Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]([OH:24])=O.[CH3:25][NH:26][CH2:27][CH2:28][OH:29]>O1CCCC1>[CH3:25][N:26]([CH2:27][CH2:28][OH:29])[C:22]([C:14]1[NH:13][C:21]2[C:16]([CH:15]=1)=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:24]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CNCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(CCO)C(=O)c1cc2ccccc2[nH]1
Reaction time: 1 h

Procedure:
1,1'-carbonyldiimidazole (1.11 g) is added to a solution of indole-2-carboxylic acid (1.0 g) in tetrahydrofuran (15 ml). The mixture is stirred 1 hour at 20°-25° and 2-(methylamino)ethanol (5.0 ml) is added. The mixture is stirred 21 hours at 20°-25° and 24 hours at reflux. The mixture is concentrated under reduced pressure, diluted with methylene chloride and extracted with water and saturated sodium bicarbonate. The phases are separated and the organic phase is dried with saline and sodium sulfate and concentrated to give the crude product. Chromatography on silica gel with a methanol/chloroform gradient followed by recrystallization from chloroform/ether to give the title compound, mp 141°-142.5°.
Reaction SMILES: [CH2:1]1[CH:12]2[CH:4]([NH:5][C:6]3[C:7]([C:13]([NH:15][C@@H:16]([CH3:20])[C:17](O)=[O:18])=[O:14])=[CH:8][CH:9]=[CH:10][C:11]=32)[CH2:3][CH2:2]1>C(O)(=O)C>[CH3:20][C@@H:16]1[NH:15][C:13](=[O:14])[C:7]2=[C:6]3[C:11](=[CH:10][CH:9]=[CH:8]2)[CH:12]2[CH2:1][CH2:2][CH2:3][CH:4]2[N:5]3[C:17]1=[O:18]
Reactant: C[C@H](NC(=O)c1cccc2c1NC1CCCC21)C(=O)O
Solvent: CC(=O)O
Product: C[C@@H]1NC(=O)c2cccc3c2N(C1=O)C1CCCC31
Temperature: 25 °C
Yield: 63.9 %

Procedure:
A solution of (2S)-2-[(1,2,3,3a,4,8b-hexahydrocyclopenta[b]indol-5-ylcarbonyl)amino]propanoic acid (6.1 mmol, 1.6 g) was dissolved in acetic acid (50 mL) and heated to reflux for 18 h. The reaction was allowed to cool to room temperature and was concentrated to dryness. The crude material was purified by flash column chromatography (silica gel; 1:1 ethyl acetate-hexanes) to provide two diastereomers: less polar product (0.88 mmol, 0.23 g, 14%) and more polar product (0.18 mmol, 45 mg, 3%). The mixed fractions were also collected to provide another 3.9 mmol (1.0 g, 64%) of material.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13].Cl[CH2:15][C:16]([NH2:18])=[O:17].C(=O)([O-])[O-].[Ca+2].[I-].[K+]>O.CC(C)=O>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:13][CH2:15][C:16]([NH2:18])=[O:17]
Reactant: NC(=O)CCl
Reactant: COCc1cc([N+](=O)[O-])ccc1O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Agent: [I-]
Solvent: CC(C)=O
Solvent: O
Product: COCc1cc([N+](=O)[O-])ccc1OCC(N)=O
Temperature: 25 °C
Yield: 61 %

Procedure:
25 g of 2-methoxymethyl-4-nitrophenol, 14 g of chloroacetamide, 18.9 g of calcium carbonate, and 12.5 g of potassium iodide in a 150 ml of acetone are heated under reflux for four hours. Subsequently the reaction mixture is cooled to room temperature and poured into water. The resulting precipitate is filtered, washed with water and subsequently dried. 20 g of a pale yellow product is obtained having a melting point of from 157 to 158° C.
Reaction SMILES: [H-].[Na+].[CH2:3]1COCC1.[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH:22][C:21](=[O:29])[CH2:20][N:19]=2)[CH:9]=1.CI>O>[CH3:3][N:22]1[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:18]([C:10]2[CH:9]=[N:8][C:17]3[C:12]([CH:11]=2)=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:19][CH2:20][C:21]1=[O:29]
Reactant: O=C1CN=C(c2cnc3ccccc3c2)c2ccccc2N1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CN1C(=O)CN=C(c2cnc3ccccc3c2)c2ccccc21
Reaction time: 0.33 h
Yield: 53 %

