Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C(O)=O.[O:7]([CH:14]1[CH2:17][NH:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N+]([NH:21][C:22](N)=[O:23])([O-])=O.C(N(CC)CC)C>CC(C)=O.O>[O:7]([CH:14]1[CH2:17][N:16]([C:22]([NH2:21])=[O:23])[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(OC2CNC2)cc1
Reactant: NC(=O)N[N+](=O)[O-]
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: NC(=O)N1CC(Oc2ccccc2)C1
Reaction time: 0.5 h
Yield: 22.5 %

Procedure:
A stirred slurry of 7 g (0.03 mole) of 3-phenoxyazetidine oxalate [1:1] in 100 ml of acetone was treated with 5.3 g (0.05 mole) of nitrourea then after 30 min, treated with 5 ml of water and 5 ml of triethylamine. After stirring for 8 hr, the reaction mixture was diluted with 125 ml of water and stirred until a fine white crystalline solid precipitated. Filtration yielded 3.85 g, m.p. 179°-186° C. The solid was recrystallized from tetrahydrofuran to yield 1.3 g (22.5%) of fine white crystals, m.p. 195°-196° C.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[I:11][C:12]1[C:13]([O:21][CH3:22])=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=[O:16]>C1COCC1>[I:11][C:12]1[C:13]([O:21][CH3:22])=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:16]
Reactant: COc1c(I)cccc1C(=O)Cl
Reactant: CC(C)(C)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1c(I)cccc1C(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
To a cooled (−5° C.) solution of tert-butanol (12.87 mL, 30 mmol) in THF (30 mL) was added, dropwise, BuLi (12.0 mL, 2.5 M in hexanes, 30 mmol). On complete addition, the solution was stirred for 20 minutes. To this solution is added a solution of 3-Iodo-2-methoxy-benzoyl Chloride (8.8 g, 29.8 mmol) in THF (12 mL). On complete addition, the cold bath was removed and stirring continued for 1.5 hours. This solution was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and concentrated. The residue was purified by silica chromatography (50 g silica; eluted with 0-20% ethyl acetate in hexanes) to give the title compound as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([OH:11])=O)[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:45][C:46]1[CH:51]=[CH:50][C:49]([CH:52]2[CH2:66][N:56]3[C:57](=[O:65])[NH:58][C:59]4[CH:60]=[CH:61][CH:62]=[CH:63][C:64]=4[C:55]3=[N:54][CH2:53]2)=[CH:48][CH:47]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([CH:52]3[CH2:66][N:56]4[C:57](=[O:65])[NH:58][C:59]5[CH:60]=[CH:61][CH:62]=[CH:63][C:64]=5[C:55]4=[N:54][CH2:53]3)=[CH:48][CH:47]=2)=[O:11])[CH2:6][CH2:7]1
Reactant: Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Reactant: CN1CCN(CC(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(CC(=O)Nc2ccc(C3CN=C4c5ccccc5NC(=O)N4C3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.5 %

Procedure:
A mixture of (4-Methyl-piperazin-1-yl)-acetic acid (3.2 mg, 0.020 mmol), N,N-diisopropylethylamine (0.017 mL, 0.10 mmol), and HBTU (9.1 mg, 0.024 mmol) in 0.6 mL DMF was stirred at rt for 10 minutes, then 3-(4-aminophenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (7.6 mg, 0.026 mmol) added and the reaction continued at rt. At 1.75 hours the reaction mixture was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated to an oily solid. The residue was chromatographed eluting with 10% MeOH/CHCl3 containing Et3N. The obtained oily solid was then partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and evaporated to give the title compound as a white solid (4.8 mg, 73%). 1H NMR (CDCl3) δ: 9.14 (s, 1H), 8.99 (br. s, 1H), 8.11 (d, J=7.9 Hz, 1H), 7.58 (d, J=8.2 Hz, 2H), 7.38-7.44 (m, 1H), 7.22-7.27 (m, 2H), 7.12 (t, J=7.6 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 4.53 (dt, J=13.1, 3.6 Hz, 1H), 3.95 (dt, J=16.2, 3.6 Hz, 1H), 3.53-3.69 (m, 2H), 3.15 (s, 2H), 3.00-3.12 (m, 1H), 2.67 (br. s, 4H), 2.52 (br. s, 4H), 2.33 (s, 3H).
Reaction SMILES: [C:1]([Si:5]([O:18][C@@H:19]1[C@:24]2([CH3:25])[C@@H:22]([O:23]2)[CH2:21][CH2:20]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[N-:26]=[N+:27]=[N-:28].[Na+].CN(C=O)C.Cl([O-])(=O)(=O)=O.[Li+]>O>[N:26]([C@@H:22]1[CH2:21][CH2:20][C@H:19]([O:18][Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@:24]1([CH3:25])[OH:23])=[N+:27]=[N-:28]
Reactant: CC(C)(C)[Si](O[C@H]1CC[C@@H]2O[C@@]21C)(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](O[C@H]1CC[C@@H](N=[N+]=[N-])[C@]1(C)O)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 226.6 %

