Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.CS(C)=O.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1([CH2:28]Br)[O:24][CH:23]([CH2:25][O:26][CH3:27])[CH2:22][O:21]1>O>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1([CH2:28][N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)[O:24][CH:23]([CH2:25][O:26][CH3:27])[CH2:22][O:21]1
Reactant: COCC1COC(CBr)(c2ccc(Cl)cc2Cl)O1
Reactant: c1nc[nH]n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COCC1COC(Cn2cncn2)(c2ccc(Cl)cc2Cl)O1
Temperature: 80 °C

Procedure:
A mixture of 13 parts of powdered potassium hydroxide (85% purity), 15 parts of 1H-1,2,4-triazole and 165 parts of dimethylsulfoxide is heated at 80° C. for 1 hour. 58 Parts of 2-(2,4-dichlorophenyl)-2-(bromomethyl)-4-(methoxymethyl)-1,3-dioxolane are added and the whole is heated at 150° C. for 12 hours. The reaction mixture is poured onto 1000 parts of water. The product is extracted with 1,1'-oxybisethane. The extract is dried, filtered and evaporated. The residue is distilled under high vacuum yielding pure 1-[2-(2,4-dichlorophenyl)-4-(methoxymethyl)-1,3-dioxolan-2-ylmethyl]-1H-1,2,4-triazole; bp. 161°-168° C. at 0.01 mm. pressure. The product crystallizes on standing, yielding a solid having a melting point of 64°-74° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[F:11][C:12]1[CH:20]=[CH:19][C:15]([CH2:16][CH2:17]Br)=[CH:14][CH:13]=1.O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>[F:11][C:12]1[CH:20]=[CH:19][C:15]([CH2:16][CH2:17][N:9]([C:6]2[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=2)[NH2:10])=[CH:14][CH:13]=1
Reactant: Fc1ccc(CCBr)cc1
Reactant: NNc1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Cl-]
Solvent: O
Product: NN(CCc1ccc(F)cc1)c1ccc(Cl)cc1
Temperature: 77.5 °C

Procedure:
The title compound was prepared by General Method 2. 4-chlorophenylhydrazine hydrochloride (2.2 g) was added to a vigorously stirred mixture of tetra-n-butylammonium chloride (200 mg) in 50% aqueous sodium hydroxide (12 mL) followed by 4-fluorophenethyl bromide (2.5 g). The mixture was heated at 75-80° C. (oil bath temp.) for 3.5 h. After cooling to room temperature, water was added and the mixture extracted with chloroform and the chloroform layer was washed with brine. The combined extract was dried (sodium sulfate), evaporated in vacuo to give a dark oil which was chromatographed over silica gel, eluting with chloroform followed by recrystallization from cyclohexane to obtain 750 mg of product.
Reaction SMILES: [CH:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([CH3:13])[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CI.O.[C:17](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(Cl)Cl>[CH:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([CH3:13])[N:8]2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(=O)n(C2CCCCC2)[nH]1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: Cc1cc(=O)n(C2CCCCC2)n1C
Temperature: 40 °C
Reaction time: 3.5 h

Procedure:
A suspension of 2-cyclohexyl-5-methyl-1H-pyrazol-3(2H)-one (525 g, 2834 mmol) in N,N-dimethylformamide (2200 mL) was heated to 40° C. and methyl iodide (532 mL, 8502 mmol) was added. The reaction mixture was heated to 70° C. for 20 h. Further methyl iodide (177 mL, 2834 mmol) was added and the mixture was stirred at 75° C. for 3.5 hours, then 80° C. for 20 hours. The resulting mixture was concentrated under reduced pressure and the residue was triturated with TBME (2000 ml). The product was collected by filtration, washing with TBME (5×500 ml) to give a solid which was suspended in DCM (2500 ml) and water (500 ml) and neutralized with 2M potassium carbonate solution (1700 ml) to pH>9. The phases were separated and the aqueous layer was extracted with DCM (3×500 ml). The organic extracts were washed with brine (1000 ml) and concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (2000 ml), dried over anhydrous sodium sulfate and filtered through 200 g of silica gel (40-63 μm), washing with ethyl acetate/methanol 9:1 (7×300 ml). The filtrate was concentrated under reduced pressure and to give the title compound as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:20](=[O:32])[N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:22]([CH3:25])[C:23]=3[CH3:24])=[O:18])=[C:11]([Cl:33])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[C:41](OC(=O)C)(=[O:43])[CH3:42]>>[C:41]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:20](=[O:32])[N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:22]([CH3:25])[C:23]=3[CH3:24])=[O:18])=[C:11]([Cl:33])[CH:10]=2)[CH:5]=[CH:4][N:3]=1)(=[O:43])[CH3:42]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C(=O)Nc2cc(F)c(Oc3ccnc(N)c3)cc2Cl)c(=O)n(-c2ccccc2)n1C
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(Oc2cc(Cl)c(NC(=O)c3c(C)n(C)n(-c4ccccc4)c3=O)cc2F)ccn1
Temperature: 30 °C
Reaction time: 12 h
Yield: 50.5 %

