Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH2:13])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:14][O:15][C:16](=[O:23])[C:17]([C:19]([F:22])([F:21])[F:20])=O.C([BH3-])#N.[Na+]>C(Cl)Cl.CO.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([NH:13][C@H:17]([C:16]([O:15][CH3:14])=[O:23])[C:19]([F:22])([F:21])[F:20])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: Nc1nc(-c2ccc(Br)cc2)cs1
Reactant: COC(=O)C(=O)C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@@H](Nc1nc(-c2ccc(Br)cc2)cs1)C(F)(F)F
Reaction time: 0.25 h
Yield: 43 %

Procedure:
4-(4-Bromophenyl)-1,3-thiazol-2-ylamine (510 mg, 2.0 mmol) and methyl-3,3,3-trifluoropyruvate (0.10 mL, 1.0 mmol) were dissolved in 50 mL methylene chloride. Titanium (IV) chloride (1M in toluene, 1.6 mL, 1.6 mmol) was added dropwise to give an orange-brown suspension. The mixture was stirred for 15 min and then added by cannula to a solution of sodium cyanoborohydride (0.26 g, 3.0 mmol) in 50 mL of methanol. The mixture was stirred for 15 min and then quenched by the addition of H2O and saturated aqueous sodium bicarbonate. The mixture was extracted three times with methylene chloride. The organics were combined, washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (100% methylene chloride) afforded methyl N-[4-(4-bromophenyl)-1,3-thiazol-2-yl]-3,3,3-trifluoroalaninate (0.17 g, 44%) as a white solid. MS (ES) m/z 392.8.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[OH:27].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:26][C:22]1[C:21]([OH:27])=[C:20]([NH:19][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1cccc(F)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(F)c1O
Yield: 50.2 %

Procedure:
The product is prepared according to the procedure described in Example 2, stage 2, using 500 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (Example 1, stage 2), 357 mg of 2-amino-6-fluorophenol and 600 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 4 ml of pyridine and 4 ml of dimethylformamide. 335 mg of N-(3-fluoro-2-hydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[F:12][C:13]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:14]=1[CH:15]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](/[N:10]=[CH:15]/[C:14]2[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:13]=2[F:12])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=Cc1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(/N=C/c2ccc(F)cc2F)cc1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
The mixture solution of 4-aminobenzoic acid methyl ester (10.8 g, 71.4 mmol), 2,4-difluoro-benzaldehyde (10.3 g, 72.4 mmol) and p-toluenesulfonic acid (271.8 mg, 1.4 mmol) in toluene (150 mL) was heated to reflux for 12 h. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-{[1-(2,4-difluoro-phenyl)-meth-(E)-ylidene]amino}-benzoic acid methyl ester (19.64 g, quant.) as a light yellow solid: MS (ESI) M+1=276.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([CH3:27])([CH3:26])[C:24]#[N:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.C([O-])([O-])=[O:30].[K+].[K+].OO>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([CH3:27])([CH3:26])[C:24]([NH2:25])=[O:30])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][C:11]2=[O:28])[CH3:9])=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)CC1=O
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)C(N)=O)(c2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of 3-((S)-1-((S)-1-(4-bromophenyl)ethyl)-2-oxo-4-phenylpiperidin-4-yl)-2,2-dimethylpropanenitrile (11 mg, 0.025 mmol) in DMSO (3 mL) were added K2CO3 (6.9 mg 0.05 mmol) and 30% H2O2 (5.7 mg 0.05 mmol). The mixture was stirred at rt overnight. After being diluted with water (2 mL), the mixture was washed with EtOAc (3×2 mL). The aqueous layer was acidified to pH=3-4, and extracted with EtOAc (3×2 mL). The combined organic layers were washed with brine (3×2 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was dried under vacuum and purified by TLC and preparative HPLC to give 3-((S)-1-((S)-1-(4-bromophenyl)ethyl)-2-oxo-4-phenylpiperidin-4-yl)-2,2-dimethylpropanamide (8 mg, 70%). LC-MS Method 2 tR=1.36 min, m/z=481, 479, 459, 457; 1H NMR (CDCl3): δ 0.78 (s, 3H), 1.08 (s, 3H), 1.40 (d, 3H), 2.0 (m, 4H), 2.18 (m, 1H), 2.66 (m, 1H), 2.81 (m, 1H), 3.32 (m, 1H), 5.58 (m, 1H), 5.84 (m, 1H), 6.18 (m, 1H), 6.68 (m, 2H), 7.16 (m, 2H), 7.20 (m, 5H).
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([OH:38])[CH:33]=1)=[O:31]>ClCCl.O>[OH:38][C:34]1[CH:33]=[C:32]([C:30](=[O:31])[CH2:29][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: CC(=O)Nc1ccc(CCOCCCCCCNCc2ccccc2)cc1
Reactant: O=C(CBr)c1cccc(O)c1
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1ccc(CCOCCCCCCN(CC(=O)c2cccc(O)c2)Cc2ccccc2)cc1
Yield: 52.1 %

