Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O)=O>C1(C)C=CC=CC=1.C(O)(=O)C.[Fe]>[NH:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:13]=[C:4]1[C:3]1[CH:16]=[C:17]([NH2:20])[CH:18]=[CH:19][C:2]=1[Cl:1]
Reactant: O=C(Nc1ccccc1[N+](=O)[O-])c1cc([N+](=O)[O-])ccc1Cl
Agent: [Fe]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Nc1ccc(Cl)c(-c2nc3ccccc3[nH]2)c1
Temperature: 125 °C
Yield: 49.7 %

Procedure:
Iron powder (15.42 g, 280 mmol) was added to a solution of amide 1 (15.00 g, 46.7 mmol) in toluene (125 ml) and acetic acid (60 ml). The mixture was heated at 125° C. for about 1 h (completion of the reaction was monitored by LCMS) and the resulting crude mixture was filtered through a cotton wool plug (to remove iron particles). The crude solution was evaporated to dryness, diluted with EtOAc, washed with saturated NaHCO3 then brine, dried over MgSO4, filtered, and concentrated at reduced pressure. The resulting brown solid was re-dissolved in CH2Cl2 and few drops of hexane were added to form a solid which was isolated by filtration to give 2 (5.66 g, 42%) as a beige solid: 1H NMR (CD3OD) δ 7.64 (broad s, 2H), 7.30-7.26 (m, 3H), 7.13 (app d, 1H), 6.84 (dd, 1H); MS (ES, positive mode): 244 [M++1].
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].I[CH:19]([CH3:21])[CH3:20]>C(O)C.C(OCC)C.O>[CH:19]([O:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])([CH3:21])[CH3:20]
Reactant: CC(C)I
Reactant: COc1ccc(C#N)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: COc1ccc(C#N)c(OC(C)C)c1
Yield: 46 %

Procedure:
To a solution of 2-hydroxy-4-methoxy-benzonitrile (16.4 g, 134.1 mmol) in ethanol were added potassium carbonate (37.07 g, 268.2 mmol) and 2-iodopropane (40.16 mL, 402.3 mmol). The reaction mixture was heated at gentle reflux for 3.5 h. The solvent was removed to afford a brown paste. It was then taken in diethyl ether (300 mL) and water (200 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (3×100 mL). The combined organic extracts were washed with brine and dried over anhydrous magnesium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 12% ethyl acetate in hexanes yielded 2-isopropoxy-4-methoxy-benzonitrile as a pale-yellow oil (11.8 g, 56%).
Reaction SMILES: [H-].[Na+].C1COCC1.[F:8][C:9]([F:41])([F:40])[C:10]1[CH:11]=[C:12]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:13][N:14]([CH2:30][CH2:31][OH:32])[C:15]([C:17]1[C:18](Cl)=[N:19][CH:20]=[CH:21][C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:16]>C(OCC)(=O)C>[F:8][C:9]([F:41])([F:40])[C:10]1[CH:11]=[C:12]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:13][N:14]1[C:15](=[O:16])[C:17]2[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:21][CH:20]=[N:19][C:18]=2[O:32][CH2:31][CH2:30]1
Reactant: O=C(c1c(-c2ccccc2)ccnc1Cl)N(CCO)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1c2c(-c3ccccc3)ccnc2OCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 86.1 %

Procedure:
Sodium hydride (60% oily) (60 mg) was added to a THF (15 ml) solution of N-[3,5-bis(trifluoromethyl)benzyl]-2-chloro-N-(2-hydroxyethyl)-4-phenyl-3-pyridinecarboxamide (Reference Example 12) (348 mg) and the mixture was stirred for 2 hours while heating under reflux. Ethyl acetate was added to the reaction mixture, which was then washed with water and dried. After the solvent was removed by distillation, the entitled compound was obtained as colorless crystals (278 mg).
Reaction SMILES: COC1C=CC=CC=1[O:9][CH3:10].Br[CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]C.[Cl:22][Sn](Cl)(Cl)Cl.COC1C=C2C(CC3C(CC4C(C2)=CC(OC)=C(OC)C=4)=CC(OC)=C(OC)C=3)=CC=1OC>ClCCCl>[Cl:22][CH2:20][C:19]1[C:14]([O:13][CH3:12])=[C:15]([O:9][CH3:10])[CH:16]=[CH:17][CH:18]=1
Reactant: CCCCCCCCOCBr
Reactant: COc1ccccc1OC
Reactant: Cl[Sn](Cl)(Cl)Cl
Agent: COc1cc2c(cc1OC)Cc1cc(OC)c(OC)cc1Cc1cc(OC)c(OC)cc1C2
Solvent: ClCCCl
Product: COc1cccc(CCl)c1OC

