Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.CN1CCOCC1.Cl.[CH3:21][O:22][C:23](=[O:28])[C@H:24]([CH2:26][OH:27])[NH2:25].C(Cl)(Cl)Cl>ClCCl>[CH3:21][O:22][C:23](=[O:28])[C@H:24]([CH2:26][OH:27])[NH:25][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CO)NC(=O)Cc1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 52.5 %

Procedure:
To an ice cooled solution of 3,5-difluorophenylacetic acid (2.16 g) in anhydrous dichloromethane (100 mL) under nitrogen was added HOBt-hydrate (4.23 g), EDAC-HC1 (3.6 g), and NMM (2.2 mL). The reaction mixture was stirred at 0° C. under nitrogen for 15 min and L-serine methyl ester-HCl (1.96 g) was added followed by NMM (1.38 mL). The reaction was stirred at 0° C. for 1 H and RT for 2 H. The reaction mixture was concentrated in vacuo and partitioned between water (100 mL) and ethyl acetate (125 mL). The organic phase was collected and consecutively washed with water, dilute aqueous sodium bicarbonate, brine, dried, filtered and the solvent removed in vacuo to yield a white solid. Trituration with CHCl3 afforded pure title compound (1.8 g). The impure filtrate was subjected to flash chromatography (20% acetone/CHCl3) to afford additional title compound (800 mg, total yield 76%). 1H NMR (300 MHz, d6-DMSO) δ3.57 (d, 2H), 3.62(s, 3H), 3.7 (m, 1H), 4.35, (m, 1H), 5.1 (bs, 1H), 7.00 (d, 2H), 7.09 (t, 1H), 8.53, (d, 1H). MS APCI, m/z=274 (M+1). LC/MS: 1.34 min.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH2:15].Cl>C(O)C>[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH:15][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CN(C)CCN
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: CN(C)CCNc1ccc([N+](=O)[O-])cc1

Procedure:
2.2 ml of (20 mmol) of 4-fluoronitrobenzene and 2.6 ml (24 mmol) of N,N-dimethylethylene-diamine are heated in 10 ml of ethanol at 120° C. in a microwave oven for 1.5 hours. Then 50 ml of 1 N hydrochloric acid are added. The reaction solution is washed with ethyl acetate. Then the aqueous phase is combined with 4 N sodium hydroxide solution until an alkaline reaction is obtained and extracted with ethyl acetate.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Br:13][C:14]1[CH:15]=[C:16]([CH:44]=[CH:45][CH:46]=1)[CH2:17][S:18][C:19]1[N:23]([CH2:24][CH2:25][CH2:26][N:27]([CH3:36])[CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[C:22]2[CH:37]=[CH:38][C:39]([C:41](O)=[O:42])=[CH:40][C:21]=2[N:20]=1.[N:47]1([CH:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)[CH2:51][CH2:50][CH2:49][CH2:48]1.N.CN=C=S>C(Cl)(Cl)Cl.CN(C)C=O.O1CCCC1.ClCCl>[Br:13][C:14]1[CH:15]=[C:16]([CH:44]=[CH:45][CH:46]=1)[CH2:17][S:18][C:19]1[N:23]([CH2:24][CH2:25][CH2:26][N:27]([CH3:36])[CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[C:22]2[CH:37]=[CH:38][C:39]([C:41]([N:55]3[CH2:56][CH2:57][CH:52]([N:47]4[CH2:51][CH2:50][CH2:49][CH2:48]4)[CH2:53][CH2:54]3)=[O:42])=[CH:40][C:21]=2[N:20]=1
Reactant: CN(CCCn1c(SCc2cccc(Br)c2)nc2cc(C(=O)O)ccc21)CCc1ccccn1
Reactant: C1CCN(C2CCNCC2)C1
Agent: CN=C=S
Agent: N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CN(CCCn1c(SCc2cccc(Br)c2)nc2cc(C(=O)N3CCC(N4CCCC4)CC3)ccc21)CCc1ccccn1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