Procedure:
A mixture of rel-tert-butyl-[[(1S,4S,5S)-5-methyl-6-oxabicyclo[3.1.0]hexan-4-yl]oxy]-diphenyl-silane (enantiomeric mixture) (1.0 g, 2.8 mmoles), sodium azide (782 mg, 11.9 mmol), and DMF (10 mL) is stirred at 60° C. for 16 h. Lithium perchlorate (604 mg, 5.7 mmol) and additional sodium azide (931 mg, 14.2 mmol) are added and the reaction is heated to 90° C. for 72 h, then cooled to room temperature. The reaction is treated with water (50 mL) and extracted with EtOAc (3×70 mL). The combined organic portions are dried over magnesium sulfate, filtered, and concentrated to afford the title compound as a pale yellow oil (2.51 g). The material is carried forward crude without further purification or characterization.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:19]=[C:18]3[C:11]([NH:12][CH:13]=[C:14]3[CH2:15][CH2:16][NH2:17])=[CH:10][CH:9]=2)[CH:2]=1.[O:21]=[C:22]([C:24](=[O:26])[OH:25])[OH:23]>>[C:24]([OH:26])(=[O:25])[C:22]([OH:23])=[O:21].[O:7]([C:8]1[CH:19]=[C:18]2[C:11]([NH:12][CH:13]=[C:14]2[CH2:15][CH2:16][NH2:17])=[CH:10][CH:9]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:1][CH:2]=1
Reactant: Cc1cccc(Oc2ccc3[nH]cc(CCN)c3c2)c1
Agent: O=C(O)C(=O)O
Product: NCCc1c[nH]c2ccc(Oc3ccccc3)cc12

Procedure:
5-m-Tolyloxytryptamine: m.p. 164-165° C.; 1H NMR (250 MHz, DMSO-d6) 2.26 (s, 3H), 2.89-3.07 (m, 4H), 4.52 (br, 2H), 6.68-6.72 (m, 2H), 6.82-6.86 (m, 2H), 7.17-7.42 (m, 4H), 11.06 (br, 1H); MS (ELECTROSPRAY) m/e: 265.1 (M−1-C2H2O4).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:12][C:13]([C:15]1[CH:19]=[CH:18][S:17][C:16]=1[NH:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]2[NH:27][CH:28]=[CH:29][C:22]=12)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][CH2:4][C@@H:5]([NH:12][C:13]([C:15]1[CH:19]=[CH:18][S:17][C:16]=1[NH:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]2[NH:27][CH:28]=[CH:29][C:22]=12)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: [N-]=[N+]=NC[C@@H](NC(=O)c1ccsc1Nc1ccnc2[nH]ccc12)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC[C@@H](NC(=O)c1ccsc1Nc1ccnc2[nH]ccc12)c1ccccc1
Yield: 92.7 %

