Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][CH:15]=[CH:14]4)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[CH3:30][O:31][C:32]1[CH:46]=[C:45](B2OC(C)(C)C(C)(C)O2)[CH:44]=[CH:43][C:33]=1[O:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>CC#N.CO.CC(C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:45]5[CH:44]=[CH:43][C:33]([O:34][CH2:35][CH2:36][N:37]6[CH2:38][CH2:39][NH:40][CH2:41][CH2:42]6)=[C:32]([O:31][CH3:30])[CH:46]=5)[CH:3]=4)[NH:8][CH:9]=3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(Br)cnc32)cc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OCCN1CCNCC1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(C)=O
Solvent: CO
Product: COc1cc(-c2cnc3[nH]cc(-c4ccc5[nH]ccc5c4)c3c2)ccc1OCCN1CCNCC1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
To a solution of 5-bromo-3-(1H-indol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Intermediate B) (92 mg, 0.20 mmol) in CH3CN (2 mL) in a Personal Chemistry microwave reaction vial was added 1-(2-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)piperazine (Intermediate AM) (72 mg, 0.20 mmol), bis(triphenylphosphine)-palladium(II)dichloride (20 mg, 0.028 mmol), and 1 M Na2CO3 (2 mL). The resulting mixture was de-gassed with Ar for 10 min, after which it was heated at 150° C. for 25 min in a Personal Chemistry Optimizer. The organic layer was separated, filtered, and concentrated in vacuo to give Intermediate AN. The residue was dissolved in MeOH (3 mL) and acetone (2 mL), and 2 M NaOH (1.5 mL) was added. The resulting mixture was stirred at 50° C. for 2 h, after which it was partitioned between EtOAc and 1 M NaOH. The organic layer was separated, dried over MgSO4, filtered, and stripped to give a residue that was subjected to preparatory HPLC to yield the title compound. HPLC retention time: 1.29 minutes; MS ESI (m/z) 468.6 (M+1)+, calc. 467.
Reaction SMILES: OCCN=[C:5]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[NH2:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12].[CH2:20]([O:22][CH:23]([O:26][CH2:27][CH3:28])[CH2:24][NH2:25])[CH3:21].C(O)(=O)C>C(O)C>[CH2:20]([O:22][CH:23]([O:26][CH2:27][CH3:28])[C:24](=[C:5]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[NH2:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])[NH2:25])[CH3:21]
Reactant: Nc1cnccc1C(=NCCO)c1ccccc1Cl
Reactant: CCOC(CN)OCC
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(OCC)C(N)=C(c1ccncc1N)c1ccccc1Cl
Yield: 54.1 %

