Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:24][CH2:23][CH:4]([CH:5]([C:7]3[N:12]=[C:11]4[N:13]([CH3:22])[C:14](=[O:21])[N:15]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:10]4=[CH:9][CH:8]=3)[CH2:6]1)[CH2:3][NH:2]2.[O:25]1[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[N:26]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O1CCOCC1>[CH3:18][C:17]([CH3:19])([CH3:20])[CH2:16][N:15]1[C:10]2[C:11](=[N:12][C:7]([CH:5]3[CH2:6][CH:1]4[CH2:24][CH2:23][CH:4]3[CH2:3][N:2]4[C:30]([C:27]3[CH:28]=[CH:29][O:25][N:26]=3)=[O:31])=[CH:8][CH:9]=2)[N:13]([CH3:22])[C:14]1=[O:21]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3CC4CCC3CN4)nc21
Reactant: O=C(O)c1ccon1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3CC4CCC3CN4C(=O)c3ccon3)nc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-(2-Azabicyclo[2.2.2]oct-5-yl)-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (5-1, 30.2 mg, 0.09 mmol, 1.0 equiv), isoxazole-3-carboxylic acid (2-6, 15.6 mg, 0.14 mmol, 1.5 equiv), DIPEA (48 μL, 0.28 mmol, 3.0 equiv) and HATU (52.4 mg, 0.14 mmol, 1.5 equiv) were added to anhydrous 1,4-dioxane (0.92 mL). After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 5-2 as a white solid. MS m/z (M+H): calculated=424.2343; observed=424.2345.
Reaction SMILES: [C:1](C1C=CC(OCC2C=CC(C(C3C=CC=C(C4NN=NN=4)C=3)NC(=O)C)=CC=2)=C(CCC)C=1O)(=[O:3])[CH3:2].[C:38]([C:41]1[CH:65]=[CH:64][C:44]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([CH:53]([NH2:63])[C:54]3[CH:55]=[C:56]([CH:60]=[CH:61][CH:62]=3)[C:57]([OH:59])=[O:58])=[CH:49][CH:48]=2)=[C:43]([CH2:66][CH2:67][CH3:68])[C:42]=1[OH:69])(=[O:40])[CH3:39]>>[C:1]([NH:63][CH:53]([C:50]1[CH:49]=[CH:48][C:47]([CH2:46][O:45][C:44]2[CH:64]=[CH:65][C:41]([C:38](=[O:40])[CH3:39])=[C:42]([OH:69])[C:43]=2[CH2:66][CH2:67][CH3:68])=[CH:52][CH:51]=1)[C:54]1[CH:55]=[C:56]([CH:60]=[CH:61][CH:62]=1)[C:57]([OH:59])=[O:58])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2ccc(C(N)c3cccc(C(=O)O)c3)cc2)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCc2ccc(C(NC(C)=O)c3cccc(-c4nnn[nH]4)c3)cc2)ccc(C(C)=O)c1O
Product: CCCc1c(OCc2ccc(C(NC(C)=O)c3cccc(C(=O)O)c3)cc2)ccc(C(C)=O)c1O

Procedure:
The title compound is prepared in a similar manner to N-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-[3-(1H-tetrazol-5-yl)-phenyl]-methyl}-acetamide employing 3-{[4-(4-Acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-amino-methyl}-benzoic acid to give a white solid (48%). 1H NMR (DMSO-d6) δ 13.01 (bs, 1H), 12.86 (s, 1H), 8.89 (d, 1H), 7.80-7.88 (m, 3H), 7.37-7.57 (m, 6H), 6.72 (d, 1H), 6.20 (d, 1H), 5.25 (s, 2H), 2.57-2.62 (m, 5H), 1.95 (s, 3H), 1.46-1.53 (m, 2H), 0.88 (t, 3H). LCMS M+1 476.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]([CH:10]([CH3:12])[CH3:11])[C:7](O)=[O:8])=[O:4].C1C=CC2N(O)N=NC=2C=1.Cl.Cl.Cl.[CH3:26][O:27][C:28](=[O:76])[NH:29][CH:30]([C:34]([N:36]1[CH:42]([C:43]2[NH:44][C:45]([C:48]3[CH:53]=[CH:52][C:51]([C:54]4[CH:63]=[CH:62][C:61]5[C:56](=[CH:57][CH:58]=[C:59]([C:64]6[NH:65][C:66]([CH:69]7[CH2:73][CH:72]([C:74]#[N:75])[CH2:71][NH:70]7)=[N:67][CH:68]=6)[CH:60]=5)[CH:55]=4)=[CH:50][CH:49]=3)=[CH:46][N:47]=2)[CH2:41][C:38]2([CH2:40][CH2:39]2)[CH2:37]1)=[O:35])[CH:31]([CH3:33])[CH3:32].CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[CH3:26][O:27][C:28](=[O:76])[NH:29][CH:30]([C:34]([N:36]1[CH:42]([C:43]2[NH:44][C:45]([C:48]3[CH:49]=[CH:50][C:51]([C:54]4[CH:63]=[CH:62][C:61]5[C:56](=[CH:57][CH:58]=[C:59]([C:64]6[NH:65][C:66]([CH:69]7[CH2:73][CH:72]([C:74]#[N:75])[CH2:71][N:70]7[C:7](=[O:8])[CH:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:10]([CH3:12])[CH3:11])=[N:67][CH:68]=6)[CH:60]=5)[CH:55]=4)=[CH:52][CH:53]=3)=[CH:46][N:47]=2)[CH2:41][C:38]2([CH2:39][CH2:40]2)[CH2:37]1)=[O:35])[CH:31]([CH3:33])[CH3:32]
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CC(C#N)CN6)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)O)C(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1CC(C#N)CC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC7(CC7)CN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 11.3 %