Procedure:
60% sodium hydride (62.8 mg, 1.57 mmol) was added to 25 mL of THF solution of 5-(3-quinolinyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (0.30 g, 1.04 mmol) at 0° C., followed by stirring at the same temperature for 20 minutes. Moreover, methyl iodide (0.18 g, 1.25 mmol) was added to the resulting solution, followed by bringing back to room temperature and stirring for 12 hours. 20 mL of water was slowly added to the reaction solution to stop the reaction. The resulting solution was extracted twice with 50 mL of ethyl acetate, and the extracted organic layers were mixed, followed by washing with 50 mL of brine and drying with magnesium sulfate. After filtering and concentrating, the resulting residue was purified by silica gel column chromatography to obtain the target compound (0.17 g, yield: 53%), which was slightly yellow amorphous.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C1(OC)C=CC=CC=1.N(CC1C=CC(OC)=CC=1)=[N+]=[N-].[F:25][C:26]1[C:27](=[O:47])[NH:28][C:29](=[O:46])[N:30]([C@H:32]2[CH2:35][C@@H:34]([CH2:36][CH2:37][O:38]CC3C=CC=CC=3)[CH2:33]2)[CH:31]=1>CO>[F:25][C:26]1[C:27](=[O:47])[NH:28][C:29](=[O:46])[N:30]([C@H:32]2[CH2:35][C@@H:34]([CH2:36][CH2:37][OH:38])[CH2:33]2)[CH:31]=1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@@H](CCOCc3ccccc3)C2)cc1F
Agent: COc1ccc(CN=[N+]=[N-])cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: CO
Product: O=c1[nH]c(=O)n([C@H]2C[C@@H](CCO)C2)cc1F
Temperature: 0 °C

Procedure:
In a 10 mL flask with AlCl3 (0.81 g, 6.2 mmol) inside, dry anisole 3 mL was added under argon to give a light yellow solution. In another flask with N3-PMB -5-fluoro-1-[cis-3-(benzyloxyethyl)cyclobutyl]uracil (0.27 g, 0.62 mmol) inside, dry anisole 2 mL was added, after which time AlCl3 solution was added to it slowly at room temperature by syringe pump. After addition finishes, the mixture was cooled to 0° C. and dry MeOH was added slowly to give a colorless solution at the end. Then the solvents were removed and the product was purified by silica gel flash chromatography (CH2Cl2:MeOH=20:1) to give a white solid (73.7 mg, 53.4%) combined with some three-membered ring by-products. 1H NMR (CD3OD, 300 MHz): δ 1.68-1.74 (m, 2H), 1.86-1.95 (m, 2H), 2.11-2.20 (m, 1H), 2.48-2.55 (m, 2H), 3.52-3.59 (m, 2H), 4.57-4.69 (m, 1H), 7.90-7.93 (d, J=6.9, 1H). 13C NMR (CDCl3, 100 MHz): δ 10.02, 10.93, 15.94, 18.55, 26.78, 36.15, 37.49, 40.11, 47.47, 53.57, 61.10, 62.87, 127.81, 128.14, 131.01, 131.35, 140.70, 143.01, 151.84, 152.19, 160.41. MS (FAB): expected for C10H13FN2O3 (M+H)+ 229.22. Found 229.09835. IR (neat) νmax 3411, 3187, 3063, 2934, 1697, 1473, 1357, 1272, 1243, 1043, 899, 807, 751, 704.
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)=[CH:6][CH:5]=1)([O-])=O>C1COCC1.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH:14]([O:17][C:18]3[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=3)[CH2:15][CH2:16]2)=[CH:27][CH:28]=1
Reactant: O=[N+]([O-])c1ccc(OCCN2CCC(Oc3ccc([N+](=O)[O-])cc3)CC2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(OCCN2CCC(Oc3ccc(N)cc3)CC2)cc1
Yield: 76.6 %

