Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH:3]([CH2:27][Cl:28])[O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[C:10]2[S:14]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15].C(N(CC)CC)C>CN(C=O)C.O>[Cl:28][CH2:27][CH:3]1[CH2:2][N:12]2[C:13]3[C:9]([C:10]([S:14]([C:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[CH:20]=[CH:19][CH:18]=4)(=[O:15])=[O:16])=[N:11]2)=[CH:8][CH:7]=[CH:6][C:5]=3[O:4]1
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2c(OC(CCl)CCl)cccc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S(=O)(c1cccc2ccccc12)c1nn2c3c(cccc13)OC(CCl)C2
Temperature: 70 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
A mixture of 7-(2-chloro-1-chloromethyl-ethoxy)-3-(naphthalene-1-sulfonyl)-1H-indazole (5) (1.76 g, 4.05 mmoles) and triethylamine (0.7 ml, 4.05 mmoles) in DMF was stirred overnight at 70° C., cooled to room temperature, diluted with water and extracted with EtOAc. The extracts were combined, washed sequentially with water and brine, dried over Na2SO4 and concentrated under vacuum to afford the title compound (1.5 g, 3.85 mmoles), identified by HNMR analysis.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](O)=[O:6].BrC1C=C(C=CC=1F)C([Cl:18])=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([Cl:18])=[O:6]
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Reactant: O=C(Cl)c1ccc(F)c(Br)c1
Product: O=C(Cl)c1ccc(Cl)c(Br)c1

Procedure:
3-Bromo-4-chlorobenzoyl chloride was prepared from 3-bromo-4-chlorobenzoic acid according to the procedure described in Example 183 for the synthesis of 3-bromo-4-fluorobenzoyl chloride.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:9][CH:8]=1.[C:18](=[O:20])=[O:19]>C1COCC1>[CH2:14]([S:13][C:10]1[CH:11]=[CH:12][C:7]([C:18]([OH:20])=[O:19])=[CH:8][CH:9]=1)[CH2:15][CH2:16][CH3:17]
Reactant: O=C=O
Reactant: CCCCSc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCSc1ccc(C(=O)O)cc1
Temperature: 25 °C

Procedure:
n-Butyllithium (6.8 ml, 10.0M in hexane, 0.068 mol) was added to a stirred, cooled (-78° C.) solution of compound 1 (16.56 g, 0.067 mol) in dry THF (200 ml), under dry nitrogen at -78° C. The mixture was maintained under these conditions for a further 0.5 h (glc analysis confirmed a complete reaction) before being poured into a slurry of `Cardice` and dry THF. The mixture was allowed to warm to room temperature overnight. The combined organic extracts were evaporated in vacuo and the residue was dissolved in boiling acetic acid. Ice (400 g) was added to the solution and the product was filtered off and dried in vacuo (KOH, P2O5).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6](=[S:8])[NH2:7])#[N:2].[CH2:17]([O:19][C:20](=[O:26])[CH:21](Cl)[C:22]([CH3:24])=O)[CH3:18]>CO>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[S:8][C:21]([C:20]([O:19][CH2:17][CH3:18])=[O:26])=[C:22]([CH3:24])[N:7]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH:14]([CH3:16])[CH3:15])#[N:2]
Reactant: CC(C)COc1ccc(C(N)=S)cc1C#N
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CO
Product: CCOC(=O)c1sc(-c2ccc(OCC(C)C)c(C#N)c2)nc1C
Temperature: 25 °C
Yield: 68 %

Procedure:
Methanol (50 mL) was placed into a round bottom flask and 3-cyano-4-isobutoxy benzothioamide (5.0 g) was added, followed by addition of ethyl-2-chloroacetoacetate (4.25 g). The mixture was heated to reflux and maintained until reaction completion. After the reaction was completed, the mass was cooled to about 25° C. and maintained for about 30 minutes. The mass was then filtered and washed with methanol. The wet solid was dried at about 70° C. to a constant weight to yield 5.0 g of the title compound. Purity by HPLC: 84.9%.
Reaction SMILES: [CH2:1](C1C=CC(C(O)=O)=CC=1C=O)[CH3:2].[CH:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=1O)=[O:15].C([Zn]CC)C>>[CH2:1]([C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:16]=1[CH:14]=[O:15])[C:20]([OH:22])=[O:21])[CH3:2]
Reactant: CCc1ccc(C(=O)O)cc1C=O
Reactant: O=Cc1ccc(C(=O)O)cc1O
Agent: CC[Zn]CC
Product: CCc1cc(C(=O)O)ccc1C=O