Procedure:
2-Methoxycarbonylamino-3-methyl-butyric acid (40 mg, 0.227 mmol) EDC-HCl (44 mg, 0.227 mmol) and HOBt (32 mg, 0.237 mmol) were combined in DMF (2 mL) and stirred for 20 min at RT. (1-{6-[5-(4-{6-[2-(4-Cyano-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester-tris-hydrochloride (150 mg, 0.189 mg) was added, the reaction mixture was cooled to 0° C. and NMM (0.104 mL, 0.947 mmol) was added dropwise. After 1.5 h, the reaction mixture was warmed to RT. 30 min later, the mixture was diluted with EtOAc and washed with NaHCO3, then 1:1 brine/5M NaOH. The organic phase was dried over MgSO4, then filtered and concentrated. The resulting residue was purified by HPLC to afford the title compound (18 mg, 11%). MS (ESI) m/z 840 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[C:17]([CH:18]=[CH:19][C:20]([OH:22])=[O:21])=[CH:16][CH:15]=[C:14]([C:23]([F:26])([F:25])[F:24])[N:13]=1>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[C:17]([CH:18]=[CH:19][C:20]([OH:22])=[O:21])=[CH:16][CH:15]=[C:14]([C:23]([F:24])([F:26])[F:25])[N:13]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)C=Cc1ccc(C(F)(F)F)nc1Oc1ccc(F)cc1
Reaction time: 0.17 h
Yield: 33.5 %

Procedure:
4-Fluoro-phenol (116 mg, 1.03 mmol) and sodium hydride (53 mg, 1.3 mmol) were added in DMF (7 mL). The reaction mixture was stirred for 10 mins and then 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (132 mg, 0.52 mmol) was added into the reaction mixture. The reaction mixture was diluted with EtOAc, and washed with water and brine. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex EtOAc=1/1) to give the title product (57 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30](=[N:32]O)[NH2:31]>N1C=CC=CC=1>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:30]2[N:31]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[O:9][N:32]=2)[CH:34]=[CH:35][CH:36]=1
Reactant: COc1cccc(C(N)=NO)c1
Reactant: O=C(O)c1ccccn1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: c1ccncc1
Product: COc1cccc(-c2noc(-c3ccccn3)n2)c1
Yield: 31.6 %