Procedure:
A solution of N-[4-[2-[[6-[(phenylmethyl)amino]hexyl]oxy]ethyl]phenyl]acetamide (1 g), 2-bromo-1-(3-hydroxyphenyl)ethanone (0.61 g) and DEA (0.8 g) in dichloromethane (20 ml) was stirred under nitrogen for 18 h, diluted with water (20 ml), and extracted with dichloromethane (25 ml). The organic layer was washed with 8% sodium bicarbonate solution (20 ml), dried and evaporated in vacuo to give the title compound as a yellow oil (0.71 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[OH:12][C:13]1[C:18]([CH2:19][CH2:20][CH3:21])=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=1[C:23](=[O:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[OH:12][C:13]1[C:18]([CH2:19][CH2:20][CH3:21])=[C:17]([O:22][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=2)[CH:16]=[CH:15][C:14]=1[C:23](=[O:25])[CH3:24]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(OCc2cccc([N+](=O)[O-])c2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add 3-bromomethyl nitrobenzene (10.00 g, 46.3 mmol) to a solution of 1-(2,4-dihydroxy-3-propyl-phenyl)-ethanone (8.99 g, 46.3 mmol) in dimethylformamide (60 mL). After 10 minutes add potassium carbonate (9.60 g, 69.4 mmol) and cesium carbonate (15.08 g, 46.3 mmol). Stir at room temperature for one hour, then heat to 70° C. for 1.5 hours. Cool and add water (250 mL). Triturate for 15 minutes. Filter. Wash the solid with water several times, and then wash with hexanes. Dry to afford the title compound as an off white/light gray powder (12.9 g, 85%): 1H NMR (DMSO-d6) δ 0.91 (t, 3H), 1.52 (m, 2H), 2.58 (s, 3H), 2.63 (m, 2H), 5.42 (s, 2H), 6.72 (d, 1H), 7.73 (t, 1H), 7.83 (d, 1H), 7.90 (d, 1H), 8.21 (d, 1H), 8.34 (s, 1H), 12.88 (bs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:10]=2[O:9][CH2:8][CH2:7][CH2:6]1)=[O:4].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:26]=2[C:27]([NH:29][CH2:30][C:31]#[CH:32])=[O:28])[C:21]([Cl:38])=[CH:20][N:19]=1>>[CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([NH:16][C:18]3[N:23]=[C:22]([NH:24][C:25]4[C:26]([C:27](=[O:28])[NH:29][CH2:30][C:31]#[CH:32])=[CH:33][CH:34]=[CH:35][C:36]=4[F:37])[C:21]([Cl:38])=[CH:20][N:19]=3)=[CH:15][C:10]=2[O:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CCCOc2cc(N)ccc21
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)OCCCN3C(=O)OC)ncc1Cl

Procedure:
3-[5-Chloro-4-(2-fluoro-6-prop-2-ynylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid methyl ester was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid methyl ester and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide in an analogous manner to Example 1410. Product isolated as an orange foam (128 mg, 64%). LCMS (m/e) 525 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.41 (s, 1H), 9.19 (s, 1H), 9.05-8.96 (m, 1H), 8.19 (s, 1H), 7.58-7.41 (m, 3H), 7.27 (s, 1H), 7.14-7.06 (m, 1H), 6.94 (d, 1H, J=8.7 Hz), 4.07-3.85 (m, 4H), 3.73-3.40 (m, 5H), 3.13-3.08 (m, 1H), 1.95-1.80 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[NH:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[Br:9]N1C(=O)CCC1=O>O1CCCC1.CO>[Br:9][C:6]1[NH:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:8][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccc[nH]1
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Br)[nH]1
Temperature: 25 °C
Yield: 22.4 %

