Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:12][O:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[C:15]=1[N:24]=[C:25]=[O:26].O>CN(C)C=O>[C:8]([CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:25]([NH:24][C:15]1[C:16]([O:22][CH3:23])=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=1[O:13][CH3:12])=[O:26])#[N:9]
Reactant: N#CCc1ccccc1
Reactant: COc1cc(OC)c(N=C=O)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)c(NC(=O)C(C#N)c2ccccc2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.4 %

Procedure:
Phenylacetonitrile (2.64 mL, 22.8 mol) was added dropwise to an ice-cooled solution of sodium hydride (0.91 g, 22.8 mmol) in dimethyl formamide (50 mL), and the mixture stirred for 15 minutes while allowing to warm to room temperature. 2,4,6-Trimethoxyphenylisocyanate (4.78 g, 22.8 mmol) was added portionwise over 2 minutes, and then the mixture was stirred vigorously for 0.5 hour and poured into water (200 mL). The solid obtained was washed with water (100 mL) and taken up in chloroform (1 L). The organic layer was separated and dried with MgSO4, filtered, and concentrated to yield a pale purple solid (6.13 g, 82%). %(found): C, 65.94; H, 5.56; N, 8.10.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH:9]([C:18]([O:20]CC)=[O:19])[CH2:10][CH:11]=[CH:12][CH2:13][C:14]([O:16]C)=[O:15].C([O:25][C:26](=[O:32])[CH2:27][CH2:28][C:29](Cl)=[O:30])C.Cl>C(Cl)Cl.O>[OH:32][C:26](=[O:25])[CH2:27][CH2:28][C:29]([NH:8][CH:9]([C:18]([OH:20])=[O:19])[CH2:10][CH:11]=[CH:12][CH2:13][C:14]([OH:16])=[O:15])=[O:30]
Reactant: CCOC(=O)CCC(=O)Cl
Reactant: CCOC(=O)C(N)CC=CCC(=O)OC
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)CC=CCC(NC(=O)CCC(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
338 mg of triethylamine were added at ambient temperature to 583 mg of 1-methyl 7-ethyl 6-amino-3-heptenedioate prepared as in Example 5D in 50 ml of methylene chloride and after the mixture was cooled to +5° C., 483 mg of ethyl4-chloro-4-oxo-butanoate were added. The mixture was stirred for 1 hour at ambient temperature and 25 ml of water and 1 ml of 2N hydrochloric acid were added. Extraction was done with methylene chloride and the extract was washed with salt water, then with sodium bicarbonate solution, dried and the solvents were evaporated. The residue was chromatographed on silica and elution with cyclohexane - ethylene acetate (1-1) yielded 750 mg of the expected product.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([OH:14])[CH:6]=1)[CH3:3].[CH3:15]O>>[CH2:2]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH3:15])=[O:10])=[C:7]([OH:14])[CH:6]=1)[CH3:3]
Reactant: CCOc1ccc(C(=O)O)c(O)c1
Reactant: CO
Agent: Cl
Product: CCOc1ccc(C(=O)OC)c(O)c1
Temperature: 15 °C

Procedure:
Hydrogen chloride was bubbled into a stirred solution of 4-ethoxy-2-hydroxybenzoic acid (10.10 g, 0.554 mol) in methanol (2000 mL) until the solution was saturated. The solution was heated under reflux for 3 days and then cooled to 15° C. This caused the product to crystallize out. The crystals were collected, rinsed with methanol and hexanes, and dried. Methyl 4-ethoxy-2-hydroxybenzoate was obtained as a pale amber solid (49.3 g) melting at 77°-78° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][O:8][C:3]1[C:2]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccccc1Br
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccccc1-c1ccc(F)cc1
Yield: 84.5 %

Procedure:
By the reaction in the same manner as in Example 4-(ii) using 2-bromoanisole (8.91 g), 4-fluorophenylboronic acid (10.0 g), 2M aqueous sodium carbonate solution (47.6 ml) and tetrakis(triphenylphosphine)palladium(0) (2.20 g), the title compound (8.14 g) was obtained as colorless needle crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[N:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:25][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:14]
Reactant: NN1CCCCC1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(NN1CCCCC1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-piperidin-1-ylisonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.30 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.47 mmol of piperidin-1-ylamine LC/MS [8.81 min; 441 (M+1)]
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2([CH2:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])O)#N.[CH:24]([OH:26])=[O:25].[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29]>C(O)C>[CH:1]([C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2=[CH:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[O:25].[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].[CH:24]([C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2=[CH:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[O:26]
Reactant: CN(C)CCCC1(O)c2ccccc2CCn2cc(C#N)cc21
Reactant: O=CO
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: CN(C)CCC=C1c2ccccc2CCn2cc(C=O)cc21