Procedure:
N-2-(4-Nitrophenoxy)ethyl-4-(4-nitrophenoxy)piperidine (1.50 g, 3.87 mmol) was hydrogenated in THF/MeOH (1:1, 60 mL) at 50 psi over 10% Pd/C (0.5 g) for 16 hours. The mixture was filtered through solka floc and the filtrate was concentrated. Purification by flash chromatography (8% MeOH/CHCl3) gave 0.97 g (80%) of N-2-(4-aminophenoxy)ethyl-4-(4-aminophenoxy)piperidine as a yellow oil. 1H NMR (DMSO-d6): δ 6.65 (d, 4H), 6.50 (d, 4H), 4.60 (br s, 4H), 4.05 (m, 1H), 3.90 (t, 2H), 2.78 (m, 2H), 2.60 (t, 2H), 2.15 (m, 2H), 1.85 (m, 2H), 1.55 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Br:13]Br>Cl>[Br:13][C:5]1[CH:6]=[N:1][C:2]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[N:3][CH:4]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: BrBr
Agent: Cl
Product: Brc1cnc(N2CCNCC2)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
This example serves to illustrate procedure B of Scheme 2. To an ice-cooled solution of 1-(2-pyrimidinyl)piperazine (16.4 g, 0.1 mole) in 1N HCl (100 mL) was added dropwise bromine (15.98 g, 0.1 mole). After stirring at 0° for 0.5 hr, the mixture was heated to 100° until dissipation of the red color had occurred. The mixture is filtered, cooled, made alkaline with 50% NaOH and extracted with ether. The dried extract (MgSO4) was concentrated in vacuo to provide 14.5 g (62%) of product, m.p. 73°-75°.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@H:5]([CH3:19])[N:6]([C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=1)[CH2:7][CH2:8][CH2:9][CH3:10])C.[OH-].[Na+:22]>CO.O>[Na+:22].[CH3:18][S:17][C:14]1[CH:13]=[CH:12][C:11]([N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[C@H:5]([C:4]([O-:20])=[O:3])[CH3:19])=[CH:16][CH:15]=1
Reactant: CCCCN(c1ccc(SC)cc1)[C@@H](C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCN(c1ccc(SC)cc1)[C@@H](C)C(=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-(4-Methylthiophenyl)-N-(n-butyl)alanine ethyl ester (3.0 g, 10.1 mmol) was dissolved in 50 mL methanol and 5 mL of water was added. Sodium hydroxide (0.41 g, 10.1 mmol) was dissolved in a minimum amount of water, and added to the aqueous methanol solution. The mixture was stirred 18 h at room temperature, and then the solvent was removed at reduced pressure. The resulting white solid was used without purification.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]([CH3:11])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[O:18]1[CH:22]=[CH:21][N:20]=[C:19]1B(O)O>C1COCC1>[O:18]1[CH:22]=[CH:21][N:20]=[C:19]1[C:2]1[CH:3]=[C:4]([CH:8]([CH3:11])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1ncco1
Reactant: CC(C#N)c1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C#N)c1cccc(-c2ncco2)c1
Temperature: 25 °C
Yield: 78.1 %

Procedure:
To a solution of 2-(3-iodophenyl)propionitrile (0.6 g, 2.33 mmol) in dry THF (10 mL) Pd(PPh3)4 (4% mol, 0.108 mg) and Na2CO3 (0.493 g, 4.66 mmol) were added sequentially under nitrogen atmosphere. After stirring 20 min commercial 1,3-oxazole-2-boronic acid (0.289 g 2.56 mmol) was added. The reaction mixture was stirred at reflux 4 h. After cooling at room temperature, THF was evaporated under reduced pressure and EtOAc (10 mL) was added to the crude and the organic phase was washed with water (3×10 mL) and brine (3×10 mL). After drying over Na2SO4 and solvent evaporation a residue was obtained that, after flash chromatography (eluent mixture n-hexane/EtOAc 8:2), afforded 2-(3-oxazol-2-ylphenyl) propionitrile as yellow oil (0.360 g, 1.82 mmol). Yield 78%.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([C:20](=[O:22])C)[CH:11]=[CH:12][C:13]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>O1CCOCC1>[Cl:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=1[CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)[C:20]([OH:22])=[O:2]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(=O)c1ccc(C2CCCCC2)c(Cl)c1
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(C2CCCCC2)c(Cl)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
An aqueous alkaline solution of potassium permanganate (2.94 g, 0.0186 mol; in 22 mL 12% aqueous sodium hydroxide) is added to solution of 1-(3-chloro-4-cyclohexylphenyl)ethanone (2.2 g, 0.0093 mol) in dioxane (11 mL). The reaction mixture is stirred at 80° C. temperature for 2 hrs. It is then filtered and the filtrate is washed with diethyl ether (2×10 mL). The pH of the aqueous layer is adjusted to 1-2 by using 6N hydrochloric acid. It is extracted in ethyl acetate (3×15 mL). Combined organic layer is dried over sodium sulfate and concentrated to get the crude, which is purified using column chromatography (230-400 mesh; ethyl acetate:n-hexane, 1:3) to yield 3-chloro-4-cyclohexyl benzoic acid.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].[O-:12][S:13]([O-:15])=[O:14].[Na+].[Na+].O>CCO>[CH3:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[S:13]([OH:15])(=[O:14])=[O:12]
Reactant: Cc1cccc([N+](=O)[O-])c1F
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cccc([N+](=O)[O-])c1S(=O)(=O)O
Yield: 205.9 %