Procedure:
The title compound was prepared in analogy to 4-ethyl-3-formyl benzoic acid starting from 4-formyl-3-hydroxy-benzoic acid and using diethyl zinc in step b). LC-MS*: tR=0.38 min, [M−H]−=177.28; 1H NMR (D6-DMSO): δ 1.21 (t, J=7.5 Hz, 3H), 3.10 (q, J=7.3 Hz, 2H), 7.93 (s, 1H), 7.94 (s, 2H), 10.34 (s, 1H), 13.36 (br s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O>C1C=CC=CC=1>[O:20]=[C:18]1[C:12]2=[CH:11][CH:10]=[C:9]3[C:14]([N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]3)=[C:13]2[CH2:15][CH2:16][CH2:17]1
Reactant: CCOC(=O)CCCc1cccc2c1N(C(=O)OCC)CC2
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: CCOC(=O)N1CCc2ccc3c(c21)CCCC3=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
The product from Example 115 (2.7 g) was dissolved in benzene (25 ml) and oxalyl chloride (2.6 ml) was added. The resulting solution was heated at 50° C. for 30 minutes, then the solvent was evaporated to dryness. The residue was dissolved in methylene chloride (30 ml), cooled to 0° C., and aluminum chloride (4 g) was added. The reaction mixture was stirred at 0° C. for 1 hour then quenched with ice and hydrochloric acid then extracted with methylene chloride. The organic layer was separated, washed with brine, dried and evaporated in vacuo affording the desired product in 50% yield.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:9](Cl)(=[O:11])[CH3:10]>C1COCC1>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1
Reactant: Cc1cnc(N)cn1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)Nc1cnc(C)cn1
Reaction time: 3 h
Yield: 86.6 %

Procedure:
To a solution of 5-methylpyrazin-2-amine (300 mg, 2.75 mmol) in dried THF (9 mL) were added acetyl chloride (0.21 mL, 2.89 mmol) and TEA (0.75 mL, 5.50 mmol). The reaction mixture was stirred for 3 hours after which, it was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, celite filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using (10% to 30% Ethyl acetate/Hexane) as a solvent to afford title compound (360 mg, 86% yield). MS m/z: 152 [M+1].
Reaction SMILES: [CH2:1]=[N:2][CH2:3][C:4]([CH3:11])([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[CH3:5].Cl.[OH-].[Na+]>>[CH3:5][C:4]1([CH3:11])[CH2:3][NH:2][CH2:1][C:7]2[S:8][CH:9]=[CH:10][C:6]1=2
Reactant: C=NCC(C)(C)c1ccsc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)CNCc2sccc21

Procedure:
6.0 g (36 mmol) methylene-(2-methyl-2-thiophene-3-yl-propyl)-amine, 11 mL (45 mmol) of a 4M HCl solution and 12 mL (0.14 mol) conc. HCl were stirred at RT over the weekend. The reaction mixture was made alkaline with a 4M sodium hydroxide solution. The precipitate formed was suction filtered, washed with water and dried. The substance was purified on Alox. The product-containing fractions were combined and concentrated to dryness by rotary evaporation.
Reaction SMILES: [F:1][C:2]([F:15])([CH2:9][C:10]([O:12]CC)=O)[CH2:3][C:4]([O:6]CC)=O.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:23]1[C:4](=[O:6])[CH2:3][C:2]([F:1])([F:15])[CH2:9][C:10]1=[O:12])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)CC(F)(F)CC(=O)OCC
Product: O=C1CC(F)(F)CC(=O)N1Cc1ccccc1

