Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [B-](F)(F)(F)F.[CH:6]1[CH:12]=[CH:11][CH+:10][CH:9]=[CH:8][CH:7]=1.[C:13](=O)(O)[O-:14].[Na+]>CO>[CH3:13][O:14][CH:6]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=[CH:7]1
Reactant: c1ccc[cH+]cc1
Reactant: O=C([O-])O
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CO
Product: COC1C=CC=CC=C1

Procedure:
reacting an aqueous solution of cycloheptatrienyl tetrafluoroborate with methanol and sodium bicarbonate to produce 7-methoxycycloheptatriene;
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:6][O:5][C:4](=[O:7])[CH:3]1[S:8][CH2:9][C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]2[C:18]=1[C:19]#[C:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1.[O:32]1CCCC1.[OH-].[Na+].C(O)(=O)C>CO.O>[OH:5][CH2:6][C:2]([CH3:31])([CH3:1])[CH:3]([S:8][CH2:9][C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]2[C:18]=1[C:19]#[C:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=1)[C:4]([OH:7])=[O:32]
Reactant: CC1(C)COC(=O)C1SCc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CC(C)(CO)C(SCc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1)C(=O)O
Reaction time: 16 h

Procedure:
130 mg (0.303 mmol) of 4,4-dimethyl-3-((3-((3-(trifluoromethyl)phenyl)ethynyl) imidazo[1,2-a]pyridin-2-yl)methylthio)dihydrofuran-2(3H)-one were dissolved in 2 ml of methanol and 2 ml of tetrahydrofurane followed by the addition of 0.334 ml (0.334 mmol) of a 1N sodium hydroxide aqueous solution. The solution was stirred for 16 h. It was acidified down to an acid pH with acetic acid, and diluted with water until precipitation of a solid, which was then filtered and washed with water. 115 mg of 4-hydroxy-3,3-dimethyl-2-((3-((3-(trifluoromethyl)phenyl)-ethynyl)imidazo[1,2-a]pyridin-2-yl)methylthio) butanoic acid were obtained as a pale brown solid. LC-MS: m/z=447 (MH+) UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 12.69 (s, 1H), 8.77 (d, J=6.7 Hz, 1H), 8.11 (s, 1H), 7.97 (d, J=7.5 Hz, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.70 (t, J=8.2 Hz, 2H), 7.54-7.41 (m, 1H), 7.16 (t, J=6.6 Hz, 1H), 4.81 (d, J=12.3 Hz, 1H), 4.70 (sl, 1H), 4.58 (d, J=12.3 Hz, 1H), 3.92 (s, 1H), 3.40 (s, 1H), 3.10 (d, J=10.4 Hz, 1H), 0.86 (s, 3H), 0.82 (s, 3H)
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH3:23])[C:8]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[OH:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:32][C:33]([O:35][CH3:36])=[O:34].C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH3:23])[C:8]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1c(-c2ccccc2O)c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)COc1ccccc1-c1c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc2n1C
Reaction time: 12 h
Yield: 97.7 %

Procedure:
A solution of intermediate 25 (0.6 g, 1.5 mmol), methyl 2-bromoacetate (0.281 g, 1.83 mmol) and potassium carbonate (0.423 g, 3.06 mmol) in MeCN 50 mL was stirred at room temperature. After 12 h, the reaction mixture was concentrated under vacuum and the residue was partitioned between CH2Cl2 and water. The organic layer was dried and evaporated under vacuum to yield 0.7 g (96%) of tert-butyl 3-cyclohexyl-2-[2-(2-methoxy-2-oxoethoxy)phenyl]-1-methyl-1H-indole-6-carboxylate 26: m/z=478 (M+H)+.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](=[S:28])[NH2:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:30][C:31]([CH:33]1[CH2:35][CH2:34]1)=O>>[CH:33]1([C:31]2[N:27]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[S:28][CH:30]=2)[CH2:35][CH2:34]1
Reactant: NC(=S)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: O=C(CBr)C1CC1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(C3CC3)cs2)C1