Carbonyldiimidazole (10.5 mg, 1.3 eq) in solution in chloroform (0.2 ml) is added to a solution of 2-[(3-bromobenzyl)thio]-1-{3-[methyl(2-pyridin-2-ylethyl)amino]propyl}-1H-benzimidazole-5-carboxylic acid (27 mg, 1 eq) in a mixture of dimethylformamide (0.2 ml) and tetrahydrofuran (0.4 ml). The mixture is stirred for 15 hours at approximately 20° C. then 4-(1-pyrrolidinyl)piperidine (15 mg, 2 eq) is added. After stirring for 15 hours at approximately 20° C., aminomethyl polystyrene resin (2 eq, acquired from Novabiochem), TBD-methyl polystyrene resin (2 eq, acquired from Novabiochem) and methylisothiocyanate polystyrene resin (4 eq, acquired from Novabiochem) are added to the mixture diluted in dichloromethane. After stirring for 6 hours at approximately 20° C., the mixture is filtered and the filtrate is concentrated under reduced pressure at 40° C. in order to produce the expected compound in the form of an oil (28 mg, 84% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(CCN(C)C)C.[Li]C(CC)C.[Br:32]CCBr>CCOCC>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][C:15]=2[Br:32])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(c1)CCN2C(=O)OC(C)(C)C
Reactant: BrCCBr
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: COc1cc(Br)c2c(c1)CCN2C(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 0.75 h

Procedure:
To 1-(tert-Butoxycarbonyl)-5-methoxyindoline (2.0 g) and TMEDA (1.57 mL, 1.3 eq.) in ether (40 mL) at −78° C. was added sec-BuLi (7.4 mL, 1.2 eq.). The reaction was warmed to −40° C. for 2 hours and then cooled to −78° C. 1,2-dibromoethane (2.07 mL, 3 eq.) was added and the reaction stirred for 45 minutes at −78° C. The bath was then removed and the reaction was stirred for 1 hour. The reaction was quenched with water and extracted with ether. The ether was washed with brine, dried over MgSO4, and concentrated. The crude product was chromatographed on silica gel, using hexane/ethyl acetate (19:1) as eluent, affording 1-(tert-butoxycarbonyl)-7-bromo-5-methoxyindoline (1.16 g).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:19]1([C:25](=[O:27])[CH3:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CN1C(=O)CCC1.O>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([N:22]2[CH2:23][CH2:24][N:19]([C:25](=[O:27])[CH3:26])[CH2:20][CH2:21]2)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1NCc1ccccc1
Reactant: CC(=O)N1CCNCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])c(NCc3ccccc3)c2)CC1
Yield: 68.8 %

Procedure:
A solution of N-benzyl-5-bromo-2-nitrobenzenamine (100 mg, 0.32 mmol) and 1-(piperazin-1-yl)ethanone (83 mg, 0.65 mmol) in NMP (1 mL) was heated to 110° C. for 16 h, cooled then diluted with H2O (15 mL) and extracted with ethyl acetate (2×15 mL). The organics were washed with brine (8 mL), dried (Na2SO4) then filtered and concentrated in vacuo. The residue was subjected flash silica column chromatography (100% ethyl acetate) to furnish 1-(4-(3-(benzylamino)-4-nitrophenyl)piperazin-1-yl)ethanone (mg, 0.22 mmol) as a yellow solid (71 mg, 0.19 mmol) 61% yield. 1H NMR (500 MHz, DMSO-D6) d (ppm) 8.83 (m, 1H), 7.93 (d, J=9.5 Hz, 1H), 7.39 (m, 4H), 7.28 (m, 1H), 6.40 (dd, J=2.5 Hz, 10 Hz, 1H), 5.96 (d, J=2.5 Hz, 1H), 4.58 (d, J=6 Hz, 2H) 3.50-3.29 (m, 8H), 2.34 (s, 3H).+ESI HRMS (calcd for C19H22N4NaO3, M+Na) 377.1590, found 377.1584
Reaction SMILES: [CH:1](=[C:8]1[C:12]2[O:13][C:14]3[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:15]=3[C:16](=[O:17])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH:1](=[C:8]1[C:12]2[O:13][C:14]3[CH:21]=[C:20]([O:22][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:19]=[CH:18][C:15]=3[C:16](=[O:17])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c2c(oc3cc(O)ccc13)C(=Cc1ccccc1)CC2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(=O)c3c(oc2c1)C(=Cc1ccccc1)CC3