Procedure:
A solution of 2-hydroxy-N-[α-(3-amino-4-pyridyl)-2-chlorobenzylidene]-ethylamine (6.28 g, 22 mmol), aminoacetaldehyde diethyl acetal (10 g, 75.1 mmol) and acetic acid (3 ml) in ethanol (150 ml) was refluxed for 30 hours. The mixture was concentrated under reduced pressure, and to the residue was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; methanol: chloroform=1:9) to give the title compound (4.27 g, 11.9 mmol) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[F:13].Cl[CH2:19][C:20]1[N:21]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[O:23][C:24]=1[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[O:23][C:24]=2[CH3:25])=[CH:8][C:7]=1[F:13]
Reactant: CCO[C@@H](Cc1ccc(O)cc1F)C(=O)OC
Reactant: Cc1ccccc1-c1nc(CCl)c(C)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3C)oc2C)cc1F)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 f], (2S)-2-ethoxy-3-(2-fluoro-4-hydroxy-phenyl)-propionic acid methyl ester (example 13 f]) was reacted with 4-chloromethyl-5-methyl-2-o-tolyl-oxazole (example 1 e]) in the presence of cesium carbonate and potassium iodide to yield (S)-2-ethoxy-3-[2-fluoro-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid methyl ester as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].P([O-])(O)(O)=[O:14].[Na+].Cl([O-])=O.[Na+]>CS(C)=O.O>[CH3:12][O:11][C:8]1[CH:7]=[CH:6][C:3]([C:4]([OH:14])=[O:5])=[C:2]([CH3:1])[C:9]=1[CH3:10]
Reactant: O=P([O-])(O)O
Reactant: COc1ccc(C=O)c(C)c1C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(C(=O)O)c(C)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
60.0 g of 2,3-dimethyl-4-methoxybenzaldehyde (DI) are dissolved in 1.20 l of dimethyl sulfoxide. A solution of 131.5 g of sodium dihydrogenphosphate and 132.2 g of sodium chlorite in 480 ml of water is subsequently added dropwise, during which the temperature of the reaction batch is kept below 40° C. The reaction mixture is then stirred at room temperature for a further 2 hours. For work-up, the suspension is diluted with 2.0 l of water and stirred for a further hour. The resultant precipitate is filtered, washed with water and dried at 100° C. in vacuo, giving 65.0 g of the title compound as colourless solid having a melting point of 214° C. (MS: 181.2 (MH+)).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N+:10]([O-])=[N:9][C:8](=[O:12])[N:7]([CH2:13][CH:14]=[CH2:15])[C:6]=2[CH:16]=1.[CH3:17][O-:18].[Na+].O>CO>[CH3:17][O:18][C:2]1[CH:3]=[CH:4][C:5]2[N:10]=[N:9][C:8](=[O:12])[N:7]([CH2:13][CH:14]=[CH2:15])[C:6]=2[CH:16]=1
Reactant: C[O-]
Reactant: C=CCn1c(=O)n[n+]([O-])c2ccc(Cl)cc21
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=CCn1c(=O)nnc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a solution of 6-chloro-4-(2-propen-1-yl)-1,2,4-benzotriazin-3(4H)-one 1-oxide (see Example 60(c) for a preparation) (420 mg, 1.77 mmol) in MeOH (10 ml) was added sodium methoxide solution (25% w/v, 8.84 mmol, 1.9 ml) and then the reaction was stirred at rt for 2 h. The reaction was then treated with water (100 ml) and extracted with DCM (2×100 ml). The combined organic phases were dried, evaporated and the crude residue purified by chromatography on silica gel using a 0-5% MeOH/DCM gradient, followed by trituration with diethyl ether (50 ml) to provide the desired compound as a yellow foam (205 mg, 53%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:29]=[CH:28][C:27]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20](=[O:30])[C:19]=2[CH:18]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:29]=[CH:28][C:27]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20](=[O:30])[C:19]=2[CH:18]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C1c2ccccc2-c2ccc(O)cc21
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc4c(c3)C(=O)c3ccccc3-4)c2cc1OC
Temperature: 160 °C
Reaction time: 7 h
Yield: 33.8 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), 2-hydroxy-9-fluorenone (269 mg), and 4-dimethylaminopyridine (164 mg) were suspended in o-dichlorobenzene (6 ml), and the suspension was stirred at 160° C. for 7 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (58 mg, yield 34%).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)(=O)C.[NH2:14][C@@H:15]1[CH2:24][CH2:23][C:22]2[C:17](=[C:18]([N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[CH:19]=[CH:20][CH:21]=2)[CH2:16]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:31][N:28]1[CH2:29][CH2:30][N:25]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:17]=2[CH2:16][C@H:15]([NH:14][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[C:5]([OH:4])[CH:6]=2)[CH2:24][CH2:23]3)[CH2:26][CH2:27]1
Reactant: CC(=O)Oc1cccc(C(=O)O)c1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2cccc(O)c2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-acetoxybenzoic acid (130 g, 0.69 mol) in thionyl chloride (400 mL) was stirred at ambient temperature for 4 days. The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (100 mg, 0.52 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (120 mg, 0.50 mmol) and triethylamine (100 μL, 0.75 mmol) in methylene chloride (20 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with dilute aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo. The residue was dissolved in 99.5% ethanol (25 mL) and concentrated hydrochloric acid (5 mL) was added. After 17 h, the pH was adjusted to 8 and the solvent evaporated in vacuo. The residue was partitioned between water and methylene chloride. The organic phase was separated, dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:4) as the eluent. Yield: 93 mg (51%) of the title compound as white crystals: mp 117° C. decomp; [α]21D -10° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 365 (22, M+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.[C:17](O)(=[O:20])[CH:18]=[CH2:19].C1CCC(N=C=NC2CCCCC2)CC1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:17]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=1)(=[O:20])[CH:18]=[CH2:19]
Reactant: C=CC(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CC(=O)N[C@@H](Cc1ccc(OC)cc1)C(=O)OC
Yield: 58 %