Procedure:
In a similar fashion using route 39 general procedure 95, 2-fluoro-3-nitrotoluene (2.5 g 16.1 mmol) in EtOH (60 ml) and Na2SO3 (4.61 g, 36.58 mmol) in EtOH: water (40 ml: 50 ml) at 70° C. for 16 h gave the title compound (7.2 g) which was used in the next step without further purification.
Reaction SMILES: S(Cl)(Cl)=O.C1(C2C=CC(C(O)=O)=CC=2)CCCCC1.C1(C2C=CC(C(Cl)=O)=CC=2)CCCCC1.[Cl:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][C:42]=1[O:43][C:44]1[C:53]2[C:48](=[CH:49][C:50]([O:56][CH3:57])=[C:51]([O:54][CH3:55])[CH:52]=2)[N:47]=[CH:46][CH:45]=1)[NH2:39].[CH:58]1([C:64]2[CH:69]=[CH:68][C:67]([C:70]([N:72]=[C:73]=[S:74])=[O:71])=[CH:66][CH:65]=2)[CH2:63][CH2:62][CH2:61][CH2:60][CH2:59]1>C1(C)C=CC=CC=1.C(O)C>[Cl:35][C:36]1[CH:37]=[C:38]([NH:39][C:73]([NH:72][C:70](=[O:71])[C:67]2[CH:68]=[CH:69][C:64]([CH:58]3[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63]3)=[CH:65][CH:66]=2)=[S:74])[CH:40]=[CH:41][C:42]=1[O:43][C:44]1[C:53]2[C:48](=[CH:49][C:50]([O:56][CH3:57])=[C:51]([O:54][CH3:55])[CH:52]=2)[N:47]=[CH:46][CH:45]=1
Reactant: O=C(N=C=S)c1ccc(C2CCCCC2)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)c1ccc(C2CCCCC2)cc1
Agent: O=C(O)c1ccc(C2CCCCC2)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(C5CCCCC5)cc4)cc3Cl)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 4-cyclohexylbenzoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 4-cyclohexyl-1-benzenecarbonyl isothiocyanate was prepared using the resultant 4-cyclohexyl-1-benzenecarbonyl chloride as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-cyclohexyl-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (47 mg, yield 54%).
Reaction SMILES: C([O:8][C:9](=[O:32])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:31])[CH:16]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[C:21]1([S:18]([NH:17][CH:16]([C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:10]2[C:9]([OH:32])=[O:8])=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29])(=[O:20])=[O:19])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: [H][H]
Reactant: CC(C)CC(NS(=O)(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)CC(NS(=O)(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Yield: 99.6 %

Procedure:
N-benzenesulfonyl-D,L-leucyl-L-proline benzyl ester (2 g) was dissolved in methanol (40 ml), and 10% palladium-carbon (200 mg) was added. The resulting mixture aerated with hydrogen was allowed to react at room temperature for 3 h, filtered and concentrated under reduced pressure to remove the solvent to give a white foam-like solid (1.6 g, 99%), which was directly used for the next reaction.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:12]([O:14][CH3:15])=[O:13])[C:4]2([CH2:9][CH2:10][CH:11]=1)[CH2:8][CH2:7][CH2:6][CH2:5]2.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>ClCCl>[CH3:1][C:2]12[O:24][CH:11]1[CH2:10][CH2:9][C:4]1([CH2:8][CH2:7][CH2:6][CH2:5]1)[CH:3]2[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)C1C(C)=CCCC12CCCC2
Solvent: ClCCl
Product: COC(=O)C1C2(CCCC2)CCC2OC21C
Temperature: 20 °C
Reaction time: 4 h
Yield: 96.6 %