Procedure:
100 mg (about 0.182 mmol) of the compound from Example 115A and 44 mg (0.273 mmol) of 2-bromo-1-cyclopropylethanone (Tetrahedron, 43, 20 1987, 4609-4619) were reacted according to the General Method 3. Yield: 49 mg (56% of theory).
Reaction SMILES: BrN1C(=O)CCC1=O.[C:9]([OH:12])(=[O:11])[CH3:10].[C:13]([OH:16])(=[O:15])[CH3:14].[C:17]([OH:20])(=[O:19])[CH3:18].[F:21][C:22]([F:56])([F:55])[C:23](O)([CH2:28][CH2:29][CH2:30][C@H:31]([C@@H:33]1[C@:51]2([CH3:52])[C@H:36]([C@H:37]3[C@H:48]([CH2:49][CH2:50]2)[C@:46]2([CH3:47])[C:40]([CH2:41][C@H:42]([CH2:44][C@@H:45]2O)O)=[CH:39][CH2:38]3)[CH2:35][CH2:34]1)[CH3:32])[C:24]([F:27])([F:26])[F:25]>C(Cl)(Cl)(Cl)Cl>[F:21][C:22]([F:55])([F:56])[C:23]([O:19][C:17](=[O:20])[CH3:18])([CH2:28][CH2:29][CH2:30][C@H:31]([C@@H:33]1[C@:51]2([CH3:52])[C@H:36]([C:37]3[C@H:48]([CH2:49][CH2:50]2)[C@:46]2([CH3:47])[C:40]([CH2:41][C@@H:42]([O:15][C:13](=[O:16])[CH3:14])[CH2:44][C@@H:45]2[O:11][C:9](=[O:12])[CH3:10])=[CH:39][CH:38]=3)[CH2:35][CH2:34]1)[CH3:32])[C:24]([F:25])([F:27])[F:26]
Reactant: C[C@H](CCCC(O)(C(F)(F)F)C(F)(F)F)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)O
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H]([C@H](C)CCCC(OC(C)=O)(C(F)(F)F)C(F)(F)F)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Reaction time: 0.33 h
Yield: 27.3 %

