Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[N:3]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.ClCCl>[S:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[CH2:9][O:8][C:4]1[N:3]=[C:2]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Clc1cccc(OCc2cccs2)n1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: c1cc(OCc2cccs2)nc(N2CCNCC2)c1
Temperature: 125 °C
Yield: 47 %

Procedure:
A mixture of the product from step 1 above (1.35 g, 5.98 mmol), piperazine (1.55 g, 17.9 mmol) and K2CO3 (0.91 g, 6.58 mmol) in acetonitrile (5 mL) was heated at 125 125° C. for 6.5 h in a sealed pyrex flask. The reaction mixture was diluted with dichlorometane, filtered and concentrated in vacuo. The semi-solid residue was purified by silica gel (16×4 cm) chromatography using CHCl3/MeOH (9:1) as eluent. Solvents were evaporated and the oily residue was redissolved in CHCl3/ether (1:1). Filtration and concentration in vacuo furnished 0.78 g (47%) of the title compound as a beige oil. HRMS m/z calcd for C14H17N3OS (M)+ 275.1092, found 275.1101. Anal. (C14H17N3OS) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:42]([OH:44])=O)=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:29])[NH:15][S:16]([C:19]3[CH:28]=[CH:27]C4C(=CC=CC=4)[CH:20]=3)(=[O:18])=[O:17])=[CH:10][C:9]=2[C:30]([N:32]2[CH2:41][CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33]2)=[O:31])[C:6]=1[CH3:7].[CH2:45]([NH:52][CH2:53][CH2:54][CH2:55][CH3:56])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[CH2:45]([N:52]([CH2:53][CH2:54][CH2:55][CH3:56])[C:42]([C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:29])[NH:15][S:16]([C:19]3[CH:20]=[CH:11][C:10]4[C:27](=[CH:12][CH:13]=[CH:8][CH:9]=4)[CH:28]=3)(=[O:17])=[O:18])=[CH:10][C:9]=2[C:30]([N:32]2[CH2:33][CH2:34][C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:41]2)=[O:31])[N:4]=1)=[O:44])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CCCCNCc1ccccc1
Reactant: Cc1c(Cl)c(C(=O)O)nn1-c1ccc(C(=O)NS(=O)(=O)c2ccc3ccccc3c2)cc1C(=O)N1CCc2ccccc2C1
Product: CCCCN(Cc1ccccc1)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Yield: 135.6 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 125, 4-chloro-5-methyl-1-(4-(naphthalen-2-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1H-pyrazole-3-carboxylic acid (Intermediate 122F, 25 mg, 0.040 mmol) and N-benzylbutan-1-amine (Aldrich, 11 μL, 0.064 mmol) were converted to the title compound (21 mg, 68%). 1H NMR (1:1 CD3OD:CDCl3) δ 8.62 (br s, 1H), 8.15 (d, J=7.9 Hz, 1H), 8.07-7.82 (m, 5H), 7.64-7.50 (m, 1H), 7.46-7.36 (m, 1.5H), 7.28-6.93 (m, 9H), 6.86 (d, J=7.3 Hz, 0.5H), 4.62 (d, J=5.9 Hz, 1H), 4.47-4.11 (m, 2.5H), 3.77-3.36 (m, 2.5H), 3.21-2.94 (m, 1.5H), 2.81-2.65 (m, 2.5H), 2.35-2.14 (m, 3H), 1.74-1.13 (m, 3H), 1.08-0.77 (m, 3H), 0.72-0.58 (m, 1H); MS(ESI+) m/z 774.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[Br-]>>[CH3:1][N:2]([CH3:11])[C:3]1[CH:8]=[CH:7][C:6]([C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:11])[CH3:1])=[CH:4][CH:5]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc([Mg]Br)cc1
Agent: [Br-]
Product: CN(C)c1ccc(-c2ccc(N(C)C)cc2)cc1
Yield: 70 %

