Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrCCBr.Cl[Si](C)(C)C.I[CH:11]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1.[C:22]([C:25]1[CH:32]=[C:31]([Cl:33])[C:28]([C:29]#[N:30])=[C:27](I)[C:26]=1[O:35][CH3:36])(=[O:24])[CH3:23].[Cl-].[NH4+]>CN(C)C(=O)C.[Zn].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].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>[C:22]([C:25]1[C:26]([O:35][CH3:36])=[C:27]([CH:11]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]2)[C:28]([C:29]#[N:30])=[C:31]([Cl:33])[CH:32]=1)(=[O:24])[CH3:23]
Reactant: COc1c(C(C)=O)cc(Cl)c(C#N)c1I
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: BrCCBr
Solvent: CC(=O)N(C)C
Product: COc1c(C(C)=O)cc(Cl)c(C#N)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
Zinc (5.0 g, 77 mmol) and oven dried Celite (520 mg) was added to a flask and the flask was heated with a heat gun while under high-vac for 5 min and then back-filled with nitrogen. N,N-dimethylacetamide (53 mL) was added, followed by 1,2-dibromoethane (400 μL, 4.6 mmol) and the mixture was heated at 70° C. for 15 min and then cooled to room temperature. The reaction mixture was treated with chlorotrimethylsilane (580 μL, 4.6 mmol) dropwise and stirred at room temperature for 1 h. The reaction mixture was treated with a solution of tert-butyl 3-iodoazetidine-1-carboxylate (16 g, 58 mmol) in N,N-dimethylacetamide (26 mL) dropwise (internal temperature was kept below 40° C. with a water bath) and heated at 40° C. for 2 h. The zinc-iodo reagent (transferred via canula) was filtered through a plastic filter (that was appropriately sealed to avoid atmospheric exposure) directly into a clean, dry flask that was flushed with nitrogen. The reaction mixture was treated with tris(dibenzylideneacetone)dipalladium(0) (670 mg, 0.73 mmol) and tri-(2-furyl)phosphine (340 mg, 1.5 mmol) and degassed with nitrogen for a few minutes. The reaction mixture was treated with a solution of 4-acetyl-6-chloro-2-iodo-3-methoxybenzonitrile (13 g, 39 mmol) in N,N-dimethylacetamide (120 mL) (degassed with nitrogen) quickly and heated at 70° C. for 2 h. The reaction mixture was poured into saturated ammonium chloride solution and extracted with ethyl acetate (3×300 mL). The combined organic extracts were washed with water (4×500 mL) and brine (1×500 mL), dried with magnesium sulfate, filtered, and concentrated to a crude dark oil. The crude material was purified by flash column chromatography using ethyl acetate in hexanes (5%-40%) to give the desired product (12 g, 85%). 1H NMR (400 MHz, DMSO-d6) δ 7.79 (s, 1H), 4.39-4.29 (m, 1H), 4.28-4.11 (m, 4H), 3.68 (s, 3H), 2.58 (s, 3H), 1.38 (s, 9H).
Reaction SMILES: [CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@H:23]1[C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([OH:30])=[O:29])=[O:25])=[O:21])[CH3:19])([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Ca+2:39].[OH-]>ClCCCl>[Ca+2:39].[CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@H:23]1[C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([O-:30])=[O:29])=[O:25])=[O:21])[CH3:19])([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@H:23]1[C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([O-:30])=[O:29])=[O:25])=[O:21])[CH3:19])([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O
Product: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.5 %

