Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:20])[CH2:10][C:11]2[NH:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[N:12]=2)=[CH:5][CH:4]=1.C[O-].[Na+].[C:24](OC)(=[O:27])[C:25]#[CH:26]>>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:10]2[CH:26]=[CH:25][C:24](=[O:27])[N:15]3[C:14]4[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=4[NH:12][C:11]=23)=[O:20])=[CH:5][CH:4]=1
Reactant: C#CC(=O)OC
Reactant: O=C(Cc1nc2c([nH]1)CCCC2)c1ccc(Cl)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: O=C(c1ccc(Cl)cc1)c1ccc(=O)n2c3c([nH]c12)CCCC3

Procedure:
The compound is prepared as described in example 25 with 80 mg (0.23 mmol) of 1-(4-Chlorophenyl)-2-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone hydrochloride (example XXXXI), 19.5 mg (0.46 mmol) of sodium methylate and 96.8 mg (0.23 mmol) methyl propiolate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,4-Difluoronitrobenzene (3.7 g, 23.2 mmol) was dissolved in ethyl acetate (10 mL). Morpholine (2.2 mL, 25 mmol), and N,N-diisopropylethylamine (4 mL, 23 mmol) were added and the mixture stirred overnight at room temperature. At 17 h, additional ethyl acetate (150 mL) was added and the combined mixture was washed with water (50 mL) and brine (50 mL), dried (Na2SO4), filtered and concentrated under vacuum. The residue was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:20]3[CH2:25][CH2:24]S[C:22]4[N:26]=[CH:27][C:28]([N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)=[CH:29][C:21]3=4)=[C:7]([CH3:19])[C:8]([C:12]3[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.O.OO.[OH:39][S:40]([O-:42])=O.[Na+]>CCOC(C)=O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:20]3[CH2:25][CH2:24][S:40](=[O:42])(=[O:39])[C:22]4[N:26]=[CH:27][C:28]([N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)=[CH:29][C:21]3=4)=[C:7]([CH3:19])[C:8]([C:12]3[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccnc(-c2nc3cc(F)ccc3c(N3CCSc4ncc(N5CCOCC5)cc43)c2C)c1
Reactant: O=S([O-])O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccnc(-c2nc3cc(F)ccc3c(N3CCS(=O)(=O)c4ncc(N5CCOCC5)cc43)c2C)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-(1-(7-fluoro-3-methyl-2-(4-methylpyridin-2-yl)quinolin-4-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-yl)morpholine (45 mg, 0.09 mmol) in EtOAc (2.5 mL) was added disodium tungstate (30.4 mg, 0.092 mol) and water (0.5 mL). The reaction was cooled at 0° C. and then H2O2 (56.6 μL, 1.85 mmol, 30%) was added. The reaction was allowed to warm to rt for 1 h. After this time more disodium tungstate (10 mg) was added followed by H2O2 (0.5 mL, 30%) and the reaction was stirred at rt overnight. After this time the reaction was diluted with EtOAc (50 mL) and treated with a saturated aqueous solution of NaHSO3 (15 mL). The separated organic layer was washed with brine (15 mL), dried over MgSO4, filtered and evaporated in vacuo to give 1-(7-fluoro-3-methyl-2-(4-methyl-2-pyridinyl)-4-quinolinyl)-7-(4-morpholinyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine 4,4-dioxide. 1H NMR (400 MHz, chloroform-d) δ ppm 8.59 (1H, d, J=4.7 Hz), 7.86-7.91 (2H, m), 7.70-7.77 (2H, m), 7.38 (1H, ddd, J=9.2, 8.0, 2.5 Hz), 7.25 (1H, dd, J=5.0, 0.9 Hz), 5.58 (1H, d, J=2.5 Hz), 4.18-4.27 (2H, m), 3.59-3.75 (6H, m), 2.84-3.02 (4H, m), 2.51 (3H, s), 2.44 (3H, s). Mass Spectrum (ESI) m/e=520.0 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=[CH:11][C:10]=2[C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[CH2:6][O:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[C:38](Cl)(=[O:42])[CH2:39][CH2:40][CH3:41].COC1C(OC)=CC=C(C2C=CC=C3C=2CCC3=O)C=1OCC1(CNC(=O)C(C)C)COC1>ClCCl.CO>[CH3:16][O:15][C:14]1[C:13]([O:17][CH3:18])=[CH:12][CH:11]=[C:10]([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[C:9]=1[O:8][CH2:7][C:3]1([CH2:2][NH:1][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])[CH2:4][O:5][CH2:6]1
Reactant: CCCC(=O)Cl
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN)COC2)c1OC
Agent: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CNC(=O)C(C)C)COC2)c1OC
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC(=O)NCC1(COc2c(-c3cccc4c3CCC4=O)ccc(OC)c2OC)COC1