Procedure:
Using modifications of the method of Shine et al., J. Heterocyclic Chem. (1989) 26:125-128, a solution of picolinic acid (123 mg, 1 mmol) in pyridine (1 mL) was treated with 1,1′-carbonyldiimidazole (162 mg, 1 mmol) and the reaction stirred at ambient temperature until the evolution of carbon dioxide ceased (30 min). The intermediate acylimidazole was then treated with 3-methoxybenzamidoxime (166 mg, 1 mmol) and the reaction heated at reflux for 1 hour. Ice cold water was added to the reaction mixture to precipitate the oxadiazole. The solid was collected by filtration, washed with water and dried to afford 80 mg (32%) of 3-(3-methoxyphenyl)-5-(2-pyridyl)-1,2,4-oxadiazole: mp 90-94° C.; GC/EI-MS gave m/z (rel. int.) 253 (M+, 100), 254 (17), 179 (2), 175 (2), 149 (77), 133 (33), 119 (4), 106 (29), 78 (45), 51 (18).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:14]=[C:6]2[N:7]=[C:8]([CH2:12][OH:13])[CH:9]=[C:10]([SH:11])[N:5]2[N:4]=1.CC(O[CH2:19][C:20]1[CH2:29][S:28][C@@H:23]2[C@H:24]([NH2:27])[C:25](=[O:26])[N:22]2[C:21]=1[C:30]([OH:32])=[O:31])=O.O.N>C(#N)C>[NH2:27][CH:24]1[C:25](=[O:26])[N:22]2[C:21]([C:30]([OH:32])=[O:31])=[C:20]([CH2:19][S:11][C:10]3[N:5]4[N:4]=[C:3]([CH2:2][OH:1])[N:14]=[C:6]4[N:7]=[C:8]([CH2:12][OH:13])[CH:9]=3)[CH2:29][S:28][C@H:23]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: OCc1cc(S)n2nc(CO)nc2n1
Agent: N
Solvent: O
Solvent: CC#N
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3cc(CO)nc4nc(CO)nn34)CS[C@H]12
Temperature: 50 °C
Reaction time: 3 h
Yield: 37.6 %

Procedure:
In 80 ml of acetonitrile were suspended 7.1 g of 2,5-bis -(hydroxymethyl)-7-mercapto-s-triazolo[1,5-a]pyrimidine and 9.1 g of 7-aminocephalosporanic acid, and 15 ml of boron trifluoride-ethyl ether complex was added to the suspension and the mixture was stirred at 50 ° C for 3 hours. After cooling the reaction mixture, 200 ml of water was added thereto and the mixture was adjusted to pH 2 with conc. aqueous ammonia. Precipitated crystal was collected by filtration, washed with water, washed with acetone and then dried to obtain 5.34 g of the title compound.
Reaction SMILES: [CH2:1]([N:5]1[C:10]([S:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=2)=[C:9]([CH2:20][CH3:21])[C:8](=[O:22])[NH:7][C:6]1=[O:23])[CH:2]=[CH:3]C.C(N1C(SC2C=C(C)C=C(C)C=2)=C(CC)C(=O)NC1=O)C=CC1C=CC=CC=1.COC(C=CCN1C(SC2C=C(C)C=C(C)C=2)=C(CC)C(=O)NC1=O)=O.C(C=CCN1C(SC2C=C(C)C=C(C)C=2)=C(CC)C(=O)NC1=O)(O)=O.ClCC=CCN1C(SC2C=C(C)C=C(C)C=2)=C(CC)C(=O)NC1=O.C(N1C(SC2C=C(C)C=C(C)C=2)=C(CC)C(=O)NC1=O)C#C.C(N1C(SC2C=C(C)C=C(C)C=2)=C(CC)C(=O)NC1=O)C#CC.C1(C#CCN2C(SC3C=C(C)C=C(C)C=3)=C(CC)C(=O)NC2=O)C=CC=CC=1.C(N1C(SC2C=C(C)C=C(C)C=2)=C(CC)C(=O)NC1=O)C=CCC.OCC=CCN1C(SC2C=C(C)C=C(C)C=2)=C(CC)C(=O)NC1=O>>[CH2:1]([N:5]1[C:10]([S:11][C:12]2[CH:13]=[C:14]([CH3:19])[CH:15]=[C:16]([CH3:18])[CH:17]=2)=[C:9]([CH2:20][CH3:21])[C:8](=[O:22])[NH:7][C:6]1=[O:23])[CH:2]=[CH2:3]
Reactant: CC=CCn1c(Sc2cc(C)cc(C)c2)c(CC)c(=O)[nH]c1=O
Agent: C#CCn1c(Sc2cc(C)cc(C)c2)c(CC)c(=O)[nH]c1=O
Agent: CC#CCn1c(Sc2cc(C)cc(C)c2)c(CC)c(=O)[nH]c1=O
Agent: CCC=CCn1c(Sc2cc(C)cc(C)c2)c(CC)c(=O)[nH]c1=O
Product: C=CCn1c(Sc2cc(C)cc(C)c2)c(CC)c(=O)[nH]c1=O

