Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][C:13]([CH3:35])=[C:14]([C@H:26]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:27]([OH:29])=[O:28])[C:15]=2[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[N:10]=1)C1C=CC=CC=1.IC>>[C:31]([O:30][C@@H:26]([C:14]1[C:15]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[C:16]2[C:11](=[CH:12][C:13]=1[CH3:35])[N:10]=[C:9]([O:8][CH3:1])[CH:18]=[CH:17]2)[C:27]([OH:29])=[O:28])([CH3:34])([CH3:32])[CH3:33]
Reactant: Cc1cc2nc(OCc3ccccc3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Solvent: CI
Product: COc1ccc2c(-c3ccc(Cl)cc3)c([C@H](OC(C)(C)C)C(=O)O)c(C)cc2n1

Procedure:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-methoxy-7-methylquinolin-6-yl)acetic acid (66) (2.3 mg) was prepared in a similar manner as compound (S)-2-(2-(benzyloxy)-5-(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-butoxyacetic acid of Example 65 except using iodomethane instead of benzyl bromide. 1H-NMR 400 MHz (CD3OD) δ 7.68 (s, 1 H), 7.6-7.5 (m, 4 H), 7.30 (d, J=8 Hz, 1 H), 6.87 (d, J=9.6 Hz, 1H), 5.16 (s, 1 H), 4.08 (s, 3 H), 2.62 (s, 3 H), 0.97 (s, 9 H); LCMS-ESI+ (m/z): [M+H]+ calcd for C23H25ClNO4: 414.1. Found: 414.2; LCMS-ESI+ (m/z): [M+H]+ calcd for C23H23ClNO4: 412.1. Found: 412.0.
Reaction SMILES: II.[Mg].Br[C:5]1[CH:10]=[CH:9]C=[CH:7][CH:6]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)([C:24]#N)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH4+].[Cl-]>C1COCC1.CO.C(Cl)(Cl)Cl>[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]([C:24]2[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=2)([N:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N#CC1(N2CCCC2)CCN(Cc2ccccc2)CC1
Reactant: Brc1ccccc1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: c1ccc(CN2CCC(c3ccccc3)(N3CCCC3)CC2)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 161.7 %

Procedure:
A little iodine was added to a mixture of 31.2 g (5 eq) magnesium and 100 ml dry THF, followed over a period of 10 min by 10 g (0.25 eq) bromobenzene, and the mixture was stirred for a further 10 min. Once the reaction had started, 194.2 g (4.75 eq) bromobenzene dissolved in 500 ml THF were added dropwise over a period of 2 h and the mixture was stirred for a further 15 min. 70 g (1 eq) 1-benzyl-4-(pyrrolidin-1-yl)piperidine-4-carbonitrile dissolved in 450 ml THF were added over a period of 2 h to the Grignard reagent prepared in the preceding step and the mixture was then heated for 12 h at 80° C. The reaction course was monitored by thin-layer chromatography (10% MeOH/CHCl3). Once the conversion was complete, the reaction solution was cooled to 0° C., mixed with saturated NH4Cl solution, extracted with ethyl acetate (3×200 ml) and the combined organic phases were dried with Na2SO4. Following removal of the solvent under reduced pressure, 33 g (40%) of crude product were obtained in the form of an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:37][CH2:36][C:8]3([CH2:13][CH2:12][N:11]([C:14]([C:16]4[CH:17]=[N:18][C:19]5[N:20]([N:30]=[CH:31][C:32]=5[C:33](O)=[O:34])[C:21]=4[NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[O:15])[CH2:10][CH2:9]3)[C:6]=2[CH:7]=1.[CH2:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH3:39]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:37][CH2:36][C:8]3([CH2:9][CH2:10][N:11]([C:14]([C:16]4[CH:17]=[N:18][C:19]5[N:20]([N:30]=[CH:31][C:32]=5[C:33]([NH:43][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[O:34])[C:21]=4[NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[O:15])[CH2:12][CH2:13]3)[C:6]=2[CH:7]=1
Reactant: Cc1ccccc1Nc1c(C(=O)N2CCC3(CC2)COc2ccc(F)cc23)cnc2c(C(=O)O)cnn12
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccccc3C)c(C(=O)N3CCC4(CC3)COc3ccc(F)cc34)cnc12
Yield: 84 %

