Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:14][C:15]1[CH:24]=[CH:23][C:18]2[O:19][CH2:20][CH2:21][O:22][C:17]=2[CH:16]=1)[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[O:26]=[C:27]1[CH:36]=[N:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]1[CH2:37][CH:38]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:14][C:15]1[CH:24]=[CH:23][C:18]2[O:19][CH2:20][CH2:21][O:22][C:17]=2[CH:16]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:38][CH2:37][N:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:35]=[CH:36][C:27]2=[O:26])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=CCn1c(=O)cnc2ccccc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cnc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
To 3 mL of dichloromethane solution containing 0.19 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 0.10 g of (2-oxoquinoxalin-1(2H)-yl)acetaldehyde and 30 μl of acetic acid were added and stirred at room temperature for 2 hours. To the reaction mixture, 0.17 g of sodium triacetoxyborohydride was added and stirred at the same temperature for 30 min. Chloroform and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; ethyl acetate] to give 0.22 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a light brown oil.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.N[C:18]1[CH:34]=[CH:33][C:32]2[C:23]3[NH:24][C:25](=[O:31])[C:26]4[N:27]([CH:28]=[CH:29][N:30]=4)[C:22]=3[CH2:21][C:20]=2[CH:19]=1.C[N:36](C)C=O>ClCCl>[C:5]1([CH2:11][CH2:12][CH2:13][C:14]([NH:36][C:28]2[N:27]3[C:22]4[CH2:21][C:20]5[CH:19]=[CH:18][CH:34]=[CH:33][C:32]=5[C:23]=4[NH:24][C:25](=[O:31])[C:26]3=[N:30][CH:29]=2)=[O:16])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)CCCc1ccccc1
Reactant: CN(C)C=O
Reactant: Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(CCCc1ccccc1)Nc1cnc2c(=O)[nH]c3c(n12)Cc1ccccc1-3
Reaction time: 8 h

Procedure:
A few drops of dimethylformamide and then, dropwise, 2.8 ml of thionyl chloride are added to 5 g of 4-phenylbutyric acid, in solution in 60 ml of anhydrous dichloromethane, at a temperature in the region of 20° C. After reacting overnight at the same temperature, the reaction mixture is concentrated to dryness under reduced pressure. The chloride of 4-phenylbutyric acid thus prepared is added dropwise to 1 g of 8-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one, in solution in 75 ml of dimethylformamide, at a temperature in the region of 20° C. The reaction mixture is heated at reflux for 7 hours. The precipitate formed is filtered and recrystallized from dimethylformamide. After filtration, washing with water and then ethyl ether and drying under partial vacuum (1 mm Hg, 0.13 kPa) at 80° C., there is obtained 0.64 g of 8-(4-phenylbutyrylamino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one in the form of an ochre solid which decomposes at 190° C. (Analysis C23H20N4O2.0.63H2O.0.79DMF, % calculated C: 71.86, H: 5.24, N: 14.57, % found C: 71.5, H: 5.1, N: 14.8).
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1CCN2C(=NCCC2)CC1.C([O:23][C:24](=O)[CH2:25][C:26]([C:28]1[C:29]([NH:36][CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[N:30][C:31]([S:34][CH3:35])=[N:32][CH:33]=1)=[O:27])C.Cl>CCOC(C)=O>[CH:37]1([N:36]2[C:29]3[N:30]=[C:31]([S:34][CH3:35])[N:32]=[CH:33][C:28]=3[C:26]([OH:27])=[CH:25][C:24]2=[O:23])[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: CCOC(=O)CC(=O)c1cnc(SC)nc1NC1CCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: CSc1ncc2c(O)cc(=O)n(C3CCCC3)c2n1
Temperature: 120 °C
Yield: 97 %

