Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7]([CH2:10][C:11](O)=O)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=1C=O>>[F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7](/[CH:10]=[CH:11]/[C:22]2[CH:21]=[CH:18][C:17]([F:16])=[CH:24][C:23]=2[F:25])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)CS(=O)(=O)Cc1ccc(F)cc1
Reactant: O=Cc1ccc(F)cc1F
Product: O=S(=O)(/C=C/c1ccc(F)cc1F)Cc1ccc(F)cc1
Yield: 68 %

Procedure:
A solution of 4-fluorobenzyl sulfonylacetic acid (0.01 mol) and 2.4-difluorobenzaldehyde (0.01 mol) was subjected to Procedure 1. The title compound was obtained in 68% yield.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([B:11]3[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]3)[CH:9]=[CH:10][C:4]=2[N:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN1CCCC1=O>[C:21]1([NH:20][C:2]2[NH:6][C:5]3[CH:7]=[C:8]([B:11]4[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]4)[CH:9]=[CH:10][C:4]=3[N:3]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccccc1
Reactant: CC1(C)OB(c2ccc3nc(Cl)[nH]c3c2)OC1(C)C
Solvent: CN1CCCC1=O
Product: CC1(C)OB(c2ccc3nc(Nc4ccccc4)[nH]c3c2)OC1(C)C
Temperature: 140 °C

Procedure:
2-Chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (200 mg, 0.718 mmol) and aniline (669 mg, 7.18 mmol) were mixed in N-methyl-2-pyrrolidinone (2 mL). The solution was heated at 140° C. for 30 minutes in a microwave reactor. The reaction mixture was concentrated to give the title compound, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.BrC1C(=O)C2C(C=1C1C=CC=CC=1)=CC=C(O)C=2.[N:44]1([CH2:50][CH2:51]O)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:51][CH2:50][N:44]4[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]4)=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Reactant: OCCN1CCCCC1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Product: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(OCCN3CCCCC3)cc21
Reaction time: 3 h
Yield: 37 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 3-(3,5-difluorophenyl)-6-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one obtained in Step 1 of Example 61 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, 2-(piperidin-1-yl)ethanol instead of 4-(2-hydroxyethyl)morpholine, being stirred for 3 h, and being purified by silica gel column chromatography (CH2Cl2/EtOAc=1:4) to obtain the title compound (37%).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10](N(CC)CC)C.CS(ON1C2C=CC=CC=2N=N1)(=O)=O>CO.CCOCC>[C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)On1nnc2ccccc21
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of benzoic acid (2.5 g) and triethylamine (5.6 ml) in methanol (5.0 ml) and anhydrous ether (30 ml) is added 1-methanesulfonyloxy-1,2,3-benzotriazole (4.3 g) under cooling. The mixture is stirred for 1 hour and then allowed to stand overnight. The reaction mixture is extracted with ether, and the extract is washed with water, an aqueous sodium hydrogen carbonate and water in order, dried over anhydrous magnesium sulfate and then the solvent is distilled off to give methyl benzoate (2.1 g) as an oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][NH:12]3)[CH:5]=[CH:6][CH:7]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:40])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:40])[NH:12]3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Fc1cccc(-c2cccc3[nH]ccc23)c1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CCO
Product: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
To the suspension of 4-(3-fluoro-phenyl)-1H-indole (1.40 g, 6.63 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (81 mL) was added pyridinium tribromide (90% purity from Aldrich, 7.07 g, 19.88 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (30 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated, and the syrupy residue was dissolved in ethyl acetate, which was washed with water, 0.5 N HCl, sat. NaHCO3 and brine, and dried over Na2SO4. After filtration and evaporation, the crude product was triturated with diethyl ether to provide product 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (1.34 g, 89%) as a tan solid.
Reaction SMILES: CSC.[Br:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([CH3:11])[CH:10]=1.ClC(O[C:16]1[CH:21]=[CH:20]C=CC=1)=O.C1([Mg]Br)CC1>O1CCCC1.[Cu](I)I>[Br:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([CH3:11])[C:10]=1[CH:20]1[CH2:21][CH2:16]1
Reactant: Cc1cncc(Br)c1
Reactant: O=C(Cl)Oc1ccccc1
Agent: I[Cu]I
Agent: Br[Mg]C1CC1
Solvent: C1CCOC1
Solvent: CSC
Product: Cc1cncc(Br)c1C1CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a mixture of copper iodide (1.082 g, 0.0056 mol), dimethyl sulphide (2.78 mL, 0.0380 mol) and 3-bromo-5-methylpyridine (1.0 g, 0.0056 mol) in anhydrous tetrahydrofuran (25 mL) at room temperature was added phenyl chloroformate (0.764 mL, 0.0060 mol) and the mixture was stirred for 40-50 min. To this suspension at −25 to −20° C. was added cyclopropyl magnesium bromide (12.13 mL, 0.0060 mol, 0.5M solution in tetrahydrofuran) over 30-40 min. The mixture was stirred at this temperature for 30 min. and then warmed slowly to room temperature over 1.0-1.5 h. The reaction mixture was quenched with 20% ammonium chloride (25 mL), followed by extraction of the aqueous layer with ethyl acetate (50 mL). The organic layer was washed with 20% ammonium chloride (25 mL), then saturated aqueous sodium chloride solution (25 mL), and dried over anhydrous sodium sulphate. Silica gel chromatography using 0-5% ethyl acetate-hexane gradient yielded crude title compound.
Reaction SMILES: [CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH2:15][CH2:14]2)[CH3:5])[CH:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+].[Cl:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=1.O>CS(C)=O.[Cu]I.CCOCC>[CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:30]1[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=1)[CH:15]=[CH:14]2)[CH3:5])[CH:2]=[CH2:3]
Reactant: C=CCN(C)CCCCOc1ccc2c(c1)CCN2
Reactant: Clc1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: C=CCN(C)CCCCOc1ccc2c(ccn2-c2ccc(Cl)cc2)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 20.3 %