Procedure:
2-Acetylpyrrole (2.00 g, 18.3 mmol) was dissolved in a mixed solvent of tetrahydrofuran (100 mL) and methanol (50 mL), and N-bromosuccinimide (3.26 g, 18.3 mmol) was added with stirring at room temperature under nitrogen atmosphere. After stirring for 1 hour, the solvent was distilled off under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution (200 mL) was added, and extraction was carried out with ethyl acetate (300 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-20%) to afford the desired compound (770 mg, yield 22%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Cl[CH2:21][C:22]1[O:26][N:25]=[C:24]([CH3:27])[CH:23]=1.C([O-])([O-])=O.[K+].[K+]>>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][C:22]1[O:26][N:25]=[C:24]([CH3:27])[CH:23]=1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: Cc1cc(CCl)on1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(CN2C(=O)C(C)(C)c3cc(N)c([N+](=O)[O-])cc32)on1
Yield: 25.8 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (3 g) is alkylated using 5-chloromethyl-3-methyl-isoxazole (1.65 g; 12.5 mmol) and K2CO3 (3,3 g; 23.9 mmol) at RT for 3 days. After aqueous work-up and purification by RP chromatography the pure material (1.07 g) is de-acetylated in MeOH (50 ml) using DBU (220 μl) at 60° C. in 18 h. After aqueous work-up 5-amino-3,3-dimethyl-1-(3-methyl-isoxazol-5-ylmethyl)-6-nitro-1,3-dihydro-indol-2-one (0.93 g) is obtained and used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C@H:6]2[O:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17]([CH2:24]Cl)=[CH:18][C:19](=[O:23])[O:20]2)=[CH:15][CH:14]=1.BrC1C(C)=CC([O:31]CCC(C)(O)C)=CC=1C.[OH-].[Na+].Cl>CCO.O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C@H:6]2[O:12][C:13]1[CH:14]=[CH:15][C:16]2[C:17]([CH2:18][C:19]([OH:31])=[O:23])=[CH:24][O:20][C:21]=2[CH:22]=1
Reactant: Cc1cc(OCCC(C)(C)O)cc(C)c1Br
Reactant: O=c1cc(CCl)c2ccc(O[C@@H]3CCc4c(Br)ccc(F)c43)cc2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1coc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc12
Temperature: 25 °C

Procedure:
To 15.0 g (35.4 mmol) 7-((R)-4-bromo-7-fluoroindan-1-yloxy)-4-chloromethyl-chromen-2-one (product from step 2) in 45 ml EtOH, 9.29 ml (177 mmol) aq. NaOH (50%) is added. The funnel is rinsed with 50 ml water and the mixture is heated to reflux for approx. 0.5 h. Then, over a time period of 30 min a mixture of 30 ml water and 14.7 ml (177 mmol) conc. HCl (37%) is added. The suspension is cooled to r.t., the product is filtered off, washed with EtOH/water (1:1, 2×30 ml) and dried. Yield: 14.0 g; Rf=0.38 (silica gel, PE/EtOAc/AcOH=6/4/0.1); Mass spectrum (ESI): m/z=405 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][CH:5]=1.[F:14][C:15]1[C:16]([O:24][CH3:25])=[C:17]([C:20]([F:23])=[CH:21][CH:22]=1)[CH:18]=O>>[F:14][C:15]1[C:16]([O:24][CH3:25])=[C:17]([CH:18]2[N:11]([CH2:10][C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:12])([F:13])[F:1])=[CH:9][CH:8]=3)[C:16](=[O:24])[CH:15]([F:14])[CH2:22]2)[C:20]([F:23])=[CH:21][CH:22]=1
Reactant: COc1c(F)ccc(F)c1C=O
Reactant: NCc1ccc(OC(F)(F)F)cc1
Product: COc1c(F)ccc(F)c1C1CC(F)C(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedures 10A2 (GP10A2), 10B (GP10B), 10F (GP10F), and 10I (GP10I) using commercially available (4-(trifluoromethoxy)phenyl)methanamine and synthesized 3,6-difluoro-2-methoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.90 min.; [M+H]+: 419.85 g/mol.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[N:16]1([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[NH:28][C:27](=[O:32])[CH2:26][CH2:25]3)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(Cl)(Cl)Cl.C(OC(NC1SC(C(N2CCN(C3C=C4C(=CC=3)NC(=O)CC4)CC2)=O)=C(C)N=1)=O)(C)(C)C>[CH3:15][O:14][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][C:9]=1[O:12][CH3:13])[C:2]([N:19]1[CH2:20][CH2:21][N:16]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[NH:28][C:27](=[O:32])[CH2:26][CH2:25]4)[CH2:17][CH2:18]1)=[N:3][CH:4]=[CH:5]2
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Reactant: COc1cc2ccnc(Cl)c2cc1OC
Agent: Cc1nc(NC(=O)OC(C)(C)C)sc1C(=O)N1CCN(c2ccc3c(c2)CCC(=O)N3)CC1
Solvent: ClC(Cl)Cl
Product: COc1cc2ccnc(N3CCN(c4ccc5c(c4)CCC(=O)N5)CC3)c2cc1OC
Yield: 37.3 %