Procedure:
Diisopropylethylamine (12 mL) and DBU (1.62 mL) were added to 3-(4-cyclopentylamino-2-methylsulfanyl-pyrimidin-5-yl)-3-oxo-propionic acid ethyl ester (3.0 g, 9.29 mmol) and the resulting mixture was heated to 120° C. for 1 h. The reaction mixture was then cooled to RT and acidified with HCl (1 M aq) to pH 1. The resulting mixture was diluted with EtOAc and washed 3× with HCl (1 M aq). The combined aqueous layers were extracted with EtOAc and then 3× with a 1:1 mixture of isopropanol and chloroform. The combined organic extracts were dried over Na2SO4, filtered and evaporated under reduced pressure to afford 2.5 g (97% yield) of 8-cyclopentyl-5-hydroxy-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[NH3:9].Cl[S:11]([OH:14])(=O)=[O:12]>>[Br:1][C:2]1[CH:3]=[C:4]([S:11]([NH2:9])(=[O:14])=[O:12])[C:5]([OH:8])=[N:6][CH:7]=1
Reactant: Oc1ccc(Br)cn1
Reactant: O=S(=O)(O)Cl
Reactant: N
Product: NS(=O)(=O)c1cc(Br)cnc1O
Reaction time: 1 h

Procedure:
A solution of 5-bromopyridin-2-ol (0.5 g, 2.8 mmol) in chlorosulfonic acid (10 mL) was heated to 150° C. for 16 h. After this time, the reaction mixture was added dropwise to a pre-cooled aqueous ammonia solution (100 mL) at 0° C. The resulting mixture was stirred for 1 h. The aqueous layer was then extracted with ethyl acetate (150 mL), dried and concentrated to yield a residue. The residue was purified by ISCO chromatography using 3% methanol in DCM to yield 5-bromo-2-hydroxypyridine-3-sulfonamide (210 mg). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.67 (br s, 1H); 8.03 (d, 1H, J=2.8 Hz); 7.98 (d, 1H, J=2.8 Hz); 7.11 (s, 1H). LCMS Method U: retention time 1.85 min; [M+1]=253.0.
Reaction SMILES: [N:1]([C:4]1[C:21](=[O:22])[CH:20]=[CH:19][C@@:18]2([CH3:23])[C:5]=1[C:6](=[CH2:25])[CH2:7][C@@H:8]1[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]1[CH2:10][CH2:11][C:12]2=[O:24])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCOCC1.O>O1CCCC1>[NH2:1][C:4]1[C:21](=[O:22])[CH:20]=[CH:19][C@@:18]2([CH3:23])[C:5]=1[C:6](=[CH2:25])[CH2:7][C@@H:8]1[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]1[CH2:10][CH2:11][C:12]2=[O:24]
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)C=CC(=O)C(N=[N+]=[N-])=C12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: O
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)C=CC(=O)C(N)=C12
Temperature: 35 °C
Reaction time: 2.5 h
Yield: 30 %

Procedure:
To a stirred solution of 4-azido-6-methylenandrosta-1,4-diene-3,17-dione (3.374 g, 10 mmol) in tetrahydrofuran (25 ml) was added portionwise triphenylphosphine (2.823 g, 10 mmol). During the reaction, which lasted about 2.5 h, the temperature raised to about 35° C. and there was nitrogen evolution. Then dioxane (100 ml) and water (10 ml) was added and the mixture was refluxed for 10 h. Finally the mixture was poured onto water and the raw product extracted with ethyl acetate. The organic phase was extracted 4× with 2N hydrochloric acid, the aqueous phase was separated and the product precipitated by alkalinization with sodium hydroxide solution. Thus almost pure 4-amino-6-methylen-androsta-1,4-diene-3,17dione was obtained in about 30% yield (0.934 g).
Reaction SMILES: [Si]([O:18][CH2:19][C@@H:20]1[CH2:24][O:23][C@@H:22]([P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])[S:21]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>O1CCCC1>[CH2:28]([O:27][P:25]([O:30][CH2:31][CH3:32])([C@H:22]1[S:21][C@H:20]([CH2:19][OH:18])[CH2:24][O:23]1)=[O:26])[CH3:29]
Reactant: CCOP(=O)(OCC)[C@@H]1OC[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)S1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOP(=O)(OCC)[C@@H]1OC[C@@H](CO)S1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 95.7 %