Procedure:
To a stirring solution of 4-[2-(3-Aminomethyl-oxetan-3-ylmethoxy)-3,4-dimethoxy-phenyl]-indan-1-one (Compound 191) (150 mg, 0.3916 mmol) in dichloromethane (15 mL), were added diisopropylethylamine (50 mg, 0.390 mmol) and butyryl chloride (41 mg, 0.391 mmol) and the resultant reaction mixture was subjected to the conditions used in the preparation of Compound 193 and purification by column chromatography (silica gel, 0-3% methanol in dichloromethane) afforded the title compound as a solid.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([NH2:14])=[N:8][NH:9]2.ClC1SC(S(N(S(C2SC(Cl)=CC=2)(=O)=O)C2C3C(=CC=CC=3OC)N(C(OC(C)(C)C)=O)N=2)(=O)=O)=CC=1.Cl[CH2:53][C:54]1[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[C:56]([O:62][CH3:63])[CH:55]=1>CS(C)=O.O>[CH3:63][O:62][C:56]1[CH:55]=[C:54]([CH2:53][N:9]2[C:10]3[C:6](=[C:5]([O:4][CH3:3])[CH:13]=[CH:12][CH:11]=3)[C:7]([NH2:14])=[N:8]2)[CH:59]=[CH:58][C:57]=1[O:60][CH3:61]
Reactant: COc1cccc2[nH]nc(N)c12
Reactant: COc1ccc(CCl)cc1OC
Agent: COc1cccc2c1c(N(S(=O)(=O)c1ccc(Cl)s1)S(=O)(=O)c1ccc(Cl)s1)nn2C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(Cn2nc(N)c3c(OC)cccc32)cc1OC
Reaction time: 0.25 h
Yield: 84 %

Procedure:
Powdered KOH (0.494 g, 8.80 mmol) was dissolved in DMSO (20 mL) under nitrogen and 4-(methyloxy)-1H-indazol-3-amine (for a preparation see Intermediate 1) (0.653 g, 4 mmol) was added. The mixture was stirred for 15 min to give a deep red solution. 4-(Chloromethyl)-1,2-bis(methyloxy)benzene (0.896 g, 4.80 mmol) was added in one portion and the mixture was stirred for 2 h. The mixture was added to water (150 mL) and extracted with dichloromethane (3×50 mL). The dried (Na2SO4) extract was evaporated and the residue was triturated with diethyl ether (3×3 mL) to give the title compound (1.05 g, 84%) as an orange solid. LCMS (System B) RT=1.42 min, ES+ve m/z 314 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][SH:16])=[CH:13][CH:12]=1.[Na]>>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:15]([S:16][CH:15](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:14]2[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][CH:13]=2)[C:14]2[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: SCc1ccc(Cl)cc1
Reactant: C#Cc1ccc(F)cc1
Agent: [Na]
Product: Fc1ccc(/C=C\C(SC(/C=C\c2ccc(F)cc2)c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1

Procedure:
A solution of 4-fluorophenylacetylene (0.02 mol) and 4-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-fluorostyryl 4-chlorobenzylsulfide. The title compound was obtained in 82% yield following oxidation. 1HNMR (CDCl3) δ 4.60 (2H, s), 6.68 (1H, d, JH,H=11.84), 7.18-7.60 (8H aromatic+1H ethylenic).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:15]2[CH:20]=[C:19]([CH3:21])[C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Cc1cc(C)c(Br)cc1C
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(N2CCN(C(=O)OC(C)(C)C)CC2)cc1C
Yield: 100.1 %