Procedure:
React an 8.1 mmol portion of the product of Example 14 with benzylamine using the general procedure set forth in Example 8, and purify by silica gel chromatography using ethyl acetate/hexane as eluant to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:23]([NH:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)=[O:24])=[CH:4][CH:3]=1.[CH:31](OCC)(OCC)OCC>>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:11]2[NH:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][CH3:31])=[CH:7][CH:6]=3)=[C:9]([C:23]([NH:25][C:26]3[S:27][CH:28]=[CH:29][N:30]=3)=[O:24])[N:10]=2)=[CH:18][CH:17]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(N)cc3)[nH]2)cc1
Reactant: CCOC(OCC)OCC
Product: CNc1ccc(-c2[nH]c(-c3ccc(C(C)(C)C)cc3)nc2C(=O)Nc2nccs2)cc1

Procedure:
5-(4-Aminophenyl)-2-(4-tert-butylphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (0.5 g) obtained in Example 77 was refluxed in triethyl orthoformate overnight and concentrated. Thereto were added ethanol and tetrahydrof uran, and sodium borohydride (0.4 g) was added. The mixture was refluxed under heating for 2 hr. After refluxing, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with saturated brine and dried. After drying, the residue was concentrated to give 2-(4-tert-butylphenyl)-5-(4-methylaminophenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (0.5 g). This was converted to hydrochloride to give 2-(4-tert-butylphenyl)-5-(4-methylaminophenyl)-N-(2-thiazolyl) imidazole-4-carboxamide hydrochloride (0.24 g), melting point 257-259° C. (decomposition).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH:13]=[N:14][C:8]=2[CH:7]=1)=[CH2:5])C.Cl.N>CO>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:12]2[C:9]3[CH:10]=[N:11][C:6]([C:4](=[O:3])[CH3:5])=[CH:7][C:8]=3[N:14]=[CH:13]2)=[CH:17][CH:18]=1
Reactant: C=C(OCC)c1cc2ncn(Cc3ccc(OC)cc3)c2cn1
Agent: Cl
Agent: N
Solvent: CO
Product: COc1ccc(Cn2cnc3cc(C(C)=O)ncc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
A mixture of 6-(1-ethoxyvinyl)-3-(4-methoxybenzyl)-3H-imidazo[4,5-c]pyridine (440 mg, 1.42 mmol) in MeOH (2 mL) was added an aqueous solution of HCl (1N, 0.5 mL) and stirred at RT for 30 min. To the reaction mixture was added an aqueous ammonia solution (35%) until the pH was approximately 8. The aqueous solution was extracted with EtOAc (50 mL×3). The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by SiO2 chromatography eluting with petroleum ether:EtOAc (1:1) to afford 300 mg (75%) of 1-(3-(4-methoxybenzyl)-3H-imidazo[4,5-c]pyridin-6-yl)ethanone as a white solid. MS (ESI): m/z=282.3 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:19])[C:17]=1[OH:18])[NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>N1C=CC=CC=1>[C:20]([O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]([NH:5][C:4]1[CH:3]=[C:2]([Cl:1])[C:17]([O:18][C:6](=[O:14])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:16]([Cl:19])[CH:15]=1)=[O:14])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Nc1cc(Cl)c(O)c(Cl)c1)c1ccccc1O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Oc1ccccc1C(=O)Nc1cc(Cl)c(OC(=O)c2ccccc2)c(Cl)c1)c1ccccc1
Yield: 88.2 %

Procedure:
3',5'-Dichloro-2,4'-dihydroxybenzanilide (1 g.) was dissolved in dry pyridine (15 ml.) in the cold at 0°- 5° C. and to it was added dropwise benzoyl chloride (1.2 ml.). With gentle stirring reaction was continued for several hours. The solution was then poured into ice-cold water and acidified with 1 N hydrochloric acid to pH 2, yielding oily material which was extracted by ethyl acetate. The ethyl acetate solution was washed with 1 N hydrochloric acid and 5% sodium bicarbonate solution in that order and dried with anhydrous sodium sulfate, followed by removal of the solvent by evaporation. The residue was subjected to recrystallization from ether and petroleum ether mixture to give white crystals (1.5 g.) of 2,4'-dibenzoyloxy-3',5'-dichlorobenzanilide. Yield: 88.2%. Melting point: 157°-160° C.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH2:20]Cl)=[CH:14][CH:15]=2)[O:10][C:9]([C:22]2[N:27]=[CH:26][N:25]3[CH:28]=[CH:29][CH:30]=[C:24]3[CH:23]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH2:20][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:14][CH:15]=2)[O:10][C:9]([C:22]2[N:27]=[CH:26][N:25]3[CH:28]=[CH:29][CH:30]=[C:24]3[CH:23]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2cc(OCCCCl)ccc12
Reactant: C1COCCN1
Product: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2cc(OCCCN3CCOCC3)ccc12
Yield: 55 %

