Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(C)=O>[CH2:15]([O:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1cccc(OCc2ccccc2)c1
Yield: 59.2 %

Procedure:
3-Bromophenol (50 g, 0.289 mol) was dissolved in acetone (500 ml), anhydrous potassium carbonate (80 g, 0.580 mmol) and benzyl bromide (59 g, 0.345 mol) were successively added thereto and the mixture was heated to reflux for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting crude reaction product was recrystallized (hexane was used as a solvent and the recrystallization operation was carried out twice) to give the title compound (45.0 g, 0.171 mol, 59%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>CO>[NH2:9][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1cc(Br)ccc1O
Temperature: 25 °C

Procedure:
To a stirred solution of 4-bromo-2-nitrophenol (5.00 g, 22.9 mmol) in MeOH (120 mL) was added tin(II) chloride dihydrate (15.53 g, 68.8 mmol). The reaction mixture was heated at reflux and monitored by LC/MS. When significant reduction was complete, the reaction mixture was cooled to rt, poured over ice, and made basic (pH 9) with 50% saturated NaHCO3. The aqueous layer was extracted with EtOAc (2×150 mL) and the combined extracts washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give 2-amino-4-bromophenol as a dark gray solid. 1H NMR (CDCl3, 300 MHz) δ 9.29 (br s, 1H), 6.71 (d, 1H), 6.56 (d, 1H), 6.49 (dd, 1H), 4.83 (br s, 2H).
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[N:9][N:10]([CH3:25])[C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[C:22](Br)[N:23]=[C:17]3[CH:16]=2)=[O:13])=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:26][C:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[CH:29][N:28]=1>>[CH3:26][C:27]1[CH:32]=[C:31]([C:22]2[N:23]=[C:17]3[CH:16]=[C:15]([NH:14][C:12]([C:11]4[N:10]([CH3:25])[N:9]=[CH:8][C:7]=4[C:5]([N:1]4[CH2:4][CH2:3][CH2:2]4)=[O:6])=[O:13])[CH:20]=[CH:19][N:18]3[N:21]=2)[CH:30]=[CH:29][N:28]=1
Reactant: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(Br)nc2c1
Reactant: Cc1cc(B(O)O)ccn1
Product: Cc1cc(-c2nc3cc(NC(=O)c4c(C(=O)N5CCC5)cnn4C)ccn3n2)ccn1
Yield: 22 %

Procedure:
The product was prepared in the same manner as described in example 66 using 4-(azetidine-1-carbonyl)-N-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide (150 mg, 371 μmol) and 2-methylpyridin-4-ylboronic acid (76.2 mg, 557 μmol) as starting materials. The crude material was applied on silicagel and purified by flash chromatography over a 20 g silicagel column using ethyl acetate/methanol 10% as eluent affording 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid [2-(2-methyl-pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (34 mg, 22.0%) as an off-white solid. mp: 210-211° C., MS: m/z=417.4 (M+H+)
Reaction SMILES: [CH2:1]([NH:8][CH2:9]CC1C2C(=CC=C(F)C=2OC)N(C)C=1)C1C=CC=CC=1.[F:24][C:25]1[C:26]([O:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH3:34])[CH:29]=[C:28]2[CH2:35][CH2:36]O>>[F:24][C:25]1[C:26]([O:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH3:34])[CH:29]=[C:28]2[CH2:35][CH2:36][N:8]([CH3:9])[CH3:1]
Reactant: Cn1cc(CCO)c2c(OCCc3ccccc3)c(F)ccc21
Reactant: COc1c(F)ccc2c1c(CCNCc1ccccc1)cn2C
Product: CN(C)CCc1cn(C)c2ccc(F)c(OCCc3ccccc3)c12
Yield: 72 %