Procedure:
To a mixture of 1-Boc-piperazine (1.39 g), 1-bromo-2,4,5-trimethylbenzene (1 g), tris(dibenzylideneacetone)dipalladium (0) (257 mg), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (481 mg) and sodium tert-butoxide (669 mg) was added toluene (10 mL), and the mixture was refluxed for 3 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (ethyl acetate:hexane) to give 4-(2,4,5-trimethylphenyl)piperazine-1-carboxylic acid tert-butyl ester (1.53 g). 4-(2,4,5-trimethylphenyl)piperazine-1-carboxylic acid tert-butyl ester (1.53 g) was dissolved in dichloromethane (10 mL), 4N hydrogen chloride/dioxane (5 mL) was added, and the mixture was stirred at room temperature for 3 hr. Diethyl ether (100 mL) was added, and the precipitate was collected by filtration. To the obtained precipitate were added ethyl acetate and 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate and washed with saturated brine. The solvent was evaporated to give 1-(2,4,5-trimethylphenyl)piperazine (920 mg). By reaction and treatment in the same manner as in Preparation Example 27 and using 6-bromonicotinic acid (412 mg) and 1-(2,4,5-trimethylphenyl)piperazine (440 mg), the title compound (800 mg) was obtained.
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([C:13]([CH3:50])([CH3:49])[C:14]([N:16]([CH3:48])[C:17]2[C:18]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=3[CH3:47])=[CH:19][C:20]([C@@H:23]3[N:27](C(OC(C)(C)C)=O)[C@@:26]([CH3:39])([C:35]([O:37][CH3:38])=[O:36])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(O)(C(F)(F)F)=O>ClCCl>[F:52][C:2]([F:1])([F:51])[C:3]1[CH:4]=[C:5]([C:13]([CH3:49])([CH3:50])[C:14]([N:16]([CH3:48])[C:17]2[C:18]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=3[CH3:47])=[CH:19][C:20]([C@@H:23]3[NH:27][C@@:26]([CH3:39])([C:35]([O:37][CH3:38])=[O:36])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: COC(=O)[C@@]1(C)CC[C@H](c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)N1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@]1(C)CC[C@H](c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a solution of 1-(1,1-dimethylethyl) 2-methyl (2R,5R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-1,2-pyrrolidinedicarboxylate (Intermediate 7, 30 mg, 0.041 mmol) in dry Dichloromethane (2 ml) was added TFA (0.6 ml, 7.79 mmol) and the reaction mixture was stirred for 2 hours at r.t. The solvent and the excess of TFA were evaporated and the residue was purified by SPE-SCX cartridge affording the title compound (25 mg, 0.039 mmol, 96% yield) as a white solid. HPLC: Rt 5.68 min. MS: m/z 640 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]12[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:14]C(=O)O[C:10]2=[O:11]>C(OCC)(=O)C>[NH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=1[C:10]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:11]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: Nc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: Nc1ccccc1C(=O)Nc1ccc(Cl)cc1
Temperature: 115 °C

Procedure:
To a solution of 4-chloroaniline (3.13 g, 24.5 mmol) in N,N-dimethylformide (20 mL) was added isatoic anhydride (4.00 g, 24.5 mmol), and the reaction mixture was heated at 115° C. for 14 h, cooled to room temperature and diluted with ethyl acetate (100 mL). The organic layer was washed with 1 N NaOH (200 mL), water (100 mL), then brine, and dried over Na2SO4. The solvent was removed under reduced pressure to give crude product, which was purified by column chromatography (silica gel 230-400 mesh; EtOAc/hexane=1:9) to give 2-amino-N-(4-chloro-phenyl)-benzamide as white solid. Yield: 1.67 g (28%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([OH:15])[CH2:11][C:12]([CH3:14])=[CH2:13]>CCOC(C)=O.[Pd]>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([OH:15])[CH2:11][CH:12]([CH3:13])[CH3:14]
Reactant: C=C(C)CC(O)c1c(Cl)ccc(F)c1Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)CC(O)c1c(Cl)ccc(F)c1Cl
Reaction time: 2.5 h