Procedure:
In the same manner as in Example 1, step 6 and using 6-(5-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)-7-(2-methylphenylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.122 g, 0.243 mmol) obtained in step 4 and ethanesulfonamide (0.133 g, 1.23 mmol), the title compound (0.121 g, 84%) was obtained.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=5[Cl:25])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1.O>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:27]=[CH:26][C:5]3[C:6]4[N:7]([CH:11]=[C:12]([C:14]5[N:18]([C:19]6[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=6[Cl:25])[N:17]=[CH:16][N:15]=5)[N:13]=4)[CH2:8][CH2:9][O:10][C:4]=3[CH:3]=2)=[CH:31][CH:30]=1
Reactant: Clc1ccccc1-n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Clc1ccc(-c2ccc3c(c2)OCCn2cc(-c4ncnn4-c4ccccc4Cl)nc2-3)cc1
Temperature: 130 °C
Yield: 20.6 %

Procedure:
9-bromo-2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (300 mg, 0.88 mmol), 4-chlorophenylboronic acid (188 mg, 1.20 mmol), Cs2CO3 (314 mg, 0.96 mmol) and dioxane/water (3:1, 5 ml) were combined in a tube. Pd(dppf)Cl2 (65 mg, 0.08 mmol)was added and N2 was bubbled through the solution. The mixture was heated in the microwave reactor at 130° C. for 30 min. The reaction mixture was filtered. The filtrate was concentrated, and purified by HPLC to give 568 (86 mg, 20%). 1H NMR (DMSO, 400 MHz) δ 8.17 (s, 1H), 7.88 (s, 1H), 7.70 (d, J=8.4 Hz, 3H), 7.64-7.60 (m, 3H), 7.54 (d, J=6.8 Hz, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.25-7.20 (m, 2H), 4.44 (s, 4H). LCMS(ESI): m/z 470.0 (M+H+)
Reaction SMILES: ClC(Cl)(Cl)C(=N)[O:4][CH:5]([C:7]1[CH:8]=[C:9]([Cl:25])[CH:10]=[C:11]2[C:15]=1[N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:13]=[C:12]2[Br:24])[CH3:6].[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2([CH2:49]O)[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)=[CH:32][CH:31]=1>ClCCl.C1CCCCC1>[Br:24][C:12]1[C:11]2[C:15](=[C:7]([CH:5]([O:4][CH2:49][C:36]3([C:33]4[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=4)[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])[CH2:40][CH2:41]3)[CH3:6])[CH:8]=[C:9]([Cl:25])[CH:10]=2)[N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:23])[CH3:21])[N:13]=1
Reactant: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(Cl)cc2c(Br)nn(COCC[Si](C)(C)C)c12
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2c(Br)nn(COCC[Si](C)(C)C)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(±)-1-(3-Bromo-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)ethyl 2,2,2-trichloroacetimidate (1.69 g, 3.07 mmol) and tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (1.05 g, 3.38 mmol) were combined in a dichloromethane/cyclohexane mixture (1:1, 8 mL) and cooled to 0° C. The reaction was treated with tetrafluoroboric acid-diethyl ether complex (86 μL, 0.61 mmol), stirred at 0° C. for 1 h, quenched by addition of saturated sodium bicarbonate and diluted with diethyl ether. The layers were separated. The ethereal was washed with water (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (18% ethyl acetate/hexanes) gave 1.2 g (56%) as a white film. 1H-NMR (CDCl3, 500 MHz) δ 7.48 (d, J=1.84 Hz, 1H), 7.19-7.21 (m, 2H), 7.08 (m, 1H), 6.97-7.00 (m, 2H), 5.49-5.56 (m, 2H), 5.01 (q, J=6.1 Hz, 1H), 3.70 (m, 2H), 3.43-3.47 (m, 2H), 3.22 (m, 2H), 3.00-3.05 (m, 2H), 2.04-2.14 (m, 2H), 1.76-1.87 (m, 2H), 1.43 (s, 9H), 1.42 (m, 3H), 0.72-0.82 (m, 2H), 0.08 (s,9H). Mass spec.: 720.42 (MNa)+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[N:18][C:17]([C:23]([OH:25])=[O:24])=[C:16]2[OH:26]>CCOCC>[OH:26][C:16]1[C:15]2[C:20](=[CH:21][CH:22]=[C:13]([NH:12][S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[CH:14]=2)[N:19]=[N:18][C:17]=1[C:23]([OH:25])=[O:24]
Reactant: Nc1ccc2nnc(C(=O)O)c(O)c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)Nc2ccc3nnc(C(=O)O)c(O)c3c2)cc1
Reaction time: 16 h