Procedure:
The same procedures as in Example 1 were carried out from the compound obtained in Example 33 (3.3 g), acrylic acid (1.1 mL), DCC (3.4 g), triethylamine (9.5 mL, 68.2 mmol), and chloroform (140 mL), to give the captioned compound (2.1 g, 58%) as crystals.
Reaction SMILES: C([O-])(=[O:5])CCC.[Na+].C([O-])(=O)[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+].S(=O)(=O)(O)O>>[C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:5])[CH3:9]
Reactant: CCCC(=O)[O-]
Reactant: O=C([O-])C=Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)c1ccccc1
Reaction time: 0.33 h

Procedure:
The same medium and parameters as the inoculum were used. A 500 ml flask containing 100 ml broth was sterilized for 20 min. at 121° C. A 2.5 ml aliquot of sterilized 20% sodium butyrate solution (pH 7.0) and 1 ml. of the 24 hours grown culture were added. The flask was incubated at 30° C. and 150 rpm for 24 hours. Sterile 10% sodium cinnamate (pH 7.0) was added to each flask as follows: 5 g/l at 24 hours, 4 g/l at 72 hours, and 6 g/l at 80 hours. Periodically, 2 ml. samples of broth were acidified to pH 4.0 using 50% sulfuric acid, extracted with an equal volume of ethyl acetate, and analyzed by GC. The acetophenone concentration was estimated by external standard. At the conclusion of the fermentation, the culture broth was acidified to pH 4 as above and extracted twice with 1/2 volume of ethyl acetate each time. The extracts were combined and solvent was removed under vacuum using a rotary evaporator. The crude product was distilled in a micro-distillation oven and the distillate analyzed by GC. The yield of 1.8 g/L having a purity of 94.3% was obtained.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([S:8][CH3:9])=[N:5][C:4]=1[N:10]=[CH:11][N:12](C)C)#[N:2].N[C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=2)[CH:19]=[CH:18][C:17]=1[S:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1.NC1C=C(OCC2C=CC=C(Br)C=2)C=CC=1SC1C=CC(O)=CC=1>>[Br:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][O:22][C:20]2[CH:19]=[CH:18][C:17]([S:31][C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=3)=[C:16]([NH:2][C:1]3[C:3]4[S:7][C:6]([S:8][CH3:9])=[N:5][C:4]=4[N:10]=[CH:11][N:12]=3)[CH:21]=2)=[CH:25][CH:26]=1
Reactant: CSc1nc(N=CN(C)C)c(C#N)s1
Reactant: Nc1cc(OCc2ccc(Br)cc2)ccc1Sc1ccc(O)cc1
Agent: Nc1cc(OCc2cccc(Br)c2)ccc1Sc1ccc(O)cc1
Product: CSc1nc2ncnc(Nc3cc(OCc4ccc(Br)cc4)ccc3Sc3ccc(O)cc3)c2s1
Yield: 27 %

Procedure:
A solution of the product from Example 167A and the product from Example 16A were reacted according to the procedure from Example 167B substituting the product from Example 16A for the product from Example 15A to provide the crude material which was purified by trituration with methanol to provide the title compound as a white solid (46 mg, 27%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 2.76 (s, 3H), 5.09 (s, 2H), 6.70 (d, J=8.46 Hz, 2H), 6.91-7.24 (m, 5H), 7.38 (d, J=8.09 Hz, 2H), 7.56 (d, J=8.09 Hz, 2H), 8.46 (s, 1H), 9.71 (s, 2H); MS (ESI)+ m/z 583/585 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19](Br)=[N:18][C:17]=3[N:16]([CH3:29])[C:14]2=[O:15])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[NH:38]1[CH2:43][CH2:42][CH2:41][C@@H:40]([NH2:44])[CH2:39]1>CN(C)C=O>[CH3:27][C:26]#[C:25][CH2:24][N:20]1[C:19]([N:38]2[CH2:39][C@H:40]([NH2:44])[CH2:41][CH2:42][CH2:43]2)=[N:18][C:17]2[N:16]([CH3:29])[C:14]([N:13]([CH2:12][C:4]3[N:3]=[C:2]([CH3:1])[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[N:5]=3)[C:22](=[O:23])[C:21]1=2)=[O:15]
Reactant: N[C@@H]1CCCNC1
Reactant: CC#CCn1c(Br)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCn1c(N2CCC[C@@H](N)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 76.7 %