Procedure:
To a solution of cis and trans 4-(t-butyldiphenylsilyloxymethyl)-2-(diethyloxyphosphinoyl)-1,3-oxathiolane (example 42) (5.00 g, 10.07 mmol) in tetrahydrofurane (300 mL) was added tetrabutylammonium fluoride (15.0 mL, 15.0 mmol, 1.5 eq) at room temperature. The solution was stirred at room temperature for 45 min and acetic acid was added (850 μL) followed by evaporation under reduced pressure. The crude material was purified by flash chromatography with ethyl acetate to give the pure compound (2.47 g) in 96% yield. 1H NMR (300 MHz, CDCl3) δ: 1.36 (2t, 6H, J=7.1 Hz, CH3), 3.20 (m, 0.33H, CHAHBO for cis), 3.64 (m, 1.33H, CH2O for trans), 3.75 (m, 1H, OH and 0.33H, CHAHBO for cis), 3.95 (dd, 0.33H, J=6.1 Hz, 9.9 Hz, CHAHBO for cis), 4.23 (m, 4H, CH2 ; 1H H-4; 0.66H, CHAHBO for trans), 4.33 (dd, 0.66H, J=7.6 Hz, 9.9 Hz, CHAHBO for trans), 4.49 (dd, 0.33H, J=3.5 Hz, 9.9 Hz, CHAHBO for cis), 5.23 (d, 0.33H, 2JHP =9.9 Hz, H-2 for cis), 5.33 (d, 0.66H, 2JHP =9.3 Hz, H-2 for trans).
Reaction SMILES: CS(C)=O.F[C:6]1[CH:29]=[CH:28][C:9]([C:10]([C:12]2[CH:27]=[CH:26][C:15]([O:16][C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)=[O:11])=[CH:8][CH:7]=1.[NH2:30][C:31]1[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1>CN(C)C=O>[NH2:30][C:31]1[CH:32]=[C:33]([CH:34]=[CH:35][CH:36]=1)[O:37][C:28]1[CH:29]=[CH:6][CH:7]=[CH:8][C:9]=1[C:10]([C:12]1[CH:27]=[CH:26][C:15]([O:16][C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=2)[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(O)c1cccc(Oc2ccc(C(=O)c3ccc(F)cc3)cc2)c1
Reactant: Nc1cccc(O)c1
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: Nc1cccc(Oc2ccccc2C(=O)c2ccc(Oc3cccc(C(=O)O)c3)cc2)c1

Procedure:
As shown by reaction (1), 4,-4-difluorobenzophenone is reacted with 3-hydroxybenzoic acid to obtain 3-[4-(4-fluorobenzoyl)phenoxy]benzoic acid. The reaction is carried out in a suitable aprotic solvent, such as dimethylsulfoxide or N,N-dimethylformamide, under an inert atmosphere, at an elevated temperature of about 100° to 140° C. for about 8 to 64 hours. The 3-[4-(4-fluorobenzoyl)phenoxy]benzoic acid (A) is then reacted with 3-aminophenol, as shown by reaction (2) to obtain 3-[4-(3-aminophenoxybenzoyl)phenoxy]benzoic acid (B). This reaction is carried out in a suitable aprotic solvent, under an inert atmosphere, at an elevated temperature of about 100° to 140° C. for about 8 to 64 hours. At the end of the reaction period, the reaction mixture is cooled, then poured into water, which is then neutralized to precipitate the monomer (B). If desired, the crude monomer can be purified by recrystallization or by dissolving it in a suitable solvent and precipitating it from solution into a suitable non-solvent.
Reaction SMILES: S(C)C.[C:4]([Li])([CH3:7])([CH3:6])[CH3:5].[C:9]([NH:28][C@H:29]([CH2:32][CH3:33])[CH:30]=[O:31])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH4+].[Cl-]>CCOCC>[CH3:5][C:4]([CH3:7])([CH:30]([OH:31])[C@H:29]([NH:28][C:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:32][CH3:33])[CH3:6]
Reactant: [Li]C(C)(C)C
Reactant: CC[C@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CSC
Product: CC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(O)C(C)(C)C
Temperature: 25 °C