Procedure:
1-Chloro-6,7-dimethoxyisoquinoline (0.63 g) and 6-(1-piperazinyl)-3,4-dihydro-2(1H)-quinolinone (1.30 g) were mixed at 200° C. for 1.5 hours under stirring. The mixture was dissolved in a mixture of chloroform and methanol (10:1 V/V) and subjected to a column chromatography on silica gel (eluent:methanol in chloroform, 0-2% V/V). The fractions containing the object compound were combined and concentrated and the residue was triturated with diisopropyl ether to give 6-[4-(6,7-dimethoxyisoquinolin-1-yl)-1-piperazinyl]-3,4-dihydro-2(1H)-quinolinone (0.44 g).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].[H-].[Na+].[CH3:37]I.O>COCCOC>[F:32][C:29]([F:31])([F:30])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][N:13]([CH3:37])[C:12]2=[O:23])[CH2:24][CH2:25]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1CN(c2ccccc2Cl)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
8-(3,5-Bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (253 mg) was suspended in 1,2-dimethoxyethane (3 mL) and sodium hydride (24 mg, 60%) was added with stirring at room temperature. After 15 minutes methyliodide (78 mg) was added and stirring was continued overnight at room temperature. Water was added and the mixture was extracted with ethylacetate. Organic phases were pooled, dried with Na2SO4 and the solvent was evaporated. Chromatography on silica gel (hexane/ethylacetate=1:1) yielded the desired product (152 mg, 59%), MS: m/e=520.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=3)[C:10]([CH2:23][CH3:24])=[C:9]([CH3:25])[N:8]=2)=[CH:4][CH:3]=1.[NH2:26][OH:27].Cl.C([O-])([O-])=O.[K+].[K+].CCO>O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([NH:26][OH:27])=[NH:22])=[CH:16][CH:15]=3)[C:10]([CH2:23][CH3:24])=[C:9]([CH3:25])[N:8]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(CC#N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(CC(=N)NO)cc1
Temperature: 25 °C
Yield: 46.7 %

Procedure:
A 50-mL round bottomed flask was charged with 2-[4-[[2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]acetonitrile (120 mg, 0.325 mmol, 1 eq.), NH2OH/HCl (160 mg, 2.3 mmol, 7 eq), K2CO3 (320 mg, 2.3 mol, 7 eq.), EtOH (10 ml) and water (1 ml). The mixture was stirred under reflux overnight. After cooling to room temperature, the volatile material was removed under reduced pressure. The residue was purified by chromatography on silica gel using 1.5˜4% of methanol in dichloromethane as eluent to give the title compound (61 mg, 47% yield).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH:16]=[CH:17][C:18]#[N:19])(=[O:15])=[O:14])=[CH:9][CH:8]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([CH:16]=[CH:17][C:18]#[N:19])(=[O:15])=[O:14])=[CH:11][CH:12]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: N#CC=CS(=O)(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)Nc1ccc(S(=O)(=O)C=CC#N)cc1
Reaction time: 48 h