Procedure:
1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine (5 gm) and N,N-dimethylformamide (DMF, 50 mL) were charged into a 500 mL round bottomed flask equipped with a mechanical stirrer. Potassium carbonate (4.57 gm) and (R)-piperidine-3-amine dihydrochloride (2.86 gm) were added to the reaction mixture at room temperature. The reaction mixture was heated to 80° C. and maintained at that temperature for 8 hours. The reaction mixture was cooled to room temperature and DMF was evaporated under vacuum, then dichloromethane (DCM, 50 mL) was added, and stirred for 15 minutes. The reaction mixture was filtered to separate out the non-dissolved material and the non-dissolved material was washed with 15 mL of dichloromethane. The dichloromethane was evaporated under vacuum to give 4 gm of crude Linagliptin.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([N:13]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N-:20]=[N+]=[N-].[Na+].[OH-].[Na+]>C(O)(=O)C>[CH2:6]([N:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:20][CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C1CCN(Cc2ccccc2)CCN1
Temperature: 5 °C
Reaction time: 2 h
Yield: 46.4 %

Procedure:
Concentrated sulfuric acid (25 mL) was added to 1-benzyl-4-piperidone (10.14 g) in acetic acid (50 mL) at room temperature, and sodium azide (3.880 g) was added thereto at 0° C. over a period of 2 hours, followed by stirring at 5° C. for 25 hours. The reaction mixture was alkalinized through addition of aqueous sodium hydroxide, followed by partitioning by use of chloroform. The aqueous layer was extracted with chloroform. The organic layers were combined, and washed with saturated brine, and then dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure, and then the residue was purified through silica gel column chromatography (chloroform-methanol), to thereby give the title compound as a solid (5.081 g, 47%).
Reaction SMILES: O[N:2]=[C:3]([C:11](=O)[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[C:20]1([C:19]2[NH:26][C:11]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[N:2]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)C(=NO)C(=O)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1nc(-c2ccccc2)[nH]c1-c1ccncc1
Yield: 38.9 %

Procedure:
tert-Butyl 2-hydroxyimino-3-oxo-3-(4-pyridyl)propionate (2.8 g) and benzylamine (2.4 g) were dissolved in acetonitrile (80 ml), and the mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 5 to give tert-butyl 2-phenyl-5-(4-pyridyl)imidazole-4-carboxylate (1.4 g), melting point 205-206° C.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:17][CH2:18][C:19]1[CH:24]=[C:23]([F:25])[C:22]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[C:21]([F:31])[CH:20]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([NH:17][CH2:18][C:19]2[CH:20]=[C:21]([F:31])[C:22]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[C:23]([F:25])[CH:24]=2)=[O:13])=[CH:14][CH:15]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1
Reactant: CS(=O)(=O)Nc1c(F)cc(CN)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(OCC(=O)NCc2cc(F)c(NS(C)(=O)=O)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To an N,N-dimethylformamide (DMF) (10 ml) solution of (4-tert-butylphenoxy)acetic acid (330 mg, 1.50 mmol) and N-[4-(aminomethyl)-2,6-difluorophenyl]methanesulfonamide hydrochloride (491 mg, 1.80 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (431 mg, 2.25 mmol), 4-(dimethylamino)pyridine (DMAP) (55 mg, 0.45 mmol) and triethylamine (607 mg, 6.0 mmol) were added and the mixture was stirred for 15 hours at ambient temperature. The reaction mixture was then quenched with saturated aqueous solution of sodium bicarbonate and then crude products were extracted with methylene dichloride The organic layer was then washed with brine, dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was applied to an amino bound silica gel chromatography column and eluted with methylene dichloride/methanol=10/1 to furnish the title compound. Further, the title compound was recrystallized from ethyl acetate and hexane to furnish 199 mg (31% yield) of the title compound as a white solid.
Reaction SMILES: [I-:1].[Na+].[CH3:3][CH:4]([CH3:14])[CH2:5][C:6]([O:8][CH:9](Cl)[CH:10]([CH3:12])[CH3:11])=[O:7]>C(#N)C>[CH3:3][CH:4]([CH3:14])[CH2:5][C:6]([O:8][CH:9]([I:1])[CH:10]([CH3:12])[CH3:11])=[O:7]
Reactant: CC(C)CC(=O)OC(Cl)C(C)C
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)CC(=O)OC(I)C(C)C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 56.5 %