Procedure:
0.138 g (1 mmole) of 1,2-dimethoxybenzene (veratrol) were reacted with 0.223 g (1 mmole) of bromomethyl octylether in 5 ml 1,2-dichloroethane in the presence of 0.12 ml (1 mmole) SnCl4 at room temperature for 1 hour. After washing with HCl and water, followed by drying on Na2SO4 the product was isolated by the evaporation of the solvent. The product (0.275 g) corresponds by mp., NMR and analysis to cyclotriveratrylene (A. J. Lindsey. J. Chem. Soc. 1685 (1965) obtained by trimerization of 3-chloromethyl-1,2-dimethoxybenzene.
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[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C(N(C(C)C)CC)(C)C.ClC(Cl)(O[C:38](=[O:44])OC(Cl)(Cl)Cl)Cl.[NH2:46][C:47]1[S:48][C:49]([CH:52]2[CH2:54][CH2:53]2)=[N:50][N:51]=1>C(Cl)(Cl)Cl.O>[CH:52]1([C:49]2[S:48][C:47]([NH:46][C:38]([NH:20][C:19]3[CH:21]=[C:22]([CH3:23])[C:16]([O:15][C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][CH:7]=4)=[CH:17][C:18]=3[CH3:24])=[O:44])=[N:51][N:50]=2)[CH2:54][CH2:53]1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1nnc(C2CC2)s1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)Nc4nnc(C5CC5)s4)cc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (100 mg) was dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 15 min. Next, 2-amino-5-cyclopropyl-1,3,4-thiadiazole (55 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by HPLC using chloroform/acetone for development to give 55 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10](OCC)[CH:11]=C=O)=[CH:4][C:3]=1[N:17]1[C:25](=[O:26])[N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][C:19]2=[N:18]1.Cl.O1CCOCC1.[C:34](=[O:37])(O)[O-:35].[Na+]>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([C:34]([OH:35])=[O:37])[CH3:11])=[CH:4][C:3]=1[N:17]1[C:25](=[O:26])[N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][C:19]2=[N:18]1
Reactant: O=C([O-])O
Reactant: CCOC(C=C=O)Oc1cc(-n2nc3n(c2=O)CCCC3)c(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(Oc1cc(-n2nc3n(c2=O)CCCC3)c(Cl)cc1Cl)C(=O)O

Procedure:
10.8 Parts of 2-[2,4-dichloro-5-(1-ethoxy-carbonylethoxy)-phenyl]-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-A]pyridin-3(2H)-one, 20.6 parts of concentrated hydrochloric acid (38%) and 175 parts of dioxane were combined and heated to 80° for 30 hours. After cooling the solution was poured into 750 parts of water. The pH of the solution was raised to 8-9 by addition of solid sodium bicarbonate. The aqueous solution of the product was then extracted three times with 250 parts of methylene chloride. The organic extracts were discarded. The aqueous solution of the product was then acidified to pH 1 by addition at concentrated hydrochloric acid (38%). The aqueous solution of product was extracted three times with 250 parts of methylene chloride. The solution of product was dried with anhydrous sodium sulfate. The solvent was removed on a rotary evaporator at reduced pressure. The glassy residue was triturated with ether. 4.4 Parts of white solid with m.p. 183°-185° were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[C@H:10]([C:24]2[NH:28][C:27]3[CH:29]=[CH:30][C:31]([C:33]#[CH:34])=[CH:32][C:26]=3[N:25]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([O:42][C:43]([N:45]1[CH2:50][CH2:49][CH2:48][CH2:47][C@H:46]1[C:51]1[NH:55][C:54]2[CH:56]=[CH:57][C:58](I)=[CH:59][C:53]=2[N:52]=1)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C=O)C.CCOC(C)=O.O.[Cu]I.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[C@H:10]([C:24]2[NH:28][C:27]3[CH:29]=[CH:30][C:31]([C:33]#[C:34][C:57]4[CH:58]=[CH:59][C:53]5[NH:52][C:51]([C@@H:46]6[CH2:47][CH2:48][CH2:49][CH2:50][N:45]6[C:43]([O:42][CH2:35][C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)=[O:44])=[N:55][C:54]=5[CH:56]=4)=[CH:32][C:26]=3[N:25]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccc2[nH]c([C@@H]3CN(C(=O)OC(C)(C)C)CCN3C(=O)OCc3ccccc3)nc2c1
Reactant: O=C(OCc1ccccc1)N1CCCC[C@H]1c1nc2cc(I)ccc2[nH]1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)[C@H](c2nc3cc(C#Cc4ccc5[nH]c([C@@H]6CCCCN6C(=O)OCc6ccccc6)nc5c4)ccc3[nH]2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7893.4 %