Procedure:
At 5° C., a solution of methyl 7-methylspiro[4.5]dec-7-ene-6-carboxylate (13.5 g, 60 mmol, prepared as described in Example 25) in dichloromethane (150 ml) was treated with MCPBA (17.8 g, 72 mmol). The resulting mixture was stirred for 4 h at 20° C., filtered, and the organic phase was washed with water (100 ml), dried (MgSO4), concentrated, and gave crude methyl 1-methyl-7-oxaspiro[bicyclo[4.1.0]heptane-3,1′-cyclopentane]-2-carboxylate (13 g). Boiling point: 130° C. (0.08 mbar).
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH3:18].C([O-])([O-])=O.[Na+].[Na+].[CH3:26][O:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1B(O)O.CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[CH3:26][O:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[C:3]1[C:2]([F:1])=[CH:10][CH:9]=[C:8]2[C:4]=1/[C:5](=[CH:12]/[C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH3:18])/[C:6](=[O:11])[NH:7]2
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: COc1ccc(B(O)O)c(OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COCCOC
Product: COc1ccc(-c2c(F)ccc3c2/C(=C/c2[nH]cnc2C)C(=O)N3)c(OC)c1

Procedure:
A solution of (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (50 mg, 0.135 mmol) (Starting Material 11), 2M aqueous Na2CO3 solution (0.14 mL), (Ph3P)2PdCl2 (11 mg, 0.0135 mmol) and 2,4-dimethoxyphenylboronic acid (61.7 mg, 0.339 mmol) (Lancaster) in a 1:4 mixture of DMF:1,2-dimethoxyethane (5 mL) was heated at 104° C. for 2 days. The reaction mixture was concentrated and the crude material was purified by C18 reverse phase chromatography to give (Z)-1,3-Dihydro-4-(2,4-dimethoxyphenyl)-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 15 mg, 29%).
Reaction SMILES: C=O.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[C:13]([NH2:29])=[N:14][CH:15]=[C:16]([C:18]2[CH:19]=[N:20][N:21]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:22]=2)[N:17]=1.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].N>CO.C(Cl)Cl>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[C:13]([NH2:29])=[N:14][CH:15]=[C:16]([C:18]2[CH:19]=[N:20][N:21]([CH:23]3[CH2:24][CH2:25][N:26]([CH3:30])[CH2:27][CH2:28]3)[CH:22]=2)[N:17]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)nc1-c1nc2ccccc2o1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)n3)cn2)CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
37% Aqueous formaldehyde (0.049 ml) was added to a stirred solution 3-(1,3-benzoxazol-2-yl)-5-[1-(4-piperidyl)pyrazol-4-yl]pyrazin-2-amine (200 mg, 0.55 mmol) dissolved in methanol (2 ml) and DCM (2 ml) over a period of 5 minutes at 0° C. under an atmosphere of argon. The resulting solution was stirred at 0° C. for 5 minutes. Sodium triacetoxyborohydride (0.141 g) was added and the mixture was stirred for 5 minutes at ambient temperature. A solution of ammonia in methanol 7N (1 ml) was added and the mixture was adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel (eluting with 1 to 5% methanolic ammonia (7 N) in dichloromethane). The solvent was evaporated to dryness and there was thus obtained 3-(1,3-benzoxazol-2-yl)-5-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyrazin-2-amine (0.165 g); Mass Spectrum: M+H+ 376; NMR Spectrum (DMSOd6): 8.67 (s, 1H), 8.36 (s, 1H), 8.03 (s, 1H), 7.90 (d, 1H), 7.88 (d, 1H), 7.84 (bs, 2H), 7.51 (dd, 1H), 7.47 (dd, 1H), 4.13-4.24 (m, 1H), 2.82-2.94 (m, 2H), 2.21 (s, 3H), 1.95-2.12 (m, 6H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH:16]3[C:23]4[CH:22]=[C:21]([C:24]([O:26]C)=[O:25])[NH:20][C:19]=4[CH2:18][CH2:17]3)[CH:10]=2)=[CH:5][CH:4]=1.[OH-].[Li+].CO>C1COCC1>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH:16]3[C:23]4[CH:22]=[C:21]([C:24]([OH:26])=[O:25])[NH:20][C:19]=4[CH2:18][CH2:17]3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(-c2ccc(CO)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1cccc(-c2ccc(CO)cc2)c1