Procedure:
To a solution of 1-(2,6-dichloro-3-fluorophenyl)-3-methylbut-3-en-1-ol (0.95 mmol) in EtOAc (5.0 mL) was added palladium 10% wt on activated carbon (30 mg). The flask was evacuated and purged with hydrogen gas (3×) and allowed to stir under hydrogen for 2.5 h. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give a light yellow oil. The material was purified by silica gel chromatography using Hexane/EtOAc (80:20) as eluent to obtain the desired product as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ=1.02 (dd, J=6.6, 4.5 Hz, 6H), 1.58 (ddd, J=13.9, 8.8, 4.5 Hz, 1H), 2.05-2.13 (m, 1H), 2.71 (d, J=10.1 Hz, 1H), 5.49 (td, J=10.0, 4.8 Hz, 1H), 7.03 (dd, J=8.8, 7.8 Hz, 1H), 7.27-7.29 (m, 1H).
Reaction SMILES: [CH2:1]([O:3]C(Cl)=O)C.[Cl:7][C:8]1[CH:9]=[C:10]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[O:11][C:12]1[C:13]([CH2:24][CH3:25])=[N:14][N:15]([CH2:19][C:20](=[NH:23])[NH:21][OH:22])[C:16]=1[CH2:17][CH3:18]>N1C=CC=CC=1.O1CCCC1.[OH-].[Na+].Cl>[Cl:7][C:8]1[CH:9]=[C:10]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[O:11][C:12]1[C:13]([CH2:24][CH3:25])=[N:14][N:15]([CH2:19][C:20]2[N:23]=[C:1]([OH:3])[O:22][N:21]=2)[C:16]=1[CH2:17][CH3:18]
Reactant: CCc1nn(CC(=N)NO)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCc1nn(Cc2noc(O)n2)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.2 %

Procedure:
Ethylchloroformate (0.30 ml, 3.08 mmol) was added to a stirred solution of the amidoxime of Example 8 (500 mg, 1.39 mmol) in pyridine (8 ml) at 0° C. under nitrogen and the resulting solution was stirred for 10 minutes. The mixture was concentrated under reduced pressure and the residue was dissolved in a mixture of water (4 ml), tetrahydrofuran (4 ml) and 1M aqueous sodium hydroxide solution (2 ml). The mixture was heated under reflux for 1 hour, cooled to room temperature and stirred for a further 2 days. The resulting solution was diluted with 2M aqueous hydrochloric acid (20 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine (50 ml), dried over magnesium sulphate, filtered and evaporated under reduced pressure to leave a yellow oil. The oil was purified by flash column chromatography on silica gel eluting with pentane:ethyl acetate (50:50, by volume) to yield a white solid. The solid was dissolved in a mixture of tetrahydrofuran (1 ml) and 1M aqueous sodium hydroxide solution (10 ml) and then heated under reflux for 24 hours. The resulting solution was diluted with 2M hydrochloric acid (20 ml) and extracted with dichloromethane (2×50 ml). The combined organic layers were washed with brine (50 ml), dried over magnesium sulphate, filtered and evaporated under reduced pressure to give the title compound (113 mg) as a white solid m.p. 94–96° C.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[O:13][CH2:12][CH2:11][C:10]=12)([CH3:3])[CH3:2].[N-:14]=[C:15]=[O:16].[Na+]>C(O)(=O)C>[CH:1]([N:4]([C:5]1[C:10]2[CH2:11][CH2:12][O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1)[C:15]([NH2:14])=[O:16])([CH3:3])[CH3:2]
Reactant: [N-]=C=O
Reactant: CC(C)Nc1cccc2c1CCO2
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)N(C(N)=O)c1cccc2c1CCO2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 7.4 g. of N-isopropyl-2,3-dihydro-4-benzofuranamine in 200 ml. of glacial acetic acid, cooled to 15°± 5°C. is added 2.5 g. of sodium isocyanate. The mixture is stirred at room temperature for 15 hours and then concentrated in vacuo. The residue is treated with 150 ml. of 2N sodium hydroxide and then extracted with chloroform. The chloroform extract is dried with anhydrous magnesium sulfate, filtered and concentrated in vacuo to give an oil of 1-isopropyl-1-(2,3-dihydro-4-benzofuranyl) urea.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[CH:22][S:23][C:16]=34)[CH:11]=[CH:10][C:5]=2[C:6]=1[C:7](Cl)=[O:8].[N:24]1([CH2:30][CH2:31][CH2:32][NH2:33])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[N:24]1([CH2:30][CH2:31][CH2:32][NH:33][C:7]([C:6]2[C:5]3[CH:10]=[CH:11][C:12]([O:14][C:15]4[CH:20]=[CH:19][N:18]=[C:17]5[CH:21]=[CH:22][S:23][C:16]=45)=[CH:13][C:4]=3[O:3][C:2]=2[CH3:1])=[O:8])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: Cc1oc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)Cl
Reactant: NCCCN1CCOCC1
Product: Cc1oc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)NCCCN1CCOCC1