Procedure:
Dibenzylphosphoryl-L-alanyl-L-prolyl-L-proline (0.5 g, 0.9 mmol) was dissolved in 1,2-dichloroethane (15 ml) which had been previously saturated with water, and calcium hydroxide (34 mg, 0.465 mmole) was added thereto. The mixture was stirred for 4 hours at room temperature. Insoluble matter was removed by filtration and from the thus obtained filtrate the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate and n-hexane was added thereto while stirring to obtain dibenzylphosphoryl-L-alanyl-L-prolyl-L-proline calcium salt (0.37 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][C:6]=2[C:14]=1[CH3:15].C([Li])CCC.Cl.[K+].[Br-].C[CH2:25][O:26]CC>CN(C=O)C>[CH3:15][C:14]1[C:6]2[O:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:25]=[O:26]
Reactant: Cc1c(Br)ccc2c1oc1ccccc12
Reactant: CCOCC
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C=O)ccc2c1oc1ccccc12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
3-Bromo4-methyldibenzofuran (26.11 g, 0.1 mol) suspended in dry ether (700 ml) was cooled to 0° C. and n-butyl lithium (1.6M in hexane, 62.5 ml, 0.1 mol) was added and the reaction stirred for 5 mins. DMF (5 ml) in ether (12 ml) was added and the reaction heated to reflux for 1 hour. The mixture was poured onto a mixture of conc. HCl (25 ml) and ice (1 l). The organic phase was separated and the aqueous extreacted with ether. The combined organic phases were dried (MgSO4) and evaporated in vacuo. The resulting solid was crystallised from IMS to give off-white needles which were dried at 60° C. under vacuum (4.68 g, 22%). Further product could be obtained from the mother liquor. (Found: C, 78.97; H, 4.56. C14H10O2 0.15H2O requires: C, 78.97; H, 4.88%); δH [2H6 ]-DMSO 10.4 (1H, s, CHO), (8.2 (1H, d), 8.15 (1H, d), 7.9 (1H, d), 7.8 (1H, d), 7.65 (1H, t), 7.45 (1H, t), 2.85 (3H, s); m/z 210 (M+); νmax (KBr disc)/cm-1 1686.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][C:12]3[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.[CH3:22][NH:23][CH3:24].C(O)(=O)C.[BH3-]C#N.[Na+]>C1COCC1.CO>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:23]([CH3:24])[CH3:22])=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(c2nc3cc(C=O)ccc3s2)CC1
Reactant: CNC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)N1CCN(c2nc3cc(CN(C)C)ccc3s2)CC1
Yield: 45.6 %

Procedure:
To a solution of 2-(4-isopropylpiperazin-1-yl)benzothiazole-5-carbaldehyde (500 mg, 1.73 mmol) and dimethylamine hydrochloride (282 mg, 3.46 mmol) in THF (27.5 mL) and MeOH (13.7 mL) was added acetic acid (166 mg, 2.77 mmol), followed by NaCNBH3 (160 mg, 2.77 mmol). The mixture was heated at reflux overnight. The mixture was concentrated under reduced pressure, neutralized with an aqueous solution of Na2CO3 to pH 7, and filtered. The residue was extracted with dichloromethane (3×10 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC to give 251 mg (46%) of [2-(4-isopropylpiperazin-1-yl)benzothiazol-5-yl-methyl]dimethylamine as a trifluoroacetate salt.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH2:10][C:11]([NH:13][C:14]([CH3:22])([CH:19]([CH3:21])[CH3:20])[C:15]([O:17]C)=O)=[O:12].CC([O-])(C)C.[K+].O>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]1[C:15](=[O:17])[C:14]([CH:19]([CH3:21])[CH3:20])([CH3:22])[NH:13][C:11]1=[O:12]
Reactant: COC(=O)C(C)(NC(=O)Cc1c(Cl)cccc1OC)C(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc(Cl)c1C1C(=O)NC(C)(C(C)C)C1=O
Temperature: 25 °C
Yield: 93.6 %