Procedure:
A mixture of p-dimethylaminophenyl magnesium bromide (1 mole) and thallous bromide (2 moles) is stirred and refluxed under nitrogen for 5 hours. The cooled solution is filtered to remove thallium, and hydrogen chloride passed into the filtrate. The colorless hydrochloride which precipitates is filtered off, stirred into dilute sodium hydroxide, and the tetramethylbenzidine extracted with ether-benzene (1:1, 2 × 30 ml.) The extracts are dried over anhydrous sodium sulfate and the solvent removed to leave a yellow solid which is sublimed at 165°/0.05 mm. to give a 70% yield of pure N,N,N',N'-tetramethylbenzidine as a colorless solid, m.p. 195°.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[C:9]([Cl:17])=[N:10][CH:11]=[C:12]([CH:16]=1)[C:13]([OH:15])=O.CN(C=O)C.CCN(C(C)C)C(C)C.[F:32][C:33]([F:43])([O:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)[CH3:34]>C(Cl)Cl.C1COCC1.CCCCCC>[Br:7][C:8]1[C:9]([Cl:17])=[N:10][CH:11]=[C:12]([CH:16]=1)[C:13]([NH:40][C:39]1[CH:41]=[CH:42][C:36]([O:35][C:33]([F:32])([F:43])[CH3:34])=[CH:37][CH:38]=1)=[O:15]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: CC(F)(F)Oc1ccc(N)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(F)(F)Oc1ccc(NC(=O)c2cnc(Cl)c(Br)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (653 μL, 7.46 mmol) was added to a mixture of 5-bromo-6-chloronicotinic acid (1.2 g, 4.97 mmol) and DMF (20 μL, 0.258 mmol) in DCM (40 mL) under nitrogen atmosphere and the RM was stirred for 2 h at RT. The solvent was evaporated, the residue was dissolved in DCM (10 mL) and evaporated again to dryness. The residue was dissolved in THF (30 mL), DIPEA (1.737 mL, 9.95 mmol) was added and the RM was cooled down to −15° C. 4-(1,1-difluoroethoxy)aniline (Stage 30.3, 0.932 g, 5.22 mmol) in THF (10 mL) was added dropwise in 15 min. period and the RM was stirred for 1 h at RT. The solvent was evaporated off under reduced pressure and the residue was diluted with EtOAc (100 mL), treated with citric acid 10% (60 mL) and extracted with EtOAc. The combined extracts were washed with sat. aq. Na2CO3 (50 mL) and brine (2×50 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was suspended in n-hexane, filtered and dried to give the title product as a beige solid. HPLC (Condition 5) tR=7.3 min, UPLC-MS (Condition 3) tR=1.16 min, m/z=391/393 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[CH2:6][N:7]([CH3:21])[CH2:8][CH:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)O.[OH-].[Na+]>ClCCl.CS(O)(=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:22]([CH:9]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=3)[CH2:8][N:7]([CH3:21])[CH2:6]2)=[CH:23][CH:24]=1
Reactant: COc1cccc(CN(C)CC(O)c2ccc3ccccc3c2)c1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc2c(c1)CN(C)CC2c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 60 %

Procedure:
A solution of the alcohol, Compound 5, (495 g, 1.54 mol) in dichloromethane (6.0 L) was split equally into two flasks. To each half of the ice-cold solution was added methanesulfonic acid (500 mL, 7.7 mmol) via additional funnel (˜1 h). The reaction solution was allowed to slowly warm to room temperature and stirred for 6-8 h before it was cooled to <10° C. and quenched slowly with an aqueous solution of sodium hydroxide (330 g, 8.3 mol in 600 mL of water). The internal temperature during the addition was kept less than 30° C. The organic layer was then separated, washed with water, dried over sodium sulfate and concentrated in vacuo. The crude product from the two batches were combined and purified by flash column chromatography (hexanes/ethyl acetate 88:12 to ethyl acetate/methanol 99.9:0.1) to give Compound 6 (280.4 g, 60% over 4 steps) as a thick oil: 1H NMR (500 MHz, CDCl3) δ 7.81-7.74 (m, 3H), 7.68 (s, 1H), 7.47-7.42 (m, 2H), 7.28-7.26 (m, 1H), 6.79 (d, J=8.5 Hz, 1H), 6.80-6.62 (m, 2H), 4.40 (dd, J=8.5, 6.0 Hz, 1H), 3.80-3.78 (m, 1H), 3.77 (s, 3H), 3.65 (d, J=15.0 Hz, 1H), 3.11-3.08 (m, 1H), 2.65 (dd, J=11.5, 6.0 Hz, 1H), 2.45 (s, 3H); ESI MS m/z 304 [M+H]+.
Reaction SMILES: BrC1C=CC([C:8]2[CH:21]=[CH:20][C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=[CH:11][C:10]=3[CH:9]=2)=CC=1.C1(B(O)O)C2C=CC3C(=CC=CC=3)C=2C=CC=1.Br[C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[C:45]([Br:50])[CH:46]=2)[CH:41]=1>>[Br:50][C:45]1[CH:46]=[C:47]2[C:42](=[CH:43][CH:44]=1)[CH:41]=[C:40]([C:14]1[C:13]3[CH:12]=[CH:11][C:10]4[C:19](=[CH:20][CH:21]=[CH:8][CH:9]=4)[C:18]=3[CH:17]=[CH:16][CH:15]=1)[CH:49]=[CH:48]2
Reactant: Brc1ccc2cc(Br)ccc2c1
Reactant: Brc1ccc(-c2ccc3c(ccc4ccccc43)c2)cc1
Agent: OB(O)c1cccc2c1ccc1ccccc12
Product: Brc1ccc2cc(-c3cccc4c3ccc3ccccc34)ccc2c1