Procedure:
2-Cyano-11-(3-dimethylaminopropyl)-11-hydroxy-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepine (.62 g.) and 6.2 g. Ni-Al 1:1 alloy powder (BDH Chemicals Ltd., Pool England) in 50 ml. 75% formic acid is refluxed for 1 hr. The dark red suspension is cooled, filtered to remove the insolubles, washed with formic acid and evaporated to dryness. The yield of this red oil is 3.4 g. (57%) and it slowly crystallizes on cooling. The oxalate salt of 2-formyl-11-(3-dimethylaminopropylidene)-6,11-dihydro-5H-pyrrolo[2,1-b][3]-benzazepine is prepared by dissolving the above product in the minimum volume of ethanol and adding dropwise a saturated ethanolic solution of oxalic acid. The resulting crystals are collected by filtration and dried to give 2-formyl-11-(3-dimethylaminopropylidene)-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepine oxalate, m.p. 181° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[Cl:19])[CH:3]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[Cl:19])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1Oc1ccc([N+](=O)[O-])cc1Cl
Reactant: CCOC(=O)CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CNc1ccc(Cl)cc1Oc1ccc([N+](=O)[O-])cc1Cl

Procedure:
A mixture of the product from step (i) (0.3 g), ethyl bromoacetate (0.22 ml) and sodium acetate (0.164 g) in dry ethanol (5 ml) was heated under reflux 7 h. Ethyl bromoacetate (0.5 ml) and sodium acetate (0.34 g) were added and heated for a further 16 h. The solvent was evaporated under reduced pressure and the residue purified by chromatography on silica eluting with 5-7% ethylacetate/isohexane, yield 0.212 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][CH:6]=2.ClC1C=CC=C(C(OO)=[O:20])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N+:9]2[O-:20])=[N:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1cnc2cccnc2c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cccc2ncc(F)cc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 71.3 %

Procedure:
To a solution of 76 mg of 3-fluoro-1,5-naphthyridine in 3 mL of chloroform, 136 mg of m-chloroperbenzoic acid was added, and the mixture was stirred at room temperature for 2.5 hours. Thereto was added 27 mg of m-chloroperbenzoic acid, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, a 5% aqueous sodium thiosulfate solution and chloroform were added, the organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using silica gel; Silica Gel 60N made by KANTO CHEMICAL CO., INC., and an eluent of chloroform:methanol=50:1 to obtain 60 mg of 7-fluoro-1,5-naphthyridine 1-oxide as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@H:9]([CH:17]=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:27]I.C([Li])CCC>C1COCC1>[C:1]([O:5][C:6]([N:8]([C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C@@H:17]1[O:18][CH2:27]1)[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCI
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@H](C=O)Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@@H](Cc1ccccc1)[C@H]1CO1
Temperature: -72.5 °C
Reaction time: 0.17 h

Procedure:
A solution of 2.5 g (7.37 mmoles) of N-(t-butoxycarbonyl)-N-benzyl-L-phenylalaninal and 0.72 mL of chloroiodomethane in 35 mL of THF was cooled to −78° C. A 4.64 mL of a solution of n-butyllithium (1.6 M in hexane, 7.42 mmoles) was added slowly, keeping the temperature below −70° C. The mixture was stirred for 10 minutes between −70 to −75° C. Two additional portions of 0.22 mL of chloroiodomethane and 1.4 mL of n-butyllithium was added sequentially and the mixture was stirred for 10 minutes between −70 to −75° C. after each addition. Four additional portions of 0.11 mL of chloroiodomethane and 0.7 mL of n-butyllithium was added sequentially and the mixture was stirred for 10 minutes between −70 to −75° C. after each addition. The mixture was warmed to room temperature for 3.5 hours. The product was quenched at below 5° C. with 24 mL of ice-cold water. The biphasic layers were separated and the aqueous layer was extracted twice with 30 mL of ethyl acetate. The combined organic layers was washed three times with 10 mL water, then with 10 mL brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2.8 g of a yellow crude oil. This crude oil (>100% yield) is a mixture of the diastereomeric epoxides N,αS-bis(phenylmethyl)-N-(t-butoxycarbonyl)-2S-oxiranemethanamine and N,αS-bis(phenylmethyl)-N-(t-butoxycarbonyl)-2R-oxiranemethanamine. The crude mixture is used directly in the next step without purification.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[SH:16][CH2:17][CH:18]([CH2:20][OH:21])[OH:19].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[OH:19][CH:18]([CH2:20][OH:21])[CH2:17][S:16][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: OCC(O)CS
Reactant: O=C(c1ccccc1)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(c1ccccc1)c1ccc(SCC(O)CO)cc1