Procedure:
To a stirring solution of (S)-2-(5-ethynyl-1H-benzoimidazol-2-yl)-piperazine-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester (77 mg, 0.16 mmol), (S)-2-(5-iodo-1H-benzoimidazol-2-yl)-piperidine-1-carboxylic acid benzyl ester (70 mg, 0.15 mmol), CuI (3 mg, 0.015 mmol) and bis(triphenylphosphine)palladium(II)dichloride (10.6 mg, 0.015 mmol) in DMF (2 mL) is added TEA (0.1 mL, 0.76 mmol). The reaction mixture is stirred at room temperature for 2 hours, diluted with EtOAc and water. The mixture is filtered to remove insoluble material and the layers of the filtrate are separated. The organic layer is dried over sodium sulfate and concentrated in vacuum to dryness. The residue is purified by flash column chromatography on silica gel (MeOH/DCM 0% to 20%) and repurified by reverse phase HPLC using a gradient of CH3CN/water to give the title compound (9.4 g, 7%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH:8]([CH3:10])[CH3:9])[NH:5][C:6]=1[Cl:7].Br[CH2:12][C:13]1[CH:32]=[CH:31][C:16]2/[C:17](=[C:27](/[CH3:30])\[C:28]#[N:29])/[C:18]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:19]=3[O:20][CH2:21][C:15]=2[CH:14]=1>>[Cl:1][C:2]1[N:3]=[C:4]([CH:8]([CH3:10])[CH3:9])[N:5]([CH2:12][C:13]2[CH:32]=[CH:31][C:16]3/[C:17](=[C:27](/[CH3:30])\[C:28]#[N:29])/[C:18]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:19]=4[O:20][CH2:21][C:15]=3[CH:14]=2)[C:6]=1[Cl:7]
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Reactant: CC(C)c1nc(Cl)c(Cl)[nH]1
Product: C/C(C#N)=C1/c2ccc(Cn3c(C(C)C)nc(Cl)c3Cl)cc2COc2cc(F)ccc21
Yield: 90.6 %

Procedure:
[step 2] Using 4,5-dichloro-2-isopropyl-1H-imidazole (68 mg, 0.381 mmol) obtained in step 1 and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (130 mg, 0.363 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (150 mg, 91%) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:14](=[O:15])[CH:13]=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:11]1)([O-])=O.C(O)(=O)C.C(O)C>[Fe].O>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:14](=[O:15])[CH:13]=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:11]1
Reactant: O=c1cc(-c2ccccc2)sn1-c1ccccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ccccc1-n1sc(-c2ccccc2)cc1=O
Temperature: 25 °C
Yield: 49.5 %

Procedure:
A mixture of 0.560 g (1.880 mmol) N-(2-nitrophenyl)-5-phenyl-4-isothiazolin-3-one, 0.450 g (excess) iron powder, 1 mL glacial acetic acid and 15 mL absolute ethanol was stirred at reflux for one hour. The mixture was allowed to cool to room temperature, poured into 150 mL water and extracted with three 100 mL portions of ethyl acetate. The organic layers were combined, dried, filtered and solvent was evaporated. The resulting solid was recrystallized from ethanol/water to provide 0.250 g (0.930 mmol, 49%) N-(2-aminophenyl) -5-phenyl-4-isothiazolin-3-one, mp=145°-146° C.- NMR (CDCl13 /TMS): 4.15 (bs, 2H), 6.6 (s, 1H), 6.8-7.6 (m, 9H). IR (Nujol): 3358, 3216, 1658. High resolution mass spectrum: Calculated; 269. 074860. Measured; 269.074265. Anal. calcd. for C15H12N2OS: C 67.14, H 4.51, N 10.44, S 11.95; Found C 66.76, H 4.43, N 10.19, S 12.09.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][C@H:19]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:24]=4[F:33])[C:18]3=[O:34])[CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)([Cl:37])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][C@H:19]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:24]=4[F:33])[C:18]3=[O:34])[CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([Cl:37])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCN(c4ncc(C(=O)O)cc4Cl)CC3)C2=O)c(F)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCN(c4ncc(C(=O)Cl)cc4Cl)CC3)C2=O)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 203.8 %