Procedure:
Following the procedure (step 6, scheme 17) used to prepare compound 17-7, compound 18-1 gave compound 18-2 in 72% yield as a colorless oil, which was converted to the hydrochloride salt. 1H NMR (DMSO-d6, 300 MHz) δ (ppm) (HCl salt): 9.92 (br, 1H), 7.23-7.32 (m, 5H), 7.21 (s, 1H), 7.10 (dd, J=9.1, 4.1 Hz, 1H), 7.04 (dd, J=12.1, 8.8 Hz, 1H), 4.40 (td, J=7.4, 1.6 Hz, 2H), 3.70 (s, 3H), 3.16-3.21 (m, 2H), 3.11 (t, J=7.1 Hz, 2H), 3.00-3.06 (m, 2H), 2.73 (s, 6H). LRMS: calc 340.2 found 341.2 [MH]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][C:14]([NH:17][CH:18]4[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]4)=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[CH:4][N:3]=1.[O:25]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26]1.C([O-])([O-])=O.[Na+].[Na+].N#N>CCO.O>[O:25]1[CH:29]=[CH:28][C:27]([C:2]2[CH:7]=[C:6]([N:8]3[C:12]4=[N:13][C:14]([NH:17][CH:18]5[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]5)=[CH:15][CH:16]=[C:11]4[N:10]=[CH:9]3)[CH:5]=[CH:4][N:3]=2)=[CH:26]1
Reactant: OB(O)c1ccoc1
Reactant: OC1CCC(Nc2ccc3ncn(-c4ccnc(Cl)c4)c3n2)CC1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC1CCC(Nc2ccc3ncn(-c4ccnc(-c5ccoc5)c4)c3n2)CC1

Procedure:
To 4-[3-(2-Chloro-pyridin-4-yl)-3H-imidazo[4,5-b]pyridine-5-ylamino]-cyclohexanol (1 eq, 100 mg, 0.29 mmol), 3-furyl boronic acid (1.05 eq, 0.3 mmol, 34 mg), Na2CO3 (2 eq, 0.58 mmol, 62 mg) in EtOH (2 ml) and H2O (0.7 ml) under inert atmosphere of N2 is added tetakis(triphenylphosphine) palladium (0.1 eq, 0.029 mmol, 21 mg). The reaction is heated in using microwave radiation at 80° C. for 2 hours. The mixture is diluted with H2O (5 ml) and extracted with EtOAc. The combined organic portions are washed with brine, dried (MgSO4) and concentrated in vacuo. The residue is purified by flash chromatography on silica eluting with 0-2.5% MeOH in EtOAc to afford the title compound; [M+H]+ 375.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:17][C:18](=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].P(=O)(O)(O)O>CN(C)C=O>[C:3]1([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:17][C:18](=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:13][CH:14]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=P(O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)COc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Sodium hydride (5.0 g, 0.114 mole) and 4-phenylphenol (15.3 g, 0.09 mol) were stirred at 0° C. in 75 mL of dimethyl formamide (hereinafter “DMF”) for 2 h. Ethyl 4-chloroacetoacetate (5.0 g, 0.03 mol) in DMF (75 mL) was added. The mixture was stirred for 1 h at 0° C. and for 12 h at room temperature, then neutralized with 50% phosphoric acid and extracted with dichloromethane. The product was purified by silica gel chromatography using (8:2) toluene:ethanol as the mobile phase.
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([N:29]3[CH2:34][CH2:33][N:32]([C:35](=[NH:50])[NH:36][C:37]([O:39][CH2:40][C:41]4[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=4)=[O:38])[CH2:31][CH2:30]3)=[O:28])[CH2:10]2)=CC=1.[F:53][C:54]([F:60])([F:59])[S:55]([OH:58])(=[O:57])=[O:56]>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[F:53][C:54]([F:60])([F:59])[S:55]([OH:58])(=[O:57])=[O:56].[SH:8][C@@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([C:27]([N:29]2[CH2:34][CH2:33][N:32]([C:35](=[NH:50])[NH:36][C:37]([O:39][CH2:40][C:41]3[CH:42]=[CH:43][C:44]([N+:47]([O-:49])=[O:48])=[CH:45][CH:46]=3)=[O:38])[CH2:31][CH2:30]2)=[O:28])[CH2:10]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C(=N)NC(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: N=C(NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1

