Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][C:7]2[N:8]([C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:11]=2)=[CH:4][CH:3]=1.Br[CH2:34][C:35]([O:37][CH3:38])=[O:36]>>[CH3:38][O:37][C:35](=[O:36])[CH2:34][NH:28][C:25]1[CH:26]=[CH:27][C:22]([N:8]2[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:11]=[C:7]2[CH2:6][C:5]2[CH:31]=[CH:32][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(-n2cc(-c3ccc(C(F)(F)F)cc3)nc2Cc2ccc(Br)cc2)cc1
Product: COC(=O)CNc1ccc(-n2cc(-c3ccc(C(F)(F)F)cc3)nc2Cc2ccc(Br)cc2)cc1

Procedure:
2-(4-Bromo-benzyl)-1-(4-Nitro-phenyl)-4-(4-trifluoromethyl-phenyl)-1H-imidazole (2.5 g, 5 mmol) was reduced to amine and was reacted with methyl bromoacetate following general procedures D & E to give {4-[2-(4-bromo-benzyl)-4-(4-trifluoromethyl-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1Cl.C([O-])([O-])=O.[K+].[K+].[CH2:17]([Zn]CC)[CH3:18]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[CH2:17][CH3:18]
Reactant: OCc1cnc(Cl)c(Cl)c1
Reactant: CC[Zn]CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCc1ncc(CO)cc1Cl
Yield: 21.4 %

Procedure:
To a solution of (5,6-dichloro-3-pyridinyl)methanol (500 mg, 2.81 mmol), K2CO3 (1165 mg, 8.43 mmol), and [1,1′-Bis(diphenylphosphino) ferrocene]dichloro-palladium(II) (206 mg, 0.281 mmol) in THF (17 ml), was added diethylzinc (5.67 ml, 5.67 mmol). The mixture was stirred under reflux for 16 h in a pressure tube. The resulting mixture was quenched upon the addition of aqueous HCl until pH 7 and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash chromatography using Flashmaster II, spherical silica gel cartridge BP-SUP 20-40μ, and mixtures of EtOAc and hexane as eluents to give 103 mg of desired compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@H:9]1[C:14]1[NH:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28](B4OC(C)(C)C(C)(C)O4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:41]1[CH:66]=[CH:65][C:44]2[NH:45][C:46]([C@@H:48]3[CH2:52][C@H:51]([CH3:53])[CH2:50][N:49]3[C:54](=[O:64])[C@@H:55]([NH:59][C:60](=[O:63])[O:61][CH3:62])[CH:56]([CH3:58])[CH3:57])=[N:47][C:43]=2[CH:42]=1.C(Cl)Cl.C([O-])(O)=O.[Na+]>CC(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@H:9]1[C:14]1[NH:15][CH:16]=[C:17]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:41]4[CH:66]=[CH:65][C:44]5[NH:45][C:46]([C@@H:48]6[CH2:52][C@H:51]([CH3:53])[CH2:50][N:49]6[C:54](=[O:64])[C@@H:55]([NH:59][C:60]([O:61][CH3:62])=[O:63])[CH:56]([CH3:57])[CH3:58])=[N:47][C:43]=5[CH:42]=4)=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[N:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2cc(I)ccc2[nH]1)C(C)C
Reactant: C[C@H]1C[C@@H](c2nc(-c3ccc(-c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)cc3)c[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2cc(-c3ccc(-c4ccc(-c5c[nH]c([C@@H]6C[C@H](C)CN6C(=O)OC(C)(C)C)n5)cc4)cc3)ccc2[nH]1)C(C)C
Temperature: 80 °C
Yield: 37.9 %