Procedure:
To a stirred suspension of CuBr.SMe2 (1.37 g, 2.2 eq, 6.66 mmol) in Et2O (100 mL) under an argon atmosphere at −78° C., was added tert-butyllithium (1.5 M in pentane, 8.0 mL, 4 eq, 12.0 mmol) dropwise and the solution allowed to warm to room temperature. The mixture was recooled to −55° C., to which was added a solution of (R)-2-(trityl-amino)-butyraldehyde (1 g, 1 eq, 3.03 mmol) in Et2O (25 mL) dropwise with stirring, and stirred at this temperature for 3 h. To the reaction mixture was added a saturated aqueous solution of NH4Cl (100 mL) and allowed to warm to room temperature over 16 h. The reaction mixture was extracted with Et2O (2×200 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel gradient column chromatography, eluted with hexane:ether (100:0→90:10) to afford the title compound as a light yellow oil. Yield: 0.57 g (49%). (55% de 3S,4R: 45% de 3R,4R). 1H-NMR (d6-DMSO, 250 MHz): δ 0.36 & 0.86 (2×t, 3H, J=7.42 Hz, —NH CH(CH2CH3)CH(C(CH3)3)OH), 0.57 & 0.71 (2×s, 9H, —NHCH(CH2CH3)CH(C(CH3)OH), 1.38-1.52 (m, 2H, —NHCH (CH2CH3)CH(C(CH3)3)OH), 1.99 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 2.27 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 2.95 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 4.22 & 4.77 (2×d, 1H, J=4.42 5.21 Hz, —NHCH(CH2CH3)CH(C(CH3)3)OH), 7.14-7.52 (m, 15H, 3×Ph).
Reaction SMILES: [OH:1][C:2]1([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH:17]3[CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[C:20]([C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=4[F:39])([C:30]#[N:31])[CH:19]([CH2:40][C:41]([CH3:44])([CH3:43])[CH3:42])[NH:18]3)=[O:16])=[N:10]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:51]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])(=[O:53])[CH3:52]>CN(C=O)C.C(OCC)(=O)C>[C:55]([O:54][C:51](=[O:53])[CH2:52][N:5]1[CH2:4][CH2:3][C:2]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C@H:17]3[C@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[C@:20]([C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=4[F:39])([C:30]#[N:31])[C@H:19]([CH2:40][C:41]([CH3:44])([CH3:43])[CH3:42])[NH:18]3)=[O:16])=[N:10]2)([OH:1])[CH2:7][CH2:6]1)([CH3:58])([CH3:57])[CH3:56]
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC3(O)CCNCC3)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccn(CC3(O)CCN(CC(=O)OC(C)(C)C)CC3)n2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(4-hydroxy-piperidin-4-ylmethyl)-1H-pyrazol-3-yl]-amide (80 mg, 0.12 mmol) was dissolved in DMF (3 mL) with cesium carbonate (100 mg, 0.31 mmol) then t-butyl acetate (0.1 mL, 0.677 mmol) was added stirred 16 hours at 25° C. The reaction mixture was diluted with ethyl acetate and separated with water (3×), the organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure. The mixture was purified by reverse phase column chromatography (20-95% acetonitrile/water) to yield compound rac-[4-(3-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-pyrazol-1-ylmethyl)-4-hydroxy-piperidin-1-yl]-acetic acid tert-butyl ester (68 mg, 74.7%).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[C:5](=[O:16])[C:4]([S:17](Cl)(=[O:19])=[O:18])=[CH:3]1.[CH3:21][NH:22][CH3:23]>>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[C:5](=[O:16])[C:4]([S:17]([N:22]([CH3:23])[CH3:21])(=[O:19])=[O:18])=[CH:3]1
Reactant: Cn1cc(S(=O)(=O)Cl)c(=O)c2ccc(C(F)(F)F)cc21
Reactant: CNC
Product: CN(C)S(=O)(=O)c1cn(C)c2cc(C(F)(F)F)ccc2c1=O
Reaction time: 27 h