Procedure:
7-(3-Morpholin-4-yl-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime was prepared in 55% yield using the method described in example 87A, starting from 7-(3-Chloro-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 143B) and morpholine.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])=[N:7][C:6]=2[CH:5]=[C:4]([Cl:18])[CH:3]=1.[CH3:19][CH:20]([OH:23])[C:21]#[CH:22].C(N(CC)CC)C>C1(C)C=CC=CC=1.[Cu]I>[Cl:18][C:4]1[CH:3]=[C:2]([C:22]#[C:21][CH:20]([OH:23])[CH3:19])[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])=[N:7][C:6]=2[CH:5]=1
Reactant: C#CC(C)O
Reactant: Clc1cc(Br)c2oc(-c3ccccc3Cl)nc2c1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(O)C#Cc1cc(Cl)cc2nc(-c3ccccc3Cl)oc12

Procedure:
15.98 g (46.6 mmol) of 7-bromo-5-chloro-2-(2-chlorophenyl)-benzoxazole and 5 5.48 ml (69.9 mmol) of (±)-3-butyn-2-ol were heated for 6 h at 90-5° C. in 47 ml of toluene with 47 ml of triethylamine, 163.5 mg (233 μmol) of bis-triphenylphosphine-palladium(II)-dichloride and 8.9 mg (46.6 23 μmol) of copper(I) iodide. The reaction was filtered and the solid washed with toluene. The filtrate was evaporated in vacuo to dryness, the residue taken up in 150 ml of dichloromethane, extracted twice with 50 ml of 1 N HCl, dried with sodium sulfate, and filtered through 120 g of silica gel in a column. The title compound (11.11 g) was recovered as an off-white solid. A recrystallized sample from di-isopropyl ether had mp 129-31° C.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:10]#[N:11])[CH2:9][CH2:8]2)[CH:2]=1.[ClH:13].[CH2:14]([OH:16])[CH3:15]>>[ClH:13].[C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:10](=[NH:11])[O:16][CH2:14][CH3:15])[CH2:8][CH2:9]2)[CH:2]=1
Reactant: CCO
Reactant: Cc1cccc(C2(C#N)CC2)c1
Agent: Cl
Product: CCOC(=N)C1(c2cccc(C)c2)CC1
Reaction time: 16 h
Yield: 96.5 %

Procedure:
To 1-(m-tolyl)cyclopropanecarbonitrile (100 mg, 0.64 mmol) was added a saturated solution of hydrogen chloride in ethanol (2 mL). After 16 h at room temperature and 2 h at 70° C. and another 16 h at room temperature, the mixture was concentrated in vacuo and the residue was dried under high vacuum to afford the title compound (147.1 mg, 96.5%) as a colorless solid. MS (ES+) (M+H) 204.1, LCMS retention time: 3.10 minutes (Method L).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([C:13]2[CH:26]=[CH:25][C:16]([O:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)=[CH:15][CH:14]=2)[O:11][CH:12]=1.C1CN2C(=NCCC2)NC1.Br[C:38]1([CH2:47][CH2:48][O:49][CH3:50])[C:43](=[O:44])[NH:42][C:41](=[O:45])[NH:40][C:39]1=[O:46]>C(#N)C>[CH3:50][O:49][CH2:48][CH2:47][C:38]1([O:24][C:21]2[CH:22]=[CH:23][C:18]([O:17][C:16]3[CH:15]=[CH:14][C:13]([C:10]4[O:11][CH:12]=[C:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])[N:9]=4)=[CH:26][CH:25]=3)=[CH:19][CH:20]=2)[C:39](=[O:46])[NH:40][C:41](=[O:45])[NH:42][C:43]1=[O:44]
Reactant: COCCC1(Br)C(=O)NC(=O)NC1=O
Reactant: Oc1ccc(Oc2ccc(-c3nc(-c4ccccc4F)co3)cc2)cc1
Agent: C1CN=C2NCCCN2C1
Solvent: CC#N
Product: COCCC1(Oc2ccc(Oc3ccc(-c4nc(-c5ccccc5F)co4)cc3)cc2)C(=O)NC(=O)NC1=O
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
4-[4-(4-(2-fluorophenyl)-oxazol-2-yl)-phenoxy]-phenol (142 mg, 0.41 mmol), and 1,5,7-triazabicyclo[4.4.0]dec-5-ene bound to polystyrene crosslinked with 2% DVB (Fluka) (473 mg @ 2.6 meq/g, 1.23 meq) in acetonitrile were shaken for 30 minutes. 5-Bromo-5-(2-methoxy-ethyl)-pyrimidine-2,4,6-trione (163 mg, 0.62 mmol) (from Preparation 3b) was then added and shaking continued for 3 days. The reaction was quenched with 20% acetic acid in methanol and after 15 minutes filtered. The filtrate was concentrated and the crude product chromatographed yielding 145 mg of 5-(2-methoxy-ethyl)-5-{4-[4-(4-(2-fluorophenyl)-oxazol-2-yl)-phenoxy]-phenoxy}-pyrimidine-2,4,6-trione as a white solid. LC-MS (m/z, APCI): 533 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][C:15]([OH:19])([CH3:18])[CH2:14][CH2:13]2)[CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][C:15]([CH3:18])([OH:19])[CH2:14][CH2:13]2)[CH2:9]1
Reactant: CC1(O)CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(O)CCN(C2CNC2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.9 %