Procedure:
23.8 g (0.073 mol) of methyl N-(2-chloro-6-methoxyphenylacetyl)-2-amino-2,3-dimethyl-butyrate, dissolved in 150 ml of absolute toluene, are added dropwise to a suspension of 18.06 g (0.16 mol) of potassium tert-butylate in 50 ml of absolute tetrahydrofuran at the boil, and the mixture was heated at reflux temperature for 1.5 hours. After the reaction mixture has cooled to room temperature, 230 ml of water are added, the aqueous phase is separated off, the toluene phase is reextracted using 110 ml of water, and the combined aqueous phases are acidified at 15-20° C. using approximately 25 ml of concentrated hydrochloric acid. The product is filtered off with suction and dried. 20.2 g (93% of theory) of 3-(2-chloro-6-methoxyphenyl)-5-isopropyl-5-methyl-pyrrolidine-2,4-dione of m.p. 172-174° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:19]=[C:20]=S.[NH2:22][C:23]1[C:38]([NH2:39])=[CH:37][C:26]([C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][CH:31]=2)=[O:28])=[C:25]([O:40][CH3:41])[CH:24]=1.CC(C)N=C=NC(C)C>CN(C=O)C>[Br:36][C:33]1[CH:32]=[CH:31][C:30]([NH:29][C:27]([C:26]2[C:25]([O:40][CH3:41])=[CH:24][C:23]3[NH:22][C:20]([NH:19][C:3]4[CH:4]=[C:5]([CH2:6][NH:7][C:8]([C:10]5([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]5)=[O:9])[CH:17]=[CH:18][C:2]=4[Cl:1])=[N:39][C:38]=3[CH:37]=2)=[O:28])=[CH:35][CH:34]=1
Reactant: O=C(NCc1ccc(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Reactant: COc1cc(N)c(N)cc1C(=O)Nc1ccc(Br)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: COc1cc2[nH]c(Nc3cc(CNC(=O)C4(C(F)(F)F)CC4)ccc3Cl)nc2cc1C(=O)Nc1ccc(Br)cc1

Procedure:
The title compound was prepared in accordance with the procedure in Example 72, step (a) using N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane carboxamide ((200 mg; 0.60 mmol) see Example 59, step (c)), 4,5-diamino-N-(4-bromophenyl)-2-methoxybenzamide (202 mg; 0.60 mmol), DIC (76 mg; 0.60 mmol) and DMF (4 mL). Yield: 63 mg (16%). 400 MHz 1H-NMR (DMSO-d6, ppm) 11.12 (0.36H, s, minor tautomer) 11.00 (0.57H, s, major tautomer) 10.22-10.14 (1H, m) 8.94 (0.57H, s, major tautomer) 8.76 (0.36H, s, minor tautomer) 8.61-8.52 (1H, m) 8.48-8.41 (1H, m) 7.86-7.69 (3H, m) 7.53-7.45 (2H, m) 7.42-7.35 (1H, m) 7.21 (0.38H, s, minor tautomer) 7.10 (0.59H, s, major tautomer) 6.87-6.79 (1H, m) 4.29 (2H, d, J=5.8 Hz) 3.93 (3H, s) 1.49-1.39 (2H, m) 1.28-1.23 (2H, m). MS m/z: 636, 638, 640 [M+H]+.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[F:21])[CH:3]=1.[Cl:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:28]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:31][CH:32]=1.[F-].[Cs+].C(=O)(O)[O-].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[C:31]([C:2]2[S:10][C:9]3[C:4](=[N:5][CH:6]=[CH:7][C:8]=3[O:11][C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=3[F:21])[CH:3]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(Br)sc23)c(F)c1
Reactant: CC1(C)OB(c2cccc(OCCCCl)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4cccc(OCCCCl)c4)sc23)c(F)c1
Yield: 77.8 %