Procedure:
260 mg (1 mmol) Allyl-[4-(2,3-dihydro-1H-indol-5-yloxy)-butyl]-methyl-amine in 2.5 ml DMSO were treated with 280 mg (2 mmol) powdered K2CO3 and 480 mg (2 mmol) 1-chloro-4-iodobenzene at 130° C. for 1 h. 19.1 mg (0.1 mmol) CuI were added and the mixture was stirred for additional 2 h at 130° C. At RT, water and ether were added, and the organic phase was washed with water, dried over Na2SO4. Column chromatography on silica gel with CH2Cl2/MeOH 19:1 yielded 75 mg (20%) Allyl-{4-[1-(4-chloro-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-amine as orange oil, MS: 369 (MH+, 1Cl).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9]C)=[CH:4][C:3]=1[N:11]1[C:20]2[C:15](=[CH:16][C:17]([F:23])=[C:18]([F:22])[C:19]=2[CH3:21])[C:14](=[O:24])[C:13]([C:25]([O:27]CC)=[O:26])=[CH:12]1.Br>C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:11]1[C:20]2[C:15](=[CH:16][C:17]([F:23])=[C:18]([F:22])[C:19]=2[CH3:21])[C:14](=[O:24])[C:13]([C:25]([OH:27])=[O:26])=[CH:12]1
Reactant: CCOC(=O)c1cn(-c2cc(OC)c(F)cc2F)c2c(C)c(F)c(F)cc2c1=O
Agent: Br
Solvent: CC(=O)O
Product: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(O)c(F)cc3F)c12
Yield: 65.8 %