Procedure:
To a suspension of (2S,4S)-4-methyl-2-{4-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (138 mg, 0.2606 mmol), methyl ((S)-1-((2S,4S)-2-(5-iodo-1H-benzo[d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (126.2 mg, 0.2606 mmol), Pd(DPPF)(Cl)2.CH2Cl2 (21.3 mg, 0.02606 mmol) in 2-propanol (1.4 mL) is added 1M aqueous NaHCO3 (1.3 mL, 1.3 mmol). The reaction mixture is heated at 80° C. for 19 hours, cooled to RT, and extracted with dichloromethane (2×10 mL). The organic layer is dried over Na2SO4, filtered, and concentrated to dryness. The residue is purified by flash column chromatography on silica gel (50 to 100% EtOAc in hexanes) to give (2S,4S)-2-[4-(4′-{2-[(2S,4S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-4-methyl-pyrrolidin-2-yl]-1H-benzoimidazol-5-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (75 mg, 38%). HPLC: Waters symmetry shield RP18 3.5 μm 4.6 mm×50 mm, solvent A: 0.01% TFA in acetonitrile, solvent B: 0.01% TFA in water, gradient: 15:85 A:B to 90:10 A:B over 10 minutes, RT=4.87 min.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([OH:28])[CH:22]=3)=[N:19][N:20]=2)[C@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:29][CH2:30][CH2:31][C:32](Cl)=[O:33]>N1C=CC=CC=1.C(Cl)Cl>[C:32]([O:28][C:23]1[CH:22]=[C:21]([C:18]2[O:17][C:16]([C@H:12]([NH:11][C:8]3[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=3[CH3:10])[C@H:13]([O:15][C:16](=[O:17])[CH2:12][CH2:13][CH3:14])[CH3:14])=[N:20][N:19]=2)[CH:26]=[CH:25][C:24]=1[F:27])(=[O:33])[CH2:31][CH2:30][CH3:29]
Reactant: CCCC(=O)Cl
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(F)c(O)c3)o2)[C@@H](C)O)ccc(C#N)c1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)Oc1cc(-c2nnc([C@H](Nc3ccc(C#N)c(Cl)c3C)[C@@H](C)OC(=O)CCC)o2)ccc1F
Reaction time: 23 h

Procedure:
To a solution of 2-chloro-4-((1R,2R)-1-(5-(4-fluoro-3-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-methylbenzonitrile (Example 41) (135.5 mg, 0.34 mmol) in pyridine (0.6 mL) and CH2Cl2 (4 mL) was added n-butyryl chloride (0.17 mL, 1.68 mmol). Upon complete addition the reaction mixture was stirred for 23 h, then quenched with 10% aqueous HCl (6 mL). The mixture was partitioned between H2O (40 mL) and CH2Cl2 (40 mL). The aqueous layer was extracted with CH2Cl2 (40 mL). The combined organic extracts were washed with NaHCO3 (45 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a yellow oil, which was purified by flash chromatography over silica gel (20-25% EtOAc in hexanes) to provide the title compound as an off white solid (137.3 mg, 74%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 7.94 (ddd, J=2.2, 4.5, 8.6 Hz, 1H), 7.86 (dd, J=2.0, 7.0 Hz, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.52 (dd, J=8.8, 10.0 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 6.13 (d, J=8.8 Hz, 1H), 5.68 (pentet, J=6.5 Hz, 1H), 5.36 (dd, J=6.5, 8.4 Hz, 1H), 2.67 (t, J=7.2 Hz, 2H), 2.28-2.22 (m, 2H), 2.07-2.03 (m, 2H), 1.82-1.71 (m, 2H), 1.53 (d, J=6.5 Hz, 3H), 1.03 (t, J=7.2 Hz, 3H), 0.82 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[O:3]1.[CH2:19]([NH2:21])[CH3:20]>>[CH2:19]([NH:21][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:1])([CH3:18])[O:3]2)=[CH:17][CH:16]=1)[CH3:20]
Reactant: CCN
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Product: CCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1