Procedure:
880 mg of (2S,4S)-4-(4-methoxybenzylthio)-2-[4-(4-nitrobenzyloxycarbonylamidino)piperazin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (d) above] were dissolved in a mixture of 4.4 ml of trifluoroacetic acid and 0.88 ml of anisole, and then 160 μl of trifluoromethanesulfonic acid were added dropwise to this solution, whilst stirring and ice-cooling. The resulting mixture was then stirred at room temperature for 3 hours, after which it was concentrated by evaporation under reduced pressure. The resulting residue was washed three times with diethyl ether, and the powder thus formed was dried to obtain 918 mg of the title compound, as a powder.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[C:26]([NH:29][C@@H:30]([C:32]([OH:34])=O)[CH3:31])(=[O:28])[CH3:27].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C1COCC1.ClCCl>[C:26]([NH:29][CH:30]([CH3:31])[C:32]([N:2]([CH3:1])[CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1)=[O:34])(=[O:28])[CH3:27]
Reactant: CNC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Reactant: CC(=O)N[C@H](C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)NC(C)C(=O)N(C)C1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
A mixture of compound 7B (15 mg, 0.044 mmol), N-acetyl-D-alanine (7 mg, 0.053 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (13 mg, 0.068 mmol), 1-hydroxybenzotriazole (9 mg, 0.068 mmol), dichloromethane (1 mL) and THF (0.5 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in minimum amount of dichloromethane and purified on silica gel column which was eluted with 0.3% ammonium hydroxide and 3% methanol in dichloromethane to give the desired product (13 mg, 65% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:14]=[C:13]([CH3:26])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[C:28]1[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=3)[CH:14]=[C:13]([CH3:26])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(Br)ccn1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)Nc2ccnc(Cl)c2)n1
Product: Cc1cc(-c2cc(C)nc(C(=O)Nc3ccnc(Cl)c3)c2)ccn1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid (2-chloro-pyridin-4-yl)-amide in accordance with the general method of example 131, step 2 using 4-Bromo-2-methylpyridine instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a white solid, MS (ISP): m/e=339.1, 341.1 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:73])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:59]=[C:58]4[C:54]([CH:55]=[CH:56][N:57]4[CH2:60][CH2:61][CH2:62][O:63][Si](C(C)(C)C)(C)C)=[CH:53][CH:52]=3)[CH:46]([O:71][CH3:72])[CH2:45]2)[CH:7]([CH3:74])[CH:6]([OH:75])[CH2:5][C:4]1=[O:76])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:73])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:59]=[C:58]4[C:54]([CH:55]=[CH:56][N:57]4[CH2:60][CH2:61][CH2:62][OH:63])=[CH:53][CH:52]=3)[CH:46]([O:71][CH3:72])[CH2:45]2)[CH:7]([CH3:74])[CH:6]([OH:75])[CH2:5][C:4]1=[O:76])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5ccn(CCCO[Si](C)(C)C(C)(C)C)c5c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5ccn(CCCO)c5c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reaction time: 3 h
Yield: 66.8 %

Procedure:
To a solution of 17-Ethyl-1,14-dihydroxy -12-[2'-(4"-(1-(3-t-butyldimethylsilyloxypropyl)indol -6-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetra -one (318 mg) in CH2Cl2 (5 mL) at rt was added a solution of p-toluene sulfonic acid (25 mg) in CH3OH (5 mL). The reaction mixture was stirred for 3 hours quenched with saturated NaHCO3, then extracted with CH2Cl2. The extracts were combined, dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by preparative TLC on silica gel (2:1,hexane/acetone) to give 190 mg of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[C:3]([NH:5][C@@H:6]1[C:12](=[O:13])[NH:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[O:8][C@@H:7]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:4].[CH:31]1([CH2:37][C:38](O)=[O:39])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[CH:31]1([CH2:37][C:38]([NH:1][C@@H:2]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:3]([NH:5][C@@H:6]2[C:12](=[O:13])[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[O:8][C@@H:7]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:4])=[O:39])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: N[C@H](C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1)c1ccc(F)cc1
Reactant: O=C(O)CC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(CC1CCCCC1)N[C@H](C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.4 %