Procedure:
Synthesis was performed in the same manner as in the synthesis of 2-(4-bromophenyl)phenanthrene except that: phenanthrene-1-boronic acid was used instead of phenanthrene-2-boronic acid; and 2,6-dibromonaphthalene was used instead of 4-bromoiodobenzene.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:17][CH:18]([CH2:22][CH:23]([CH3:27])[C:24]([OH:26])=O)[C:19]([OH:21])=O>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:19](=[O:21])[CH:18]([CH3:17])[CH2:22][CH:23]([CH3:27])[C:24]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[CH2:10][O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:26])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Reactant: CC(CC(C)C(=O)O)C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(CC(C)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1)C(=O)N1CCC[C@@H]1COCc1ccccc1
Yield: 66.1 %

Procedure:
Using General Procedure A with 6.05 g (25 mmol) D-Proline benzyl ester hydrochloride and 2.0 g (12.5 mmol) 2,4-dimethylglutaric acid afforded, after flash chromatography (EtOAc), 4.3 g (64%) of the title compound as a light yellow oil. MS m/e (%): 535 (M+H+, 100).
Reaction SMILES: [C:1]([C:4]1[C:12]2[N:11]=[C:10]([CH:13]3[CH2:22][CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]3C(OC(C)(C)C)=O)[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[NH2:2].Cl>CO>[NH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:21][CH2:22][CH:13]1[C:10]1[NH:9][C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:12]=2[N:11]=1
Reactant: CC(C)(C)OC(=O)N1c2ccccc2CCC1c1nc2c(C(N)=O)cccc2[nH]1
Agent: Cl
Solvent: CO
Product: NC(=O)c1cccc2[nH]c(C3CCc4ccccc4N3)nc12
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl 2-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (17 mg, 0.043 mmol) and HCl in methanol (1.25 M, 1 mL) was stirred at 40° C. overnight. Methanol was removed under reduced pressure, aq. sodium bicarbonate solution was added and extracted with DCM. The DCM layer was washed with brine, dried over anhydrous sodium sulfate and evaporated to afford 2-(1,2,3,4-Tetrahydroquinolin-2-yl)-1H-benzo[d]imidazole-4-carboxamide. MS (ES+): m/z 315.13 [M+Na]+
Reaction SMILES: [Na].CS[C:4]1[N:5]([CH2:14][CH2:15][CH3:16])[C:6](=[O:13])[C:7]2[CH:12]=[CH:11][S:10][C:8]=2[N:9]=1>C(O)CC>[CH2:6]([O:13][C:4]1[N:5]([CH2:14][CH2:15][CH3:16])[C:6](=[O:13])[C:7]2[CH:12]=[CH:11][S:10][C:8]=2[N:9]=1)[CH2:7][CH3:8]
Reactant: CCCn1c(SC)nc2sccc2c1=O
Agent: [Na]
Solvent: CCCO
Product: CCCOc1nc2sccc2c(=O)n1CCC
Yield: 106.2 %

Procedure:
In a sulfonation flask, 12.5 g (0.15 mol) of sodium propylate and 12.0 g (0.05 mol) 2-methylsulfanyl-3-propyl-3H-thieno[2.3-d]pyrimidin-4-one are stirred in 120 ml of absolute n-propanol for 4 hours under nitrogen at reflux temperature. The n-propanol is then removed in a water-jet vacuum and the residue taken up in ethyl acetate/water and the organic phase is extracted twice with water. The organic phase is dried over sodium sulfate and the solvent removed in the water-jet vacuum, giving the crude product, which is then purified by column chromatography over silica gel (eluant: ethyl acetate/hexane=1:3). 6.7 g of 2-propoxy-3-propyl-3H-thieno[2.3-d]pyrimidin-4-one are obtained in the form of a brown resin (1H-NMR-data see table 1 1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[CH:7]=1.C([O:20][C:21](=[O:46])[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]Br)[C:27]=1[CH2:39][CH2:40][C:41]([O:43]CC)=[O:42])C.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].Cl>O.CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]([O:17][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][C:28]2[C:27]([CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[C:26]([CH:31]=[CH:30][CH:29]=2)[O:25][CH2:24][CH2:23][CH2:22][C:21]([OH:46])=[O:20])[CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([N:14]([CH3:15])[CH3:16])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: CN(C)c1ccc(-c2cc(O)cc(Br)c2)cc1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(C)c1ccc(-c2cc(Br)cc(OCCCCCCc3cccc(OCCCC(=O)O)c3CCC(=O)O)c2)cc1
Temperature: 90 °C
Yield: 42.5 %

