Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][CH2:18][C:19](OC)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH:34]([OH:37])([CH3:36])[CH3:35]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][CH2:18][C:19]([O:37][CH:34]([CH3:36])[CH3:35])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Product: CC(C)OC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1

Procedure:
To a solution of 0.312 g methyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-octanoate (example 4a) in 5 ml isopropanol is added a solution of a catalytic amount of sodium hydride in 1 ml isopropanol. The mixture is refluxed for 18 h and the solvent is evaporated. The residue is dissolved in methylene chloride and the solution is washed with saturated ammonium chloride solution. The organic phase is dried, filtered, evaporated to give a clear oil which is purified by flash column chromatography using ethyl acetate/hexane (2:3) as the eluent to give as a clear oil isopropyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-octanoate.
Reaction SMILES: Br[C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH3:20])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]2[O:9][C:10](=[O:12])[CH3:11])[C:5]2[CH:21]=[C:22]([Cl:26])[C:23]([Cl:25])=[CH:24][C:4]=2[N:3]=1.[CH:27]([Sn](CCCC)(CCCC)CCCC)=[CH2:28].CN(C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.ClCCl>[Cl:25][C:23]1[C:22]([Cl:26])=[CH:21][C:5]2[N:6]([C@@H:7]3[O:19][C@H:18]([CH3:20])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]3[O:9][C:10](=[O:12])[CH3:11])[C:2]([CH:27]=[CH2:28])=[N:3][C:4]=2[CH:24]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(Br)nc2cc(Cl)c(Cl)cc21
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=Cc1nc2cc(Cl)c(Cl)cc2n1[C@@H]1O[C@H](C)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 90 °C
Yield: 51.1 %

Procedure:
2-Bromo-5,6-dichloro-1-(2,3-di-O-acetyl-5-deoxy-beta-D-ribofuranosyl)-1H-benzimidazole (0.22 g, 0.47 mmol), vinyltributyltin (Aldrich, 0.5 ml, 2.4 mmol), tetrakis(triphenylphosphine)palladium(0) (Aldrich, 0.054 g, 0.047 mmol) and DMF (Aldrich Sure Seal, 5 mL) were combined and flushed with argon for 30 min. The solution was warmed to 90° C. After 1 h the DMF was distilled off under reduced pressure. The residue was taken up in ethyl acetate (50 mL) and extracted with 20 mL of saturated NH4Cl. The organic layer was dried with magnesium sulfate (anhyd), filtered, and evaporated. The crude residue was purified on a silica gel column (2.5×14 cm, 230-400 mesh) with 1:40 methanol:dichloromethane to give the title compound (0.1 g, 0.24 mmol, 51%); MS (ES+): m/z (rel. intensity) 436 (100, M++Na); 1H NMR (DMSO-d6) δ8.06 (s,1H, ArH), 7.97 (s, 1H, ArH), 7.10 (dd, 1H, CH, J=11 Hz, J=16.8 Hz), 6.50 (dd, 1H, CH, J=1.8 Hz, J=16.8 Hz), 6.32 (d, 1H, CH, J=6.9 Hz), 5.85 (dd, 1H, CH, J=1.8 Hz, J=11 Hz), 5.51 (apparent triplet, 1H, CH, J=7.0 Hz), 5.27 (apparent triplet, 1H, CH, J=6.5 Hz), 4.27-4.18 (m, CH, 1H), 2.15 (s, 3H, OAc), 1.99 (s, 3H, OAc), 1.53 (d, 3H, CH3, J=6.3 Hz).
Reaction SMILES: [O:1]([C:8]1[N:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]#[N:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ni]>[O:1]([C:8]1[C:9]([CH2:10][NH2:11])=[CH:12][CH:13]=[CH:14][N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccnc1Oc1ccccc1
Agent: [Ni]
Product: NCc1cccnc1Oc1ccccc1

Procedure:
2-phenoxynicotinonitrile and Raney/nickel were processed according to the Example 78B to afford the title compound. MS (ESI+) m/z 201 (M+H)+
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][CH2:16][O:17][C:18]2[CH:27]=[C:26]3[C:21]([C:22]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]5[O:35][CH2:36][O:37][C:30]=45)=[N:23][CH:24]=[N:25]3)=[CH:20][C:19]=2[O:38][CH3:39])([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:14][C:11]1([CH2:15][CH2:16][O:17][C:18]2[CH:27]=[C:26]3[C:21]([C:22]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]5[O:35][CH2:36][O:37][C:30]=45)=[N:23][CH:24]=[N:25]3)=[CH:20][C:19]=2[O:38][CH3:39])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1OCCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1OCCC1(O)CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.5 %