Procedure:
14.0 g (0.07 mol) of 4-chlorobenzophenone, 10.0 g (0.93 mol) of 1-thioglycerol and 28.5 g (0.21 mol) of potassium carbonate in 60 ml of dimethylacetamide are kept at 110° C. for 6 hours, under N2 gas and with stirring. After cooling, the reaction mixture is poured into 200 ml of water. The crude product, which is obtained in the form of an oil, is taken up in ethyl acetate, the solution is washed with water until neutral, dried over K2CO3 and concentrated, isopropanol is poured over the concentrate and the resulting mixture is stirred. The product, which is obtained in the form of crystals, is filtered off. 9.4 g (47%); melting point 86°-88° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]([O:23][C:24](=[O:26])[NH2:25])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1.O>[CH2:33]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]([O:23][C:24](=[O:26])[NH2:25])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NC(=O)OC(CCN1CCN(c2ccc(O)cc2)CC1)c1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)OC(CCN1CCN(c2ccc(OCc3ccccc3)cc2)CC1)c1ccccc1
Temperature: 70 °C
Reaction time: 10 h

Procedure:
The compound ‘carbamic acid 3-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-1-phenyl-propyl ester (2 mmol) prepared in Example 84 was dissolved in tetrahydrofuran (25 mL), and potassium carbonate (K2CO3, 2.4 mmol) and benzylbromide (2.4 mmol) were added thereto, and the resulting mixture was stirred at 70° C. for 10 hours. The reaction mixture was diluted with water, and extracted several times with ethyl acetate to obtain an organic phase. The prepared organic phase was dried over magnesium sulfate, and concentrated under a reduced pressure. The resulting pellet was purified with column chromatography (hexane:ethyl acetate=1:1) to obtain a title compound.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]([C:15]([F:18])([F:17])[F:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.[NH2:30][CH2:31][CH2:32][C:33]([O:35]C)=[O:34].C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C>ClCCl.C([O-])(O)=O.[Na+]>[C:1]1([N:7]2[CH:11]=[C:10]([C:12]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:14])[C:9]([C:15]([F:18])([F:17])[F:16])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cn(-c2ccccc2)nc1C(F)(F)F
Reactant: COC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CCNC(=O)c1cn(-c2ccccc2)nc1C(F)(F)F
Reaction time: 24 h
Yield: 97 %