Procedure:
In a round bottom vial charged with 100 mg (0.342 mmol) of 5-bromo-4′-dimethylamino-biphenyl-3-ol, 160 mg (0.342 mmol) of 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester, potassium carbonate (94 mg, 0.684 mmol) and 10 mL of DMA were sequentially added. This mixture was heated overnight at 90° C. HPLC analysis of the reaction mixture at this time, indicated the formation of the di-ester intermediate. At this time, 1 mL of 1 N NaOH aq. was added and the reaction mixture was heated again at 90° C. overnight. At this time, the reaction was diluted with water and acidified with 2 N HCl until pH=˜7 was achieved. The aqueous phase was thrice extracted with ethyl acetate. The combined organic phases were dried with MgSO4, filtered and washed with ethyl acetate. The filtrate was concentrated in vacuo to provide an oil (91 mg, 42%). This intermediate was used in subsequent steps without further purification.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1Br)[CH:18]([NH:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:26][CH:25]=1)[CH2:17][CH2:16]2)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37]([Cu])#[N:38].N>CN1C(=O)CCC1>[CH2:1]([O:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[C:37]#[N:38])[CH:18]([NH:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:26][CH:25]=1)[CH2:17][CH2:16]2)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[Cu]
Reactant: CC(C)(C)OC(=O)c1ccc(NC2CCc3cc(NC(=O)COCc4ccccc4)c(Br)cc32)cc1
Agent: N
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)c1ccc(NC2CCc3cc(NC(=O)COCc4ccccc4)c(C#N)cc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.4 %

Procedure:
To a stirred solution of tert-butyl 4-[N-(5-(2-benzyloxyethanoylamino)-6-bromoindan-1-yl)amino]benzoate (0.210 g, 0.38 mmol) in anhydrous NMP (2.2 ml) was added CuCN (0.068 g, 0.76 mmol). The reaction flask was placed in an oil bath preheated to 150° C. and it was stirred at this temperature for 3 h under argon. The mixture was then allowed to cool to room temperature and poured into a mixture of liquid ammonia (d=0.88, 2 ml) and ice-water (5 ml). This mixture was stirred at room temperature for 5 min, the brown precipitate was then collected by filtration and washed with water. This precipitate was then suspended in CH2Cl2 (70 ml), dried (Na2SO4), and concentrated in vacuo. Purification of the residue by column chromatography, on elution with 35% AcOEt in hexane, afforded a brown solid (0.084 g, 45%); mp 194-195° C.; 1H-NMR (250 MHz, CDCl3, TMS) 1.55 (s, 9H, C(CH3)3), 1.95, 2.64 (2×m, 1H each, 2-CH2 indanyl), 2.99 (m, 2H, 3-CH2 indanyl), 4.13, 4.72 (2×s, 2H each, PhCH2 and OCH2CO), 4.22 (d, J=8.1 Hz, 1H, N10—H), 5.05 (m, 1H, 1-CH indanyl), 6.65 (d, J=8.7 Hz, 2H, 3,5-ArH), 7.39 (m, 5H, PhCH2), 7.54, 8.37 (2×s, 1H each, 4-H and 7-H), 7.86 (d, J=8.7 Hz, 2H, 2,6-ArH), 9.06 (s, 1H, CONH); MS (ESI, m/z) 520 {(M+Na)+, 100%,}; Found: C, 72.26; H, 6.26; N, 8.41; C30H31N3O4 requires C, 72.41; H, 6.28; N, 8.44%.
Reaction SMILES: [CH:1]1([N:6]([CH3:33])[S:7]([C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:20](=[O:21])[C:19]([CH:22]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:23][C:24]([O-:26])=O)=[CH:18][NH:17]3)=[N:14][CH:15]=2)(=[O:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[F:43][C:44]([F:48])([F:47])[CH2:45][NH2:46].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH:1]1([N:6]([CH3:33])[S:7]([C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:20](=[O:21])[C:19]([CH:22]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:23][C:24]([NH:46][CH2:45][C:44]([F:48])([F:47])[F:43])=[O:26])=[CH:18][NH:17]3)=[N:14][CH:15]=2)(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NCC(F)(F)F
Reactant: CN(C1CCCC1)S(=O)(=O)c1ccc(-n2[nH]cc(C(CC(=O)[O-])c3ccccc3)c2=O)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C1CCCC1)S(=O)(=O)c1ccc(-n2[nH]cc(C(CC(=O)NCC(F)(F)F)c3ccccc3)c2=O)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 13.5 %