Procedure:
1-(2-butenyl)-5-ethyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione; 1-cinnamyl-5-ethyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione; 1-(methoxycarbonylallyl)-5-ethyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione; 1-(carboxyallyl)-5-ethyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione; 1-(4-chloro-2-butenyl)-5-ethyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione; 1-propargyl-5-ethyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione; 1-(2-butynyl)-5-ethyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione; 1-(3-phenyl-2-propynyl)-5-ethyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione; 1-(2-pentenyl)-5-ethyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione; 1-(4-hydroxy-2-butenyl)-5-ethyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione;
Reaction SMILES: C[O:2][C:3]1[CH:9]=[CH:8]C(O)=[CH:5][CH:4]=1.[CH3:10][CH:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17].C(C(CC)=O)=C.[Cl-].[Na+]>C1C=CC=CC=1.O.C(O)(=O)C>[CH3:10][C:11]1([CH2:5][CH2:4][C:3](=[O:2])[CH2:9][CH3:8])[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17]
Reactant: CC1C(=O)CCC1=O
Reactant: COc1ccc(O)cc1
Agent: C=CC(=O)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CCC(=O)CCC1(C)C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 360 h

Procedure:
A total of 88 mg. of hydroquinone monomethyl ether was added to 10 ml. of ether vinyl ketone to stabilize the latter compound. There was then added to the above mixture 0.08 ml. of glacial acetic acid, 26 ml. of dimeneralized water and 11.2 g. of 2-methyl-1,3-cyclopentanedione. The resulting mixture was stirred under argon at room temperature for 15 days. An additional 9 ml. of ethyl vinyl ketone was added at the fourth day and 9.5 ml. of ethyl vinyl ketone was added at the ninth day. After 15 days, 50 ml. of benzene was added and sufficient sodium chloride was added to the aqueous phase to allow separation after shaking. The phases were separated and the aqueous phase re-extracted with 50 ml. of benzene. The combined benzene extracts were treated with a mixture of sodium sulfate, magnesium sulfate and activated charcoal. The solids were filtered off and were washed with a mixture of chloroform and ether. The combined filtrates were evaporated in vacuo and the residue was treated with an additional portion of benzene followed by concentration to dryness in vacuo. There was obtained 21.1 g. of an oil residue which was fractionally distilled at 0.05 mmHg and the fraction boiling in the range of 105°-118°C. was collected; yield 17.47 g. (89 percent). This fraction was redistilled at 0.025 mmHg to give a fraction boiling at 97°-115°C.; yield 16 g. (83.5 percent) of the above-captioned product.
Reaction SMILES: Br[C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][C:7]3([C:15]42[N:19]=[C:18]([NH2:20])[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][C:10]([F:14])([F:13])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1.O[C@H]1C[NH:28][C@H](C(O)=O)C1.C([O-])([O-])=O.[K+].[K+].N>CS(C)=O.CCOC(C)=O.[Cu]I>[F:14][C:10]1([F:13])[CH2:9][CH2:8][C:7]2([C:15]3([N:19]=[C:18]([NH2:20])[C:17]([CH3:21])=[N:16]3)[C:22]3[C:5](=[CH:4][CH:3]=[C:2]([NH2:28])[CH:23]=3)[CH2:6]2)[CH2:12][CH2:11]1
Reactant: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CCC(F)(F)CC1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Agent: [Cu]I
Agent: N
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC1=NC2(N=C1N)c1cc(N)ccc1CC21CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
6′-Bromo-4,4-difluoro-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine (Example 27, 116 mg, 0.30 mmol), trans-4-hydroxy-L-proline (40 mg, 0.30 mmol), copper(I) iodide (29 mg, 0.15 mmol) and K2CO3 (126 mg, 0.91 mmol) were mixed in dry dimethylsulfoxide (3 mL) in a microwave vial. The mixture was stirred under argon at r.t. for 30 min. Ammonia (30-33% in H2O) (0.285 mL, 4.55 mmol) was added, the vial was sealed and heated at 110° C. for 3 h in a microwave synthesizer. Additional copper(I) iodide (29 mg, 0.15 mmol) and trans-4-hydroxy-L-proline (40 mg, 0.30 mmol) were added and the mixture was then heated to 110° C. for 4 h. The mixture was diluted with EtOAc (10 mL) and washed with brine (10 mL). The aqueous layer was extracted with EtOAc (2×10 mL). The organic layers were combined and concentrated in vacuo. The residue was applied on a short column of silica (4 g SiO2) and eluted with 0-100% (7 M NH3 in MeOH and DCM 1:9) in DCM to give the title compound (46 mg, 48% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 1.17 (t, 1H), 1.48 (br. s., 2H), 1.64-1.96 (m, 5H), 2.11-2.17 (m, 3H), 2.83 (d, 1H), 2.90 (d, 1H), 4.75 (s, 2H), 5.83 (d, 1H), 6.37 (dd, 1H), 6.50 (s, 2H), 6.90 (d, 1H); MS (ES+) m/z 319.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCCC1.Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[CH:12][C:13]([OH:15])=[O:14]
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccc(F)c(Cl)c1
Temperature: 0 °C