Procedure:
The title compound was prepared according to the procedures of Intermediate 3 using instead 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and ethylamine. MS (m/z): 276 (M+H)+
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([CH2:19][CH3:20])=[C:6]([CH2:10]P(=O)(OCC)OCC)[CH:7]=[CH:8][CH:9]=1.O=[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1.O>O1CCCC1>[Br:3][C:4]1[C:5]([CH2:19][CH3:20])=[C:6]([CH:10]=[C:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(Cc1cccc(Br)c1CC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1c(Br)cccc1C=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a suspension of NaH (0.155 g, 3.88 mmol) in Tetrahydrofuran (THF) (30 mL) was added diethyl [(3-bromo-2-ethylphenyl)methyl]phosphonate (D135) (1 g, 2.98 mmol) at 0° C. The reaction solution was warmed to room temperature and stirred for 1 hour. The reaction solution was cooled to 0° C. again and 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (0.713 g, 3.58 mmol) was added. The reaction solution was warmed to room temperature and stirred overnight. Water was added and extracted with ethyl acetate, the organic phases were dried over sodium sulphate, concentrated and purified by ISCO column chromatography to afford 1,1-dimethylethyl 4-[(3-bromo-2-ethylphenyl)methylidene]-1-piperidinecarboxylate (D136) (0.73 g). MS (ES): C19H26BrNO2 requires 379.1. found 324.1 (M+H+-56).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=2)[N:3]=1.[CH:17]1[CH:18]=[CH:19][N:20]2[CH2:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[NH:23][CH2:22][C:21]=12.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([N:23]3[C:24]4[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=4[CH2:26][N:20]4[CH:19]=[CH:18][CH:17]=[C:21]4[CH2:22]3)=[O:13])=[CH:10][CH:9]=2)[N:3]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: Cc1cc(C)n(-c2ccc(C(=O)Cl)cc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C)n(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
The 4-(3,5-dimethylpyrazol-1-yl)benzoyl chloride (0.75 g) was added to an ice-cooled solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.55 g) and diisopropylethylamine (0.42 g) in dichloromethane (25 ml). After stirring at room temperature for 18 hours, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the title compound (0.79 g) was obtained as an amorphous solid, MS m/z: 383 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH:25]([C:29]#[N:30])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH:25]([C:29]#[N:30])[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: CC(C)(C)OC(=O)N1CCNC(C#N)C1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3ccnc(Cl)n3)c2)C(C#N)C1

Procedure:
Intermediate 1 was coupled with 3-cyano-piperazine-1-carboxylic acid tert-butyl ester (generated according to literature procedure (ref 3)) following procedure B. LC-MS showed the product had the expected M+H+ of 414.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:18])C=1.C(Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)=[O:18]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(N)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CS(=O)c1ccc(N)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
20 g (143.66 mmol) of 4-methylthioaniline was placed in a flask and dissolved in 660 mL of CH2Cl2. The solution was cooled to 0° C. and 35.42 g (143.66 mmol) of m-chloroperbenzoic acid was added. The mixture was stirred for 3 h at room temperature and poured into CHCl3. It was then washed with saturated NaHCO3 solution, dried over MgSO4 and the solvent was removed, yielding a crude product that was purified by chromatography on silica gel, using MeOH/EtOAc/hexane mixtures of increasing polarity as eluent. The title compound of the example was obtained as a white solid (17.84 g, 80%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH3:9])=[CH:4][CH:3]=1.Cl[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([CH:26]([F:28])[F:27])=[N:24][N:25]=2)[N:22]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:10]2[CH2:11][CH2:12][N:13]([C:17]3[CH:18]=[CH:19][C:20]4[N:21]([C:23]([CH:26]([F:27])[F:28])=[N:24][N:25]=4)[N:22]=3)[CH2:14][CH2:15]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: FC(F)c1nnc2ccc(Cl)nn12
Reactant: C[C@H](c1ccc(Br)cc1)N1CCNCC1
Product: C[C@H](c1ccc(Br)cc1)N1CCN(c2ccc3nnc(C(F)F)n3n2)CC1
Yield: 75 %

Procedure:
A mixture of (R)-1-[1-(4-bromophenyl)ethyl]piperazine and 6-chloro-3-difluoromethyl-[1,2,4]-triazolo[4,3-b]pyridazine was allowed to react by an analogous method to Example 269 to give 6-[4-[(1R)-1-(4-bromophenyl)ethyl]piperazin-1-yl]-3-(difluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine in 75% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:17])=[C:13]([CH:16]=1)[CH:14]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(=[CH:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:17])=[C:13]([CH:14]=[CH:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(OCc2ccccc2)cc1C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1cc(OCc2ccccc2)ccc1C
Temperature: 60 °C
Reaction time: 15 h
Yield: 62 %