Procedure:
A solution of p-toluenesulphonyl chloride (7.0 g.) in ether (30 ml.) was added to a stirred solution of 6-amino-4-hydroxycinnolin-3-yl carboxylic acid (1.025 g.) in N-sodium hydroxide solution (15 ml.). The heterogeneous mixture was stirred vigorously for 16 hours. The aqueous phase was separated, washed with ether (2 × 25 ml.), and acidified to pH 2 with 5N-hydrochloric acid. The solid which separated was filtered off, washed with water and dried as much as possible on the filter. The product was purified by chromatography on a silica column (30 g., Kieselgel 60), eluted with a mixture of ethanol (15 parts by volume), chloroform (85 parts by volume) and formic acid (1 parts by volume), to give 4-hydroxy-6-(p-toluenesulphonylamino)cinnolin-3-yl carboxylic acid, m.p. 272°-273° C. EXAMPLE 16
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12][O:13][C:14]3[CH:19]=[C:18]([C:20]4([O:26][CH3:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:17]=[C:16]([F:28])[CH:15]=3)[CH:8]=2)[N:3]=1.[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C.CCOC(C)=O.O>[F:28][C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([C:20]2([O:26][CH3:27])[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[CH:17]=1)[O:13][CH2:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]1[N:29]=[N:30][N:31]=[C:2]1[CH:11]=[CH:10]2
Reactant: [N-]=[N+]=[N-]
Reactant: COC1(c2cc(F)cc(OCc3ccc4nc(Cl)ccc4c3)c2)CCOCC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC1(c2cc(F)cc(OCc3ccc4c(ccc5nnnn54)c3)c2)CCOCC1
Temperature: 130 °C

Procedure:
To 9b (29 mg, 0.07 mmol) in DMF (1 mL) was added sodium azide (9 mg, 0.09 mmol). The reaction was heated at 130° C. overnight, then cooled to room temperature and diluted with EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The crude material was purified by silica gel chromatography (50% EtOAc in hexanes) to give the desired product, 9c.
Reaction SMILES: [CH2:1]([N:3]([CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12]C)[C:4](=[O:8])[CH:5]([Br:7])[CH3:6])[CH3:2].C1(C)C(S(O)(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([N:3]([CH2:9][CH:10]1[O:11][CH2:12][CH2:16][CH2:15][O:14]1)[C:4](=[O:8])[CH:5]([Br:7])[CH3:6])[CH3:2]
Reactant: CCOC(CN(CC)C(=O)C(C)Br)OCC
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCN(CC1OCCCO1)C(=O)C(C)Br

Procedure:
N-Ethyl-N-(2,2-diethoxyethyl)-α-bromoproprionamide (10 grams), propandiol-1,3 (3 ml) and trace amounts of toluenesulfonic acid are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated until no more ethanol is given off. After this time sodium carbonate (1 gram) is added to the mixture with stirring and the resulting mixture is distilled to yield the desired product N-ethyl-N-(1,3-dioxan-2-ylmethyl)-α-bromoproprionamide.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: N#Cc1ccc(F)cc1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(N2CCCCC2)cc1
Temperature: 120 °C
Reaction time: 20 h
Yield: 91.7 %