Procedure:
To a solution of (S)-5-chloro-6-(4-(3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinic acid (0.40 g, 0.38 mmol) in DCM (20 mL) was added sulfurous dichloride (0.28 g, 2.3 mmol) and DMF (1 drop) and the reaction was stirred at ambient temperature for 3 hours. The reaction was concentrated under vacuum to give (S)-5-chloro-6-(4-(3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinoyl chloride (0.41 g, 100%). The material was used directly in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18]3=[N:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22][N:17]3[CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1>C1COCC1.CO.[Pt](=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[O:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]2[C:18]3=[N:19][S:20](=[O:23])(=[O:24])[CH2:21][CH2:22][N:17]3[CH2:16][CH2:15][CH2:14]2)=[CH:11][CH:12]=1
Reactant: COc1cccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)c1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(Oc2ccc(C3CCCN4CCS(=O)(=O)N=C34)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
Platinum(IV) oxide (37 mg) was added to a solution of 9-[4-(3-methoxyphenoxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (129 mg) in THF (dry) (20 mL) and MeOH (20 mL) and the mixture was stirred at room temperature under hydrogen overnight. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (70.2 mg) as colorless crystals.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:29][C:30]1[N:34]([CH3:35])[N:33]=[C:32]([NH2:36])[CH:31]=1>>[Cl:29][C:30]1[N:34]([CH3:35])[N:33]=[C:32]([NH:36][C:8](=[O:9])[CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:27])([F:26])[F:28])[CH:13]=[N:12]2)[CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:31]=1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2C(F)(F)F)cc1=O
Reactant: Cn1nc(N)cc1Cl
Product: Cn1nc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3C(F)(F)F)cc2=O)cc1Cl
Yield: 30.6 %

Procedure:
Using the method described in Example 11, 3-cyclopentyl-2-[6-oxo-4-(2-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionic acid (Intermediate 21) and 5-chloro-1-methyl-1H-pyrazol-3-ylamine (Intermediate 6) afforded N-(5-chloro-1-methyl-1H-pyrazol-3-yl)-3-cyclopentyl-2-[6-oxo-4-(2-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionamide as a white solid (51.7 mg, 30.6%); ES+-HRMS m/e calcd for C23H23N5O3F3Cl [M+H+] 510.1515 found 510.1514. 1H-NMR (300 MHz, DMSO-d6) δ ppm 0.98-1.84 (m, 9H), 1.93 (m, 1H), 2.23 (m, 1H), 3.70 (s, 3H), 5.44 (dd, J=4.4, J=10.4 Hz, 1H), 5.92 (d, J=3.0 Hz, 1H), 6.48 (s, 1H), 7.49-7.64 (m, 2H), 7.83 (t, J=7.9 Hz, 1H), 7.90 (d, J=7.9 Hz, 1H), 8.18 (d, J=3.0 Hz, 1H), 10.95 (s, 1H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23]([NH:30][C@@H:31]([C:35](O)=[O:36])[CH:32]([CH3:34])[CH3:33])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[C:26]([O:25][C:23](=[O:24])[NH:30][CH:31]([C:35](=[O:36])[NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:32]([CH3:33])[CH3:34])([CH3:27])([CH3:29])[CH3:28]
Reactant: Nc1ccccc1NCc1ccccc1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N1-Benzyl-benzene-1,2-diamine obtained from Example 5b and triethylamine (0.19 ml, 1.35 mmol) in dry DMF (5 ml), was added Boc-D-valine (294 mg, 1.35 mmol) followed by TBTU (289 mg, 0.9 mmol). The reaction mixture was stirred at room temperature overnight. Ethyl acetate was added. The organic layer was washed with saturated NaHCO3, dried over MgSO4, filtered, and the filtrated was concentrated in vacuo. The crude material was purified by flash chromatography to yield [1-(2-Benzylaminophenylcarbamoyl)-2-methyl-propyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:8][CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[CH2:27][CH2:28]Br.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C.C(OCC)(=O)C.O>[C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:28][CH2:27][C:26]3[CH:30]=[CH:31][CH:32]=[C:24]([O:23][CH3:22])[CH:25]=3)[CH2:12][CH2:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cccc(CCBr)c1
Reactant: c1ccc(C(OCC2CCNCC2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: COc1cccc(CCN2CCC(COC(c3ccccc3)c3ccccc3)CC2)c1
Yield: 53.9 %