Procedure:
Bromothienopyridine 50 (0.88 g, 2.38 mmol), boronate 363 (1.00 g, 3.40 mmol), and tetrakis(triphenylphosphine)palladium (0.10 g, 0.086 mmol) were dissolved in dry DME (100 mL). Cesium fluoride (1.26 g, 8.3 mmol) and sodium bicarbonate (0.70 g, 8.3 mmol) were dissolved in water (5 ml each) and added to the reaction mixture, which was then heated to reflux for 4 h, cooled, and concentrated. The residue was partitioned between ethyl acetate and water, washed with brine, dried (anhydrous MgSO4), filtered, and concentrated. The residue was purified by flash chromatography (eluent 75% dichloromethane/hexanes) to afford 364 (0.85 g, 78% yield). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.60 (d, J=6.3, 1H); 8.27-8.24 (m, 2H); 8.18 (s, 1H); 7.58-7.54 (m, 1H); 7.45-7.36 (m, 2H); 7.31 (t, J=2.0, 1H); 7.07-7.04 (m, 1H); 6.78 (d, J=6.1, 1H); 4.21 (t, J=5.9, 2H); 3.79 (t, J=6.3, 2H); 2.29 (quint, J=6.1, 2H). LRMS (M+H): 459.1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25](OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+].ClC1[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][N:47]=1>C(Cl)Cl.CS(C)=O>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][N:47]=4)[CH2:21][CH2:20]3)=[CH:15][N:16]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(c4ccc(C(F)(F)F)cn4)CC3)cn2)cc1

Procedure:
The title compound (73 mg, 66%) was prepared as a white solid from 1,1-dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (prepared as in Example 150, Step 2, 0.10 g, 0.22 mmol) and TFA (0.18 mL) in CH2Cl2 (6 mL) then K2CO3 (0.62 g) and 2-chloro-5-(trifluoromethyl)pyridine (50 mg, 0.27 mmol) in DMSO (5 mL) in a manner similar to Example 80. The crude material was purified by chromatography on a silica gel column eluted with 1:16 acetone/CH2Cl2 to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.40 (d, 1H, J=2.9 Hz), 8.36 (s, 1H), 8.24 (d, 2H, J=8.3 Hz), 8.02 (d, 1H, J=8.8 Hz), 7.95 (d, 2H, J=8.3 Hz), 7.75-7.70 (m, 1H), 7.51 (dd, 1H, Ja=8.8 Hz, Jb=3.0 Hz), 6.94 (d, 1H, J=9.1 Hz), 4.50-4.40 (m, 2H), 3.99 (d, 2H, J=6.4 Hz), 3.21 (s, 3H), 3.00-2.90 (m, 2H), 2.20-2.05 (m, 1H), 1.90-1.80 (m, 2H), 1.35-1.20 (m, 2H); LRMS (ESI), m/z 492 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][NH:20][CH3:21])=[C:13]([C:22]([F:25])([F:24])[F:23])[CH:12]=3)[N:7]=[C:6]([C:26]#[N:27])[C:5]=2[N:4]=[CH:3]1.[CH3:28][N:29]([CH3:36])[C:30]1([C:33](O)=[O:34])[CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOC(C)=O.CCOCC>[C:26]([C:6]1[C:5]2[N:4]=[CH:3][N:2]([CH3:1])[C:10]=2[CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]([CH3:21])[C:33]([C:30]3([N:29]([CH3:36])[CH3:28])[CH2:32][CH2:31]3)=[O:34])=[C:13]([C:22]([F:25])([F:23])[F:24])[CH:12]=2)[N:7]=1)#[N:27]
Reactant: CNCCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F
Reactant: CN(C)C1(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CN(CCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F)C(=O)C1(N(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
1-Methyl-6-(4-(2-(methylamino)ethoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (54 mg), 1-(dimethylamino)cyclopropane-carboxylic acid (37.2 mg), HATU (82 mg) and DIPEA (0.119 ml) were combined in NMP (2 ml) and stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (25 mL) and washed with 1:1 saturated sodium bicarbonate solution/water (3×15 mL). Organics were dried over sodium sulphate and solvent evaporated under reduced pressure. Purification by flash chromatography (10 g silica column, DCM to 5% MeOH in DCM gradient) followed by preparative HPLC (acidic) and SCX afforded N-(2-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl)-1-(dimethylamino)-N-methylcyclopropane-carboxamide (22% yield) as a white solid after trituration with ether and oven drying.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:39]=[CH:38][C:12]([C:13]([NH:15][CH:16]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:17]([CH3:31])([CH3:30])[C:18]([N:20]3[CH2:25][CH2:24][CH:23]([CH2:26][C:27]([O-:29])=[O:28])[CH2:22][CH2:21]3)=[O:19])=[O:14])=[CH:11][CH:10]=2)=[NH:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(=O)C>CO.[C].[Pd]>[N:1]1([C:7]([C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:15][CH:16]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:17]([CH3:31])([CH3:30])[C:18]([N:20]3[CH2:21][CH2:22][CH:23]([CH2:26][C:27]([OH:29])=[O:28])[CH2:24][CH2:25]3)=[O:19])=[O:14])=[CH:38][CH:39]=2)=[NH:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CC(C)(C(=O)N1CCC(CC(=O)[O-])CC1)C(NC(=O)c1ccc(C(=N)N2CCOCC2)cc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C(=O)N1CCC(CC(=O)O)CC1)C(NC(=O)c1ccc(C(=N)N2CCOCC2)cc1)c1ccccc1
Reaction time: 8 h
Yield: 69.6 %