Procedure:
To a solution of 200 mg (0.43 mmol) of 3-(2-{5-[cyclopentyl(methyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-3-phenylpropanoate, 0.3 mL (1.7 mmol) of DIEA and 30 μL (0.43 mmol) of 2,2,2-trifluoroethylamine in 1 mL of DCM are added, at 0° C., 207 mg (0.64 mmol) of TBTU. The medium is stirred for 12 hours at room temperature. A further 0.3 mL of 2,2,2-trifluoroethylamine is then added and the medium is heated at 40° C. for 6 hours. The medium is taken up in 20 mL of DCM, washed successively with water (2×10 mL) and brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure, and then purified by chromatography on a column of silica gel, eluting with a cyclohexane/EtOAc gradient of 0 to 10% EtOAc. 32 mg of 3-(2-{5-[cyclopentyl(methyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-3-phenyl-N-(2,2,2-trifluoroethyl)propanamide are thus obtained in the form of a powder.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:11]([O:18][CH3:19])=[N:12][CH:13]=[N:14][C:15]=1[O:16][CH3:17])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH3:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[N:25]=1>>[CH3:19][O:18][C:11]1[C:10]([CH:2]2[N:1]([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([C:24]4[N:25]=[C:21]([CH3:20])[S:22][CH:23]=4)[CH:27]=3)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]2)=[C:15]([O:16][CH3:17])[N:14]=[CH:13][N:12]=1
Reactant: COC(=O)CCCC(N)c1c(OC)ncnc1OC
Reactant: Cc1nc(-c2cccc(C=O)c2)cs1
Product: COc1ncnc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2csc(C)n2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(4,6-dimethoxypyrimidin-5-yl)pentanoate with commercially available 3-(2-methylthiazol-4-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.74 min.; [M+H]+: 424.92 g/mol.
Reaction SMILES: [Cl-].[CH2:2]([NH:6][C:7]([CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:8])[CH2:3][CH2:4][CH3:5].C([Li])CCC.[Na+:34].[CH:35]([C:37]1[O:41][C:40]([S:42]([O-:45])(=[O:44])=[O:43])=[CH:39][CH:38]=1)=O>O1CCCC1>[Na+:34].[CH2:2]([NH:6][C:7]([CH:9]=[CH:35][C:37]1[O:41][C:40]([S:42]([O-:45])(=[O:44])=[O:43])=[CH:39][CH:38]=1)=[O:8])[CH2:3][CH2:4][CH3:5]
Reactant: O=Cc1ccc(S(=O)(=O)[O-])o1
Reactant: CCCCNC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCNC(=O)C=Cc1ccc(S(=O)(=O)[O-])o1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 69.1 %