Procedure:
To a solution of N-(4-((2-aminopyridin-4-yl)oxy)-2-chloro-5-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (200 mg, 0.43 mmol) in acetic anhydride (4 mL) was added Et3N (400 mg, 2.6 mmol). The mixture was stirred at 30° C. for 12 hours and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/CH3OH (v/v)=40/1) to give the title compound as a light yellow solid (110 mg, 50.5%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:25]#[CH:26])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].C([O-])([O-])=O.[Cs+].[Cs+].C([O-])(O)=O.[Na+]>C1COCC1.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.[Cu]I>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:25]#[C:26][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:4][CH:3]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: C#Cc1ccc(OC)c(OC)c1
Reactant: CC(=O)NC(C)Cc1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: COc1ccc(C#Cc2ccc(CC(C)NC(C)=O)cc2)cc1OC
Temperature: 25 °C

Procedure:
To 0.40 g (1.32 mmol) N-[2-(4-iodo-phenyl)-1-methyl-ethyl]-acetamide (I52.1) and 0.21 g (1.32 mmol) 3,4-dimethoxyphenyl acetylene in 5 mL THF are added 0.10 g (0.13 mmol) bis-(triphenylphosphin)-palladium(II)-chlorid, 26.0 mg (0.14 mmol) CuI and 0.56 g (1.72 mmol) Cs2CO3. The mixture is stirred in a sealed tube at r.t. over night. The reaction mixture is poured onto sat. aq. NaHCO3 solution and extracted with EtOAc (2×). The organic layer is dried with Na2SO4 and the solvent is removed in vacuo. The residue is purified by HPLC (ACN/MeOH/TFA).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][C:11]([F:19])([F:18])[CH2:12][CH2:13][B-](F)(F)F>>[F:10][C:11]([F:19])([F:18])[CH2:12][CH2:13][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: F[B-](F)(F)CCC(F)(F)F
Product: O=Cc1ccc(CCC(F)(F)F)cc1
Yield: 89.4 %

Procedure:
The compound was synthesized as in Example 3.1 using 4-bromobenzaldehyde (250 mg, 1.35 mmol) in place of 5-bromo-2-formylfuran and 3,3,3-trifluoropropyltrifluoroborate (455 mg, 2.23 mmol) in place of hexylboronic acid to give 4-(3,3,3-trifluoropropyl)benzaldehyde (244 mg, 89%). Used without further characterization.
Reaction SMILES: Cl.Cl.[N:3]1([NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:16][CH:17]=2)=[O:11])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[H-].[Na+].Cl[CH2:27][C:28]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[O:29]>CN(C=O)C>[N:30]1([C:28](=[O:29])[CH2:27][N:6]2[CH2:5][CH2:4][N:3]([NH:9][C:10]([C:12]3[CH:17]=[N:16][C:15]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[N:14][CH:13]=3)=[O:11])[CH2:8][CH2:7]2)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: O=C(CCl)N1CCOCC1
Reactant: O=C(NN1CCNCC1)c1cnc(-c2ccccc2)nc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NN1CCN(CC(=O)N2CCOCC2)CC1)c1cnc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.6 %

Procedure:
A solution of 2-phenyl-pyrimidine-5-carboxylic acid piperazin-1-ylamide dihydrochloride (0.43 mmol) and NaH (60%, 2.15 mmol) in DMF (10 mL) is stirred under N2 at rt for 20 min. 2-Chloro-1-morpholin-4-yl-ethanone (0.65 mmol)) is added and the reaction mixture is stirred at rt overnight. The reaction mixture is quenched with water, and extracted with EtOAc. The organic layer is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0-4% methanol in DCM to afford 2-phenyl-pyrimidine-5-carboxylic acid [4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazin-1-yl]-amide (24 mg, 14%) as a solid. MS: 411 (M+H); 1H NMR (300 MHz, CDCl3): δ 2.85-3.10 (m, 2H), 3.60-4.00 (m, 12H), 4.46 (d, 2H), 4.84 (s, 2H), 7.44-7.62 (m, 3H), 8.34-8.58 (m, 2H), 9.20-9.38 (d, 2H). IC50=831.5 nM.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[Cl:37])[C@@H:14]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[C@@:12]3([CH2:38][OH:39])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:40]>O1CCOCC1>[NH2:40][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:14][O:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[C@@H:27]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[Cl:37])[C@@:12]3([CH2:38][OH:39])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OC[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(Cl)ncnc21
Reactant: N
Solvent: C1COCCO1
Product: Nc1ncnc2c1ccn2[C@@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@]1(O)CO
Temperature: -78 °C