Procedure:
N-bromosuccinimide (14 mg) was added to a refluxing solution of 35 mg of triacetate (6) in 2 ml of CCl4 and the reaction mixture was refluxed further under argon atmosphere. After cooling in an ice-water bath, the resulting precipitate was filtered off. The filtrate was evaporated to dryness below 40° C. The residue is xylene (1 ml) was added dropwise to a refluxing solution of xylene (1.5 ml) and s-collidine (0.5 ml) and refluxing was continued under argon atmosphere for 20 min. The reaction mixture was extracted with AcOEt, washed with 2 N-HCl, sat. NaHCO3, brine and the solution was dried over MgSO4. After removal of the solvent, the residue was treated with a catalytic amount of pTsOH in acetone (10 ml) at room temperature for 16 hr under argon in the dark. The mixture was extracted with AcOEt and the extract was washed with sat. NaHCO3 and brine, and then dried over MgSO4. Removal of the solvent gave a crude 5,7-diene, which was purified by preparative TLC developed twice with a solvent of n-hexane-AcOEt (10:1). The band of Rf value 0.26 was scraped off and eluted with AcOEt. Removal of the solvent gave 8.8 mg (25%) of the product (7); UV(EtOH)λmax, 294, 282, 272 nm.
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[OH:11].[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(Cl)Cl>[OH:11][C@@H:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@H:2]1[NH:1][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: ClCCl
Product: CC(=O)N[C@@H]1c2ccccc2C[C@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1R,2S)-1-amino-2-indanol (2.0 g) is suspended in 100 mL CH2Cl2 and at RT combined with acetic anhydride (1.27 mL). The reaction mixture is stirred for 1 h at RT. After the reaction has ended the solvent is eliminated using the rotary evaporator and the crude product (HPLC-MS: tRet.=0.81 min; MS (M+H)+=192) is used in subsequent reactions without further purification.
Reaction SMILES: [Cl-].[NH2:2][CH2:3][C:4]1([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2=[NH+:13][CH:14]=[CH:15][N:5]12.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH:42]1([C:48](O)=[O:49])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>CN(C=O)C.C(Cl)CCl>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([C:4]2([CH2:3][NH:2][C:48]([CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)=[O:49])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]3=[N:13][CH:14]=[CH:15][N:5]23)=[CH:17][CH:18]=1
Reactant: O=C(O)C1CCCCC1
Reactant: NCC1(c2ccc(Br)cc2)c2ccccc2-c2[nH+]ccn21
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1(c2ccc(Br)cc2)c2ccccc2-c2nccn21)C1CCCCC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(aminomethyl)-5-(4-bromophenyl)-5H-imidazo[2,1-a]isoindol-1-ium chloride (40 mg), EDC (28 mg) and HOAT (13 mg) in DMF (1 mL) was added Hunig's base (75 mg) followed by cyclohexanecarboxylic acid (19 mg). After stirring at 40° C. overnight the mixture was purified by reversed phase HPLC (21×100 mm Phenomenex Gemini, 15-75% MeCN/water containing 0.05% NH4OH over 20 min at 20 mL/min) to give title compound as a white solid. HRMS. Found, 450.1186; calcd for (M+H)+, 450.1176. 1H NMR (500 MHz, CDCl3): δ 7.85 (d, J=7.59 Hz, 1 H); 7.48 (d, J=8.42 Hz, 2 H); 7.46-7.40 (m, 1 H); 7.35-7.28 (m, 3 H); 7.07 (d, J=8.43 Hz, 2 H); 7.03 (d, J=1.34 Hz, 1 H); 4.84 (t, J=6.19 Hz, 1 H); 4.55 (dd, J=13.97, 6.66 Hz, 1 H); 4.24 (dd, J=13.99, 5.93 Hz, 1 H); 1.75-1.49 (m, 5 H); 1.39 (d, J=9.99 Hz, 1 H); 1.28 (d, J=12.70 Hz, 1 H); 1.05 (m, 4 H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:20][NH:21][C:22]1[C:27]([CH3:28])=[C:26]([N:29]2[CH2:34][CH2:33][CH:32]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([N:41]4C(C)=CC=C4C)[N:36]=3)[CH2:31][CH2:30]2)[N:25]=[CH:24][N:23]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.NO>C(O)C.O>[NH2:41][C:37]1[N:36]=[C:35]([CH:32]2[CH2:31][CH2:30][N:29]([C:26]3[N:25]=[CH:24][N:23]=[C:22]([NH:21][CH2:20][CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:27]=3[CH3:28])[CH2:34][CH2:33]2)[CH:40]=[CH:39][CH:38]=1
Reactant: Cc1c(NCC(NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)ncnc1N1CCC(c2cccc(-n3c(C)ccc3C)n2)CC1
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: O
Product: Cc1c(NCC(NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)ncnc1N1CCC(c2cccc(N)n2)CC1
Temperature: 90 °C
Yield: 35.6 %

Procedure:
100 mg (0.15 mmol) of tert-butyl 2-benzyloxycarbonylamino-3-{6-[6-(2,5-dimethyl-pyrrol-1-yl)-3′,4′,5′,6′-tetrahydro-2′H-[2.4′]bipyridinyl-1′-yl]-5-methyl-pyrimidin-4-ylamino}-propionate is dissolved in 3 ml of ethanol and 0.3 ml of water. 50 mg (0.75 mmol) of hydroxylamine hydrochloride is added and the reaction medium is heated for 18 hours at 90° C. The solvents are evaporated off under reduced pressure (2 kPa) and the crude residue is purified by chromatography on silica gel eluting with a CH2Cl2/MeOH mixture 90:10. 30 mg of expected product is obtained in the form of a resin.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3]C1.[Mg].Br[C:14]1[CH:23]=[CH:22][C:17]2[O:18][CH2:19][CH2:20][O:21][C:16]=2[CH:15]=1>C1COCC1>[O:18]1[C:17]2[CH:22]=[CH:23][C:14]([C:7]3([OH:10])[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]3)=[CH:15][C:16]=2[O:21][CH2:20][CH2:19]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Brc1ccc2c(c1)OCCO2
Agent: [Mg]
Solvent: C1CCOC1
Product: O=C1CCC(O)(c2ccc3c(c2)OCCO3)CC1
Reaction time: 16 h