Procedure:
To a suspension of (N-n-butylcarbamoyl)methyltriphenylphosphonium chloride (16.63 g, 40.38 mmol), from Example B above, in tetrahydrofuran (200 mL) at 0-5° C. was added a solution of n-butyllithium in hexanes (18 mL, 2.5 M, 45 mmol). Upon addition of the n-butyllithium solution, the solution became homogeneous and the reaction mixture was stirred for 10 min at 5° C. 5-Formylfuran-2-sulfonic acid sodium salt (8.0 g, 40.38 mmol) was then added in one portion and the reaction mixture was stirred for 45 min at 0-5° C. and then at room temperature for 1.75 h. The mixture was filtered and the solid obtained was stirred with THF (100 mL) for several hours and then filtered. The solid was mixed with ethanol (200 mL) and filtered to remove the undissolved solid. Removal of solvent provided 8.24 g (69.1% yield) of the title compound as a slightly yellowish powder, m.p.=318.1° C. (dec) (Rf =0.55 on a silica gel plate using 2:1 EtOAc/EtOH). This product consisted of 70% trans-isomer and 30% cis-isomer.
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]1[NH:15][N:14]=[C:13]([CH2:16][CH3:17])[C:12]=1[O:18][C:19]1[CH:20]=[C:21]([C:27]#[N:28])[CH:22]=[C:23]([CH:26]=1)[C:24]#[N:25])C1C=CC=CC=1>ClCCl.[Fe](Cl)(Cl)Cl>[CH2:16]([C:13]1[C:12]([O:18][C:19]2[CH:26]=[C:23]([C:24]#[N:25])[CH:22]=[C:21]([CH:20]=2)[C:27]#[N:28])=[C:11]([CH2:10][CH2:9][OH:8])[NH:15][N:14]=1)[CH3:17]
Reactant: CCc1n[nH]c(CCOCc2ccccc2)c1Oc1cc(C#N)cc(C#N)c1
Agent: Cl[Fe](Cl)Cl
Solvent: ClCCl
Product: CCc1n[nH]c(CCO)c1Oc1cc(C#N)cc(C#N)c1
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
Iron(III)Chloride (217 mg, 1.30 mmol) was added to a solution of the pyrazole from Example 153 (50 mg, 0.13 mmol) in dichloromethane (5 ml) under nitrogen at room temperature. After stirring for 30 minutes the mixture was diluted with dichloromethane (20 ml), washed with water (100 ml) then saturated aqueous sodium ethylenediaminetetraacetate solution (20 ml), dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (98:2 changing to 95:5, by volume) to provide the title compound (20 mg) as a white solid.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:21])=[C:8]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][O:12][C:9]2=[CH:10][N:11]=1)=[O:5])C.[NH2:22][C@@H:23]([C:25]([OH:27])=[O:26])[CH3:24]>>[OH:21][C:7]1[C:6]([C:4]([NH:22][C@H:23]([CH3:24])[C:25]([OH:27])=[O:26])=[O:5])=[N:11][CH:10]=[C:9]2[O:12][N:13]=[C:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]=12
Reactant: CCOC(=O)c1ncc2onc(-c3ccccc3)c2c1O
Reactant: C[C@@H](N)C(=O)O
Product: C[C@@H](NC(=O)c1ncc2onc(-c3ccccc3)c2c1O)C(=O)O

Procedure:
Prepared in analogy to Example 11 from 4-hydroxy-3-phenyl-isoxazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and D-alanine; ESI MS (m/z): 328.20 (M+H+); 326.16 (M−H+).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([CH2:9][C:10]([OH:12])=O)[CH2:2]2.[CH:13]([C:16]1[CH:17]=[C:18]([C:22]([NH2:25])([CH3:24])[CH3:23])[CH:19]=[CH:20][CH:21]=1)([CH3:15])[CH3:14]>>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH:3]([CH2:9][C:10]([NH:25][C:22]([C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH:13]([CH3:15])[CH3:14])[CH:17]=1)([CH3:24])[CH3:23])=[O:12])[CH2:2]2
Reactant: CC(C)c1cccc(C(C)(C)N)c1
Reactant: O=C(O)CC1CN2CCC1CC2
Product: CC(C)c1cccc(C(C)(C)NC(=O)CC2CN3CCC2CC3)c1
Yield: 10 %

Procedure:
Using general procedure I, (1-aza-bicyclo[2.2.2]oct-3-yl)-acetic acid (200 mg, 1.20 mmol) and 1-(3-isopropyl-phenyl)-1-methyl-ethylamine gave the title compound as a white solid (42 mg, 10%). 1H NMR (400 MHz, DMSO-d) δ 7.15-1.20 (m, 3H), 7.05 (d, J=8.4 Hz, 1H), 3.41-3.45 (m, 1H), 3.26 (s, 2H), 3.15-3.22 (m, 2H), 2.71-2.82 (m, 2H), 2.41-2.47 (m, 3H), 2.05-2.12 (m, 1H), 1.79-1.90 (m, 4H), 1.61 (d, J=8.0 Hz, 6H), 1.21 (d, J=6.4 Hz, 6H) ppm. 13C NMR (400 MHz, DMSO-d) δ 171.1, 148.7, 147.3, 128.1, 123.9, 122.8, 122.2, 55.6, 52.1, 46.5, 45.9, 38.8, 34.5, 30.7, 28.9, 28.5, 23.8, 23.4, 18.0 ppm. Purity: 96.8% HPLCMS (210 nm); retention time 1.93 min; (M+1) 329.