Procedure:
A mixture of 4-fluorobenzonitrile (1 g, 8.26 mmol), piperidine (0.90 mL, 9.08 mmol) and potassium carbonate (2.28 g, 16.51 mmol) in dry 1-methyl-2-pyrrolidinone (10 mL) was stirred at 120° C. under nitrogen for 20 hours. The cooled reaction mixture was then diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic extract was washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford an orange oil. Purification by flash chromatography using a solvent gradient of 1 to 7% ethyl acetate in hexane gave an orange oil that was crystallized from hexane to afford the title compound (1.41 g, 92%) as an orange crystalline solid, m.p. 54° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([CH:14]=1)[C:10](OC)=[O:11])(=[O:4])=[O:3].[NH2:15][NH2:16]>CO>[CH3:1][S:2]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([CH:14]=1)[C:10]([NH:15][NH2:16])=[O:11])(=[O:4])=[O:3]
Reactant: NN
Reactant: COC(=O)c1cncc(S(C)(=O)=O)c1
Solvent: CO
Product: CS(=O)(=O)c1cncc(C(=O)NN)c1
Temperature: 70 °C
Yield: 82.9 %

Procedure:
Methyl 5-(methylsulfonyl)nicotinate (100 mg, 0.465 mmol) were added to hydrazine (17.87 mg, 0.558 mmol) in methanol (10 mL) and refluxed for 12 h at 70° C. The reaction was monitored by TLC. Upon completion of the reaction and following cooling, the solvent was removed by vacuum and the compound was purified by flash column chromatography (3% CH3OH/CH2Cl2) afforded the title compound (83 mg, 80% yield) as a solid. 1H NMR (400 MHz, CDCl3): δ 9.20 (d, 1H, J=2.0 Hz), 9.17 (d, 1H, J=2.0 Hz), 8.61 (s, 1H), 3.11 (s, 3H). ESI-MS: 216.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH:26]2[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]2)[S:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=2)[N:19]=1.[BH4-].[Na+].CC(C)=O>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C@@H:26]2[CH2:31][CH2:30][C@H:29]([OH:32])[CH2:28][CH2:27]2)[S:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=2)[N:19]=1
Reactant: CC(C)c1nnc2ccc(-c3sc(C4CCC(=O)CC4)nc3-c3ccc(F)cc3F)nn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Product: CC(C)c1nnc2ccc(-c3sc([C@H]4CC[C@@H](O)CC4)nc3-c3ccc(F)cc3F)nn12
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
The 4-(4-(2,4-difluorophenyl)-5-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thiazol-2-yl)cyclohexanone (0.495 g, 1.09 mmol, Example #26, Step B) was dissolved in MeOH (5 mL) then cooled to about −5° C. Sodium borohydride (0.0413 g, 1.09 mmol) was added and the mixture was stirred for about 5 min. Acetone was added then the solvents were concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel with DCM/MeOH (95:5) as an eluent then by RP-HPLC (Table 1, Method f) to give the title compound: (0.029 g, 6%): LC/MS (Table 1, Method a) Rt=2.41 min; MS m/z: 456.2 (M+H)+.
Reaction SMILES: O(CC1CCCN1[S:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[O:27])(=[O:16])=[O:15])C1C=CC=CC=1.N1C2C(=CC(S(O)(=O)=O)=CC=2)C(=O)C1=O.[Na].P(Cl)(Cl)([Cl:46])=O.C(N1C=CC=C1CO)(OC(C)(C)C)=O.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1S(=O)(=O)CCC1.N1C=CC=CC=1>[Cl:46][S:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[O:27])(=[O:16])=[O:15]
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CCCC3COc3ccccc3)cc2C1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: CC(C)(C)OC(=O)n1cccc1CO
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C1Nc2ccc(S(=O)(=O)O)cc2C1=O
Solvent: c1ccncc1
Solvent: O=S1(=O)CCCC1
Product: O=C1Nc2ccc(S(=O)(=O)Cl)cc2C1=O