Procedure:
A 25 mL round-bottomed flask was charged with a solution of 3-(4-hydroxy-4-methylpiperidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (0.2 g, 0.74 mmol) in DCM/TFA (3 mL/3 mL). The reaction mixture was stirred for 4 h at room temperature. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH to give 1-Azetidin-3-yl-4-methylpiperidin-4-ol as a colourless oil (0.107 g, 85%). 1H NMR (CDCl3, 400 MHz) δ 3.61 (t, J=7.3 Hz, 2H); 3.54 (t, J=7.3 Hz, 2H); 3.29-3.15 (m, 1H); 3.04 (s, 2H); 2.40 (d, J=10.8 Hz, 2H); 2.30-2.18 (m, 2H); 1.67-1.56 (m, 4H); 1.23 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.C(N(CC)CC)C.O1[C:20]2([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[O:19]CC1>C(#N)C>[Cl:8][C:4]1[N:3]=[C:2]([N:23]2[CH2:24][CH2:25][C:20](=[O:19])[CH2:21][CH2:22]2)[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: C1CC2(CCN1)OCCO2
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCN(c2cncc(Cl)n2)CC1
Temperature: 10 °C
Yield: 70.9 %

Procedure:
A solution of 3.0 g (20 mmol) 2,6-dichloropyrazine, 2.0 g (20 mmol) triethylamine, and 2.9 g (20 mmol) 1,4-dioxa-8-azaspiro[4.5]decane in 60 ml acetonitrile is refluxed 17 hours. The solvent is removed in vacuo, and the residue is dissolved in ethylacetate. After washing with water and brine, the organic fraction is dried (MgSO4) and evaporated to an oil. The oil is dissolved in 30 ml acetone and mixed with 30 ml 1N HCl. After heating this solution on the steam bath 30 minutes, the acetone is evaporated, and the concentrate is cooled to 10° C. A solid separates which is filtered and dried to afford 3 g (71%) of the desired product.
Reaction SMILES: C(OC([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]1[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:21])C)=O)C.[H-].[Na+]>C1(C)C(C)=CC=CC=1>[O:21]=[C:19]1[CH:6]2[CH2:14][C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]2[CH2:15][CH2:16][CH2:17][NH:18]1
Reactant: CCOC(=O)C1Cc2ccccc2N1CCCNC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: O=C1NCCCN2c3ccccc3CC12
Reaction time: 2 h