Procedure:
A stirred mixture of 3-chloro-4-fluorobenzaldehyde (55 g, 0.35 mole), malonic acid (47 g, 0.45 mole) and 3.5 ml of piperidine in 138 ml of pyridine was heated on a steam bath for 2 hours. The reaction solution was poured into a mixture of 200 ml of concentrated hydrochloric acid and 320 g of ice to give after filtration and water wash 44 g (63%). The crude intermediate was used without further purification in part D.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].[CH3:38][N:39]([CH3:43])[C:40](Cl)=[O:41]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][C:40](=[O:41])[N:39]([CH3:43])[CH3:38])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Reactant: CN(C)C(=O)Cl
Product: COc1ccc(CC2c3cc(OC(=O)N(C)C)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with N,N-dimethylcarbamoyl chloride
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=1)(=[O:3])[CH3:2].[NH2:12][C@@H:13]([CH3:30])[CH2:14][N:15]1[CH:19]=[CH:18][C:17]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([Cl:28])[C:21]=2[CH3:29])=[N:16]1>>[C:1]([C:4]1[O:5][CH:6]=[C:7]([C:9]([NH:12][C@@H:13]([CH3:30])[CH2:14][N:15]2[CH:19]=[CH:18][C:17]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([Cl:28])[C:21]=3[CH3:29])=[N:16]2)=[O:11])[N:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1nc(C(=O)O)co1
Reactant: Cc1c(-c2ccn(C[C@H](C)N)n2)ccc(C#N)c1Cl
Product: CC(=O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3C)n2)co1
Yield: 12.47 %

Procedure:
(S)-2-acetyl-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propan-2-yl)oxazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2-acetyloxazole-4-carboxylic acid (372 mg, 2.400 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (549 mg, 2.000 mmol). The product was triturated using diethyl ether and purified by Flash-chromatography, respectively. Yield 12.47%. 1H-NMR (400 MHz; CDCl3): δ 1.27 (d, 3H), 2.59 (s, 3H), 2.60 (s, 3H), 4.31 (dd, 1H), 4.45 (dd, 1H), 4.64 (m, 1H), 6.45 (d, 1H), 7.51 (d, 1H), 7.56 (m, 2H), 7.68 (d, 1H), 8.31 (s, 1H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][CH:18]=[C:17]3[CH:23]=[CH:24][N+:25]([O-])=O)=[CH:10][CH:9]=1>C1COCC1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:20]([NH:19][CH:18]=[C:17]3[CH2:23][CH2:24][NH2:25])=[CH:21][CH:22]=2)=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])C=Cc1c[nH]c2ccc(-c3ccc(F)cc3)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCc1c[nH]c2ccc(-c3ccc(F)cc3)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine LiAlH4 (2.66 g, 70.17 mmol) and dry THF (70.0 ml) and cool the suspension in an ice bath. Add dropwise a solution of 5-(4-fluorophenyl)-3-(2-nitrovinyl)-1H-indole (3.30 g, 11.69 mmol) in dry THF (30.0 ml). Heat to reflux. After 1 hour, cool to ambient temperature and stir. After 15 hours, quench with saturated Na2SO4 (100 ml/mol) and stir at ambient temperature. After 1 hour, filter, rinse the precipitate with THF, and evaporate the filtrate to residue. Chromatograph the residue on silica gel eluting with dichloromethane/2N NH3(methanol) (80/20) to give the title compound. Prepare the HCl salt in diethyl ether: mp>250° C. MS (ACPI): m/e 255.0 (M+1). Analysis for C16H16ClFN2: Calcd: C, 66.09; H, 5.55; N, 9.63; found: C, 65.78; H, 5.48; N, 9.58.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][CH:5]=1.I[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20]>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:20][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH:11]=2)=[CH:6][CH:5]=1)=[O:12]
Reactant: C#Cc1ccc(C(=O)OC)cc1
Reactant: Oc1ccccc1I
Product: COC(=O)c1ccc(-c2cc3ccccc3o2)cc1