Procedure:
The compound from Step A (150 mg, 0.23 mmol) was dissolved in the minimum amount of 1,4-dioxane (10 mL) and placed in a stainless steel bomb. The bomb was cooled to −78° C. and liquid ammonia was added. The bomb was sealed and heated at 90° C. for 24 h. The ammonia was allowed to evaporate and the residue concentrated to a white solid which was used in the next step without further purification.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[NH:24][C:25]([CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([OH:37])=[O:36])[CH2:30][CH2:29]1)=[O:26].[OH:38][CH:39]([C:50]1[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=1)[C:40]([C:42]1[CH:47]=[CH:46][C:45]([CH2:48][CH3:49])=[CH:44][CH:43]=1)=O.CN(C1C=CC=CN=1)C>CN(C)C=O.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH3:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH3:16])[C:18]=1[NH:24][C:25]([CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([O:37][CH:40]([C:42]2[CH:43]=[CH:44][C:45]([CH2:48][CH3:49])=[CH:46][CH:47]=2)[C:39](=[O:38])[C:50]2[CH:51]=[CH:52][C:53]([CH2:56][CH3:57])=[CH:54][CH:55]=2)=[O:36])[CH2:30][CH2:29]1)=[O:26]
Reactant: CCc1ccc(C(=O)C(O)c2ccc(CC)cc2)cc1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(CC(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1ccc(C(=O)C(OC(=O)CN2CCN(CC(=O)Nc3c(C)cccc3C)CC2)c2ccc(CC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.5 %

Procedure:
1,3-Dicyclohexylcarbodiimide (DCC; 0.81 g, 3.92 mmol) was added in one portion to a rapidly-stirred mixture of 4-[[[(2,6-dimethylphenyl)amino]carbonyl]methyl]-1-piperazineacetic acid (1.0 g, 3.27 mmol), 2-hydroxy-1,2-di-(4-ethylphenyl)ethanone (IX; 0.88 g, 3.27 mmol) and dimethylaminopyridine (DMAP: 40 mg) in anhydrous dimethylformamide (25 mL). After 2 hours at ambient temperature, an additional equivalent of DCC and DMAP were added. The mixture was stirred further for 22 hours at room temperature before it was heated to 70° C. for 6 hours. Upon cooling, the mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and brine, dried and concentrated. Purification of the residue by flash chromatography on silica gel (gradient elution with 50% ethyl acetate in hexanes followed by ethyl acetate) afforded 0.50 g of the benzoin ester product (VI) as an off-white solid. The ester was used in subsequent reactions without additional purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]=O)=[C:12]([Cl:19])[CH:11]=1.[BH3-]C#N.[Na+].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CO.C(Cl)Cl>[Cl:19][C:12]1[CH:11]=[C:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH:15]=[CH:14][C:13]=1[CH2:16][CH2:17][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: C1COCCN1
Reactant: O=CCc1ccc(-c2nc3ccccc3o2)cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Clc1cc(-c2nc3ccccc3o2)ccc1CCN1CCOCC1