Procedure:
A solution of 1,4-cyclohexanedione monoethylene ketal (7.8 g, 50 mmole) in 50 ml dry THF was added to a of the Grignard reagent prepared from magnesium metal (1.34 g, 55 mmole) and 6-bromo-1,4-benzodioxane (10.75 g, 50 mmole). The mixture was stirred for 16 hr, quenched with saturated NH4Cl and extracted with ether. The ether extracts were dried with Na2SO4 and the solvent removed in vacuo. Acetone (75 ml) and 1N HCl (75 ml) were added and the solution was stirred 18 hr to give a tan precipitate which was filtered and air dried (6.38 g, 59.1%). This material was used without further purtification.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[NH2:12]/[C:13](/[CH3:19])=[CH:14]\[C:15]([O:17][CH3:18])=[O:16].[C:20]([O:26][CH2:27][C:28]([CH3:40])([CH3:39])[CH2:29][N:30]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:31])(=[O:25])[CH2:21][C:22]([CH3:24])=O>CC(O)C>[CH3:24][C:22]1[NH:12][C:13]([CH3:19])=[C:14]([C:15]([O:17][CH3:18])=[O:16])[CH:6]([C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N+:1]([O-:3])=[O:2])[C:21]=1[C:20]([O:26][CH2:27][C:28]([CH3:40])([CH3:39])[CH2:29][N:30]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:31])=[O:25]
Reactant: CC(=O)CC(=O)OCC(C)(C)CN(C)Cc1ccccc1
Reactant: COC(=O)/C=C(/C)N
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)(C)CN(C)Cc2ccccc2)C1c1ccccc1[N+](=O)[O-]
Yield: 37.3 %

Procedure:
A mixture of 152 mg of 2-nitrobenzaldehyde, 118 mg of methyl 3-aminocrotonate and 292 mg of 3-(N-benzyl-N-methylamino)-2,2-dimethylpropyl acetoacetate in 1 ml of 2-propanol was reacted and then purified in the same way as in Example 9 to yield 195 mg of the desired compound (300).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([O:11][CH:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[CH3:23][N:24]([CH3:39])[CH2:25][CH2:26][NH:27][C:28]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)=[O:29]>>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[CH:12]([O:11][N:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:34]3[CH:35]=[C:30]([CH:31]=[CH:32][CH:33]=3)[C:28]([NH:27][CH2:26][CH2:25][N:24]([CH3:39])[CH3:23])=[O:29])[CH:3]=2)[CH:8]=[CH:9]1)[CH3:13]
Reactant: CC(On1ccc2ncc(Br)cc21)c1c(Cl)ccc(F)c1Cl
Reactant: CN(C)CCNC(=O)c1cccc(B(O)O)c1
Product: CC(On1ccc2ncc(-c3cccc(C(=O)NCCN(C)C)c3)cc21)c1c(Cl)ccc(F)c1Cl

Procedure:
The entitled compound was prepared from 6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridine and (3-{[2-(dimethylamino)ethyl]carbamoyl}phenyl)boronic acid according to the procedure described in example 4.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[C:9]([C:22]([OH:24])=O)[C:10]3[CH2:11][CH2:12][CH:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:14][C:15]=3[C:4]=2[N:3]=1.F[B-](F)(F)F.[N:30]1(OC(N(C)C)=[N+](C)C)[C:34]2C=CC=[CH:38][C:33]=2N=N1.N1CCC1.O>ClCCl>[N:30]1([C:22]([C:9]2[C:10]3[CH2:11][CH2:12][CH:13]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[O:14][C:15]=3[C:4]3[N:3]=[C:2]([CH3:1])[N:6]([CH3:7])[C:5]=3[CH:8]=2)=[O:24])[CH2:38][CH2:33][CH2:34]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1nc2c3c(c(C(=O)O)cc2n1C)CCC(c1ccccc1)O3
Agent: C1CNC1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O
Product: Cc1nc2c3c(c(C(=O)N4CCC4)cc2n1C)CCC(c1ccccc1)O3
Temperature: 40 °C
Reaction time: 3 h
Yield: 61.1 %