Procedure:
This material was prepared from 2-methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carbonyl chloride 101 and 3-(morpholin-4-yl)propylamine in a similar manner as that described for example 108. 1H NMR (DMSO-d6) δ8.50 (1H, d, J=5.6 Hz), 8.14 (1H, d, J=5.6 Hz), 8.07 (1H, bm), 7.80 (1H, d, J=8.6 Hz), 7.64 (1H, d, J=2.0 Hz), 7.59 (1H, d, J=5.6 Hz), 7.24 (1H, dd, J=8.3, 2.0 Hz), 6.61 (1H, d, J=5.6 Hz), 3.56 (4H, bm), 3.35-3.27 (4H, m), 2.63 (3H, s), 2.36 (4H, bm), 1.73 (2H, bm).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=1.[S:17](N)(N)(=[O:19])=[O:18].S(=O)(=O)(O)N>COCCOCCOC>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][S:17]1(=[O:19])=[O:18]
Reactant: NS(N)(=O)=O
Reactant: Cc1ccc(Nc2ccccc2N)c(F)c1
Agent: NS(=O)(=O)O
Solvent: COCCOCCOC
Product: Cc1ccc(N2c3ccccc3NS2(=O)=O)c(F)c1
Temperature: 25 °C
Yield: 51.9 %

Procedure:
A solution of N-(2-fluoro-4-methylphenyl)benzene-1,2-diamine (3.9 g, 18 mmol) in diglyme (36 mL) was treated with sulfamide (2.1 g, 22 mmol) and added dropwise over 10 min to a refluxing solution of sulfamic acid (0.9 g, 9 mmol) in diglyme (36 mL), and the reaction mixture was kept at reflux for an additional 15 minutes, then cooled to room temperature and concentrated. The residue was dissolved in ethyl ether (300 mL), washed with 2 N hydrochloric acid (100 mL), evaporated, and flash chromatographed (SiO2, 050% ethyl acetate/hexanes) provided 1-(2-fluoro-4-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (2.6 g) as a red solid:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([OH:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:15][C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:13](=[O:14])[CH:12]=2)=[CH:19][CH:18]=1
Reactant: O=c1cc(O)cnn1-c1ccc(Cl)cc1
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccc(Cl)cc2)cnn1-c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 80.2 %

Procedure:
In 50 ml of N,N-dimethylformamide were dissolved 2.0 g (9.0 m mol) of 2-(4-chlorophenyl)-5-hydroxy-3(2H)-pyridazinone and 1.5 g (9.3 m mol) of p-chlorobenzyl chloride, and thereto was added 1.7 g of anhydrous potassium carbonate. The reaction mixture was heated under stirring on an oil bath at 100°-120° C. for one hour. Then, the procedure in Synthesis Example 13 were repeated to give 2.5 g of the intended compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][C:7]([F:10])([F:9])[CH2:6][CH2:5][N:4]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[Cl:18][C:19]1[CH:20]=[C:21]2[C:27]([C:28]3[N:33]=[C:32](S(C)=O)[C:31]([F:37])=[CH:30][N:29]=3)=[CH:26][N:25]([S:38]([C:41]3[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=3)(=[O:40])=[O:39])[C:22]2=[N:23][CH:24]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:18][C:19]1[CH:20]=[C:21]2[C:27]([C:28]3[N:33]=[C:32]([NH:1][CH2:2][CH:3]4[CH2:8][C:7]([F:10])([F:9])[CH2:6][CH2:5][N:4]4[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:31]([F:37])=[CH:30][N:29]=3)=[CH:26][N:25]([S:38]([C:41]3[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=3)(=[O:40])=[O:39])[C:22]2=[N:23][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(Cl)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(F)CC1CN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NCC4CC(F)(F)CCN4C(=O)OC(C)(C)C)n3)c3cc(Cl)cnc32)cc1
Temperature: 130 °C