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Benzylidene-6-hydroxy-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one (1.5 g) was reacted with ethyl 2-bromo-acetate (1.67 g) in dimethylformamide (60 ml), in the presence of anhydrous K2CO3 (1.38 g), under stirring at room temperature for 3 hours. The reaction mixture was diluted with ice water containing NaH2PO4 and the precipitated product was filtered and washed with water: crystallization from CH2Cl2 /methanol gave (3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yloxy)-acetic acid, ethyl ester, m.p. 152°-154° C. (1.75 g), which was dissolved in dimethylformamide (22 ml) and treated with 2N NaOH (11.5 ml) at room temperature for 2 hours. The reaction mixture was acidified with 2N HCl and then diluted with ice water: the precipitated product was filtered and washed with water until neutral. Crystallization from CHCl3 /ethanol gave 1.4 g of (3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1] benzopyran-6-yloxy)-acetic acid, m.p. 277°-279° C.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH:9]([S:14]([OH:17])(=[O:16])=[O:15])[CH2:10][C:11]([OH:13])=[O:12].C(Cl)CCl.O[N:23]1[C:27](=[O:28])[CH2:26][CH2:25][C:24]1=[O:29]>CC(N(C)C)=O>[O:7]=[C:4]1[CH:5]=[CH:6][C:2](=[O:1])[N:3]1[CH2:8][CH:9]([S:14]([OH:17])(=[O:15])=[O:16])[CH2:10][C:11]([O:13][N:23]1[C:27](=[O:28])[CH2:26][CH2:25][C:24]1=[O:29])=[O:12]
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)CC(CN1C(=O)C=CC1=O)S(=O)(=O)O
Solvent: CC(=O)N(C)C
Solvent: ClCCCl
Product: O=C(CC(CN1C(=O)C=CC1=O)S(=O)(=O)O)ON1C(=O)CCC1=O
Yield: 74.4 %

Procedure:
4-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3-sulfobutanoic acid (110 mg, 0.418 mmol), EDC (240 mg, 1.25 mmol) and N-hydroxysuccinimide (58 mg, 0.504 mmol) was stirred in 10 ml of DMA for overnight, evaporated and purified on SiO2 chromatography eluted with CH3OH/CH2Cl2/HAc (100:900:1 to 100:600:1) to afford 112 mg (75%) of the title product. 1H NMR (DMF-d7) 6.93 (s, 2H), 4.06 (dd, 1H, J=4.8, 13.1 Hz), 3.80 (dd, 1H, J=10.7, 13.9 Hz), 3.35 (dd, 1H J=3.3, 17.8 Hz), 3.25 (m, 1H), 3.10 (dd, 1H, J=2.2, 16.4 Hz), 2.87 (m, 4H); 13C NMR 172.27, 170.88, 169.29, 135.55, 55.28, 40.22, 32.69, 26.66; ESI MS m/z− 261.70 (M−H).
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.C(N1CCO[C@H](CC2C=CC=C(CO)C=2)C1)(OC(C)(C)C)=O.[C:52]([N:59]1[CH2:64][CH2:63][O:62][C@H:61]([CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([CH:72]=[CH2:73])[CH:67]=2)[CH2:60]1)([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:52]([N:59]1[CH2:64][CH2:63][O:62][C@H:61]([CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([CH:72]=[CH:73][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:67]=2)[CH2:60]1)([O:54][C:55]([CH3:56])([CH3:58])[CH3:57])=[O:53]
Reactant: C=Cc1cccc(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)c1
Reactant: Brc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(CO)c2)C1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(C=Cc3cccnc3)c2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60.7 %

Procedure:
To a small reaction vessel was added palladium acetate (1.5 mg, 7micromol), tris-(ortho-toluyl)phospine (4.2 mg, 14micromol) and 3-bromopyridine (22 mg, 0.13 mmol) as a solution in acetonitrile (1.5 mL) in one portion. The mixture was stirred for 5 minutes at room temperature under an atmosphere of nitrogen gas and then intermediate (b), N-Boc-(R)-2-(3-vinylbenzyl)morpholine (0.083 g, 0.27 mmol) was added as a solution in acetonitrile (1.5 mL). The reaction vessel was then subjected to microwave power to heat the reaction to 140° C. for 5 minutes and then cooled to room temperature. The crude reaction was added directly to a silica column and the mixture washed with solvent (10-60% ethyl acetate:isohexane). The desired material was concentrated in vacuo and purified by column chromatography (silica; 50% ethyl acetate: isohexane) to obtain the desired coupling product intermediate (a), N-Boc-(R)-2-(3-(2-(3-pyridinyl)vinyl)-benzyl)morpholine as a colorless oil (30 mg, 57%).