Procedure:
The crude aldehyde was treated with NaCNBH3 and morpholine in MeOH/CH2Cl2 (2 mL). The crude mixture was adsorbed onto silica gel and purified by automated flash chromatography using an EtOAc/hexanes gradient to afford the desired 2-[3-chloro-4-(2-morpholin-4-ylethyl)phenyl]-1,3-benzoxazole: 1H NMR (CDCl3, 300 MHz) δ 8.26–8.25 (d, 1H), 8.09–8.06 (m, 1H), 7.79–7.74 (m, 1H), 7.43–7.34 (m, 3H), 3.78–3.75 (m, 4H), 3.05–3.00 (m, 2H), 2.68–2.59 (m, 6H). MS (ESI) 343 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH2:8][NH2:9])[CH:5]=[N:6][CH:7]=1.N1C=CC=C(CN)C=1.[CH3:18][C:19]1[N:20]=[C:21]([N:27]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36])[C:28]2=[O:39])[S:22][C:23]=1[C:24](O)=[O:25]>>[CH3:18][C:19]1[N:20]=[C:21]([N:27]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][C:35]([F:36])([F:37])[F:38])[C:28]2=[O:39])[S:22][C:23]=1[C:24]([NH:9][CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[CH:2][CH:3]=1)=[O:25]
Reactant: Cc1nc(N2CCN(CCCC(F)(F)F)C2=O)sc1C(=O)O
Reactant: NCc1cncc(F)c1
Agent: NCc1cccnc1
Product: Cc1nc(N2CCN(CCCC(F)(F)F)C2=O)sc1C(=O)NCc1cccnc1
Yield: 50 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with pyridin-3-ylmethanamine to react with 4-methyl-2-(2-oxo-3-(4,4,4-trifluorobutyl)imidazolidin-1-yl)thiazole-5-carboxylic acid in place of 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 50% yield: mp 167-169° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.62-8.52 (m, 2H), 7.69-7.66 (m, 1H), 7.26-7.24 (m, 1H), 6.28-6.25 (m, 1H), 4.57 (d, J=5.9 Hz, 2H), 4.14-4.09 (m, 2H), 3.62-3.56 (m, 2H), 3.40-3.36 (m, 2H), 2.60 (s, 3H), 2.18-2.09 (m, 2H), 1.89-1.79 (m, 2H); MS (ES+) m/z 428.1 (M+1).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[N:15]([S:31]([C:34]4[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=4)(=[O:33])=[O:32])[C:16]([C:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=4)=[CH:17][C:10]=23)O1.Br[C:43]1[CH:44]=[CH:45][C:46]2[N:50]=[N:49][N:48]([CH2:51][CH:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)[C:47]=2[CH:58]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[O:55]1[CH2:56][CH2:57][CH:52]([CH2:51][N:48]2[C:47]3[CH:58]=[C:43]([C:9]4[CH:14]=[CH:13][N:12]=[C:11]5[N:15]([S:31]([C:34]6[CH:35]=[CH:36][C:37]([CH3:38])=[CH:39][CH:40]=6)(=[O:33])=[O:32])[C:16]([C:18]6[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=6)=[CH:17][C:10]=45)[CH:44]=[CH:45][C:46]=3[N:50]=[N:49]2)[CH2:53][CH2:54]1
Reactant: Cc1ccc(S(=O)(=O)n2c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc3c(B4OC(C)(C)C(C)(C)O4)ccnc32)cc1
Reactant: Brc1ccc2nnn(CC3CCOCC3)c2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc3c(-c4ccc5nnn(CC6CCOCC6)c5c4)ccnc32)cc1
Temperature: 80 °C

Procedure:
A mixture of Example 36D (0.800 g, 1.380 mmol), 6-bromo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-benzo[d][1,2,3]triazole (0.450 g, 1.519 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.045 g, 0.055 mmol), and aqueous sodium bicarbonate (6 mL, 1.380 mmol) in N,N-dimethylformamide (20 mL) was degassed and the mixture was heated at 80° C. for 2.5 hours. The reaction mixture was diluted with ethyl acetate and washed with aqueous NaHCO3/brine and water, dried over MgSO4, filtered, and purified on a 40 g column using the ISCO Companion flash system eluting with heptanes/ethyl acetate (4:6 to 3:7) to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:14][C:15]1[N:19]([CH2:20][CH3:21])[N:18]=[CH:17][CH:16]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Cu+2].O.C(O)(=O)C>[CH2:20]([N:19]1[C:15]([NH:14][C:2]2[C:3](=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=2)[C:4]([OH:6])=[O:5])=[CH:16][CH:17]=[N:18]1)[CH3:21]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CCn1nccc1N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nccc1Nc1ccc([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C
Yield: 68.8 %

Procedure:
A mixture of 2-chloro-5-nitrobenzoic acid (4.03 g, 0.02 mol), 5-amino-1-ethylpyrazole (2.22 g, 0.02 mol), DMF (25 ml), K2CO3 (2.76 g, 0.02 mol) and Cu(OAc)2.H2O (0.5 g) was refluxed for 24 hours. The reaction mixture was cooled to room temperature, poured into ice-water and acidified with acetic acid to a pH of 5. A solid formed which was collected by filtration and dried to afford 3.8 g (68%) of N-(1-ethylpyrazol-5-yl)-5-nitroanthranilic acid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]2)[CH2:3][CH2:2]1.ClC(Cl)C.[CH3:35][C:36]([CH3:41])([CH3:40])[CH2:37][CH:38]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(N(CC)CC)C.C1COCC1>[CH3:35][C:36]([CH3:41])([CH3:40])[CH2:37][CH2:38][N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)CC=O
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C2CCNCC2)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC(Cl)Cl
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C2CCN(CCC(C)(C)C)CC2)cn1
Reaction time: 8 h