Procedure:
The general procedure was used to convert 4-Ethynyl-benzoic acid methyl ester and 2-iodophenol to the title product. Purification by flash chromatography (10% ethyl acetate in hexanes) gave the analytically pure product as a white solid (300 mg, 67% yield). 1H NMR δ 8.09 (dd, J=8.70, 2H), 7.90 (d, J=8.70, 2H), 7.52-7.62 (dd, J=8.10, 2H), 7.24-7.33 (m, 2H), 7.13 (s, 1H), 3.93 (s, 3H). 13C NMR δ 167.00, 155.50, 155.00, 134.80, 130.50, 130.00, 129.30, 125.40, 125.0, 123.60, 121.60, 111.70, 103.80, 52.60. Anal. Calcd. for C16H12O3: C, 76.18; H, 4.79. Found C, 75.97; H, 4.75. m.p. 176-178° C. (lit., 5176-177° C.).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11]([NH2:13])=[O:12])[CH2:8]1.[C:19](OC=O)(=[O:21])C.C([O-])=O.[Na+].C(Cl)(=O)C>CCOCC>[CH:19]([NH:13][C:11]([N:9]1[CH2:8][CH:7]([O:6][C:5]2[CH:14]=[CH:15][CH:16]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=2)[CH2:10]1)=[O:12])=[O:21]
Reactant: CC(=O)OC=O
Reactant: NC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Agent: O=C[O-]
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CCOCC
Product: O=CNC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 54 h
Yield: 61 %

Procedure:
A mixture of 0.524 g (0.002 mole) of 3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide and 1.5 ml of formic acetic anhydride (prepared by reacting sodium formate and acetyl chloride in ether at 23°-27° C. for 5.5 hr, filtering and evaporating off the ether) was stirred at room temperature for about 54 hr. The mixture was evaporated to dryness and the residue was partitioned between 7 ml methylene chloride and 2 ml water. The methylene chloride layer was separated, dried over sodium sulfate and evaporated to dryness. The residue was triturated with ether and the mixture subjected to filtration to give a solid white filter cake weighing 0.398 g after drying. The solid was stirred with more ether for 10 minutes and the mixture filtered to give 0.350 g (61%) white powder, m.p. 117.5°-119° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[N+:14]([O-])([OH:16])=[O:15].[OH-].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Clc1ccc(-c2ccccc2)nn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccccc1-c1ccc(Cl)nn1
Temperature: 0 °C

Procedure:
To an ice-cold solution of 3-chloro-6-phenylpyridazine (Aldrich, 1.4 g, 7.5 mmol) in conc. sulfuric acid (30 mL) was added 90% nitric acid (0.6 mL, 15 mmol). After 15 min. the mixture was poured over ice (200 mL) and neutralized with 25% aq. NaOH. The resulting precipitate was collected by filtration and dried under vacuum. The crude product (1.84 g) was a 1:1:0.5 mixture of ortho:meta:para isomers.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][C:6]1[C:10]([C:11]2[CH:12]=[C:13]([C:23]([OH:32])([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH:24]=[O:25])[C:14]3[N:18]=[C:17]([O:19]CC)[NH:16][C:15]=3[CH:22]=2)=[C:9]([CH3:33])[O:8][N:7]=1>CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O>[OH:32][C:23]([C:13]1[C:14]2[NH:18][C:17](=[O:19])[NH:16][C:15]=2[CH:22]=[C:11]([C:10]2[C:6]([CH3:5])=[N:7][O:8][C:9]=2[CH3:33])[CH:12]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[CH:24]([OH:25])[CH2:1][CH3:2]
Reactant: CCOc1nc2c(C(O)(C=O)c3ccccn3)cc(-c3c(C)noc3C)cc2[nH]1
Reactant: CC[Mg]Br
Agent: CN1c2c([nH]c(N)nc2=O)NCC1CNc1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1
Product: CCC(O)C(O)(c1ccccn1)c1cc(-c2c(C)noc2C)cc2[nH]c(=O)[nH]c12
Reaction time: 0.25 h

Procedure:
Ethyl magnesiumbromide (3M, 0.61 mL, 1.84 mmol) was added to a solution of 2-(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)-2-hydroxy-2-(pyridin-2-yl)acetaldehyde (120 mg, 0.31 mmol) in methyl-THF at 0° C. After 15 min, the reaction mixture was quenched with 1M HCl, concentrated and a portion of this material was purified by reverse-phase HPLC to give the major diastereomer 4-(1,2-dihydroxy-1-(pyridin-2-yl)butyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one.