Procedure:
To a solution of 5-(benzyloxy)-2-methylbenzaldehyde (250 mg) in toluene (20 mL) was added ethyl (triphenylphosphoranylidene)acetate (379 mg), and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was concentrated, diethyl ether was added, and the insoluble material was filtered off. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (200 mg) as a yellow oil.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>O1CCCC1>[CH3:16][S:17]([N:4]1[CH2:5][CH2:6][C@H:2]([O:1][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:3]1)(=[O:19])=[O:18]
Reactant: O[C@H]1CCNC1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)O[C@H]1CCN(S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)-3-Hydroxypyrrolidine (2 g, 23 mmol) is dissolved in 40 mL of tetrahydrofuran. DIPEA (10 mL, 57.36 mmol) is added and the reaction mixture is stirred for 30 min at room temperature. The reaction mixture is cooled to 0° C., methanesulfonyl chloride (3.73 mL, 48.21 mmol) is added dropwise and the reaction mixture is allowed to reach room temperature. After stirring for 2 h, the reaction mixture is concentrated under vacuum, water is added and the reaction mixture is extracted with ethyl acetate. The organic phase is collected, dried over sodium sulfate, separated and concentrated under vacuum. The crude product obtained is triturated with a solution of cyclohexane/dichloromethane 1:1 to give the title compound. (Yield: 2.2 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:16][CH2:15][C:14](O[Si](C)(C)C)=[C:13](O[Si](C)(C)C)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:27].Cl.[NH2:29][CH2:30][C:31]([NH2:33])=[NH:32]>>[ClH:27].[ClH:27].[NH2:33][C:31]1[CH:30]=[N:29][C:14]2[CH2:15][CH2:16][N:10]([CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:11][CH2:12][C:13]=2[N:32]=1
Reactant: C[Si](C)(C)OC1=C(O[Si](C)(C)C)CCN(CCCc2ccccc2)CC1
Reactant: N=C(N)CN
Agent: Cl
Product: Nc1cnc2c(n1)CCN(CCCc1ccccc1)CC2

Procedure:
This compound was prepared analogous to Example 22 from 1-(3-phenyl-propyl)-2,3,6,7-tetrahydro-4,5-bis(trimethylsilyloxy)-azepine and α-amino-acetamidine dihydrochloride.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:23])=[CH:4][C:5]([O:21][CH3:22])=[C:6]([CH:20]=1)[CH2:7][NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[O:18][CH3:19].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([C:37](O)=[O:38])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[Br:1][C:2]1[C:3]([Cl:23])=[CH:4][C:5]([O:21][CH3:22])=[C:6]([CH:20]=1)[CH2:7][N:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[O:18][CH3:19])[C:37]([CH:34]1[CH2:35][CH2:36][N:31]([C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:32][CH2:33]1)=[O:38]
Reactant: COc1ccc(CNCc2cc(Br)c(Cl)cc2OC)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2cc(Br)c(Cl)cc2OC)C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The mixture of N-(5-bromo-4-chloro-2-methoxybenzyl)-1-(2,4-dimethoxyphenyl)methanamine (190 mg, 0.47 mmol), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (109 mg, 0.47 mmol), HATU (180 mg, 0.47 mmol) and Et3N (101 mg, 1 mmol) in DMF (5 mL) was stirred at room temperature for 4 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the desired product. The crude product was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([NH2:16])([CH3:15])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1.[OH:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O.FC(F)(F)C(O)=O>>[CH3:1][O:2][C:3]([C:4]1([CH3:15])[CH2:5][C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[CH:22]([C:21]2[CH:24]=[CH:25][CH:26]=[C:19]([OH:18])[CH:20]=2)[NH:16]1)=[O:17]
Reactant: COC(=O)C(C)(N)Cc1c[nH]c2ccccc12
Reactant: O=Cc1cccc(O)c1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(C)Cc2c([nH]c3ccccc23)C(c2cccc(O)c2)N1
Yield: 14 %