Procedure:
Ethyl 1-(2,4-difluoro-5-methoxyphenyl)-6,7-difluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (2.32 g) was added to a mixed liquid (1:1, v/v; 30 ml) of 47% hydrobromic acid and acetic acid, and the mixture was stirred and refluxed for 44 hours. After distilled water (20 ml) was added to the reaction mixture, it was allowed to cool. Deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (1.37 g) as a colorless powder.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[O:19]([C:16]1[CH:17]=[CH:18][C:13]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:14][CH:15]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1c(Cl)n(-c2ccc(Oc3ccccc3)cc2)c2ccccc12
Reactant: C1CNCCN1
Product: O=Cc1c(N2CCNCC2)n(-c2ccc(Oc3ccccc3)cc2)c2ccccc12
Yield: 40 %

Procedure:
2-chloro-1-(4-phenoxyphenyl)-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 to afford 1-(4-phenoxyphenyl)-2-piperazin-1-yl-1H-indole-3-carboxaldehyde (40% yield). ESI/MS 398 (M+H); RT=2.95 min; NMR (CDCl3) 10.28 (1H, s); 8.28 (1H, d, J=9 Hz); 7.46-7.10 (1H, m); 7.00 (1H, d, J=9 Hz); 3.31 (4H, m); 2.81 (4H, m).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21](O)=[O:22])=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21]([N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])=[O:22])=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNCC
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2ccc(OCC(=O)O)cc2C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)COc1ccc2c(c1)C[C@@H](NC(=O)OC(C)(C)C)CC2

Procedure:
3 g (0.009 mole) of (2S)-2-tert-butoxycarbonylamino-7-hydroxycarbonylmethoxy-tetralin, 0.93 ml of N,N-diethylamine (0.009 mole), 4 g (0.009 mole) of BOP and 1.9 ml (0.0135 mole) of triethylamine in 90 ml of anhydrous DMF were stirred at ambient temperature for 6 hours. The solvent was evaporated off and the residue was taken up in ethyl acetate. It was washed with a sodium bicarbonate solution. An emulsion was obtained which was filtered over celite. The filtered solution was washed with acetic acid and then with water. The organic phase was dried over sodium sulfate and the solvent was evaporated off under reduced pressure. The product was purified by flash chromatography, eluting with a 1:1 ethyl acetate/hexane mixture. The product of the heading was obtained in the form of a very dense oil.
Reaction SMILES: O[C:2]1[C:7]2[C:8]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:9]=3[S:10][C:6]=2[C:5]([C:19]#[N:20])=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:2]1[C:7]2[C:8]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:9]=3[S:10][C:6]=2[C:5]([C:19]#[N:20])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(O)c2c1sc1cc(C(F)(F)F)ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1cnc(Cl)c2c1sc1cc(C(F)(F)F)ccc12
Reaction time: 0.17 h