Procedure:
To a stirred solution of (2S)-2-amino-2-(4-fluorophenyl)-N-[(2R,3S)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]acetamide (65b) (81 mg, 0.199 mmol) in dichloromethane (2 mL) under nitrogen was added cyclohexylacetic acid (35 mg, 0.246 mmol), HOBt (35 mg, 0.259 mmol), NMM (30 mg, 0.297 mmol) and EDAC-HCl (50 mg, 0.261 mmol). The mixture was stirred 5 h at ambient temperature then evaporated. The residue was dissolved in ethyl acetate and extracted in succession with saturated sodium bicarbonate, 1N aqueous HCl, and brine. The organic solution was dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 6:1 (v/v) dichloromethane:ethyl acetate to afford the title compound (89 mg, 84%) as a white solid. TLC Rf=0.42 (6:1 dichloromethane:ethyl acetate). 1H NMR (300 MHz, CDCl3) δ0.81-1.37 (m, 5H), 1.59-1.87 (m, 6H), 2.09 (d, 2H, J=6.5 Hz), 5.09 (t, 1H, J=7.0 Hz), 5.26 (d, 1H, J=7.0 Hz), 5.83 (d, 1H, J=7.0 Hz), 6.24 (br d, 1H, J=6.5 Hz), 6.48 (br d, 1H, J=6.5 Hz), 6.88-7.05 (m, 3H), 7.12-7.30 (m, 5H), 7.36 (s, 5H), 7.56 (br s, 1H). MS APCI, m/z=530 (M+1). LC/MS: 2.69 min.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClCC1[N:49]=[C:48]([CH3:50])[O:47][N:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[N:49]=[C:48]([CH3:50])[O:47][N:46]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1nc(CCl)no1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: Cc1nc(Cn2nnc3c(N4CCC(F)(F)C4)nc(C(C)(C)C)nc32)no1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(chloromethyl)-5-methyl-1,2,4-oxadiazole and isolated as yellow gum. MS(m/e): 379.3 (MH+).
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[C:30](=[O:34])[N:31]([CH3:33])[CH3:32]>>[Cl:23][C:24]1[CH:25]=[C:26]([C:2]2[NH:22][C:5]3=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]4[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=4)[N:9]=[C:4]3[CH:3]=2)[CH:27]=[CH:28][C:29]=1[C:30]([N:31]([CH3:33])[CH3:32])=[O:34]
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Reactant: CN(C)C(=O)c1ccc(B(O)O)cc1Cl
Product: COc1cc(CCc2cnc3[nH]c(-c4ccc(C(=O)N(C)C)c(Cl)c4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and 3-chloro-4-(dimethylcarbamoyl)phenylboronic acid (from Combi-Blocks). LCMS calculated for C25H26ClN4O3 (M+H)+: m/z=465.2. Found 465.1.
Reaction SMILES: [CH2:1]1[CH2:7][S:4](=[O:6])(=[O:5])[O:3][CH2:2]1.[CH3:8][C:9]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10]1>CC(=O)CC>[CH3:8][C:9]1([NH:14][CH2:2][CH2:1][CH2:7][S:4]([OH:3])(=[O:6])=[O:5])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=S1(=O)CCCO1
Reactant: CC1(N)CCCC1
Solvent: CCC(C)=O
Product: CC1(NCCCS(=O)(=O)O)CCCC1

Procedure:
A solution of 1,3-propanesultone (9.4 g, 75 mmol) in 2-butanone (35 mL) was added dropwise to a the crude solution of 1-methyl-1-cyclopentylamine (mixture of solvent from previous step).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7]2>C(O)(=O)C>[Br:1][CH:8]1[CH2:7][C:6]2[C:10](=[CH:11][CH:12]=[C:4]([F:3])[CH:5]=2)[C:9]1=[O:13]
Reactant: BrBr
Reactant: O=C1CCc2cc(F)ccc21
Solvent: CC(=O)O
Product: O=C1c2ccc(F)cc2CC1Br
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
Bromine (1.98 mL) was added to a solution of 5-fluoroindanone (5.53 g) in acetic acid (100 mL), and the reaction solution was stirred at 60° C. for 10 minutes. After allowing the reaction solution to be cooled to room temperature, the solvent was evaporated under reduced pressure. Ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added to the residue and the organic layer was partitioned. The resulting organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent:heptane-ethyl acetate system) to obtain 8.43 g of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:17]=[N:18][C:19]([CH2:22][O:23][CH3:24])=[CH:20][CH:21]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8]2.[C:25]([O:30][CH2:31][CH3:32])(=[O:29])[C:26]#[C:27][CH3:28].C(P(CCCC)CCCC)CCC.O1CCCC1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:17]=[N:18][C:19]([CH2:22][O:23][CH3:24])=[CH:20][CH:21]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:14][CH:27]([CH2:26][C:25]([O:30][CH2:31][CH3:32])=[O:29])[CH2:28][N:13]=1)=[CH:8]2
Reactant: COCc1ccc(Oc2cc(OC)c3[nH]c(C(N)=S)cc3c2)cn1
Reactant: CC#CC(=O)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(COC)nc4)cc(OC)c3[nH]2)S1
Temperature: 50 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
A mixture of 7-methoxy-5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-1H-indole-2-carbothioamide (2.04 g), ethyl 2-butynoate (1.8 mL), tributylphosphine (1.5 mL), tetrahydrofuran (25 mL) and toluene (30 mL) was stirred at 50° C. for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90 to 70/30, volume ratio) to give the title compound (1.36 g, 52%) as a yellow amorphous solid. MS 578 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[F:9][C:10]1[CH:27]=[CH:26][C:13]([O:14][CH2:15][C@H:16]2[CH2:25][N:20]3[CH2:21][CH2:22][NH:23][CH2:24][C@@H:19]3[CH2:18][CH2:17]2)=[CH:12][CH:11]=1.Cl>>[F:9][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][C@H:16]2[CH2:25][N:20]3[CH2:21][CH2:22][N:23]([C:2]4[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=4)[CH2:24][C@@H:19]3[CH2:18][CH2:17]2)=[CH:26][CH:27]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: Fc1ccc(OC[C@@H]2CC[C@H]3CNCCN3C2)cc1
Agent: Cl
Product: Fc1ccc(OC[C@@H]2CC[C@H]3CN(c4ccc(Cl)cn4)CCN3C2)cc1