Procedure:
23 grams (0.2 mol) of methanesulfonyl chloride (CH3SO2Cl) are dissolved in 600 milliliters of chloroform, and 42 grams (0.2 mol) of 3-(4-aminobenzenesufonyl)acrylonitrile, prepared as described in copending application Ser. No. 228,410 filed Feb. 22, 1972, are added with stirring and cooling in an ice bath followed portionwise by a solution of 16 g (0.2 mol) of pyridine in 200 ml of pyridine. The reaction mixture is allowed to reach room temperature and is thereafter left at about 20° C for about 48 hours. The solution is filtered and then washed with water, a 5% solution of HCl in water, a 5% sodium bicarbonate solution in water, and water, in sequence.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:6][CH2:7]1)=[O:37]
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-phenyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example D.f12) and commercially methoxyacetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]([F:23])([S:19](F)(=[O:21])=[O:20])[C:3]([F:18])([F:17])[C:4]([F:16])([F:15])[C:5]([F:14])([F:13])[C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[F:8].C[Si](C)(C)[O-:26].[K+:29]>CCOCC>[F:1][C:2]([F:23])([S:19]([O-:26])(=[O:21])=[O:20])[C:3]([F:18])([F:17])[C:4]([F:16])([F:15])[C:5]([F:14])([F:13])[C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[F:8].[K+:29]
Reactant: C[Si](C)(C)[O-]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [K+]
Solvent: CCOCC
Product: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 53.6 %

Procedure:
The procedure of Example 1 was followed using perfluorohexanesulfonyl fluoride (7.9 g, 19.6 mmol), potassium trimethylsilanolate (2.52 g, 19.6 mmol), dry ether (150 mL), and a reaction time of nine days. Potassium perfluorohexanesulfonate (4.6 g, 53% yield) was isolated as a white solid: 19F NMR (methanol) δ -81.1 (m, --CF3 --, 3F), -114.4 (m, --CF2SO3⃝, 2F), -120.6 (m, --CF2CF2SO3⃝, 2F), -121.7 (m, --CF2 (CF2)2SO3⃝, 2F), -122.6 (m, CF3CF2CF2, 2F), 126.1 ppm (m, CF3CF2 --, 2F).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH2:12][CH3:13])[C:5]([OH:7])=[O:6].[C:14](OCC)(OCC)(OCC)[CH3:15]>CCO>[CH2:12]([N:11]1[C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[N:1]=[C:14]1[CH3:15])[CH3:13]
Reactant: CCOC(C)(OCC)OCC
Reactant: CCNc1ccc(C(=O)O)cc1N
Solvent: CCO
Product: CCn1c(C)nc2cc(C(=O)O)ccc21
Temperature: 25 °C

Procedure:
A mixture of 1.4 g (7.7 mmol) of the title B compound, 3-amino-4-ethylamino-benzoic acid and 15 mL (104 mmol) of triethyl orthoacetate in 20 mL of EtOH is refluxed for 7 h. The reaction mixture is allowed to cool to RT and the precipitated solid is collected by filtration, washed with EtOH (2×), then with methyl-t-butylether (MTBE) and dried in vacuo to give 1-ethyl-2-methyl-1H-benzoimidazole-5-carboxylic acid as a grey solid: mp>250° C.; 1H-NMR (DMSO-d6) δ 12.65 (s, 1H), 8.11 (s, 1H), 7.82 (dd, 1H), 7.59 (d, J=8.46, 1H), 4.26 (q, 2H), 2.57 (s, 3H), 1.30 (t, 3H); [M−1]−=203.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[NH:8][C:9](=[S:11])[NH:10][C:4]=2[CH:3]=1.[OH-].[K+].I[CH3:15]>CCO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[NH:8][C:9]([S:11][CH3:15])=[N:10][C:4]=2[CH:3]=1
Reactant: CI
Reactant: S=c1[nH]c2cnc(Cl)cc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CSc1nc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirring solution of 6-chloro-1H-imidazo[4,5-c]pyridine-2(3H)-thione (1.49 g, 8.03 mmol) and potassium hydroxide (540 mg, 9.63 mmol) in anhydrous EtOH (49.7 mL) was added iodomethane (0.50 mL, 8.03 mmol). The reaction solution was stirred at RT for 3.5 h, and then partitioned between EtOAc (64 mL) and 2N HCl (11.3 mL). The aqueous layer was separated, and the pH was adjusted to a slightly basic pH with the addition of saturated NaHCO3, followed by extraction with EtOAc (100 mL). The combined organic layers were concentrated, and dried under vacuum to afford the title compound as a solid. LC-MS: calculated for C7H6ClN3S 199.00 observed m/e: 200.04 (M+H)+ (Rt 1.12/2.0 min).