Reaction SMILES: Cl[CH2:2][CH2:3]Cl.COCCO.C(=O)([O-])[O-].[K+].[K+].[C:16]([O:23][CH3:24])(=[O:22])[CH2:17][C:18]([O:20][CH3:21])=[O:19]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:17]1([C:16]([O:23][CH3:24])=[O:22])([C:18]([O:20][CH3:21])=[O:19])[CH2:3][CH2:2]1
Reactant: ClCCCl
Reactant: COC(=O)CC(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: COCCO
Solvent: O
Product: COC(=O)C1(C(=O)OC)CC1
Yield: 95 %

Procedure:
296.9 g of 1,2-dichloroethane (3 mol), 5 g of polyethylene glycol monomethyl ether (mean molar mass 550 g/mol) and 177.1 g of potassium carbonate (1.265 mol) were initially introduced, and the reaction mixture was heated until the 1,2-dichloroethane refluxes. 125.5 g of dimethyl malonate (0.95 mol) and 1.25 g of tetrabutylammonium bromide (3.88 mmol) were then added at the boil. The mixture was stirred using a paddle stirrer for 6.5 hours. Water formed during the reaction was removed by azeotropic distillation with 1,2-dichloroethane throughout the reaction. Further work-up was carried out analogously to Comparative Example 2. The yield was 95%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:10]([C:19]([OH:21])=O)[CH2:9][S:8]2)[CH:2]=1.[NH2:22][C:23]1[CH:24]=[C:25]([CH:34]=[CH:35][CH:36]=1)[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>C(Cl)Cl>[C:26]([C:25]1[CH:24]=[C:23]([NH:22][C:19]([CH:10]2[CH2:9][S:8][CH:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[N:11]2[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[O:21])[CH:36]=[CH:35][CH:34]=1)(=[O:27])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Nc1cccc(C(=O)c2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N1C(C(=O)O)CSC1c1cccnc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C(C(=O)Nc2cccc(C(=O)c3ccccc3)c2)CSC1c1cccnc1
Yield: 115 %

Procedure:
To a solution of 2-(3-pyridinyl)-3-tert-butoxycarbonyl-4-thiazolidinecarboxylic acid (944 mg; 1.2 eq.; 3.05 mmoL), prepared as described above, and 3-aminobenzophenone (500 mg; 2.54 mmol) in methylene chloride (0.15M) was added triethylamine (0.46 mL) at room temperature under nitrogen with stirring, followed by addition of bis(2-oxo-3-oxazolidinyl)phosphinic chloride (773 mg; 1.2 eq) and the resulting mixture was stirred at ambient temperature for 16 hours. This mixture was concentrated to an oil on a rotory evaporator which was partitioned between ethyl acetate (30 mL) and sodium bicarbonate (30 mL). The aqueous phase was extracted twice with ethyl acetate and the resulting combined organic layers were washed with brine and dried magnesium sulfate. After filtering, the solvent was removed to yield the title compound (1.43 g) as a thick orange oil. The compound was further purified by flash chromatography on silica gel to yield 1010 mg (82% yield) N-(3-benzoylphenyl) 2-(3-pyridinyl)-3-tert-butoxycarbonyl-4-thiazolidinecarboxamide as a white foam.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1.C(N(C(C)C)CC)(C)C.[CH3:35][C:36]1[S:37][C:38]([CH3:45])=[CH:39][C:40]=1[S:41](Cl)(=[O:43])=[O:42]>O1CCCC1.C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:21][CH2:22][N:23]([S:41]([C:40]3[CH:39]=[C:38]([CH3:45])[S:37][C:36]=3[CH3:35])(=[O:43])=[O:42])[CH2:24][CH2:25]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: Cc1cc(S(=O)(=O)Cl)c(C)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)c3cc(C)sc3C)CC2)nc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a solution of [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (50 mg, 0.145 mmol, Example 59) and diisopropylethylamine (Aldrich, 330 μL, 1.894 mmol) in anhydrous tetrahydrofuran (15 mL) cooled to 5° C., was added a solution of 2,5-dimethyl-3-thiophenesulfonyl chloride (Maybridge, 45.3 mg, 0.218 mmol) in methylene chloride (3 mL). The reaction mixture was stirred at room temperature overnight and then diluted with 50 mL of methylene chloride. The resulting solution was washed with saturated aqueous sodium bicarbonate (2×10 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32–63 μm, 60 Å silica gel) eluting with 25% ethyl acetate in hexane yielded [4-amino-2-[1-(2,5-dimethyl-thiophene-3-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (69 mg, 92%) as white solids. HR-MS (ES, m/z) calculated for C23H26FN5O4S2 [(M+H)+] 520.1483, observed 520.1494.