Procedure:
A mixture of 7-[2-(N-tert-butoxycarbonyl-4-hydroxypiperidin-4-yl)ethoxy]-6-methoxy-4-(2,3-methylenedioxyanilino)quinazoline (0.067 g), trifluoro acetic acid (0.5 ml) and methylene chloride (3 ml) was stirred at ambient temperature for 1 hour. The solvent was evaporated and the residue was partitioned between methylene chloride and a saturated aqueous sodium bicarbonate solution. The organic phase was washed with brine, dried over magnesium sulphate and evaporated. There was thus obtained the title compound (0.015 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 1.75 (m, 4H), 2.05 (t, 2H), 3.1 (m, 4H), 4.0 (s, 3H), 4.35 (t, 2H), 6.1 (s, 2H), 6.95 (m, 3H), 7.4 (s, 1H), 8.1 (s, 1H), 8.85 (s, 1H); Mass Spectrum: M+H+ 439.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[C:5]([O:18][CH3:19])=[CH:6][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:8][CH:9]=1.[CH3:20]I>CN(C=O)C>[I:3][C:4]1[C:5]([O:18][CH3:19])=[CH:6][C:7]([N:10]([CH3:20])[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[N:8][CH:9]=1
Reactant: CI
Reactant: COc1cc(NC(=O)OC(C)(C)C)ncc1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(N(C)C(=O)OC(C)(C)C)ncc1I
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 86.2 %

Procedure:
Sodium hydride (37.70 mg, 0.9425 mmol) was added to a stirred suspension of tert-butyl N-(5-iodo-4-methoxy-2-pyridyl)carbamate (300 mg, 0.8568 mmol) in DMF (3 mL) and the reaction was stirred at 0° C. for 15 minutes. MeI (145.9 mg, 63.99 μL, 1.028 mmol) was added and the reaction allowed to warm to ambient temperature over 1 hour. The mixture was quenched by the addition of water, diluted with EtOAc and the layers separated. The organic layer washed with saturated aqueous NaHCO3 (×1), brine (×2), dried (MgSO4) filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 40 g column, eluting with 0 to 30% EtOAc/Petroleum Ether, loaded in DCM) to give tert-butyl (5-iodo-4-methoxypyridin-2-yl)(methyl)carbamate as a colourless oil (269 mg, 86% Yield). MS (ES+-t-Bu) 309.4.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:47]=[CH:46][C:26]([C:27]([NH:29][N:30]5[CH2:35][CH2:34][N:33](C(OCC6C=CC=CC=6)=O)[CH2:32][CH2:31]5)=[O:28])=[CH:25][C:24]=4[O:48][CH3:49])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:47]=[CH:46][C:26]([C:27]([NH:29][N:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[O:28])=[CH:25][C:24]=4[O:48][CH3:49])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)NN2CCN(C(=O)OCc3ccccc3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: [Pd]
Solvent: CCO
Product: COc1cc(C(=O)NN2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Yield: 92.5 %

Procedure:
Benzyl 4-(4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamido)piperazine-1-carboxylate (850 mg, 1.25 mmols) was dissolved in ethanol (15 mL), added 10% Pd—C (170 mg, 20% wt) under inert atmosphere and hydrogenated using a balloon for 8 hrs. Then filtered the solution through celite bed and evaporated to give the product (630 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.89 (m, 10 H) 2.70-2.85 (m, 8 H) 3.31 (s, 3 H) 3.93 (s, 3 H) 4.06 (t, J=13.26 Hz, 2 H) 4.46 (m, 1 H) 7.42 (d, J=8.0 Hz, 1 H) 7.44 (s, 1 H) 7.90 (s, 1 H) 8.21 (s, 1 H) 8.26 (d, J=8.08 Hz, 1 H) 9.38 (s, 1 H). [M+H] calculated for C26H34F2N8O3, 545; found 545.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH3:7])[S:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9].N1C=CC=CC=1.[O:18](S(C(F)(F)F)(=O)=O)[S:19]([C:22]([F:25])([F:24])[F:23])(=O)=[O:20]>ClCCl>[CH3:7][C:5]1[S:4][C:3]([C:8]([O:10][CH3:11])=[O:9])=[C:2]([O:1][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:20])=[O:18])[CH:6]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1sc(C)cc1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1sc(C)cc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C

Procedure:
Into a 100-mL round-bottom flask, was placed methyl 3-hydroxy-5-methylthiophene-2-carboxylate (1.04 g, 5.74 mmol), dichloromethane (7 mL), pyridine (1.44 mL, 17.81 mmol). This was followed by the addition of Tf2O (1.45 mL, 8.61 mmol) dropwise with stirring at 0° C. The resulting solution was stirred for 2.0 h at 0° C. in a water/ice bath. The reaction progress was monitored by GCMS. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×15 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2×20 mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:9). This resulted in 1.74 g (99%) of methyl 5-methyl-3-(((trifluoro methyl)sulfonyl)oxy)thiophene-2-carboxylate as yellow oil.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][C:11]12[CH2:18][CH2:17][C:14]([C:19]3[NH:27][C:26]4[C:25](=[O:28])[N:24]([CH2:29][CH2:30][CH3:31])[C:23](=[O:32])[N:22]([CH2:33][CH2:34][CH3:35])[C:21]=4[N:20]=3)([CH2:15][CH2:16]1)[CH2:13][CH2:12]2)(=[O:8])[O:5]CC)C.C[Si](Br)(C)C.O>C(Cl)Cl>[O:32]=[C:23]1[N:22]([CH2:33][CH2:34][CH3:35])[C:21]2[N:20]=[C:19]([C:14]34[CH2:15][CH2:16][C:11]([CH2:10][CH2:9][P:4](=[O:3])([OH:5])[OH:8])([CH2:12][CH2:13]3)[CH2:18][CH2:17]4)[NH:27][C:26]=2[C:25](=[O:28])[N:24]1[CH2:29][CH2:30][CH3:31]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(CCP(=O)(OCC)OCC)(CC3)CC4)nc2n(CCC)c1=O
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: O
Product: CCCn1c(=O)c2[nH]c(C34CCC(CCP(=O)(O)O)(CC3)CC4)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {2-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-ethyl}-phosphonic acid diethyl ester (30 mg, 59 μmol) in CH2Cl2 (8 ml) was added TMSBr (excess) and the resulting mixture was stirred at rt overnight. Additional TMSBr was added and the reaction was heated at 55° C. for 6 h. The solvent was removed in vacuo to give an orange solid whose color was discharged upon trituration with water. The material was collected, washed with water and dried (20 mg, 77%). MS: 453 (MH+).
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.CCN(C(C)C)C(C)C.[C:42](O)(C(F)(F)F)=[O:43]>CN(C=O)C>[F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]3[CH2:23][CH2:24][N:25]([CH:42]=[O:43])[CH2:26][CH2:27]3)=[CH:20][CH:21]=2)[CH:7]=1
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1cccc(F)c1F
Reactant: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1cnc(Nc2ccc(C3CCN(C=O)CC3)cc2)cc1NCc1cccc(F)c1F

Procedure:
Compound 4-(2,3-difluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 209) (70 mg, 0.15 mmol) was stirred in 4 mL DMF with DIEA (300 μL) at 120° C. in a sealed tube for two days. The mixture was acidified with 0.5 mL TFA and subjected to reverse phase preparative HPLC to isolate the title compound (41 mg). MS found for C25H25F2N5O2 as (M+H)+ 466.4. UV: λ=259 nm. 1H NMR: (CD3OD) δ 8.15 (1H, s), 8.06 (1H, s), 7.33 (2H, dt, J=8.8; 2.0 Hz), 7.28 (1H, m), 7.16 (1H, m), 7.13-7.07 (3H, m), 5.80 (1H, s), 4.56 (2H, s), 4.48 (1H, m), 3.86 (1H, m), 3.27 (1H, m), 2.93 (1H, m), 2.82 (1H, m), 1.94 (2H, m), 1.64 (2H, m) ppm.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:21])=[CH:10][CH2:11][CH2:12][C:13]([CH3:20])=[CH:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[C:3]([OH:5])=O.[CH2:22]([NH:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH:23]([CH3:25])[CH3:24]>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:21])=[CH:10][CH2:11][CH2:12][C:13]([CH3:20])=[CH:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[C:3]([N:26]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:5]
Reactant: CC(C)CNCC(C)C
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Product: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)N(CC(C)C)CC(C)C

Procedure:
Starting materials: 2,6,10-trimethyl-14-oxo-2,6,10-pentadecatrienoic acid and diisobutylamine.
Reaction SMILES: [F:1][CH:2]([F:15])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:12](=O)[CH3:13])[CH:8]=[C:9]([CH3:11])[CH:10]=1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[F:1][CH:2]([F:15])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]([NH:22][S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH3:13])[CH:8]=[C:9]([CH3:11])[CH:10]=1
Reactant: CC(=O)c1cc(C)cc(OCC(F)F)c1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(OCC(F)F)cc(C(C)N[S@](=O)C(C)(C)C)c1
Yield: 77 %

Procedure:
The title compound is prepared in 77% yield (0.97 g, colorless oil) from 1-(3-(2,2-difluoroethoxy)-5-methylphenyl)ethanone (0.85 g, 3.9 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)=[CH:27][CH:26]=1)[C:20](=O)[CH2:21][CH3:22])C>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[CH:34][CH:33]=[N:32]3)=[CH:27][CH:26]=1)=[C:20]([CH2:21][CH3:22])[NH:13]2
Reactant: CCOC(=O)C(Cc1ccc(-n2cccn2)cc1)C(=O)CC
Reactant: COC(=O)COc1ccc(F)c(N)c1
Solvent: C1COCCO1
Solvent: O
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(-n2cccn2)cc1
Temperature: 120 °C
Reaction time: 18 h
Yield: 42.7 %

Procedure:
A solution of (3-amino-4-fluorophenoxy)acetic acid methyl ester (0.42 g) and 3-oxo-2-(4-pyrazol-1-ylbenzyl)pentanoic acid ethyl ester (0.63 g) in 1,4-dioxane (20 mL) was added to polyphosphoric acid (3 g) at 100° C., and the resulting mixture was stirred at 120° C. for 18 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate to afford title compound (0.39 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1/[CH:8]=[C:9]1/[C:10](=[O:23])[C:11]2[C:16]([CH2:17][CH2:18]/1)=[CH:15][C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2>[Pt]>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]1=[O:23]
Reactant: COc1cc2c(cc1OC)C(=O)/C(=C/c1ccncc1Br)CC2
Agent: [Pt]
Product: COc1cc2c(cc1OC)C(=O)C(Cc1ccncc1Br)CC2

Procedure:
The title compound 100 is prepared according to the procedure reported in Example 36.1 with compound 84 (374 mg, 1.0 mmol) and Pt/C (5 wt % loading, 38 mg) as reactants. White solid. (Yield 0.251 g, 99%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]3[CH2:24][CH2:23][NH:22][CH2:21]3)=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:32]([O:35][CH2:36][CH2:37][CH2:38]Br)(=[O:34])[CH3:33]>CN(C)C=O.[I-].[Na+]>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]3[CH2:24][CH2:23][N:22]([CH2:38][CH2:37][CH2:36][O:35][C:32](=[O:34])[CH3:33])[CH2:21]3)=[CH:16][CH:15]=2)(=[O:11])=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)OCCCBr
Reactant: CC(C)c1ccc(S(=O)(=O)Nc2ccc([C@@H]3CCNC3)cc2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)OCCCN1CC[C@@H](c2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cc2)C1
Temperature: 0 °C
Reaction time: 15 h
Yield: 94.3 %

Procedure:
0.21 g of 4-isopropyl-N-[4-((S)-pyrrolidin-3-yl)-phenyl]-benzenesulfonamide (0.62 mmol) were dissolved in 5 ml dimethylformamide. 0.0019 mg of sodium iodide (0.01 mmol) and 0.13 ml of triethylamine (0.94 mmol) were added, followed by addition of 0.136 mg of 3-acetoxy-1-bromo-propane (0.75 mmol). Stirring continued for 15 h at room temperature before the reaction mixture was poured onto 50 ml of crushed ice. The aqueous layer was extracted three times with ethyl acetate and the combined organic phases washed with water and saturated sodium chloride solution. The ethyl acetate phase was dried over magnesium sulfate, filtered, and evaporated to dryness under reduced pressure to yield 0.26 g of the crude product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[C:17]([C:23]4[CH:28]=[C:27]([C:29](=[O:40])[NH:30][C:31]5([C:34]6[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=6)[CH2:33][CH2:32]5)[CH:26]=[CH:25][C:24]=4[CH3:41])=[CH:16][C:11]=3[C:12]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.Cl.[CH3:43][NH2:44]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[C:17]([C:23]4[CH:28]=[C:27]([C:29](=[O:40])[NH:30][C:31]5([C:34]6[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=6)[CH2:33][CH2:32]5)[CH:26]=[CH:25][C:24]=4[CH3:41])=[CH:16][C:11]=3[C:12]=2[C:13]([NH:44][CH3:43])=[O:15])=[CH:6][CH:7]=1
Reactant: CN
Reactant: Cc1ccc(C(=O)NC2(c3ccccc3)CC2)cc1-c1cc2c(C(=O)O)c(-c3ccc(F)cc3)oc2cc1[N+](=O)[O-]
Agent: Cl
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(-c3cc(C(=O)NC4(c5ccccc5)CC4)ccc3C)cc12

Procedure:
Prepared by the coupling of 2-(4-fluorophenyl)-5-(2-methyl-5-(1-phenylcyclopropylcarbamoyl)phenyl)-6-nitrobenzofuran-3-carboxylic acid with methylamine hydrochloride under the conditions as described. LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: Xterra MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)+=564.36, HPLC Rt=1.768 min.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>>[F:21][C:22]([F:33])([F:34])[O:23][C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:31]([NH:1][CH2:2][C:3]2[C:12](=[O:13])[C:11]3[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=3)[N:5]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:4]=2)=[O:32])=[CH:28][CH:29]=1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Nc1ccc(OC(F)(F)F)cc1

Procedure:
1-(4-trifluoromethoxy-phenyl)-3-(7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-yl-methyl)-urea was prepared starting from intermediate D and 4-trifluoromethoxy-phenylisocyanate. MS calcd. for C24H8ClF3N3O3 [(M+H)+] 488.1, obsd. 488.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH:14]=[C:15]([C:21]([OH:23])=O)[NH:16]3)=[CH:5][CH:4]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][C:28]([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][C@H:37]([OH:40])[C@@H:36]([CH3:41])[CH2:35]2)([OH:31])[CH2:27][CH2:26]1>>[OH:31][C:28]1([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][C@H:37]([OH:40])[C@@H:36]([CH3:41])[CH2:35]2)[CH2:29][CH2:30][CH:25]([NH:24][C:21]([C:15]2[NH:16][C:17]3[C:13]([CH:14]=2)=[C:12]([O:11][CH2:10][CH2:9][C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:20]=[CH:19][CH:18]=3)=[O:23])[CH2:26][CH2:27]1
Reactant: COc1ccc(CCOc2cccc3[nH]c(C(=O)O)cc23)cn1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Product: COc1ccc(CCOc2cccc3[nH]c(C(=O)NC4CCC(O)(CCN5CC[C@H](O)[C@@H](C)C5)CC4)cc23)cn1

Procedure:
This compound is synthesized analogously to example 1 from 4-[2-(6-methoxy-pyridin-3-yl)-ethoxy]-1H-indole-2-carboxylic acid 16n and amine 14.
Reaction SMILES: [Na].[CH2:2](C#N)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:11]([O:15]CC)(=O)[CH2:12][CH3:13]>>[CH2:2]([C:11]([CH2:12][CH3:13])=[O:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC
Reactant: N#CCc1ccccc1
Agent: [Na]
Product: CCC(=O)Cc1ccccc1
Yield: 53.3 %

Procedure:
In a 2-liter flask provided with a thermometer, stirrer, dropping funnel and reflux condenser 600 ml of absolute alcohol are treated portionwise while stirring with 30 g of sodium metal and the mixture is held at reflux temperature until the metal has dissolved. Within 0.5 hour there is added dropwise to the boiling solution a mixture of 117.2 g of benzyl cyanide and 153.2 g of ethyl propionate and the mixture is heated for a further 3 hours. The alcohol is then distilled off and there are added 300 ml of toluene, followed by 250 ml of ice/water. The aqueous phase is separated, washed with 300 ml of toluene and then 540 g of 96% sulphuric acid are added. The mixture is held at reflux temperature until the evolution of carbon dioxide ceases, cooled, diluted with 250 ml of ice/water and extracted with two 300 ml portions of toluene. The toluene extracts are washed with water, with 10% sodium carbonate solution and again with water, dried over sodium sulphate and evaporated. Distillation gives 79 g of ethyl benzyl ketone of boiling point 69° C./3 mmHg; nD20 =1.5109; yield 53%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[CH3:23])[CH2:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[NH2:25][C:26]1([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)[CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:12][CH:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[CH3:23])[CH2:14]2)=[C:6]([CH:10]=1)[C:7]([NH:25][C:26]1([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)[CH2:28][CH2:27]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: Cc1cc(F)ccc1NC1CN(c2ncc(F)cc2C(=O)O)C1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(F)cnc3N3CC(Nc4ccc(F)cc4C)C3)CC2)cc1
Yield: 24.1 %

Procedure:
The title compound (D190) (26 mg) was prepared according to the experimental procedure described in Description 169 starting from 5-fluoro-2-(3-((4-fluoro-2-methylphenyl)amino)azetidin-1-yl)nicotinic acid (D135) (70 mg, 0.219 mmol) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (D7) (50 mg, 0.219 mmol).