Procedure:
The synthesis of 5-(2-phenoxymethylpyrrolidine-1-sulfonyl)isatin analogues is shown in Scheme 1 (FIG. 5). The 5-chlorosulfonylisatin 6 was prepared by reaction of 5-isatinsulfonic acid, sodium salt hydrate (5) with phosphorus oxychloride in tetramethylene sulfone at 60° C. for 3 h. The hydroxyl group of N-Boc-2-pyrrolmethanol (7) was first tosylated with p-toluenesulfonyl chloride in pyridine to give compound 8, followed by displacement of the tosylate group by sodium phenoxide in DMF to afford N-Boc-2-(phenoxymethyl)pyrrolidine 9. The N-Boc group of 9 was removed with TFA, and the secondary amine was coupled with 6 in THF using triethylamine as an acid scavenger to afford the 5-(2-phenoxymethyl-pyrrolidinesulfonyl)-1H-2,3-dione 10 in 84% yield. The isatin nitrogen was alkylated by treatment of 10 with sodium hydride in DMF at 0° C. followed by addition of various alkyl halides to give compounds 2 and 11a-e,g-i. Compound 11f was prepared by hydrolysis of 11e with sodium hydroxide in aqueous methanol.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH:11]1([CH2:16][CH2:17][N:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:19]([CH3:23])[CH2:20][CH2:21][NH2:22])[CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([CH2:16][CH2:17][N:18]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:19]([CH3:23])[CH2:20][CH2:21][NH:22][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(CCN)N(CCC1CCCC1)c1ccccc1
Product: CC(CCNc1ccc([N+](=O)[O-])cc1)N(CCC1CCCC1)c1ccccc1

Procedure:
In a manner similar to Preparation 1 react 4-fluoro1-nitrobenzene with N-[2-(cyclopentyl)ethyl]-N-phenyl-methyl-1,3-propanediamine to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[C:4]([N:6]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)[C:7]1[S:8][C:9]([C:12](O)=[O:13])=[CH:10][N:11]=1)=[O:5]>CCN(CC)CC>[CH2:4]([N:6]([CH2:15][CH3:16])[C:12]([C:9]1[S:8][C:7]([N:6]([C:4](=[O:5])[C:3]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:2]=2[Cl:1])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)=[N:11][CH:10]=1)=[O:13])[CH3:3]
Reactant: COc1ccc(N(C(=O)c2ccc(Cl)cc2Cl)c2ncc(C(=O)O)s2)cc1OC
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1cnc(N(C(=O)c2ccc(Cl)cc2Cl)c2ccc(OC)c(OC)c2)s1

Procedure:
According to the procedure described fort he synthesis of Example 125 further derivatives have been synthesised from 2-[(2,4-Dichloro-benzoyl)-(3,4-dimethoxy-phenyl)-amino]-thiazole-5-carboxylic acid and various commercially available amines and comprise Examples 126-Example 135 below. In cases of Example 135 additionally 2 eq. NEt3 were added to the reaction mixture as the amine hydochloride was used as starting material.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[O:9]C.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[OH:9]
Reactant: COc1c(F)cccc1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1c(F)cccc1I
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.2 %

Procedure:
To a solution of 2-fluoro-6-iodoanisole (Justus Liebigs, Ann. Chem., 746:134, 1971; 4.31 g, 17.1 mmol) in dichloromethane (35 ml) is added a 1M solution of borontribromide in dichloromethane (18.2 ml). The mixture is kept under argon and stirred for 4 hours at room temperature. The mixture is poured into a saturated aqueous sodium bicarbonate solution and the aqueous layer is extracted with ethyl acetate. The combined organic extracts are dried over sodium sulfate and concentrated under reduced pressure to give 2-fluoro-6-iodophenol (4.2 g).
Reaction SMILES: [CH3:1][C:2]([O:4][CH:5]([O:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[CH3:6])=[S:3].FC(F)(F)[C@@H](C1C2C(C=C3C=1C=CC=C3)=CC=CC=2)O>>[CH3:1][C:2]([O:4][C@@H:5]([O:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[CH3:6])=[S:3]
Reactant: CC(=S)OC(C)OC(=O)C(C)C
Agent: O[C@H](c1c2ccccc2cc2ccccc12)C(F)(F)F
Product: CC(=S)O[C@H](C)OC(=O)C(C)C

