70 g, 21%). 1H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 8.73 (s, 1H), 8.43 (d, J=5.6 Hz, 1H), 8.28 (d, J=9.2 Hz, 1H), 7.92 (s, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.56-7.49 (m, 2H), 7.45-7.40 (m, 1H), 7.03 (d, J=5.6 Hz, 1H), 2.37 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[O:32][CH3:33])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([OH:28])=[O:27])=[C:15]([CH2:18]OC(=O)CC(=O)C)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[CH3:34][C:35]1[CH:40]=[CH:39][N:38]2[N:41]=[N:42][CH:43]=[C:37]2[CH:36]=1>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[O:32][CH3:33])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([CH2:18][N:42]4[CH:43]=[C:37]5[CH:36]=[C:35]([CH3:34])[CH:40]=[CH:39][N:38]5[NH2+:41]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Cc1ccn2nncc2c1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)CC(C)=O)CS[C@H]12)c1csc(N)n1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CN3C=C4C=C(C)C=CN4[NH2+]3)CS[C@H]12)c1csc(N)n1

Procedure:
7β-[2-(2-Aminothiazol-4-yl)-2(Z)-methoxyiminoacetamido]-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid and 5-methyl[1,2,3]triazolo[1,5-a]pyridine are treated by the same procedure as that in Example 1, to yield the desired compound.
Reaction SMILES: [CH2:1]([C:4]([CH2:9][OH:10])([CH2:7][OH:8])[CH2:5][OH:6])[CH2:2][CH3:3].[I:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=O)=[CH:14][CH:13]=1>>[I:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]23[O:10][CH2:9][C:4]([CH2:1][CH2:2][CH3:3])([CH2:7][O:8]2)[CH2:5][O:6]3)=[CH:14][CH:13]=1
Reactant: CCCC(CO)(CO)CO
Reactant: O=C(Cl)c1ccc(I)cc1
Product: CCCC12COC(c3ccc(I)cc3)(OC1)OC2

Procedure:
1-(4-Iodophenyl)-4-propyl-2,6,7-trioxabicyclo[2,2,2]octane was prepared from 2-n-propyl-2-hydroxymethyl-propan-1,3-diol and 4-iodobenzoyl chloride using the method described in Example 1 stage (i)-(iii)
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH:12][C:1](=[O:4])[CH:2]=[CH2:3])=[CH:9][CH:8]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Acryloyl chloride (86.9 g) was added dropwise with stirring to a solution of 4-chlorobenzylamine (135.8 g) and triethylamine (133.5 ml) in dichloromethane (500 ml) at -15 to -20° C., under nitrogen. After the addition the mixture was stirred at ambient temperature for 2.5 hours. The mixture was washed with dilute aqueous sodium hydroxide solution and then with water. The dichloromethane solution was dried and evaporated under reduced pressure. The solid residue was recrystallised from ethyl acetate to give N-(4-chlorobenzyl)acrylamide, m.p. 103°-104° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:11]([CH:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>O1CCCC1>[CH2:11]([CH:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCC1Cc2ccccc2C1=O
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCCCCCC1Cc2ccccc2C1
Temperature: 0 °C
Yield: 98.6 %

Procedure:
Then, 1140 ml of tetrahydrofuran (THF) was placed in a 3 liter-reaction vessel. Under stirring, 361.4 g (2.7M) of anhydrous aluminum chloride was added to the above THF in 25 minutes below 20° C. To the mixture, 34.3 g (9.03×10-1M) of lithium aluminum hydride was added in 10 minutes below 20° C. Further, to the resultant mixture, a solution of 100 g (4.1×10-1M) of the above-prepared 2-octyl-1-indanone in 430 ml of THF was added dropwise in 40 minutes below 5° C., followed by stirring for 30 minutes below 5° C., and heat-refluxing for 1 hour. After the reaction, the reaction mixture was cooled and washed with ethyl acetate and water in this order to decompose the 2-octyl-1-indanone. The resultant reaction mixture was poured into 2 liters of ice water and subjected to extraction with ethyl acetate, followed by washing with saturated aqueous solution of common salt, drying with anhydrous magnesium sulfate and distilling-off of the solvent to obtain 93.0 g of 2-octylindan.