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][CH:39]1[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:45][CH:42]3[CH2:43][CH2:44][CH:39]([CH3:38])[CH2:40][CH2:41]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CC1CCC(N)CC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: CC1CCC(Nc2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCCCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 4-methylcyclohexylamine according to conditions described in general procedure C. Mp: 101-102° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.82 (d, J=6.6 Hz, 3 H), 0.86-1.59 (m, 15 H), 3.27-3.36 (m, 5 H), 6.27 (bs, 1 H), 6.96 (d, J=12.8, 2 H), 7.15 (d, J=8.4 Hz,1 H), 7.36-7.39 (m, 1H), 7.43 (s, 1 H), 7.54-7.60 (m, 3 H), 7.79-7.83 (m, 1 H), 7.96 (d, J=7.3 Hz, 1 H), 8.18 (s, 1H), 10.40 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:32])[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:18][CH2:17][C@H:16]([O:19][C:20]4[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][C:21]=4[F:30])[C:15]3=[O:31])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[OH-].[Li+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([F:32])[C:5]([N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[CH2:18][CH2:17][C@H:16]([O:19][C:20]4[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]=4[F:30])[C:15]3=[O:31])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(O[C@H]2CCN(C3CCN(c4ncc(Cl)cc4F)CC3)C2=O)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(O[C@H]2CCN(C3CCN(c4ncc(Cl)cc4F)CC3)C2=O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
To a solution of (S)-methyl 4-(1-(1-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)-3-fluorobenzoate (1.5 g, 3.2 mmol) in THF (30 mL) was added 3 N lithium hydroxide (4.3 mL, 13 mmol) and the reaction was stirred overnight at ambient temperature. Additional 3 N LiOH (4.3 mL, 13 mmol) was added, and the reaction was stirred for an additional 3 hours. The THF was removed with a stream of nitrogen. The aqueous layer was acidified by addition of HCl (1 N) and the solid that formed was filtered and washed with water. The solid was dried under vacuum to yield (S)-4-(1-(1-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)-3-fluorobenzoic acid (1.3 g, 2.9 mmol, 89% yield).
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[C:10]1[C:15]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=1.Cl>CN(C)C=O.C(OCC)(=O)C>[CH:3]1([O:8][C:10]2[C:15]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: NS(=O)(=O)c1cccnc1Cl
Reactant: OC1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cccnc1OC1CCCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
10.9 g of a 55% dispersion of sodium hydride are suspended in 40 ml of dimethylformamide and then 13.6 ml of cyclopentanol are added dropwise. Then a solution of 19.24 g of 2-chloropyridin-3-ylsulfonamide in 40 ml of dimethylformamide is added dropwise and the reaction mixture is stirred for 2 hours at 35°-40° C. and then taken up in a mixture of 250 ml of ethyl acetate, 250 ml of ice-water and 125 ml of 1N hydrochloric acid. After extraction with 3×100 ml of ethyl acetate the combined organic phases are washed with 4×100 ml of water. The organic solution is washed and dried, affording an oily residue which crystallises after trituration with 50 ml of ether to give 19.64 g of 2-cyclopentyloxypyridin-3-ylsulfonamide with a melting point of 134°-135° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C@H:10]([NH:21][CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)=[O:34]>C(Cl)Cl>[F:42][C:39]1[CH:40]=[CH:41][C:36]([O:35][C:33](=[O:34])[N:21]([C@H:10]2[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[CH2:12][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9]2)[CH3:22])=[CH:37][CH:38]=1
Reactant: O=C(Cl)Oc1ccc(F)cc1
Reactant: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 3.35 g (10 mmol) (3S,4R)-1-benzyl-4-(3,4-dichlorophenyl)-N-methylpyrrolidin-3-amine (example 159, h), 1.61 g (12.5 mmol) DIPEA and 1.92 g (11 mmol) 4-fluorophenyl chloroformate in 50 mL DCM at 0-5° C. was stirred at 0° C. for 1 h and evaporated to dryness. The residue was subjected to column chromatography on silica eluting with a gradient formed from heptane and t-butyl-methylether to yield after evaporation of the product containing fractions 3.07 g (65%) of the title compound as colourless viscous oil. MS m/e: 473.1 [M+H]+.