Procedure:
To a solution of 2-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-3-carboxylic acid ((S)-2-azido-1-phenyl-ethyl)-amide (40 mg, 0.1 mmol), 5% Pd/C (cat) in methanol (5 mL) was subjected to an atmosphere of hydrogen (balloon). After completion the solution was filtered and concentrated in vacuo. The residue was purified by ISCO Companion (silica, 10% methanol, methylene chloride, 1% ammonium hydroxide) to afford 2-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-3-carboxylic acid ((S)-2-amino-1-phenyl-ethyl)-amide (35 mg) (ESI) 378 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 12.61 (1H, br. s.) 11.45 (1H, s) 9.32 (1H, d, J=8.20 Hz) 8.28 (3H, br. s.) 8.08 (1H, d, J=6.88 Hz) 7.75 (1H, d, J=5.81 Hz) 7.47 (2H, d, J=5.86 Hz) 7.33 (2H, dd, J=7.57, 1.81 Hz) 7.12-7.24 (3H, m) 6.81 (1H, dd, J=2.49, 1.22 Hz) 6.68 (1H, d, J=6.88 Hz) 5.28 (1H, dd, J=10.54, 4.73 Hz) 3.40 (1H, td, J=11.53, 5.44 Hz) 3.12 (1H, dd, J=7.39, 4.61 Hz)
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10](COCC[Si](C)(C)C)[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:35][CH2:36][CH2:37][OH:38])=[C:26]([C:28]([O:30]C(C)(C)C)=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[ClH:47].CO>C(Cl)Cl.CCOCC>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:35][CH2:36][CH2:37][OH:38])=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[ClH:47]
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1CCCO
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)O)c(CCCO)s1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 2-(8-(benzo[d]thiazol-2-yl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-hydroxypropyl)thiazole-4-carboxylate (38E) (68 mg, 0.1 mmol) in DCM (2 mL) was added 2 mL of 2N HCl in ether. The mixture was stirred at rt overnight. MeOH (0.5 mL) was added to the mixture to dissolve the solid. The mixture was stirred at rt for another 2 hours. The reaction mixture was concentrated under reduced pressure to provide the desired product as an HCl salt: 1H NMR (300 MHz, DMSO-D6) δ ppm 8.03 (1H, d), 7.79 (1H, d), 7.67 (1H, d), 7.41 (5H, m), 4.83 (2H, s), 3.73 (4H, t), 3.50 (2H, t), 3.41 (2H, t), 3.04 (4H, t), 1.69 (2H, m). MS (ESI(+)): m/z 495 (M+H).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[N:13]=[C:14]([CH2:26][CH2:27][O:28][CH3:29])[N:15]([CH2:16][CH2:17][NH:18]C(=O)OC(C)(C)C)[C:11]=2[C:10]2[N:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1.[Cl:30]CCl.CO>O1CCOCC1>[ClH:30].[NH2:18][CH2:17][CH2:16][N:15]1[C:11]2[C:10]3[N:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[C:3]([NH2:2])[C:12]=2[N:13]=[C:14]1[CH2:26][CH2:27][O:28][CH3:29]
Reactant: ClCCl
Reactant: COCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COCCc1nc2c(N)nc3cccnc3c2n1CCN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of hydrochloric acid in dioxane (58 mL of 4 M) was added to a solution of tert-butyl N-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]ethyl}carbamate (3 g) in a small amount of dichloromethane/methanol. The reaction mixture was stirred overnight at ambient temperature and then concentrated under reduced pressure to provide 3.7 g of crude 1-(2-aminoethyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c][1,5]naphthyridine-4-amine hydrochloride.
Reaction SMILES: [O:1]1[CH2:23][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][C:11]([CH3:16])([CH3:15])[O:12]2)=[CH:7][CH:6]=1.[CH3:24][NH:25][CH3:26]>C(O)C>[OH:1][CH:2]([CH2:23][N:25]([CH3:26])[CH3:24])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][C:11]([CH3:16])([CH3:15])[O:12]2)=[CH:7][CH:6]=1
Reactant: CNC
Reactant: CC1(C)CC(c2ccccc2)c2ccc(OCC3CO3)cc2O1
Solvent: CCO
Product: CN(C)CC(O)COc1ccc2c(c1)OC(C)(C)CC2c1ccccc1
Yield: 97 %

Procedure:
A mixture of 7-(2,3-epoxypropoxy)-2,2-dimethyl-4-phenylchroman (6.1g), anhydrous dimethylamine (15ml) and ethanol were left to stand at ambient temperature until tlc showed that reaction was complete (c. 2hrs.). Removal of the solvent in vacuo gave 7-(2-hydroxy-3-dimethylaminopropoxy)-2,2-dimethyl-4-phenylchroman (6.8g, 97%) isolated as the hydrochloride salt, m.p. 210°-215°, from acetone-ethanol.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:14]2[C@@H:10]([C:11](=[O:16])[O:12][C@H:13]2[CH3:15])[CH:9]=[C:8]2[C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7]2>C(O)C.[Pt]=O>[OH:1][C@H:2]1[C@@H:14]2[C@@H:10]([C:11](=[O:16])[O:12][C@H:13]2[CH3:15])[CH2:9][C@@H:8]2[C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7]2
Reactant: C[C@@H]1OC(=O)[C@H]2C=C3CCCC[C@@H]3[C@@H](O)[C@@H]12
Agent: O=[Pt]
Solvent: CCO
Product: C[C@@H]1OC(=O)[C@H]2C[C@H]3CCCC[C@@H]3[C@@H](O)[C@@H]12
Reaction time: 16 h
Yield: 95.9 %