Procedure:
1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (150 mg, 0.57 mmol), EDCI (280.6 mg, 1.5 mmol), methyl 3-aminopropionate (163.5 mg, 1.17 mmol), HOBt (118.7 mg, 0.8 mmol) and ethyldiisopropylamine (265.5 mg, 2.1 mmol) dissolved in dichloromethane (15 mL) were stirred for 24 hours. The reaction mixture was diluted with aqueous NaHCO3 and extracted with dichloromethane. The extract was washed with brine and dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography to obtain the desired compound (181 mg, 91%) as a white solid.
Reaction SMILES: OS(O)(=O)=O.[O:6]=[C:7]1[N:13]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C@@H:23](OC)[C:24](=C=O)[C:25]3[CH:30]=[C:29]([Br:31])[C:28]([O:32]COCC[Si](C)(C)C)=[C:27]([Br:41])[CH:26]=3)=[O:21])[CH2:16][CH2:15]2)[CH2:12][CH2:11][C:10]2[CH:46]=[CH:47][CH:48]=[CH:49][C:9]=2[NH:8]1>C1COCC1.CO>[O:6]=[C:7]1[N:13]([CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C@@H:23]([C:20]([O:22][CH3:23])=[O:21])[CH2:24][C:25]3[CH:26]=[C:27]([Br:41])[C:28]([OH:32])=[C:29]([Br:31])[CH:30]=3)=[O:21])[CH2:18][CH2:19]2)[CH2:12][CH2:11][C:10]2[CH:46]=[CH:47][CH:48]=[CH:49][C:9]=2[NH:8]1
Reactant: CO[C@H](OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1)C(=C=O)c1cc(Br)c(OCOCC[Si](C)(C)C)c(Br)c1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Under a nitrogen atmosphere 5.46 mL methanolic H2SO4 (0.5 M) were added to a solution of 4.30 g (5.69 mmol) of (R)-2-[3,5-dibromo-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-methoxy-carbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 40 mL THF and 40 mL MeOH and the reaction solution was stirred for 6 h at RT. The reaction mixture was evaporated down i.vac and the residue was reacted further without purification.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7](Br)[C:6]([F:11])=[C:5]([F:12])[C:3]=1[NH2:4].[CH3:13][O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC>[F:1][C:2]1[C:8]([F:9])=[C:7]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([O:14][CH3:13])[CH:20]=2)[C:6]([F:11])=[C:5]([F:12])[C:3]=1[NH2:4]
Reactant: COc1cccc(B(O)O)c1
Reactant: Nc1c(F)c(F)c(Br)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: COc1cccc(-c2c(F)c(F)c(N)c(F)c2F)c1
Temperature: 90 °C

Procedure:
2,3,5,6-Tetrafluoro-4-bromoaniline (7.5 g, 30.7 mmol) is dissolved in DME (150 mL) and treated with 3-methoxyphenylboronic acid (4.7 g, 30.7 mmol), a catalytic amount of tetrakistriphenylphosphine palladium(0) (0.70 g, 0.6 mmol) and triphenylphosphine (0.66 g, 2.5 mmol). Potassium carbonate (8.5 μg in 50 mL of water) is added and the reaction mixture stirred and heated to 90° C. for 24 hours. After cooling to room temperature most of the DME is removed by rotary evaporator under high vacuum. The resulting material is partitioned between EtOAc (200 mL) and water (250 mL). The organic layer is washed with brine, dried (Na2SO4) and concentrated by rotary evaporator. The crude reaction product is purified by flash chromatography (9:1 hexanes/EtOAc, then 6:4 hexanes/EtOAC) to give 2,3,5,6-tetrafluoro-4-(3′-methoxyphenyl)aniline (m.p. 94–96° C.).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]([C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=2)=[CH2:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[OH-].[K+].Cl>CO>[CH3:1][C:2]1[C:3]([C:16]([C:18]2[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)=[CH2:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: C=C(c1ccc(C(=O)OC)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=C(c1ccc(C(=O)O)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a suspension of the ester 32 (0.058 g, 0.16 mmol) in 75% aqueous methanol (2 mL) was added one pellet of potassium hydroxide (0.1 g). The mixture was stirred at 70° C. for 1 h during which time the material dissolved. The solution was cooled to room temperature, acidified with 1N aqueous hydrochloric acid, and then extracted with 80% ethyl acetate/hexane. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated to afford a white solid. Recrystallization from dichloromethane/hexane afforded the desired acid 33 as a white, crystalline solid (42 mg, 91%): m.p. 230°-231° C. The structure of the product was also confirmed using IR, 1H NMR and mass spectroscopy.
Reaction SMILES: F[C:2]1[C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]1.C[O-].[Na+].O.[C:26](OCC)(=[O:28])C>CN(C)C=O.CO>[CH3:26][O:28][C:2]1[C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]1
Reactant: CCOC(C)=O
Reactant: CCCN1CCC(c2cccc(OC(F)(F)F)c2F)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CCCN1CCC(c2cccc(OC(F)(F)F)c2OC)CC1
Temperature: 150 °C