Procedure:
A suspension of 1-hydroxy-7-(trifluoromethyl)[1]benzothieno[3,2-c]pyridine-4-carbonitrile in POCl3 (1 M) was placed in a microwave reactor at 210° C. (normal absorption) for 10 min. The reaction mixture was carefully poured onto ice, stirred for 10 min and the solid filtered off to provide the title compound.
Reaction SMILES: [Cl:1][CH:2]([C:13]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=1[F:20])[S:3]([C:6]1[CH2:10][C:9]([CH3:12])([CH3:11])[O:8][N:7]=1)(=[O:5])=[O:4].[Cl:21]N1C(=O)CCC1=O>C1COCC1>[Cl:1][C:2]([Cl:21])([C:13]1[C:14]([F:20])=[CH:15][CH:16]=[CH:17][C:18]=1[F:19])[S:3]([C:6]1[CH2:10][C:9]([CH3:12])([CH3:11])[O:8][N:7]=1)(=[O:4])=[O:5]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1(C)CC(S(=O)(=O)C(Cl)c2c(F)cccc2F)=NO1
Solvent: C1CCOC1
Product: CC1(C)CC(S(=O)(=O)C(Cl)(Cl)c2c(F)cccc2F)=NO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
Phosphazene base 1-tert-butyl-2,2,4,4,4-pentakis(dimethylamino)-2 lambda5-5,4-lambda5-5-catenadi(phosphazene) (P2-tBu) (2M in THF) (0.38 ml, 0.77 mmol) was added dropwise at 0° C. to a solution of 3-[chloro-(2,6-difluoro-phenyl)methanesulfonyl]-5,5-dimethyl-4,5-dihydroisoxazole (prepared according to Example P3) (0.2 g, 0.64 mmol) in THF (5 ml). The solution was stirred for 10 minutes at room temperature. N-chlorosuccinimide (NCS) (0.10 g, 0.77 mmol) was added and the mixture was stirred for 1 hour at room temperature. The reaction was quenched by addition of aqueous hydrochloric acid (2M). The mixture was diluted with ethyl acetate and the two phases were separated. The organic phase was washed several times with brine, dried over magnesium sulfate and concentrated. The crude product was recrystallised from ethanol to give the product (Compound No. 1.26 of Table 27) as a white solid (110 mg, 48% yield).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10]C(C)C)=[O:9])=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:5]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])=[C:4]([CH3:29])[N:3]=1.[OH-].[K+]>C(O)C.O>[CH:26]([O:25][C:23]([C:5]1[C:4]([CH3:29])=[N:3][C:2]([CH3:1])=[C:7]([C:8]([OH:10])=[O:9])[C:6]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)=[O:24])([CH3:28])[CH3:27]
Reactant: Cc1nc(C)c(C(=O)OC(C)C)c(-c2cccc([N+](=O)[O-])c2)c1C(=O)OC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc(C)c(C(=O)OC(C)C)c(-c2cccc([N+](=O)[O-])c2)c1C(=O)O

Procedure:
1 g (2.5 mmols) of diisopropyl 2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate was heated under reflux for 5 hours in a solution of 140 mg (2.5 mmols) of potassium hydroxide in 10 ml of ethanol and 1 ml of water. After cooling down, the mixture was evaporated to dryness, the residue was taken up in water and extracted several times with chloroform. The aqueous phase was adjusted to pH 3 to 4 with dilute hydrochloric acid, the precipitated product was filtered off with suction and dissolved again with saturated sodium bicarbonate solution. After adding a little animal charcoal, the mixture was filtered and the filtrate was adjusted to pH 3 to 4 with dilute hydrochloric acid. The precipitated product was filtered off with suction and dried in vacuo.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[C:12](Cl)(Cl)=[S:13].C(OCC)(=O)C>C(Cl)Cl.CCCCCC>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([N:6]=[C:12]=[S:13])[CH:7]=[CH:8][CH:9]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: FC(F)(F)c1cccc(N=C=S)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.1 %

Procedure:
To a stirred solution of 3-(trifluoromethyl)aniline (20 g, 124.2 mmol) in DCM (100 mL) was added thiophosgene (21.24 g, 186.4 mmol) at 5-10° C. and the reaction mixture was stirred at room temperature for 1-2 h. The reaction was monitored by TLC (mobile phase-40% ethyl acetate in n-Hexane, Rf. S.M.—0.25, product—0.5). Upon disappearance of the starting material, the reaction mass was diluted with DCM, the organic layer was washed with 10% NaHCO3, water and brine. The organic layer was dried and concentrated in vacuo at a temperature lower than 45° C. to afford the product as a yellow oil (Yield: 19.2 g, 76.19% of theoretical).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH2:24]([O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1)[CH2:25][CH2:26][CH3:27].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:24]([O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([N:21]2[CH2:22][CH2:23][CH:18]([N:4]([CH:1]3[CH2:3][CH2:2]3)[S:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=3)(=[O:6])=[O:7])[CH2:19][CH2:20]2)(=[O:37])=[O:36])=[CH:31][CH:30]=1)[CH2:25][CH2:26][CH3:27]
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Reactant: CCCCOc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOc1ccc(S(=O)(=O)N2CCC(N(C3CC3)S(=O)(=O)c3cccc(C(F)(F)F)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
150 mg (0.434 mmol) of N-cyclopropyl-N-piperidin-4-yl-3-trifluoromethylbenzenesulfonamide (available from Lancaster) and 108 mg (0.434 mmol) of 4-butoxyphenylsulfonyl chloride (available from Matrix Scientific) were each dissolved in 10 mL of DCM and then combined. 1.5 eq. of DIEA (0.113 mL) was added to the mixture by syringe. The mixture was stirred overnight at room temperature and then concentrated under vacuum. The resultant product 29 was purified through a column of silica gel with a gradient of 0% to 20% EtOAc in hexanes and the pure material was concentrated (yield 25%, white solid). 1H NMR (CDCl3): δ 8.058 (s, 1H), 8.003-7.983 (d, 1H), 7.851-7.831 (d, 1H), 7.688-7.641 (m, 3H), 7.017-6.980 (m, 2H), 4.055-4.022 (t, 2H), 3.843-3.746 (m, 3H), 2.286-2.226 (t, 2H), 2.068-1.901 (m, 3H), 1.843-1.773 (m, 2H), 1.6151-1.470 (m, 4H), 1.014-0.976 (t, 3H), 0.944-0.903 (m, 2H), 0.793-0.744 (m, 2H). LC: 100%. MS (e/z): 562 (M+H+).
Reaction SMILES: [CH:1]([CH:4]([C:10]([O:12]CC)=O)[C:5]([O:7]CC)=O)([CH3:3])[CH3:2].C[O-].[Na+].[NH2:18][C:19]([NH2:21])=[O:20]>CO>[CH3:3][CH:1]([CH:4]1[C:5](=[O:7])[NH:21][C:19](=[O:20])[NH:18][C:10]1=[O:12])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)C(C)C
Reactant: NC(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)C1C(=O)NC(=O)NC1=O
Temperature: 20 °C
Yield: 69.7 %

Procedure:
456 g (2.25 mol) of diethyl isopropylmalonate, 650 ml of a 30% methanolic sodium methoxide solution and 910 ml of methanol are charged to a 2 liter reactor equipped with an anchor stirrer. The mixture is brought to reflux for thirty minutes before adding 135 g (2.25 mol) of urea in the solid form while maintaining the reflux. The reaction mixture at the end of the reaction is a thick white suspension which is brought to dryness by evaporation of the methanol under vacuum. The residue is taken up in 1370 ml of water and then filtered after cooling to 20° C. The filtrate is treated by addition of the amount of hydrochloric acid needed to bring the pH to 2-3, and the precipitate obtained is filtered off under cold conditions and washed with ice-cold water in order to obtain 267 g of 5-(1-methylethyl)pyrimidine-2,4,6(1H,3H,5H)-trione.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[C:4]([F:13])[C:3]=1[N:14]1[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]1=[O:26].[Cl:27][CH2:28][C:29](Cl)=[O:30]>O1CCOCC1>[Cl:27][CH2:28][C:29]([NH:1][C:2]1[C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[C:4]([F:13])[C:3]=1[N:14]1[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]1=[O:26])=[O:30]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc3c(c2N)NC(=O)CO3)c1=O
Reactant: O=C(Cl)CCl
Solvent: C1COCCO1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc3c(c2NC(=O)CCl)NC(=O)CO3)c1=O
Yield: 72.9 %

Procedure:
3-[5-Amino-7-fluoro-2H-1,4-benzoxazine-3(4H)-on-6-yl]-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione (400 mg, 1.07 mmol) was dissolved in anhydrous dioxane and chloroacetyl chloride (135.6 mg, 1.20 mmol) was added. Solution was heated to reflux for 2 hr and solvent removed in vacuo. The residue was washed with ether to afford the title compound (351.9 mg, 0.78 mmol).
Reaction SMILES: C=O.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9].Cl.[CH2:15](NCC)C>>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11]([CH2:15][O:9][C:8]2=[O:10])=[CH:12][CH:13]=1
Reactant: COc1cccc(C(=O)O)c1
Reactant: CCNCC
Agent: C=O
Agent: Cl
Product: COc1ccc2c(c1)C(=O)OC2
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 32.6 %

Procedure:
Formaldehyde 48% v/v (65 ml, 0.86 moles) under stirring, then 3-methoxy-benzoic acid (100 g, 0.66 moles) were added to concentrated HCl (1 l) and the mixture was heated at 100° C. by checking the development of gas for 30 minutes. The cooling of the mixture brought to the formation of a precipitate which was filtered and put aside, while the mixture was washed with water, then with 5% NaOH. The new precipitate was extracted twice with CH2Cl2, the extract was anhydrified, concentrated, joined to the previously filtered solid, and both were dissolved in CH2Cl2 and treated with diethylamine (120 ml, 1.15 moles). After 24 hours it was extracted with 10% HCl and the phases were separated with CH2Cl2. The organic phase was washed with 10% NaOH, decoloured with charcoal, anhydrified and concentrated. The residue was dissolved in CH2Cl2 and treated, under stirring, with 10% HCl for 30 minutes. The organic phase was washed with water, anhydrified and concentrated. The residue was dissolved in CH2Cl2 and treated with 10% NaOH under stirring for 30 minutes. The organic phase was washed with water, dried and concentrated to give a solid which was crystallised from aqueous CH3OH. The filtrate was dried at 50° C. on P2O5, then crystallised again from aqueous CH3OH to give 35.28 g of the title compound (yield: 32%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[CH3:10][O:11][CH2:12][C:13]([O:15]C)=O>C1COCC1.C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([C:13]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[CH:7]=2)([OH:15])[CH2:12][O:11][CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc([Mg]Br)c1
Reactant: COCC(=O)OC
Solvent: C1CCOC1
Solvent: O=CO
Product: COCC(O)(c1cccc(F)c1)c1cccc(F)c1

Procedure:
A solution of 1,1-bis(3-fluorophenyl)-2-methoxyethanol (156.7 g) (obtained by the reaction of 3-fluorophenylmagnesium bromide with methyl 2-methoxyacetate in THF) in formic acid (160 cc) is heated to reflux for 16 hours, cooled and poured into a mixture of saturated sodium carbonate solution (800 cc) and ethyl acetate (500 cc). The organic phase is washed with water (2×500 cc) and with saturated sodium chloride solution (500 cc), then dried and concentrated to dryness under reduced pressure (2.7 kPa) to give bis(3-fluorophenyl)acetaldehyde (144.5 g) in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]([OH:23])=[O:22])=[CH:20][C:15]=3[N:14]=[C:13]2[C:24](=[O:35])NC2CCN(C(C)C)CC2)=[O:10])=[N:6][CH:7]=1.NCC[OH:39]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]([OH:23])=[O:22])=[CH:20][C:15]=3[N:14]=[C:13]2[C:24]([OH:39])=[O:35])=[O:10])=[N:6][CH:7]=1
Reactant: NCCO
Reactant: CC(C)N1CCC(NC(=O)c2nc3cc(C(=O)O)ccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Product: O=C(Cn1c(C(=O)O)nc2cc(C(=O)O)ccc21)Nc1ccc(Cl)cn1

Procedure:
5-[(2-hydroxy-ethyl)-amide]2-[(1-isopropyl-piperidin-4-yl)-amide]1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-1H-benzoimidazole-2,5-dicarboxylic acid 5-[(2-hydroxy-ethyl)-amide]2-[(1-isopropyl-piperidin-4-yl)-amide] was prepared by a procedure according to example 22 starting from 50 mg (0.10 mmol) 1-[(5-chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-5-carboxylic acid and 6.8 mg (0.11 mmol) 2-amino-ethanol. The title compound was obtained as its formiate in form of a white amorphous solid.