Procedure:
Acetonitrile (200 ml) is warmed to 60° C. and in this solvent is dissolved 35 g of sodium iodide. To this solution is added 12 g of 1-chloro-2-methylpropyl 3-methylbutyrate as obtained by the above procedure (a), and the mixture is stirred for 40 minutes, poured into 500 ml of ice water and extracted with hexane. The extract is washed with water and then with 5% aqueous sodium thiosulfate and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure to give 10 g of 1-iodo-2-methylpropyl 3-methylbutyrate.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[Cl:8][CH2:9][C:10]#[C:11][CH2:12]Cl.C([Li])CCC>>[Cl:8][CH2:9][C:10]#[C:11][CH2:12][CH2:7][C:5]1[O:4][N:3]=[C:2]([CH3:1])[CH:6]=1
Reactant: ClCC#CCCl
Reactant: Cc1cc(C)on1
Agent: [Li]CCCC
Product: Cc1cc(CCC#CCCl)on1

Procedure:
The intermediate 5-(5-chloro-3-pentynyl)-3-methylisoxazole was prepared from 3,5-dimethylisoxazole and 1,4-dichloro-2-butyne in the presence of n-butyllithium.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)=[CH:13][CH:12]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>>[C:29]([O:28][C:26](=[O:27])[CH2:25][N:20]1[CH2:21][CH2:22][CH2:23][C@@H:19]1[CH2:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([N:3]2[C:2]([Cl:1])=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]3)=[N:4]2)=[CH:16][CH:15]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: Clc1c2ccccc2nn1-c1ccc(OC[C@H]2CCCN2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)CN1CCC[C@@H]1COc1ccc(-n2nc3ccccc3c2Cl)cc1
Yield: 82.3 %

Procedure:
The title compound was prepared from 3-chloro-2-[4-((R)-1-pyrrolidin-2-ylmethoxy)-phenyl]-2H-indazole (0.4 g, 1.1 mmol) and t-butyl bromoacetate (0.27 g, 1.4 mmol) using the procedure of step 7 of the Example 5 to provide the title compound (0.4 g, 80%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:14](=[O:15])[CH2:13][C:12]([CH3:17])([CH3:16])[C:11]2=[O:18])[CH:7]=[CH:8][CH:9]=1)([O-])=O.Cl.C(O)C.[OH-].[Na+]>[Fe].O>[NH2:1][C:4]1[CH:5]=[C:6]([N:10]2[C:14](=[O:15])[CH2:13][C:12]([CH3:16])([CH3:17])[C:11]2=[O:18])[CH:7]=[CH:8][CH:9]=1
Reactant: CC1(C)CC(=O)N(c2cccc([N+](=O)[O-])c2)C1=O
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(C)CC(=O)N(c2cccc(N)c2)C1=O
Temperature: 70 °C

Procedure:
One hundred and sixty three g. of N-m-nitrophenyl-2,2-dimethylsuccinimide, as prepared in Example I, was added portion wise at reflux temperature to a mixture of 115 g. of powdered iron, 7 ml. of concentrated HCl, 250 ml. of ethyl alcohol and 200 ml. of water. At completion of addition (approximately one hour), the mixture was allowed to cool to 70° C. and 7 g. of 50% sodium hydroxide was added and the iron oxide was removed by filtration through a Dicalite filter which was washed with several portions of hot ethyl alcohol. Stripping of the filtrate under vacuum yielded 106 g. of a product having a m.p. of 143°-145° C. A portion of the product was recrystallized to a m.p. of 147°-147.5° C. The product was identified as the title compound by analysis of infrared spectra.
Reaction SMILES: [S:1]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[N:22](C(C)=C)[C:21]2[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=2[N:19]=1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[O-][Mn](=O)(=O)=O.[K+].[OH-].[Na+]>CC(O)(C)C>[S:1]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[NH:22][C:21]2[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=2[N:19]=1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:2])=[O:3]
Reactant: C=C(C)n1c(OCCCCCOS(=O)(=O)c2ccc(C)cc2)nc2ccccc21
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: Cc1ccc(S(=O)(=O)OCCCCCOc2nc3ccccc3[nH]2)cc1
Reaction time: 1 h
Yield: 60.7 %

Procedure:
0.62 g of the compound obtained in Example 14b was dissolved in 10 ml of t-BuOH, added dropwise slowly with a mixed solution (30 ml) of 1.92 g of KMnO4 and 50 ml of 0.1 N NaOH, and then the mixture was stirred for 1 hour. The reaction mixture was extracted three times with chloroform, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain 0.34 g of the title compound (yield: 61%).