Procedure:
To a solution of tert-butyl 2-(aminomethyl)-4,4-difluoro-piperidine-1-carboxylate, 13i, (0.10 g, 0.41 mmol) and 5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine (0.18 g, 0.38 mmol) in THF (2 mL) was added iPr2NEt (0.20 mL, 1.15 mmol). The reaction mixture was heated in microwave at 130° C. for 15 minutes. The reaction was cooled to room temperature and the volatiles were removed under reduced pressure. The crude residue was purified via silica gel chromatography (0-100% EtOAc/hexanes) to afford the desired product, 13j.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:15][C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22]([N+:24]([O-:26])=[O:25])=[C:21]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:20]=2[CH:33]=1>C(O)C>[N+:24]([C:22]1[O:23][C:19]2[CH:18]=[CH:17][C:16]([CH2:15][O:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=3)=[CH:33][C:20]=2[C:21]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1oc2ccc(CBr)cc2c1-c1ccccc1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1ccc(OCc2ccc3oc([N+](=O)[O-])c(-c4ccccc4)c3c2)cc1

Procedure:
To a mixture of 1 g. (0.0066 mole) of 4-hydroxyphenylacetic acid and 0.53 g. of sodium hydroxide in 100 ml. of ethanol is added 2 g. (0.006 mole) of 5-bromomethyl-2-nitro-3-phenylbenzofuran, and the mixture is heated at its reflux temperature for 16 hours. The reaction mixture is evaporated to provide a residue which is extracted thoroughly with chloroform. The residue is separated from chloroform and dissolved in water. The water is acidified to pH 3. The precipitate is separated by filtration, dissolved in dichloromethane, and the dichloromethane solution is dried. The dichloromethane solution is evaporated to provide a yellow solid which is recrystallized from ethanol to provide 4-[(2-nitro-3-phenylbenzofuran-5-yl)methoxy]phenylacetic acid, m.p. 179°-180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:19])[C:8]=1[O:9][C:10]([F:18])([F:17])[CH:11]([F:16])[C:12]([F:15])([F:14])[F:13])[NH2:5].[F:20][C:21]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:22]=1[C:23]([N:25]=[C:26]=[O:27])=[O:24]>C1(C)C=CC=CC=1>[F:20][C:21]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:22]=1[C:23]([NH:25][C:26]([NH:5][C:4]1[CH:3]=[C:2]([Cl:1])[C:8]([O:9][C:10]([F:17])([F:18])[CH:11]([F:16])[C:12]([F:15])([F:14])[F:13])=[C:7]([Cl:19])[CH:6]=1)=[O:27])=[O:24]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Nc1cc(Cl)c(OC(F)(F)C(F)C(F)(F)F)c(Cl)c1
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(OC(F)(F)C(F)C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4.3 g of 3,5-dichloro-4-(1,1,2,3,3,3-hexafluoropropyloxy)aniline are dissolved with stirring in 50 ml of dry toluene and, with exclusion of moisture, a solution of 2.41 g of 2,6-difluorobenzoylisocyanate in 10 ml of dry toluene is added at room temperature. The batch is stirred for a further 12 hours at room temperature. About 75% of the solvent is then removed by rotary evaporation, the precipitated residue is filtered with suction, washed with a small amount of cold toluene and hexane and then dried in vacuo, affording the title compound of the formula ##STR13## in the form of a crystalline white powder with a melting point of 171°-172° C. (compound 1).