Procedure:
A mixture of 4-(diphenylmethoxymethyl)piperidine (1.40 g, 5.0 mmol--see Preparation 2), 3-methoxyphenethyl bromide (1.08 g, 5.0 mmol), sodium carbonate (1.06 g) and sodium iodide (0.50 g) in acetonitrile (30 ml) was heated under reflux for 16 hours, diluted with ethyl acetate and water and the layers separated. The organic layer was washed with water, dried over magnesium sulphate and evaporated. The residue was purified by chromatography on silica using dichloromethane plus 0-5% methanol as eluant. Appropriate fractions were combined and evaporated to give the title compound (1.12 g) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[NH:17][C:18]([O:20][CH3:21])=[O:19])=[CH:6][CH:5]=[CH:4][N:3]=1.S(O[CH:27]([CH2:31][C:32]#[CH:33])[C:28](=O)[CH3:29])(C)(=O)=O>C(O)C>[CH3:21][O:20][C:18]([NH:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]2[N:3]([C:27]([CH2:31][C:32]#[CH:33])=[C:28]([CH3:29])[N:1]=2)[CH:4]=[CH:5][CH:6]=1)=[O:19]
Reactant: COC(=O)Nc1cccc(C)c1COc1cccnc1N
Reactant: C#CCC(OS(C)(=O)=O)C(C)=O
Solvent: CCO
Product: C#CCc1c(C)nc2c(OCc3c(C)cccc3NC(=O)OC)cccn12

Procedure:
A mixture of 2-amino-3-(2-methoxycarbonylamino-6-methylbenzyloxy)pyridine (4.22 g) and 3-mesyloxy-5-hexyn-2-one (2.74 g) in ethanol (42 ml) was refluxed for 62 hours and then evaporated in vacuo. To the residue was added and aqueous solution of sodium bicarbonate and the insoluble material was collected by filtration. The crude product was purified by column chromatography on silica gel (150 g) with methylene chloride and then a mixture of methylene chloride and acetonitrile (10:1) as eluents to afford a solid, which was recrystallized from a mixture of ethyl acetate and cyclohexane to give 8-(2-methoxycarbonylamino-6-methylbenzyloxy)-2-methyl-3-(2-propynyl)imidazo[1,2-a]pyridine.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:25])([CH3:24])[C@@H:11]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH:12]=[O:13])(=[O:7])=[O:6].CC(C)=[O:28]>>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:25])([CH3:24])[C@@H:11]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:12]([OH:28])=[O:13])(=[O:7])=[O:6]
Reactant: CC(C)=O
Reactant: COc1ccc(CO[C@@H](C=O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Product: COc1ccc(CO[C@@H](C(=O)O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Yield: 96 %

Procedure:
Following the general procedure for the oxidation of aldehydes to carboxylic acids of Description 13, (3R)-3-[(4-methoxyphenyl)methoxy]-2,2-dimethyl-4-oxobutyl (3-chloropropyl)sulfonate (13b) (2.0 g, 5.1 mmol) dissolved in 30 mL of acetone was reacted with 2.6 mL of Jones-reagent (2.0 M in water). After work-up, 2.0 g (96% yield) of the title compound (13) was obtained as a colorless oil. 1H NMR (400 MHz, CDCl3): δ=1.09 (s, 3H), 1.10 (s, 3H), 2.28-2.35 (m, 2H), 3.27-3.31 (m, 2H), 3.66-3.69 (m, 2H), 3.82 (s, 3H), 3.88 (s, 1H), 4.02 (d, J=9.2 Hz, 1H), 4.19 (d, J=9.2 Hz, 1H), 4.45 (d, J=10.8 Hz, 1H), 4.60 (d, J=10.8 Hz, 1H), 6.90 (d, J=8.8 Hz, 2H), 7.28 (d, J=8.8 Hz, 2H) ppm. MS (ESI) m/z 430.90 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:24]=[N:23][N:22]([CH:25]([CH3:27])[CH3:26])[C:16]=2[N:17]=[C:18]([CH:20]=[CH2:21])[CH:19]=1)=[O:13].C[N+]1([O-])CCOCC1.[OH2:36].C[OH:38].C(Cl)Cl>C(Cl)Cl.O=[Os](=O)(=O)=O>[OH:36][CH:20]([C:18]1[CH:19]=[C:14]([C:12]([NH:11][CH2:10][C:3]2[C:4](=[O:9])[NH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])=[O:13])[C:15]2[CH:24]=[N:23][N:22]([CH:25]([CH3:27])[CH3:26])[C:16]=2[N:17]=1)[CH2:21][OH:38]
Reactant: C=Cc1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2cnn(C(C)C)c2n1
Reactant: CO
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(C(O)CO)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-vinyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.8 g, 2.19 mmol) in DCM (10 mL), N-Methylmorpholine-N-oxide (0.769 g, 6.57 mmol) was added at 0° C. Then OsO4 (2.5% in t-BuOH) (0.139 g, 5.56 mL, 0.547 mmol) was added to it. Resulting solution was stirred at room temperature for 1 h. After completion of reaction, water was added to it and extraction was carried out using 20% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired product