Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Br[CH2:9][CH2:10][CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:13]1(=[O:22])[N:12]([CH2:11][CH2:10][CH2:9][O:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Oc1ccncc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1c2ccccc2C(=O)N1CCCOc1ccncc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 16.4 %

Procedure:
To a solution of 4.76 g (50 mmol) of 4-hydroxypyridine and 14.75 g (55 mmol) of N-(3-bromopropyl)phthalimide in 80 ml of DMF was added 8.23 ml (55 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene. The mixture was stirred at room temperature for 6 hours. After the solvent was distilled off, the mixture was poured into water and extracted with ethyl acetate. The mixture was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 2.32 g of the desired compound (yield: 16.4% colorless crystals).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](Br)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2OC2C=CC=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:55][C:56]1[S:57][CH:58]=[CH:59][N:60]=1.C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:55][C:56]2[S:57][CH:58]=[CH:59][N:60]=2)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nccs1
Reactant: Brc1ccc(OCc2ccccc2)cn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2Oc2ccccc2P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: c1ccc(COc2ccc(Nc3nccs3)nc2)cc1
Yield: 34 %

Procedure:
5-Benzyloxy-2-bromo-pyridine (0.25 mmol), sodium-tert.-butylate (1.4 eq.), tris-(dibenzylideneaceton)-dipalladium (0.1 eq.), bis(2-diphenylphosphinophenyl)-ether (0.4 eq.) and 2-amino-thiazole (1.5 eq.) are filled under nitrogen in a microwave reaction vessel. Degassed toluene (45 eq.) is added. The reaction suspension is heated for 60 min to 150° C. and 60 minutes to 180° C. Ethyl acetate is added to the reaction suspension and filtrated over celite. The solvent of the filtrate is removed in vacuo. (5-Benzyloxy-pyridine-2-yl)-thiazole-2-yl-amine (“A30”) is obtained after reversed phase column chromatography (water/acetonitrile+0.1% TFA) as orange oil in a yield of 34%. HPLC (method C): 1.69 min; LC-MS (method A): 1.44 min, 285.15 (MH+); 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] 11.108 (s, 1H), 8.072 (d, 1H, J=2.9 Hz), 7.500-7.447 (m, 3H), 7.412-7.383 (m, 2H), 7.349-7.320 (m, 2H), 7.064 (d, 1H, J=9 Hz), 6.926 (d, 1H, J=3.5 Hz), 5.139 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:25][C:26]([F:35])([F:36])[C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:15]2[C:14](=[O:17])[N:11]3[N:12]=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[C:9]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[C:10]3=[N:16]2)=[CH:29][CH:28]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 90 °C
Yield: 27.7 %

Procedure:
A solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (300 mg, 0.84 mmol), prepared as described in Example 1, 4-(trifluoromethyl)benzyl bromide (200 mg, 0.84 mmol) and K2CO3 (290 mg, 2.1 mmol) in DMF (10 ml), was heated at 90° C. for 2 hours. After this time, the reaction mixture was cooled to RT and diluted with ethyl acetate. The resultant solution was then washed with water. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by preparative HPLC to give the title compound, 2-(4-(trifluoromethyl)benzyl)-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (120 mg, 28%) as a yellow solid. MS M+H=515; 1H NMR (CDCl3) δ 8.19 (1H), 7.60 (2H), 7.50 (2H), 7.34 (4H), 7.28 (2H), 7.10 (2H), 5.27 (2H).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:8][CH2:9][C@@H:10]1[CH2:24][C@H:23]2[C@@H:13]([CH2:14][C:15]3[C:25]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]2=4)[NH:17][CH:16]=3)[N:12]([CH3:26])[CH2:11]1>CN(C)C=O>[CH3:26][N:12]1[C@H:13]2[C@@H:23]([C:22]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:25]=3[C:15]([CH2:14]2)=[CH:16][NH:17]4)[CH2:24][C@@H:10]([CH2:9][NH:8][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:11]1
Reactant: CN1C[C@H](CN)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: CCOC(=O)CBr
Solvent: CN(C)C=O
Product: CCOC(=O)CNC[C@@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Yield: 72 %

Procedure:
A solution of 1.3 ml of ethyl bromoacetate in 30 ml of dimethylformamide was added to a warmed solution of 6 g of 8β-aminomethyl-6-methyl-ergoline in 90 ml of dimethylformamide. At the end of the reaction, the solution was reduced in volume by evaporation in vacuo, poured into iced water and extracted with chloroform. The organic layer was removed in vacuo and the residue was purified by column chromatography on silica gel, using ethyl acetate:methanol (9:1 by volume) as eluent, to give 3.5 g of 6-methyl-8β-(N-ethoxycarbonylmethyl-aminomethyl)-ergoline (II: R1 =R2 =R3 =H, R4 =CH3, n=1, A=CHR6, R6 =H, B=CO2C2H5), m.p. 174°-176° C., after crystallization from diethyl ether. 3.5 of 6-methyl-8β-(N-ethoxycarbonylmethyl-aminomethyl)-ergoline were treated with 1.75 g of potassium cyanate, as described in Example 1, and the title compound, m.p. >300° C., was obtained in 72% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH:11]=[C:12]([C:16]1[S:17][C:18]([CH3:21])=[N:19][N:20]=1)[C:13](=O)[CH3:14])[C:6]#[N:7].[NH2:22]/[C:23](/[CH3:27])=[CH:24]\[C:25]#[N:26]>C(O)(C)C>[C:6]([C:5]1[CH:8]=[CH:9][C:10]([CH:11]2[C:12]([C:16]3[S:17][C:18]([CH3:21])=[N:19][N:20]=3)=[C:13]([CH3:14])[NH:22][C:23]([CH3:27])=[C:24]2[C:25]#[N:26])=[C:3]([O:2][CH3:1])[CH:4]=1)#[N:7]
Reactant: C/C(N)=C/C#N
Reactant: COc1cc(C#N)ccc1C=C(C(C)=O)c1nnc(C)s1
Solvent: CC(C)O
Product: COc1cc(C#N)ccc1C1C(C#N)=C(C)NC(C)=C1c1nnc(C)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg (0.501 mmol) of the compound from example 25A and 41 mg (0.501 mmol) of 3-amino-crotononitrile are dissolved in 5 ml of isopropanol and stirred at the reflux temperature overnight. After cooling to room temperature, the volatile components are removed in a rotary evaporator, and the crude product is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). Crystallization from ethyl acetate/diethyl ether results in 30 mg (16% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:37])[CH2:11][N:12]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([CH3:36])([CH3:35])[C:28]([O:30]C(C)(C)C)=[O:29])=[CH:22][CH:21]=1)[CH2:13][C:14]1[O:15][CH:16]=[CH:17][CH:18]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:37])[CH2:11][N:12]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][C:27]([CH3:35])([CH3:36])[C:28]([OH:30])=[O:29])=[CH:24][CH:25]=1)[CH2:13][C:14]1[O:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1ccc(NC(=O)CN(Cc2ccc(CC(C)(C)C(=O)OC(C)(C)C)cc2)Cc2ccco2)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(NC(=O)CN(Cc2ccc(CC(C)(C)C(=O)O)cc2)Cc2ccco2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A solution of 192 mg (0.380 mmol) of tert-butyl 3-(4-{[(2-(2,4-dimethylphenyl)-amino-2-oxoethyl)(2-furylmethyl)amino]methyl}phenyl)-2,2-dimethylpropionate (Example 1-1) in 1 ml of dichloromethane is treated with 1 ml of trifluoroacetic acid and stirred at room temperature for 2 h. The mixture is then concentrated under reduced pressure, the residue is taken up in ethyl acetate and the organic phase is washed 2× with water, 1× with 20% strength sodium acetate solution, 1× with water and 1× with sat. NaCl solution, dried over sodium sulphate and freed from the solvent under reduced pressure. Chromatographic purification of the residue on silica gel (dichloromethane→dichloromethane/methanol 20:1) gives 150 mg (88%) of 3-(4-{[(2-(2,4-dimethylphenyl)amino-2-oxoethyl)(2-furylmethyl)amino]methyl}phenyl)-2,2-dimethylpropionic acid.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].O.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29]>O1CCCC1.C(OCC)(=O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)(=[O:26])=[O:25])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29]
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(S(=O)(=O)N2CCCc3ccccc32)ccc1Cl
Yield: 67.2 %

Procedure:
To a suspension of 1,2,3,4-tetrahydroquinoline (3.12 g) and sodium hydrogen carbonate (2.66 g) in tetrahydrofuran (60 mL) were added water (6 mL) and a solution of 4-chloro-3-nitrobenzenesulfonyl chloride (5.4 g) in tetrahydrofuran (30 mL) successively, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with water, 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 1-[(4-chloro-3-nitrophenyl)-sulfonyl]-1,2,3,4-tetrahydroquinoline (5.0 g). This material was dissolved in tetrahydrofuran (45 mL). To the solution were added methanol (45 mL), nickel(II) bromide (0.15 g) and sodium borohydride (1.61 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1) to give the title compound (4.33 g).
Reaction SMILES: Cl[C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[S:14]1(=[O:25])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:17]1[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:14](=[O:25])[CH2:15][CH2:16]1)[NH:11][C:10]2=[O:12]
Reactant: Cc1ccc2nc(Cl)[nH]c(=O)c2c1
Reactant: O=S1CCNCc2ccccc21
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)[nH]c(=O)c2c1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a stirred solution of 2-chloro-6-methylquinazolin-4(3H)-one (15 g, 77.3 mmol) and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (16.8 g, 103 mmol) in toluene (200 mL) was added triethylamine (16.1 mL, 116 mmol). After being refluxed overnight, the reaction mixture was cooled to room temperature. The formed solid was collected by filtration, washed with ethanol (50 mL) and ethyl acetate (100 mL), and then dried in vacuo to afford 21.0 g of the desired product as a white solid (yield was 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:32]([F:35])([F:34])[F:33])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][C:28](=[O:30])[NH:27][CH2:26]4)=[O:24])=[C:19]([CH3:31])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CN(C)C=O.[H-].[Na+].FC(F)(F)S(O[CH2:49][C:50]([F:53])([F:52])[F:51])(=O)=O>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:32]([F:33])([F:34])[F:35])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][C:28](=[O:30])[N:27]([CH2:49][C:50]([F:53])([F:52])[F:51])[CH2:26]4)=[O:24])=[C:19]([CH3:31])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C(=O)N1CNC(=O)C1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C(=O)N1CC(=O)N(CC(F)(F)F)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylphenyl)carbonyl]imidazolidin-4-one (80 mg, 0.15 mmol, 1.00 equiv), N,N-dimethylformamide (5 mL). This was followed by the addition of NaH (60%) (12.3 mg, 0.51 mmol, 2.00 equiv) in several batches at 0° C. The resulting solution was stirred for 30 min at 0° C. To this was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (71 mg, 0.31 mmol, 2.00 equiv). The resulting solution was allowed to react, with stirring, for an additional 3 h at room temperature. The reaction was then quenched by the addition of 20 mL of water/ice. The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined. The mixture was dried over anhydrous sodium sulfate. This resulted in 14 mg (15%) of 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylphenyl)carbonyl]-3-(2,2,2-trifluoroethyl)imidazolidin-4-one as a light yellow solid. (ES, m/z): [M+CH3CN]+ 643; 1H NMR (300 MHz, CDCl3): δ 7.82 (s, 1H), 7.76 (s, 1H), 7.697 (s, 1H), 7.58-7.61 (m, 2H), 7.28-7.34 (m, 1H), 5.196 (s, 1H), 4.911 (s, 1H), 4.646 (s, 1H), 4.03-4.18 (m, 2H), 3.998 (s, 1H), 3.70-3.76 (m, 1H), 2.399 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[C:12]2B1OC(C)(C)C(C)(C)O1.Cl[C:38]1[N:43]=[C:42]([O:44][C@@H:45]2[CH2:50][CH2:49][CH2:48][N:47]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:46]2)[CH:41]=[N:40][CH:39]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=1)(=[O:19])=[O:20])[CH:13]=[C:12]2[C:38]1[N:43]=[C:42]([O:44][C@@H:45]2[CH2:50][CH2:49][CH2:48][N:47]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:46]2)[CH:41]=[N:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(Cl)n2)C1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4c(F)cccc4F)ccc32)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(O[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)n3)c3cc(-c4c(F)cccc4F)ccc32)cc1
Temperature: 110 °C
Yield: 88.3 %

Procedure:
A glass microwave reaction vessel was charged with 5-(2,6-difluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indole (2.75 g, 5.40 mmol) and (R)-tert-butyl 3-(6-chloropyrazin-2-yloxy)piperidine-1-carboxylate (1.694 g, 5.40 mmol) in p-dioxane/H2O (4:1, 16 mL) followed by A-Phos (0.191 g, 0.270 mmol) and potassium phosphate (2.92 g, 10.80 mmol). The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 110° C. for 80 min. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 10-20% EtOAc in Hexanes) to give (R)-tert-butyl 3-(6-(5-(2,6-difluorophenyl)-1-tosyl-1H-indol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate (3.15 g, 4.77 mmol, 88% yield) as a solid. MS (ESI, pos. ion) m/z: 661 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12]2([CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[O:11][CH2:10][C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.Br[CH2:29][CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH2:1]([N:8]1[CH2:13][C:12]2([CH2:18][CH2:17][N:16]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:29][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[O:11][CH2:10][C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCN1CCCC1
Reactant: O=C1COC2(CCN(c3ccc(O)cc3)CC2)CN1Cc1ccccc1
Agent: Br
Product: O=C1COC2(CCN(c3ccc(OCCCN4CCCC4)cc3)CC2)CN1Cc1ccccc1

Procedure:
The entitled compound was obtained as a yellow solid, according to the same method as in Example 4-(c) or according to a method similar to it but using 4-benzyl-9-(4-hydroxyphenyl)-1-oxa-4,9-diazaspiro[5,5]undecan-3-one produced in Example 4-19-(b) and 1-(3-bromopropyl)pyrrolidine hydrobromide produced according to a method described in a patent (U.S. Pat. No. 4,751,302).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15](=[O:16])[CH2:14][C:9]2([CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:8][C:7]1=[O:17].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[S:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[OH:36])[CH2:29][CH2:28][CH2:27]1>CN(C)C=O>[O:16]=[C:15]1[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][O:36][C:34]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:35]=2[S:26][CH2:27][CH2:28][CH2:29]3)[C:7](=[O:17])[CH2:8][C:9]2([CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:14]1
Reactant: O=C1CC2(CCCC2)CC(=O)N1CCCCBr
Reactant: Oc1cccc2c1SCCC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CC2(CCCC2)CC(=O)N1CCCCOc1cccc2c1SCCC2

Procedure:
2 g (6.62 mmol) of 8-(4-bromobutyl)-8-azaspiro[4.5]decane-7,9-dione, 2.5 g (18.04 mmol) of potassium carbonate and a catalytic amount of potassium iodide are added, with stirring, to 1 g (6.015 mmol) of 8-thiochromanol dissolved in 10 cm3 of N,N-dimethylformamide.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:34][C:35]([CH:37]3[CH2:39][CH2:38]3)=[O:36])[CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]1>>[C:12]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C:9]([NH:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35]([CH:37]4[CH2:39][CH2:38]4)=[O:36])[CH:31]=[CH:32][CH:33]=3)[CH2:24][CH2:23]2)=[O:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Reactant: NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Product: O=C(CC(c1ccccc1)c1ccccc1)NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1

Procedure:
Example 151 was prepared from 3,3-diphenylpropanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide according to the procedures described in Scheme 9: ESMS m/e: 510.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.I[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: Ic1ccccc1
Reactant: COc1ccc2cc[nH]c2c1
Product: COc1ccc2ccn(-c3ccccc3)c2c1

Procedure:
Prepared by Procedure C and Scheme O using 1H-indol-6-yl methyl ether and iodobenzene: ESMS m/e: 224.0 (M+H)+.
Reaction SMILES: CC(S([NH:7][C@H:8]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(C)C.[ClH:27]>CO.O1CCOCC1>[ClH:27].[C:11]1([CH2:10][CH2:9][C@H:8]([NH2:7])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)S(=O)N[C@@H](CCc1ccccc1)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@@H](CCc1ccccc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-methyl-N-{(1S)-3-phenyl-1-[4-(trifluoromethyl)phenyl]propyl}propane-2-sulfinamide (JACS, 2005, 127, 1092-3) (8.3 g, 21.7 mmol) was dissolved in methanol (50 mL) and a 4M solution of HCl in dioxane (10.8 mL) was added. The solution was stirred at RT for 1 h then concentrated. The residue was triturated with isohexane to give a colourless solid which was collected by filtration. 1H NMR (400 MHz), δ (ppm) (DMSO-D6): 8.7 (3H, s), 7.85 (2H, d, J 8.3 Hz), 7.77 ((2H, d, J 8.3 Hz), 7.29-7.26 (2H, m), 7.20-7.13 (3H, m), 4.36 (1H, m), 2.4-2.35 (2H, m), 2.35-2.25 (m, 1H), 2.2-2.1 (1H, m).
Reaction SMILES: CC(OC([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1)=O)(C)C.[CH3:18]OC(OC)(C)C.Cl.CCOCC>CO>[CH3:18][O:17][C:15]([CH:12]1[CH2:11][CH2:10][CH:9]([NH2:8])[CH2:14][CH2:13]1)=[O:16]
Reactant: CC(C)(C)OC(=O)NC1CCC(C(=O)O)CC1
Reactant: COC(C)(C)OC
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C1CCC(N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.8 %

Procedure:
(1r,4r)-4-(tert-Butoxycarbonylamino)cyclohexanecarboxylic acid (25 g, 103 mmol) was dissolved in MeOH (250 ml), to which 2,2-dimethoxypropane (10.70 g, 12.63 ml, 103 mmol) and then 2M HCl in ether (51 ml, 103 mmol) were added. The reaction mixture was stirred at room temperature overnight, then concentrated and the residue was treated with ether (100 ml). The resulting white suspension was filtered then dried to afford a white powder (16.8 g, 84% yield).
Reaction SMILES: C([O:8][C:9](=[O:39])[C@@H:10]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:14]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:13]=1)C1C=CC=CC=1>CO.[Pd]>[C:35]([O:34][C:32]([NH:31][C@@H:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:14]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:13]=1)[C:9]([OH:39])=[O:8])=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: CCOC(=O)COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1CC(=O)OCC
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1CC(=O)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.8 %

Procedure:
To a solution of (S)-2-tert-butoxycarbonylamino-3-(4-ethoxycarbonylmethoxy-3-ethoxycarbonylmethyl-phenyl)-propionic acid benzyl ester (796 mg, 1.46 mmol) in MeOH (8 mL) was added 10% Pd/C (4 mg). The heterogeneous mixture was degassed under reduced pressure and allowed to stir at rt for 18 h under H2. The catalyst was removed by filtration and the filtrate evaporated to dryness to give the product as a colorless foam (515 mg, 78%) Electrospray Mass Spectrum (50/50 acetonitrile/water) m/z 476 (M+Na).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:19][CH2:20][C:21]([NH2:23])=[O:22].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:19][CH2:20][C:21](=[O:22])[NH2:23])=[O:15])=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC(N)=O
Reactant: O=C(O)c1ccc(OCc2ccccc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: NC(=O)CNC(=O)c1ccc(OCc2ccccc2)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 6-benzyloxy-nicotinic acid (500 mg, 2.18 mmol), glycinamide HCI (265 mg, 2.4 mmol), 4-dimethylamino pyridine (133 mg; 1.09 mmol), N-(3-dimethylamino-propyl)-N′-ethylcarbodiimide HCl (460 mg; 2.4 mmol) and methylene chloride (10 ml) was stirred at 0° C. for 1 h then at r.t. overnight. The precipitate was filtered off and washed with methylene chloride and water. The title compound was obtained as a white solid (328 mg; 53%). MS: m/e=286.2 (M+H+).