Procedure:
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (1-piperidin-4-yl-1H-imidazol-4-yl)-amide (100 mg, 2.4 mmol) was charged with 1 mL of THF, 1 mL of Dichloroethane, 0.06 mL of triethyamine, 0.03 mL of 3,3-dimethylbutyraldehyde, and 63 mg of sodiumtriacetoxyborohydride. The reaction was stirred overnight, quenched with sodiumbicarbonate, extracted with methylene chloride, and the resultant oil purified by silica gel chromatography to afford the title compound: C13 NMR (100 MHz, CDCl3) 13.9, 18.8, 29.7, 29.9, 33.3, 36.0, 40.9, 43.1, 52.9, 53.1, 54.5, 55.9, 102.8, 103.1, 105.9, 112.3, 112.4, 112.5, 112.6, 131.5, 137.6, 169.2; MS 504.3 m/z (M+1)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([N:20](CC)CC)[CH3:19].ClCC#N>CC(C)=O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([O:14][CH2:19][C:18]#[N:20])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)O)c1
Agent: N#CCCl
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)Nc1cccc(C(=O)OCC#N)c1
Yield: 94.5 %

Procedure:
A mixture of 3-(t-butyloxycarbonylamino)benzoic acid (20 g), triethylamine (12.8 g), chloroacetonitrile (9.4 g) and acetone (150 ml) is refluxed for 4 hours. After acetone is distilled off under reduced pressure, the residue is dissolved in ethyl acetate (200 ml), and the solution is washed with water, and ethyl acetate is distilled off under reduced pressure. The residue is recrystallized from 80% aqueous acetonitrile solution to give the title compound (22 g, 99%) as white short needles.
Reaction SMILES: [NH:1]([C:5]1[CH:40]=[CH:39][C:8]([C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH2:22][C:21]([CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])([CH2:23][C:24](=[O:30])[O:25]C(C)(C)C)[O:20][N:19]=3)[CH:13]=2)=[O:10])=[CH:7][CH:6]=1)[C:2]([NH2:4])=[NH:3].[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>>[F:44][C:43]([F:46])([F:45])[C:41]([OH:47])=[O:42].[NH:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][C:12]2[CH:13]=[C:14]([C:18]3[CH2:22][C:21]([CH2:31][C:32]([OH:34])=[O:33])([CH2:23][C:24]([OH:30])=[O:25])[O:20][N:19]=3)[CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:39][CH:40]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)CC(c2cccc(OC(=O)c3ccc(NC(=N)N)cc3)c2)=NO1
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)Nc1ccc(C(=O)Oc2cccc(C3=NOC(CC(=O)O)(CC(=O)O)C3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(5,5-bis(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazol-3-yl)phenyl 4-carbamimidamidobenzoate (94.1 mg) and TFA (1 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and then, the residue was washed with diethyl ether to obtain the title compound (63.3 mg).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5](=[O:28])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[C:15]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[N:16][O:17][C:18]=2[CH:19]=[O:20])=[N:8][CH:7]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH3:3][O:4][C:5](=[O:28])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[C:15]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)=[N:16][O:17][C:18]=2[CH2:19][OH:20])=[N:8][CH:7]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2C=O)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nc1
Yield: 91 %

Procedure:
Sodium borohydride (719 mg, 18.2 mmol) was added in portions to 6-[3-(4-chloro-phenyl)-5-formyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (3.4 g, 9.12 mmol) in methanol (170 mL). After stirring for 1 h at room temperature a solution of citric acid (10% in water) was added. Extraction with ethyl acetate and chromatography (silica, ethyl acetate:heptane=1:9 to 1:1) afforded the title compound (3.11 g, 91%) as a white solid. MS: m/e=375.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C1COCC1.O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(-c2ccc(C(=O)OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Yield: 71.1 %

Procedure:
A mixture of methyl 4-(4-butylphenyl)benzoate (89.0 g, 0.332 mol), NaOH (26.6 g, 0.664 mol) in THF/H2O (500 mL/100 mL) was heated to reflux overnight. After TLC showed the reaction was complete, THF was removed. The residue was adjusted pH ˜3-4 with 2 N HCl solution. The resulting mixture was filtered and the cake was washed with water, dried to give 4-(4-butylphenyl)benzoic acid (60.0 g, yield: 71.1%), as a white solid. (ESI) m/z 255.0 (M+H)+.