Procedure:
To 375.1 mg(1.69 mmol) of (3S,3aS,4R,4aS,9aS)-4-hydroxy-3-methyl-3a,4,4a,5,6,7,8,9a-octahydronaphtho[2,3-c]furan-1(3H)-one in 5 ml of ethanol solution were added 40.0 mg(10% by weight) of platinum oxide, and catalytic reduction was conducted at ambient temperature under 98.1 Kpa. After stirring for 16 hours, the reaction mixture was filtered through celite and the residue was washed using 20 ml of ethyl acetate. Combined organic layers were distilled off under reduced pressure and the residue was purified by means of silica gel column chromtography(methylene chloride:ethyl acetate=4:1) to obtain 363.7 mg of (3S,3aS,4R,4aS,8aR,9aS)-4-hydroxy-3-methyl-decahydronaphtho[2,3-c]furan-1(3H)-one (yield 96%).
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[CH:28][C:29]#[N:30])[CH:22]=1>>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:14]1[N:15]=[C:11]2[CH:10]=[C:27]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[CH:28]=[C:29]([NH2:30])[N:12]2[N:13]=1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccco2)n1)c1ccccc1
Reactant: N#CC=Cc1cccnc1
Product: Nc1cc(-c2cccnc2)cc2nc(-c3ccco3)nn12

Procedure:
The title compound, MS m/e (%): 277 (M+, 100), was prepared in accordance with the general method of example 1 from 3-benzenesulfonylmethyl-5-furan-2-yl-1H-[1,2,4]triazole and 3-(3-pyridinyl)-2-propenenitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH:37]1(O)[CH2:43][CH2:42]C[CH2:40][CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH:26]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:43][CH2:42]2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: OC1CCCCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC4CCCCCC4)c(C)c3C)c2cc1OC
Yield: 92.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-cycloheptanol (26 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (66 mg, yield 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([OH:22])=O)[N:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[F:23][C:24]([F:33])([F:32])[C:25]1[O:29][N:28]=[C:27]([CH2:30][NH2:31])[CH:26]=1>>[F:33][C:24]([F:23])([F:32])[C:25]1[O:29][N:28]=[C:27]([CH2:30][NH:31][C:20]([C:10]2[N:11]=[N:12][C:13]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH:9]=2)=[O:22])[CH:26]=1
Reactant: NCc1cc(C(F)(F)F)on1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Product: O=C(NCc1cc(C(F)(F)F)on1)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1

Procedure:
The title compound was synthesized in analogy to Example 41 using 5-(4-chlorophenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic acid (example M) and 5-trifluoromethyl-isoxazol-3-methanamine (example BF) as starting materials; LC-MS (UV peak area/ESI), 94.3%, 481.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:18][C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=2)[C:22](OC)=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[NH3:30]>CO>[Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:18][C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=2)[C:22]([NH2:30])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: N
Reactant: COC(=O)c1cccc(Cn2ccc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Solvent: CO
Product: NC(=O)c1cccc(Cn2ccc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 75 °C
Yield: 64 %

Procedure:
A sealed tube containing a solution of methyl 3-[3-bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]benzoate (0.1 g, 0.21 mmol) and NH3 (3 mL of a 7 N solution in MeOH, 21 mmol) was heated at 75° C. for 16 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. Trituration with Et2O/MeOH afforded a white solid (0.06 g, 64%): mp 198-201° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.02-8.00 (m, 2H), 7.85-7.75 (m, 2H), 7.70-7.60 (m, 1H), 7.45-7.30 (m, 4H), 7.17 (t, J=3 Hz, 1H), 6.60 (d, J=9 Hz, 1H), 5.32 (s, 2H), 5.18 (s, 2H). ES HRMS m/z 449.0295 (M+H C20H16BrF2N2O3 requires 449.0307).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.F[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([O:14][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1
Reactant: Cc1csc(Nc2cc(O)ccn2)n1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1csc(Nc2cc(Oc3ccc(C#N)cc3)ccn2)n1
Yield: 22.2 %