Procedure:
The compound of Example 69, i.e. benzyl-N-(N-(4-(4-morpholinoimidoyl)benzoyl-β-phenyl-α,α-dimethyl-β-alanyl)-4-piperidineacetate (54 mg, 0.086 mmol) was dissolved in a 80% aqueous methanol solution (10 ml) containing 2% acetic acid. To the resulting solution was added 5% palladium carbon (10 mg) and the mixture was stirred overnight under a hydrogen atmosphere. After the solvent was distilled off, the residue was dissolved in a 1N aqueous solution of acetic acid and purified by HPLC in the same manner as in Example 44 to yield the titled compound (32 mg, 69%).
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:17]([CH2:18][C:19]([F:22])([F:21])[F:20])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:23]([CH3:25])[CH3:24])[S:14]2)[C@H:10]1[O:26]CC1C=CC=CC=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO.[NH4+].[OH-]>ClCCl>[CH3:25][N:23]([CH3:24])[C:13]1[S:14][C@H:15]2[O:16][C@H:17]([CH2:18][C:19]([F:22])([F:20])[F:21])[C@@H:9]([OH:8])[C@H:10]([OH:26])[C@H:11]2[N:12]=1
Reactant: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](CC(F)(F)F)O[C@@H]2S1
Agent: ClB(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CC(F)(F)F)O[C@@H]2S1
Reaction time: 1 h
Yield: 52.3 %

Procedure:
A solution of compound 112 (300 mg, 0.6 mmol) in dichloromethane (10 mL) was added BCl3 (3 mL, 3 mmol, 1M in dichloromethane) at −78° C. The resulting solution was kept at −20° C. for 1 hour, then quenched by the addition of methanol (10 mL). Volatiles were distilled out under vacuum to give a residue, which was dissolved into methanol (5 mL) and neutralized by Con. NH4OH (2 ml, 26% aqueous solution). After concentration, the crude product was purified by a silica gel column, eluted with 10% methanol in dichloromethane to give the title compound as a white solid (94.2 mg, 49%). (ES, m/z): [M+H]+ 300.9; 1H NMR (D2O, 300 MHz) δ 6.16 (d, J=6.3 Hz, 1H), 4.11-4.15 (m, 1H), 3.93-3.97 (m, 1H), 3.77-3.83 (m, 1H), 3.44-3.48 (m, 1H), 2.91 (s, 6H), 2.52-2.68 (m, 1H), 2.37-2.49 (m, 1H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.C1C2C(=CC=CC=2)C=CC=1C(O)=O.IC1C=CC(N)=CC=1>>[CH2:1]([S:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH:24][C:23]1[CH:25]=[CH:26][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1SCc1ccccc1
Reactant: COc1ccc(N)cc1
Agent: Nc1ccc(I)cc1
Agent: O=C(O)c1ccc2ccccc2c1
Product: COc1ccc(NC(=O)c2ccccc2SCc2ccccc2)cc1