Procedure:
The title compound was prepared according to Preparation 11 using 2,5-dichloropyridine and (7R,9aS)-7-(4-fluorophenoxy)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (Preparation 8). mp (.HCl) 237–238° C. 13C NMR (base, CDCl3): δ 27.0, 29.1, 36.4, 45.3, 50.9, 54.6, 58.7, 60.5, 71.6, 107.7, 115.36, 115.47, 115.60, 115.90, 120.1, 137.1, 146.3, 155.1, 155.6, 157.6, 158.8. HRMS calcd for C20H23ClFN3O: 375.1514; found, 375.1544.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:12].C(N(CC)CC)C.[Cl:20][C:21]1[C:22]([N:27]2[C:31]([C:32](Cl)=[O:33])=[CH:30][C:29]([C:35]([F:38])([F:37])[F:36])=[N:28]2)=[N:23][CH:24]=[CH:25][CH:26]=1>C(Cl)Cl>[Cl:20][C:21]1[C:22]([N:27]2[C:31]([C:32]([NH:12][C:3]3[C:4]([C:5]([OH:7])=[O:6])=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=3[Cl:1])=[O:33])=[CH:30][C:29]([C:35]([F:38])([F:36])[F:37])=[N:28]2)=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: Nc1c(Cl)cc(Cl)cc1C(=O)O
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)c1cc(Cl)cc(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3,5-dichloroanthranilic acid (7.89 g, 38.3 mmol) in methylene chloride (130 mL) at 0° C. was added triethylamine (18.6 mL, 134.0 mmol). A solution of 2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl chloride (13.7 g, 44.0 mmol) in methylene chloride (130 mL) at 0° C. was then added, the reaction allowed to warm to room temperature and then stirred further for 16 h. The reaction was concentrated in vacuo and used directly in the following reaction step.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH:14]([CH3:16])[CH3:15])[N:4]=[CH:3]1>C1CCCCC1.[Rh].[O-2].[Al+3].[O-2].[O-2].[Al+3]>[CH3:1][C:2]1([CH3:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([CH:14]([CH3:15])[CH3:16])[N:4]=[CH:3]1
Reactant: CC(C)C1CC=CCCC=CCC(C)(C)C=N1
Agent: [Rh]
Agent: [Al+3]
Agent: [O-2]
Solvent: C1CCCCC1
Product: CC(C)C1CCCCCCCCC(C)(C)C=N1
Yield: 89.5 %

Procedure:
466.8 g (2 mols) of 3,3-dimethyl-12-isopropyl-1-aza-1,5,9-cyclododecatriene is dissolved in 4 liters of cyclohexane, and the solution is hydrogenated at 20°-25° C. under an initial pressure of 100 bars, in the presence of 50 g of rhodium/aluminium oxide, for 4 hours in a steel autoclave. The solvent is then distilled off to obtain as the main fraction, 425 g (1.79 mols) of 3,3-dimethyl-12-isopropyl-1-aza-cyclododecene; b.p. 92°-94° C./4 Pa; nD20 =1.4706.