Procedure:
Following the method of Example 1, Step D, 2-(4-methylthiazol-2-ylamino)pyridin-4-ol (0.100 g, 0.483 mmol), 4-fluorobenzonitrile (0.064 g, 0.531 mmol) and potassium carbonate (0.167 g, 1.21 mmol) were reacted to provide 4-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzonitrile (0.033 g; 20.0% yield) as white solid. 1H NMR (CDCl3) δ 8.27 (d, 1H), 7.72 (m, 1H), 7.70 (m, 1H), 7.18 (m, 1H), 7.16 (m, 1H), 6.52 (dd, 1H), 6.49 (m, 1H), 6.38 (s, 1H), 2.28 (d, 3H). HPLC (5 to 95) Rt=2.69 min; Mass spectrum (esi) m/z=309 (M+H).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([CH:13]=O)[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].C[OH:18]>>[CH3:13][C:11]1[C:10]([OH:18])=[CH:9][CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=1
Reactant: CO
Reactant: O=Cc1cccc(-c2ccccc2)n1
Agent: [BH4-]
Agent: [Na+]
Product: Cc1nc(-c2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a solution of 0.250 g (1.36 mmol) of 6-phenyl-2-pyridine aldehyde in 5 mL of methanol was added sodium borohydride (0.08 g, 2.05 mmol) portionwise with stirring under N2 at ambient temperature. After 10 min, the reaction was quenched with 5 mL of saturated aqueous ammonium chloride solution. This solution was extracted with 3×50 mL EtOAc. The organic fractions were pooled, dried over Na2SO4 and concentrated. After removing the volatiles in vacuo, the resultant yellow oil was chromatographed on silica with 10% EtOAc/hexanes. Clean fractions were combined and the volatiles were removed to provide 0.250 g of 2-methylhydroxyl-6-phenyl pyridine as a clear oil (>99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH2:20])=[CH:15][CH:14]=2)[CH:3]=1.B1C2CCCC1CCC2.[OH-:30].[Na+].OO>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:30])=[CH:15][CH:14]=2)[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: C=Cc1ccc(Oc2cc(Cl)cc(C(F)(F)F)c2)cc1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCc1ccc(Oc2cc(Cl)cc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
To the solution of 1-chloro-3-[(4-ethenylphenyl)oxy]-5-(trifluoromethyl)benzene (2.63 g, 8.81 mmol) in dry THF (25 mL), was added 9-BBN (30 mL, 15.00 mmol) at 0° C. The mixture was stirred at room temperature overnight, and quenched with water (2 mL), followed by aq. NaOH (11 mL, 33.0 mmol), and 30% H2O2 (10 mL). The reaction mixture was heated at 50° C. for 3 h. Then THF was removed under reduced pressure, and the residue was diluted with EA. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, concentrated and purified by flash chromatography to afford the title compound (2.8 g, 8.84 mmol, 100% yield) as a colorless oil. LCMS: rt=3.70 min, [M+H+]=299
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)CC)C.Cl.[CH3:27][N:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1>C(O)C>[CH3:27][N:28]1[CH2:33][CH2:32][C:31]2[N:8]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]3[CH:4]=[CH:3][C:2]([CH3:10])=[CH:7][C:6]=3[C:30]=2[CH2:29]1
Reactant: Cc1ccc(NN)cc1
Reactant: CN1CCC(=O)CC1
Reactant: CCOC(=O)CCBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CCn1c2c(c3cc(C)ccc31)CN(C)CC2
Temperature: 90 °C
Reaction time: 16 h
Yield: 26.4 %

Procedure:
Preparation of the title compound was carried out according to General Method 1. p-Tolylhydrazine hydrochloride (20 g, 126 mmol), ethyl 3-bromopropionate (22.8 g, 126 mmol) and triethylamine (38.1 g, 378 mmol) in ethanol (200 ml) were stirred at 25° C. for 1 h after which the contents were heated at 90° C. for 3 h. The contents were cooled to 25° C. and evaporated to dryness. The residue was acidified with ethanolic HCl and the volatiles were removed under reduced pressure. Ethanol (200 mL) was added followed by N-methyl-4-piperidone hydrochloride (2.87 g, 18.9 mmol). Heating was continued at 90° C. for 16 h. The contents were concentrated in vacuo, basified by adding saturated aqueous NaHCO3, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by chromatography on neutral alumina using methanol-dichloromethane gradient to obtain 1.5 g of ethyl 3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoate.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[C:21]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])[CH:22]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[C:21]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[O:28][C:29]=3[CH3:30])[CH:22]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2cncc(OCc3nc(-c4ccccc4)oc3C)c2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2cncc(OCc3nc(-c4ccccc4)oc3C)c2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-yl]propionate (613 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, 1N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-yl]propionic acid (532 mg, yield: 92%). This was recrystallized from ethanol-hexane. Melting point: 133–134° C.