Procedure:
The title compound was synthesized from methyl 4-((4′-(hydroxymethyl)biphenyl-3-yl)methyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.012 g, 0.033 mmol) and lithium hydroxide (0.016 g, 0.38 mmol in 0.5 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (1 mL) was used. The resulting product was purified by reverse phase HPLC, eluting with a gradient of 40-100% MeOH: water (with 0.1% formic acid) to afford the title compound: 4.5 mg, 39% yield. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.10-2.18 (m, 1H), 2.52-2.63 (m, 3H), 2.79-2.91 (m, 2H), 3.33 (d, J=1.61 Hz, 1H), 4.64 (s, 2H), 6.39 (s, 1H), 7.19 (s, 1H), 7.34 (s, 2H), 7.42 (s, 3H), 7.56 (d, J=8.30 Hz, 2H); LCMS-MS (ESI−) 346.2 (M−H); HPLC (UV=93.1%), (ELSD=100%).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[C:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][C:34]([F:37])([F:36])[F:35])=[N:21][O:22][C:23]=3[CH:24]([CH3:26])[CH3:25])=[CH:13][C:12]=2[CH3:38])=[C:8]([CH3:10])[CH:9]=1)=O.O.[NH2:40][NH2:41]>CCO>[CH:24]([C:23]1[O:22][N:21]=[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][C:34]([F:37])([F:36])[F:35])[C:19]=1[CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:7]2[S:6][C:5]([C:3]([NH:40][NH2:41])=[O:2])=[CH:9][C:8]=2[CH3:10])=[C:12]([CH3:38])[CH:13]=1)([CH3:26])[CH3:25]
Reactant: COC(=O)c1cc(C)c(-c2ccc(OCc3c(-c4ccccc4OC(F)(F)F)noc3C(C)C)cc2C)s1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1cc(OCc2c(-c3ccccc3OC(F)(F)F)noc2C(C)C)ccc1-c1sc(C(=O)NN)cc1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of 5-{4-[5-isopropyl-3-(2-trifluoromethoxy-phenyl)-isoxazol-4-ylmethoxy]-2-methyl-phenyl}-4-methyl-thiophene-2-carboxylic acid methyl ester (980 mg, 1.8 mmol) in EtOH (7 mL) is added hydrazine hydrate (5 mL) and the mixture is stirred at 80° C. overnight. The reaction mixture is concentrated under reduced pressure. The residue is partitioned between EtOAc and water. The layers are separated and the organic phase is concentrated under reduced pressure to give 5-{4-[5-isopropyl-3-(2-trifluoromethoxy-phenyl)-isoxazol-4-ylmethoxy]-2-methyl-phenyl}-4-methyl-thiophene-2-carboxylic acid hydrazide (890 mg, 90%) as a light yellow foam. LC-ES/MS m/e 546 (M+1), 100%.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]4([C:23](O)=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:3][CH2:2]1.S(Cl)(Cl)=O.C[N:36](C)C=O>>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]4([C:23]([NH2:36])=[O:24])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH2:3][CH2:2]1
Reactant: CN(C)C=O
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C3(C(=O)O)CCOCC3)ccc2n1CC1CC1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C3(C(N)=O)CCOCC3)ccc2n1CC1CC1
Yield: 92 %

Procedure:
A mixture of 4-{[1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]sulfonyl}tetrahydro-2H-pyran-4-carboxylic acid (Step B, 288 mg, 0.66 mmol), thionyl chloride and N,N-dimethylformamide (few drops) was stirred under reflux for 3 h. After concentration, the residue was dissolved in dichloromethane (10 mL) and aqueous ammonia (1 mL) was added. The mixture was stirred at room temperature for 4 days. Water was added and the organic layer was separated. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by pTLC (hexane:ethyl acetate=1:10 as eluent) to give the title compound (264 mg, 92%) as a white solid.