Procedure:
A solution of 2.9 g of 1-(3-acetamidopropyl)-indoline-2-carboxylic acid ethyl ester (obtainable by catalytic hydrogenation of 1-(2-cyanoethyl)-indoline-2-carboxylic acid ethyl ester in acetic anhydride) in 35 ml of xylene is treated with 1 g of sodium hydride (in the form of a 20% suspension in paraffin oil) and the mixture is boiled for 2 hours. The mixture is evaporated and worked up with water and chloroform to give 1-oxo-2,3,4,5,11,11a-hexahydro-1H-1,4-diazepino[1,2-a]indole, m.p. 159° (from isopropanol/ether).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]1(B(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:16][O:17][CH2:18][CH2:19][O:20][CH2:21][N:22]([C:32]1[O:36][N:35]=[C:34]([CH3:37])[C:33]=1[CH3:38])[S:23]([C:26]1[S:27][C:28](Br)=[CH:29][CH:30]=1)(=[O:25])=[O:24]>C(O)C.C1C=CC=CC=1.O.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>[CH3:16][O:17][CH2:18][CH2:19][O:20][CH2:21][N:22]([C:32]1[O:36][N:35]=[C:34]([CH3:37])[C:33]=1[CH3:38])[S:23]([C:26]1[S:27][C:28]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:29][CH:30]=1)(=[O:25])=[O:24]
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccc(Br)s1
Reactant: OB(O)c1ccccc1
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+]
Solvent: O
Solvent: c1ccccc1
Solvent: CCO
Product: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccc(-c2ccccc2)s1
Yield: 61.9 %

Procedure:
Sodium carbonate (2 mL of a 2 M aqueous solution) followed by phenyl boronic acid (86 mg, 0.71 mmol) in 2 mL of 95% ethanol were added to a solution of N-(methoxyethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide (200 mg, 0.47 mmol) and tetrakis(triphenylphosphine)palladium (0) (23 mg, 0.02 mmol) in dry benzene (4 mL) under argon. The mixture was refluxed for 12 h, diluted with 5 mL of water and extracted into ethyl acetate (3×25 mL). The combined organic extracts was washed with brine (1×25 mL), dried and evaporated. The residue was flash chromatographed on silica gel using 25% ethyl acetate/hexanes to afford 123 mg (62%) of the sulfonamide as a colorless gum.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:5]=[C:4]([C:19]([NH:21][NH2:22])=[O:20])[CH:3]=1.O.[F:24][C:25]([F:32])([C:28]([F:31])([F:30])[F:29])[CH:26]=O.O>C(O)(=O)C.C(OCC)(=O)C.O>[F:24][C:25]([F:32])([C:28]([F:31])([F:30])[F:29])[CH:26]=[N:22][NH:21][C:19](=[O:20])[C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=2)[N:5]=1
Reactant: Cc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN)c1
Reactant: O=CC(F)(F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN=CC(F)(F)C(F)(F)F)c1

Procedure:
4-methyl-6-[3-(trifluoromethyl)phenoxy] picolinic acid hydrazide (0.38 g, 0.0012 mol) was dissolved in 5 ml of acetic acid. The obtained solution was mixed with 2,2,3,3,3-pentafluoropropionaldehyde monohydrate (0.40 g, 0.0012×2 mol), and then the resultant mixture was stirred at 80° C. for 3 hours. Thereafter, a chilled water was poured into the obtained reaction solution which was then distributed in ethyl acetate-water. The organic phase separated from the solution was washed with water and then dried with anhydrous sodium sulfate. After distilling off the solvent from the dried product, the obtained distillation residues were purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]1[C:20]([O:22]CC)=[O:21].[OH-].[K+]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]1[C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1C
Agent: [K+]
Agent: [OH-]
Product: Cn1c(C(=O)O)c(-c2ccccc2)c2cc([N+](=O)[O-])ccc21

Procedure:
1-Methyl-5-nitro-3-phenyl-1H-indole-2-carboxylic acid was prepared from ethyl 1-methyl-5-nitro-3-phenyl-1H-indole-2-carboxylate by KOH hydrolysis as a yellowish solid: 1H NMR (DMSO-d6) δ 4.08 (s, 3H, 7.48-7.55 (m, 5H, 7.86 (d, J=9.2 Hz, 1H), 8.21 (dd, J=9.2, 2.3 Hz, 1H, 8.30 (d, J=2.3 Hz, 1H; MS (ESI) m/z 295 [M-H]−; HRMS calcd for C16H13N2O4: 297.0873; found (ESI+): 297.0867; Anal. calcd for C16H12N2O4.0.15H2O: C, 63.32; H, 4.25; N, 9.23. Found: C, 63.34; H, 3.87; N, 9.12.