Procedure:
To a suspension of 0.31 g (0.96 mmol) 2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylic acid in dichloromethane (10 ml) were added 0.34 g (1.4 mmol) O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) and the suspension was heated at 40° C. for 4 h. 102 mg (1.0 mmol) Azetidine were added and the mixture was stirred for 3 h. The reaction mixture was poured into water and the extracted with dichloromethane. The organic layers were dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (toluene/dioxane=1:5) and crystallized with diisopropyl ether to afford 212 mg (61%) of the title compound as a white solid. m.p. 246°-248° C.
Reaction SMILES: I[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=2)[CH:3]=1.C([Mg]Cl)(C)C.[Cl:26][C:27]1[CH:38]=[CH:37][C:30]([C:31](N(OC)C)=[O:32])=[CH:29][CH:28]=1>C1COCC1>[Cl:26][C:27]1[CH:38]=[CH:37][C:30]([C:31]([C:2]2[C:11](=[O:12])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=3)[CH:3]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: CON(C)C(=O)c1ccc(Cl)cc1
Reactant: Cc1cccc(Cn2cc(I)c(=O)c3ccccc32)n1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1cccc(Cn2cc(C(=O)c3ccc(Cl)cc3)c(=O)c3ccccc32)n1
Reaction time: 2 h

Procedure:
A −78° C. solution of 3-iodo-1-(6-methyl-pyridin-2-ylmethyl)-1H-quinolin-4-one (113 mg, 0.3 mmol, 1 equiv) in 3 mL of THF was treated with 1.65 mL of isopropyl magnesium chloride (1.1 equiv) for 2 hours. Then 4-chloro-N-methoxy-N-methyl-benzamide (46 μL, 1.2 equiv) was added and stirring continued at rt for 2 hours. The reaction was quenched by slow addition of saturated aqueous solution of NH4Cl. Standard workup followed by HPLC purification gave 3-(4-chloro-benzoyl)-1-(6-methyl-pyridin-2-ylmethyl)-1H-quinolin-4-one. LCMS (ES) M+H 389.1
Reaction SMILES: O1CCCC1.[C:6]1([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[N:21][OH:22])=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:24]([C:26]1[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[C:6]1([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]4[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=4)[O:22][N:21]=3)=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(Nc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(Nc3ccccc3)cc2)no1
Temperature: 50 °C
Reaction time: 7 h
Yield: 38.2 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-phenylamino-phenyl)-acetohydroximoyl chloride (150 mg, 0.576 mmol) described in Manufacturing Example 69-1-4 and 3-ethynyl-pyridin-2-ylamine (43 mg, 0.367 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (201 μL, 1.44 mmol) at room temperature, which was stirred for 7 hours at 50° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=4:1-2:1) to obtain the title compound (48 mg, 24%).
Reaction SMILES: C(NC1C=CC([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38](C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=[CH:37][CH:36]=1.[F:59][C:60]([F:71])([F:70])[C:61]1[CH:69]=[CH:68][C:64]([C:65](Cl)=[O:66])=[CH:63][N:62]=1>>[CH3:33][CH:31]([CH3:32])[C@H:26]([N:21]1[CH2:20][C:19]2[C:23](=[CH:24][CH:16]=[C:17]([C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:65](=[O:66])[C:64]4[CH:68]=[CH:69][C:61]([C:60]([F:71])([F:59])[F:70])=[N:62][CH:63]=4)=[CH:40][CH:39]=3)[CH:18]=2)[C:22]1=[O:25])[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Reactant: O=C(Cl)c1ccc(C(F)(F)F)nc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)nc4)cc3)ccc2C1=O
Yield: 65 %

Procedure:
The compound of example 210 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 6-trifluoromethyl nicotinoyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:21])=[CH:11][CH:12]=2)N(C)[CH:6]=1)=[O:4].COC(C1C2C=CC(Br)=CC=2[S:30]C=1)=O.[CH3:37][O:38][C:39]([C:41]1[S:45][C:44]2[CH:46]=[C:47](Br)[CH:48]=[CH:49][C:43]=2[CH:42]=1)=[O:40]>>[CH3:37][O:38][C:39]([C:41]1[S:45][C:44]2[CH:46]=[C:47]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:21])[CH:48]=[CH:49][C:43]=2[CH:42]=1)=[O:40].[CH3:1][O:2][C:3]([C:5]1[C:13]2[CH:12]=[CH:11][C:10]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:21])=[CH:9][C:8]=2[S:30][CH:6]=1)=[O:4]
Reactant: COC(=O)c1csc2cc(Br)ccc12
Reactant: COC(=O)c1cn(C)c2cc(-c3ccc(O)cc3C)ccc12
Reactant: COC(=O)c1cc2ccc(Br)cc2s1
Product: COC(=O)c1cc2ccc(-c3ccc(O)cc3C)cc2s1
Product: COC(=O)c1csc2cc(-c3ccc(O)cc3C)ccc12