Procedure:
1.00 g (4.30 mmol) of the commercially available 2-amino-3-(1H-indol-3-yl)-2-methyl-propionic acid methyl ester are reacted with 600 mg (4.73 mmol) 3-hydroxy-benzaldehyde in the presence of trifluoroacetic acid according to the Pictet-Spengler reaction. The resulting mixture of diastereomers is separated by column chromatography (toluene, ethyl acetate 4:1). 1.17 g (68%) of the title compound and 320 mg (14%) of (1SR,3SR)-1-(3-hydroxy-phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid methyl ester (compound A2) are obtained as white solids.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[N:45]=[C:44]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)[CH:43]=[CH:42][CH:41]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[C:44]([N:46]3[CH2:47][CH2:48][O:49][CH2:50][CH2:51]3)[N:45]=2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: ClCc1cccc(N2CCOCC2)n1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(Cc3cccc(N4CCOCC4)n3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 53.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.65 g) and 6-chloromethyl-2-morpholinopyridine (0.29 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(6-morpholinopyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.44 g) was obtained.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)[N:20]=1>>[N:22]1[CH:23]=[CH:24][N:25]=[CH:26][C:21]=1[C:19]1[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[CH:29]=[C:28]([C:30]([F:32])([F:33])[F:31])[S:27][C:17]=2[N:18]=1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: FC(F)(F)c1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyrazin-2-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([N:28]([C:30]4[S:31][CH:32]=[C:33]([C:35]5[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=5)[N:34]=4)[CH3:29])=[C:21]([CH2:23][CH2:24][C:25]([OH:27])=O)[N:22]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+:43]>CN(C=O)C.[Cl-].[Na+].O>[NH2:43][C:25](=[O:27])[CH2:24][CH2:23][C:21]1[N:22]=[C:17]2[CH:16]=[CH:15][C:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]3)=[CH:19][N:18]2[C:20]=1[N:28]([C:30]1[S:31][CH:32]=[C:33]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[N:34]=1)[CH3:29]
Reactant: [NH4+]
Reactant: CN(c1nc(-c2ccc(F)cc2)cs1)c1c(CCC(=O)O)nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1nc(-c2ccc(F)cc2)cs1)c1c(CCC(N)=O)nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cn12
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of 3-(6-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-2-yl)propanoic acid (220 mg, 0.38 mmol, 1 eq.) and TEA (211 μL, 1.52 mmol, 4 eq.) in DMF (3 mL) was stirred for 10 min at r.t. Propane phosphonic acid anhydride (226 μL, 0.76 mmol, 2 eq.) followed by ammonium chloride (40.7 mg, 0.76 mmol, 2 eq.) were added and the resulting mixture was stirred at r.t. for 4 days. TEA (211 μL, 1.52 mmol, 4 eq.), propane phosphonic acid anhydride (226 μL, 0.76 mmol, 2 eq.) and ammonium chloride (40.7 mg, 0.76 mmol, 2 eq.) were added and the reaction mixture kept stirring for 2 h. Brine was added (100 mL) and the mixture was extracted with DCM (3×20 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The crude product was purified by chromatography on silica gel (elution with DCM/MeOH 100/0 to 80/20) to give tert-butyl 4-(2-(3-amino-3-oxopropyl)-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidine-1-carboxylate (Gen-10-am).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][C:14]([NH:20][C@H:21]2[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22]2)=[N:15]3)=O)=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32].C(=O)([O-])[O-].[Na+].[Na+].O>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][C:14]([NH:20][C@H:21]2[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22]2)=[N:15]3)=[N:31][OH:32])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(c1ccc(F)cc1)c1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C(c1ccc(F)cc1)c1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Yield: 32.9 %

Procedure:
A stirred suspension of (4-fluoro-phenyl)-[2-((R)-indan-1-ylamino)-quinolin-5-yl]-methanone (example 83) (100 mg, 0.26 mmol), hydroxylamine hydrochloride (55 mg, 0.79 mmol) and sodium carbonate (83 mg, 0.78 mmol) in EtOH (2 ml) was heated under reflux conditions for 18 hours, the reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (heptane/ethyl acetate) and crystallization (diethyl ether/heptane) to yield the title compound as off-white solid (34 mg, 33%).