Procedure:
To a solution of 4-[2-fluoro-3-(trifluoromethoxy)phenyl]-1-propylpiperidine (1.92 g, 6.3 mmol) in N,N-dimethylformamide (20 ml) was added a solution of sodium methoxide in methanol (30%, 3 ml) and the mixture was heated to 150° C. for 1 h. Water (50 ml) and ethyl acetate (50 ml) was added and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×50 ml) and the combined organic phases was dried (MgSO4) and evaporated under reduced pressure to give an oil. The residue was purified by flash column chromatography (ethyl acetate/methanol, 1:1) to give the title compound (1.32 g). MS m/z (rel. intensity, 70 eV) 317 (M+, 6), 289 (17), 288 (bp), 204 (6), 175 (8).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:28]([NH2:30])=[O:29])[CH:19]=[C:20]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)[CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].C([O-])([O-])=O.[K+].[K+].[I-].[Na+].[NH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C=O)C>[N:39]1([CH2:2][CH2:3][CH2:4][S:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:22]4[C:17](=[C:18]([C:28]([NH2:30])=[O:29])[CH:19]=[C:20]([C:23]5[S:24][CH:25]=[CH:26][CH:27]=5)[CH:21]=4)[NH:16][N:15]=3)[CH2:10][CH2:9]2)(=[O:7])=[O:6])[CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: NC(=O)c1cc(-c2cccs2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2cccs2)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)n[nH]c12
Yield: 42.5 %

Procedure:
The title compound was prepared according to the general procedure of Example 38b. Thus, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(2-thienyl)-1H-indazole-7-carboxamide (0.076 mmol) in DMF (4 mL) was reacted with K2CO3 (22 mg, 0.16 mmol), sodium iodide (2 mg) and pyrrolidine (26.98 mg, 0.4 mmol) to afford the title compound (16.2 mg, 42%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([O:6]/[N:7]=[C:8](/[C:14](=O)[CH2:15]Cl)\[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1=[O:18].[C:19]([NH:22][C:23]([NH2:25])=[S:24])(=[O:21])[CH3:20].CN(C)C1C=CC=CC=1>C(O)C>[C:19]([NH:22][C:23]1[S:24][CH:15]=[C:14](/[C:8](=[N:7]/[O:6][CH:3]2[CH2:4][CH2:5][NH:1][C:2]2=[O:18])/[C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:25]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)NC(N)=S
Reactant: CCOC(=O)/C(=N\OC1CCNC1=O)C(=O)CCl
Solvent: CN(C)c1ccccc1
Solvent: CCO
Product: CCOC(=O)/C(=N\OC1CCNC1=O)c1csc(NC(C)=O)n1
Reaction time: 4 h
Yield: 49.9 %

Procedure:
2.77 g of ethyl (Z)-2-[(2-pyrrolidon-3-yl)oxyimino]-3-oxo-4-chloro-n-butyrate and 1.2 g of acetylthiourea are added to 20 ml of ethanol, and 2.0 g of N,N-dimethylaniline are added thereto. The mixture is stirred at 20° to 30° C. for 4 hours. Then, the mixture is concentrated under reduced pressure to drynss. The residue is dissolved in chloroform, and the solution is washed with water and an aqueous sodium bicarbonate solution, successively. The chloroform solution is dried and concentrated under reduced pressure to remove solvent. The residue is crystallized with isopropanol, and the crystals are collected by filtration. 1.7 g of ethyl (Z)-2-(2-acetamidothiazol-4-yl)-2-[(2-pyrrolidon-3-yl)oxyimino]acetate are obtained.
Reaction SMILES: [OH:1][CH:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]1[CH:4]=[C:5]([C:16]([O:18]CC)=[O:17])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:8]=1.[OH-].[Li+].Cl>O1CCOCC1.O>[OH:1][CH:2]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:3]1[CH:4]=[C:5]([C:16]([OH:18])=[O:17])[CH:6]=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[CH:8]=1
Reactant: CCOC(=O)c1cc(-c2ccc(C)cc2)cc(C(O)c2ccccc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(O)c3ccccc3)c2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 5-(hydroxy(phenyl)methyl)-4′-methylbiphenyl-3-carboxylate (230 mg, 0.66 mmol) in 1,4-dioxane (2 mL) and water (1 mL) was added lithium hydroxide (48 mg, 2 mmol). The reaction mixture was stirred at 60° C. overnight. After cooling, the mixture was acidified with 15% HCl (aq.) to pH=5, and extracted with EtOAc. The organic layer was dried and concentrated in vacuo to afford the title compound as a white solid. 1H NMR (300 MHz, acetone-d6): 8.14 (t, 1H, J=2.0 Hz), 8.09 (m, 1H), 7.97 (m, 1H), 7.60-7.47 (m, 4H), 7.37-7.19 (m, 5H), 6.00 (s, 1H), 2.37 (s, 3H).