Procedure:
The title compound is prepared essentially according to the preparation of 6-(4-hydroxy-2-methyl-phenyl)-1-methyl-1H-indole-3-carboxylic acid methyl ester, utilizing a 7:3 mixture of 6-bromo-benzo[b]thiophene-3-carboxylic acid methyl ester and 6-bromo-benzo[b]thiophene-2-carboxylic acid methyl ester. ES/MS m/e 297.0 (M−1).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:25])[C:22](O)=[O:23])=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH3:26])=[O:7])([CH3:4])[CH3:3].[CH2:27]1CCC(N=C=NC2CCCCC2)CC1.ON1C2C=CC=CC=2N=N1.[F:52][C:53]1[CH:58]=[CH:57][C:56]([NH:59][CH:60]2[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)=[CH:55][CH:54]=1.C(O)C(N)(CO)CO.[N-]=C=O>C(Cl)Cl.CN(C=O)C.C(Cl)Cl>[F:52][C:53]1[CH:58]=[CH:57][C:56]([NH:59][CH:60]2[CH2:65][CH2:64][N:63]([C:22](=[O:23])[CH:21]([C:18]3[CH:17]=[CH:16][C:15]([CH2:14][N:11]4[CH2:12][C@H:13]([CH3:27])[N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:1])[CH3:3])=[O:7])[C@H:9]([CH3:26])[CH2:10]4)=[CH:20][CH:19]=3)[CH3:25])[CH2:62][CH2:61]2)=[CH:55][CH:54]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C(=O)O)c1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Reactant: Fc1ccc(NC2CCNCC2)cc1
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Agent: [N-]=C=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C(=O)N1CCC(Nc2ccc(F)cc2)CC1)c1ccc(CN2C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Reaction time: 8 h

Procedure:
A mixture of D46 (100 mg, 0.27 mmol), polymer-supported DCC (310 mg, 1.3 mmol/g, 0.40 mmol) and 1-hydroxybenzotriazole (50 mg, 0.324 mmol) in 2:1 DMF/DCM (3 ml) was treated with D2 (51 mg, 0.26 mmol) and the mixture stirred overnight. Scavenger resins (PS-trisamine, PS-isocyanate and Si-carbonate) together with DCM (˜3 ml) were added. The mixture was stirred for ˜3 h and then filtered and concentrated to give 1,1-dimethylethyl (2R,6S)-4-{[4-(2-{4-[(4-fluorophenyl)amino]-1-piperidinyl}-1-methyl-2-oxoethyl)phenyl]methyl}-2,6-dimethyl-1-piperazinecarboxylate. MS (ES): MH+ 553. This whole was dissolved in DCM (2 ml) and TFA (1 ml) then stirred for 1.5 h. The solvents were removed in vacuo and the residue re-evaporated from toluene and ether. Purification using an Isolute SCX cartridge eluting with MeOH followed by 2M NH3 in MeOH gave the title compound. MS (ES): MH+ 453. This whole was dissolved in DCM and treated with 1.1 eq 1M HCl in ether to give a hydrochloride salt of the title compound (122 mg). MS (ES): MH+ 453.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]([NH:7][C:8]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])=[O:6].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[ClH:22].[C:25]([CH2:24][N:3]([CH3:2])[CH2:4][C:5]([NH:7][C:8]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])=[O:6])([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)CBr
Reactant: CNCC(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CN(C)CC(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Yield: 122 %

Procedure:
1.7 g of 2-(methylamino-acetamido)-5-chlorobenzophenone hydrochloride, 0.85 g of ethyl bromacetate and 0.7 g of anhydrous potassium carbonate were heated for 20 hours under a reflux in 100 mls. of anhydrous acetone whilst stirring. After cooling, the inorganic salt was filtered off under suction concentrated in vacuo, and the oily residue was dried in vacuo. The yield of oily crude base was 1.4 g. It was dissolved in 30 mls. of absolute dioxane, the solution was filtered and diluted with 30 mls. absolute ether, 1.3 g of 2-(4-carbethoxy-3-methyl-3-aza-butyramido)-5-chlorobenzophenone hydrochloride with a melting point of 178°-180° being obtained by passing in dry hydrogen chloride. The product was identical with that obtained in Example 5.