Procedure:
1-Methyl-4-oxo-7-trifluoromethyl-1,4-dihydroquinoline-3-sulphonyl chloride (12.4 g) was added to a stirred solution of dimethylamine in industrial methylated spirit (33% w/w; 230 ml) and the mixture was kept at ambient temperature for 27 hours. The mixture was evaporated to dryness and the residue was recrystallised from industrial methylated spirit using charcoal to give the novel compound 1,N,N-trimethyl-4-oxo-7-trifluoromethyl-1,4-dihydroquinoline-3-sulphonamide, m.p. 221°-223°.
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:22]1[CH2:28][C:26](=[O:27])[N:25]([CH2:29][C:30]([OH:32])=[O:31])[C:23]1=[S:24].[Cl-].[NH4+].N>C(O)C>[C:1]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[C:28]2[S:22][C:23](=[S:24])[N:25]([CH2:29][C:30]([OH:32])=[O:31])[C:26]2=[O:27])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)c2ccccc2)n1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)c2ccccc2)n1

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 3.04 g of ethyl 2-benzamidothiazol-4-ylglyoxylate, 1.91 g of rhodanine-3-acetic acid, 1 g of ammonium chloride, 1 ml of 28% v/v aqueous ammonia and 20 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=O.[Si:8]([O:15][C@H:16]([C@H:19]1[C@@H:22]([C:23]#[C:24][S:25]C2C=CC=CC=2)[NH:21][C:20]1=[O:32])[CH2:17][CH3:18])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].C(=O)([O-])O.[Na+].O>C(Cl)Cl.C(OCC)(=O)C>[Si:8]([O:15][C@H:16]([C@H:19]1[C@@H:22]([CH2:23][C:24]([C:3]2[CH:2]=[CH:18][CH:17]=[CH:16][CH:19]=2)=[S:25])[NH:21][C:20]1=[O:32])[CH2:17][CH3:18])([C:11]([CH3:12])([CH3:13])[CH3:14])([CH3:9])[CH3:10]
Reactant: O=C(O)C(F)(F)F
Reactant: CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1C(=O)N[C@@H]1C#CSc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1C(=O)N[C@@H]1CC(=S)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 152.5 %

Procedure:
Trifluoroacetic acid (0.58 ml, 7.51 mmol) was added to a solution of the compound (564 mg, 1.50 mmol) prepared in Example 6 in methylene chloride (10 ml) at 0° C. in an argon atmosphere. The mixture was stirred for two hours at this temperature and one hour at room temperature. After the addition of sodium hydrogencarbonate (189 mg, 2.25 mmol), water (7 ml), and ethyl acetate (28 ml), the mixture was stirred at room temperature for 40 minutes and diluted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine in this order and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1) to obtain 432 mg (yield 73%) of the title compound as a colorless oily substance.
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[CH2:16]([N:18]1[C:24]2[CH:25]=[C:26]([F:30])[C:27]([NH2:29])=[CH:28][C:23]=2[O:22][CH2:21][CH2:20][CH2:19]1)[CH3:17].Cl[C:32]1[N:37]=[C:36]([NH:38][C@@H:39]2[CH2:44][CH2:43][CH2:42][CH2:41][C@H:40]2[NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[C:35]([Cl:50])=[CH:34][N:33]=1.C(=O)([O-])[O-]>C(O)(C)C.C(Cl)Cl>[Cl:50][C:35]1[C:36]([NH:38][C@@H:39]2[CH2:44][CH2:43][CH2:42][CH2:41][C@H:40]2[NH:45][S:46]([CH3:49])(=[O:48])=[O:47])=[N:37][C:32]([NH:29][C:27]2[C:26]([F:30])=[CH:25][C:24]3[N:18]([CH2:16][CH3:17])[CH2:19][CH2:20][CH2:21][O:22][C:23]=3[CH:28]=2)=[N:33][CH:34]=1
Reactant: CCN1CCCOc2cc(N)c(F)cc21
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CC(C)O
Product: CCN1CCCOc2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)c(F)cc21
Reaction time: 1 h