Procedure:
The title compound was synthesized by the same procedure as for Example 15, except 2-benzylsulfanyl-benzoic acid and 4-methoxyaniline were used instead of 2-napthoic acid and 4-iodoaniline. M+364.2
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH2:9])[CH:5]=[C:4]([Br:10])[CH:3]=1>C1COCC1.[OH-].[OH-].[Pd+2]>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[C:4]([Br:10])[CH:3]=1
Reactant: C=Cc1cc(Br)cc(Br)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.6 %

Procedure:
A mixture of 1,3-dibromo-5-vinyl-benzene (4.55 g, 17.4 mmol) and 20% Pd(OH)2/C (2.0 g) in THF (60 mL) is purged with N2 and then H2, and the mixture is stirred under a H2 balloon at rt for 5 hours. The mixture is filtered through hyflo, and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 15/1 hexanes/ethyl acetate to afford 3.38 g (74%) of the title compound. Rf=0.63 (9/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3).
Reaction SMILES: N1([C:6]2[CH2:14][C@H:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[C:8](=O)[CH:7]=2)CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].C([OH:26])C>O1CCCC1>[CH2:12]1[C@@H:13]2[N:9]([CH2:8][CH2:7][C:6](=[O:26])[CH2:14]2)[CH2:10][CH2:11]1
Reactant: CCO
Reactant: O=C1C=C(N2CCCC2)C[C@@H]2CCCN12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1CCN2CCC[C@H]2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
(S)-7-(1-Pyrrolidinyl)-1,2,3,5,8,8a-hexahydroindolizin-5-one (645 mg (3.13 mmol), prepared as described in 4)) was dissolved in tetrahydrofuran (10 ml). To the solution was added lithium aluminum hydride (356 mg, 9.39 mmol) under ice cooling, and the resulting mixture was stirred at room temperature overnight. To the reaction mixture were added an aqueous solution of 1N sodium hydroxide (1.44 ml) and ethanol, and insoluble material was filtered off. The filtrate was concentrated by distillation under reduced pressure and the resulting residue was purified by column chromatography through alumina (eluent, ethyl acetate), to give the title compound (236 mg) as a light brown oil (yield 54%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH3:13].CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:30].[N:31]1([CH2:37][CH2:38][N:39]2[CH2:44][C:43]3[CH:45]=[C:46](/[CH:49]=[CH:50]/[C:51](O)=[O:52])[CH:47]=[N:48][C:42]=3[NH:41][C:40]2=[O:54])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[ClH:30].[CH3:1][N:2]([CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH3:13])[C:51](=[O:52])/[CH:50]=[CH:49]/[C:46]1[CH:47]=[N:48][C:42]2[NH:41][C:40](=[O:54])[N:39]([CH2:38][CH2:37][N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)[CH2:44][C:43]=2[CH:45]=1
Reactant: CNCc1c(C)oc2ccccc12
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)C(=O)N2
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: Cl
Product: Cc1oc2ccccc2c1CN(C)C(=O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)C(=O)N2
Yield: 82 %

Procedure:
According to the procedure of Example 1, except substituting methyl-(2-methyl-benzofuran-3-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-[3-(2-morpholin-4-yl-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3,-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.17 g, 82%) was prepared as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 10.70-10.59 (m, 1H), 10.13 (s, 1H), 8.41-8.35 (m, 1H), 8.10-7.99 (m, 1H), 7.58-7.46 (m, 3H), 7.22-7.15 (m, 3H), 5.31-4.93 (m, 2H), 4.72-4.52 (m, 3H), 4.01-3.91 (m, 2H), 3.81-3.71 (m, 4H), 3.60-3.50 (m, 2H), 3.39-3.30 (m, 2H), 3.19-3.01 (m, 4H), 2.51 (s, 3H); MS (ESI) m/e 490 M+H)+.