Procedure:
For comparison, racemic 1-methylthiocarbonyloxyethyl-2-methylpropanoate: 1H-NMR in presence of (R)-(−)-2,2,2-trifluoro-1-(9-anthryl)ethanol as chiral solvating agent (CDCl3): δ 1.18 (m, 6H), 1.49 (d, J=5.2 Hz, 1.5H), 1.50 (d, J=5.6 Hz, 1.5H), 2.33 (s, 1.5H), 2.34 (s, 1.5H), 2.55 (septet, J=7.2 Hz, 0.5H), 2.56 (septet, J=7.2 Hz, 0.5H), 6.92 (q, J=5.6 Hz, 0.5H), 6.92 (q, J=5.6 Hz, 0.5H) ppm.
Reaction SMILES: [Al:1].[Cl-:2].[Al+3].[Cl-].[Cl-].[Ti:6](Cl)(Cl)(Cl)[Cl:7].[CH:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Cl-:7].[Cl-:2].[Ti+2:6].[Cl-:7].[Al+3:1].[Cl-:7].[Cl-:7].[CH:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cl[Ti](Cl)(Cl)Cl
Reactant: [Al]
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: [Ti+2]
Temperature: 130 °C

Procedure:
51 grams of aluminum powder (BDH fine powder) and 80 grams of anhydrous aluminum chloride were introduced into a 2 liter, three-necked flask and the mixture of solids was heated at 130° C. for 0.5 hours. The mixture was then allowed to cool. 500 ml of benzene was added and then 33.3 grams of titanium tetrachloride was added with stirring. The mixture was refluxed for 20 hours and then allowed to cool. The cool solution was filtered into 1 liter of heptane, and this mixture was cooled to -10° C. and maintained at this temperature for 24 hours. The supernatant liquid was decanted from the purple solid which had been formed. The solid was washed four times using 1 liter of heptane for each wash, and then was dried under reduced pressure (1 mm mercury) at ambient temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].S(Cl)(Cl)=O.[CH3:19][N:20]([CH3:26])[C@@H:21]1[CH2:25][CH2:24][NH:23][CH2:22]1.CCN(CC)CC>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:23]3[CH2:24][CH2:25][C@@H:21]([N:20]([CH3:26])[CH3:19])[CH2:22]3)=[O:13])[S:10][C:3]=12
Reactant: CN(C)[C@@H]1CCNC1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CN(C)[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Yield: 43.3 %

Procedure:
This material was prepared from lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylate (0.214 g, 1.0 mmole) by treatment with thionyl chloride followed by reaction of the resultant acyl chloride with (3R)-N,N-dimethylpyrrolidin-3-amine (0.114 g, 1.0 mmole) and Et3N (0.139 ml, 1.0 mmole), in a manner as previously described for example 9d to give a brown solid (0.134 g, 43%). 1H NMR (300 MHz, CD3OD) δ7.24 (1H, d, J=5.1 Hz), 6.57 (1H, d, J=8.48 Hz), 6.15 (1H, d, J=5.1 Hz), 2.70 (1H, m), 2.51 (2H, m), 2.24 (1H, m), 2.04 (1H, m), 1.49 (1H, m), 0.93 (3H, s), 0.90 (3H, s), 0.52 (1H, m); ESIMS (MH+): 310.10.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][NH:11][C:10]1=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][C:19]=1[CH2:29]Br>C1COCC1>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][C:19]=1[CH2:29][N:11]1[CH2:12][CH2:13][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:10]1=[O:14]
Reactant: CC(C)(C)OC(=O)NC1CCNC1=O
Reactant: CS(=O)(=O)Oc1ccc(Br)c(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(Cc2cc(OS(C)(=O)=O)ccc2Br)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(tert-butoxycarbonylamino)-2-oxopyrrolidine, as described above in Step A, (1.00 g, 4.99 mmol) in THF (10 mL) was added sodium hydride (230 mg of a 60% dispersion in oil, 5.75 mmol) in THF (5 mL), dropwise. The resulting mixture was stirred for 30 min at ambient temperature, then a solution of methanesulfonic acid 4-bromo-3-bromomethylphenyl ester, as described above in Step C, (1.96 g, 5.70 mmol) in THF (6 mL) was added dropwise and stirring was continued for 2 hours. The reaction was quenched with saturated aqueous NH4Cl (3 mL), then concentrated in vacuo. The residue was partitioned between saturated aqueous NaHCO3 and EtOAc. The layers were separated and the organic extract was washed with H2O, then brine, then dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with CH2Cl2—5% MeOH, to yield the titled product.