Procedure:
10-Camphorsulfonic acid (70 mg, 0.30 mmol) was added to 9-Ethyl-2-fluoro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamine (58 mg, 0.28 mmol) and N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (94 mg, 0.28 mmol) in Isopropyl alcohol (1 mL). The mixture was irradiated in a CEM microwave (140° C., min). MP-Carbonate (2.69 mmol/g loading; 0.22 g, 0.5793156293 mmol) and DCM (2 mL) were added and the mixture stirred for 1 h, then filtered onto a 5 g SiO2 cartridge, which was air dried. The sample was chromatographed (ISCO, 2×12 g SiO2, 0-50% EtOAc:Hex) to afford N-{(1R,2R)-2-[5-Chloro-2-(9-ethyl-2-fluoro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as a purple film (40 mg, 30%). LCMS 513 (M+H), 1H-NMR (CDCl3): 7.92 (s, 1H), 7.76 (d, 1H, J=8.4 Hz), 6.76 (s, 1H), 6.62 (d, 1H, J=13.3 Hz), 5.39 (d, 1H, J=7.4 Hz), 5.11 (d, 1H, J=7.1 Hz), 4.09 (t, 2H, J=6.0 Hz), 3.93 (m, 1H), 3.25 (m, 5H), 2.81 (s, 3H), 2.20 (m, 2H), 2.00 (m, 2H), 1.82 (m, 2H), 1.43 (m, 4H), 1.20 (t, 3H, J=7.0 Hz). 19F-NMR: −135.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([C:13]([C:16]1[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=1)[C:19]([NH:21][C:22]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:23]=1[CH3:29])=[O:20])([CH3:15])[CH3:14])#[N:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:11]([C:13]([C:16]1[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=1)[C:19]([NH:21][C:22]1[CH:27]=[C:26]([O:28][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH:25]=[CH:24][C:23]=1[CH3:29])=[O:20])([CH3:15])[CH3:14])#[N:12]
Reactant: Cc1ccc(O)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 75.7 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (1.41 g, 8.92 mmol) and 3-(1-cyano-1-methylethyl)-N-(5-hydroxy-2-methylphenyl)benzamide (2.5 g, 8.5 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (1.85 g, 13.3 mmol), and the mixture was stirred at 80° C. for 18 hr. The reaction mixture was cooled to room temperature, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (200 mL), and washed with water (200 mL). The aqueous layer was extracted with ethyl acetate (100 mL), and the combined organic layer was washed with water (200 mL) and saturated brine (200 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30→20/80). The obtained solution was concentrated under reduced pressure to give the title compound (2.68 g, 76%) as a yellow amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][C:11](=O)[C:10]([CH3:15])([CH3:14])[CH2:9]2)=[CH:4][CH:3]=1.C(OC([N:25]([CH3:27])C)N(C)C)(C)(C)C.O.[NH2:29]N>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[CH:27]=[N:25][NH:29][C:11]=3[C:10]([CH3:15])([CH3:14])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(c2ccc(Cl)cc2)CC1=O
Reactant: NN
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: O
Solvent: CC(C)O
Product: CC1(C)CC(c2ccc(Cl)cc2)c2cn[nH]c21
Temperature: 100 °C
Yield: 12.7 %

Procedure:
(+/−)-4-(4-Chlorophenyl)-2,2-dimethyl-cyclopentanone (0.250 g, 1.12 mmol) is dissolved in isopropanol (5 mL) and stirred. tert-Butoxybis(dimethylamino)methane (0.33 mL, 1.57 mmol) is added drop wise to the reaction. The reaction is heated in a sealed vial at 100° C. for 12 hours, cooled to room temperature, and concentrated to dryness. The residue is diluted with isopropanol (5 mL). Hydrazine hydrate (0.11 mL, 2.25 mmol) is added to the reaction and heated to 100° C. in a sealed vial for 5 hours. The reaction is concentrated in vacuo. The residue is purified by silica gel flash chromatography eluting with 20% ethyl acetate in hexanes to obtain the title compound (0.035 g, 13%) as a yellow film. ES/MS (m/z) 247.0 (M+1).