Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:13][CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CCO.CCOC(C)=O>[Si:16]([O:15][C@@H:14]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CNCC[C@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 72 h
Yield: 99 %

Procedure:
To a solution of (3R,4R)-benzyl 3-(tert-butoxycarbonylamino)-4-(tert-butyldimethylsilyloxy)piperidine-1-carboxylate (1.0 equiv.) in 1:1 EtOH/EtOAc, at a concentration of 0.1 M, was added 10% palladium on carbon (0.1 eq.). The resultant heterogeneous solution was put under an atmosphere of hydrogen and was stirred for 72 hours. At this time the mixture was filtered through a pad of celite eluting with EtOAc. The volatiles were removed in vacuo yielding tert-butyl (3R,4R)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate (99%). LCMS (m/z): 331.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([C:7]1[C:12]([O:13]COC)=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6].S(=O)(=O)(O)O.CC(C)=O.[OH-].[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([C:7]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6]
Reactant: COCOc1cccnc1C(=O)c1cccc(Br)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(c1cccc(Br)c1)c1ncccc1O
Yield: 93.1 %

Procedure:
A mixture of 2-(3-bromobenzoyl)-3-methoxymethoxy pyridine (5.55 g), 3.6N-sulfuric acid (11 mL) and acetone (30 mL) was subjected to reflux for 3 hours. The reaction mixture was poured into water, neutralized with an aqueous solution of sodium hydroxide, and extracted with ethyl acetate. The extract was washed with water and a saturated aqueous saline solution, successively, and dried (sodium sulfate) and then concentrated. The concentrate was purified by means of a silica gel column (ethyl acetate--hexane) to afford 2-(3-bromobenzoyl)-3-hydroxypyridine (4.46 g) (compound C-1). Physical properties and spectrum date of the product are shown in Table 5 and Table 6. In substantially the same manner as above, compounds C-2 to C-4 and C-6 to C-9 shown in Table 5 were produced.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH2:3][C:2]21[O:14][CH2:13][CH2:12][O:11]2.C(N([CH2:20][CH3:21])CC)C>C(Cl)Cl>[C:21]1([O:14][C:2](=[O:11])[NH:10][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[CH2:1][C:2]2([O:11][CH2:12][CH2:13][O:14]2)[CH2:3]3)[CH:20]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: Nc1ccc2c(c1)CC1(C2)OCCO1
Solvent: ClCCl
Product: O=C(Nc1ccc2c(c1)CC1(C2)OCCO1)Oc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 1′,3′-Dihydro-spiro[[1,3]dioxolane-2,2′-inden]-5′-ylamine (1.0 g, 5.23 mmol) in CH2Cl2 (15 mL) was added phenyl chloroforamte (0.66 mL, 5.23 mmol) drop wise at room temperature followed by triethylamine (1.15 mL, 8.3 mmol). The reaction mixture was stirred at r.t for 30 min and then solvent was removed under vacuum. Water was added to the resulting crude product and the precipitate was filtered and dried to give the crude (1′,3′-Dihydro-spiro[[1,3]dioxolane-2,2′-inden]-5′-yl)-carbamic acid phenyl ester as a pale yellow solid (1.62 g, quantitative).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31].C(=O)([O-])O.[Na+]>CN1CCCC1=O>[Cl:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[N:11]=2)=[CH:3][C:2]=1[NH:1][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][CH:35]=[C:27]([C:26]([F:25])([F:36])[F:37])[CH:28]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1Cl)c1cccc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
A mixture of N-[6-(3-amino-4-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (103 mg, 0.30 mmol), 3-(trifluoromethyl)benzoyl chloride (75 mg, 0.36 mmol) and N-methylpyrrolidone (3.0 mL) was heated to 50° C., and the mixture was stirred for 10 min. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/19→ethyl acetate) to give the title compound (131 mg, 85%) as a white powder.
Reaction SMILES: C([N:8]1[C@H:12]([C:13]#[CH:14])[CH2:11][O:10]C1(C)C)(OC(C)(C)C)=O.[F:17][C:18]1[C:19](I)=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])/[C:21]/2=[CH:28]\[C:29]1[NH:30][CH:31]=[CH:32][C:33]=1[O:34][CH3:35].O>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.FC(F)(F)C(O)=O.C(Cl)Cl.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>[NH2:8][C@@H:12]([CH2:11][OH:10])[C:13]#[C:14][C:19]1[C:18]([F:17])=[CH:26][CH:25]=[C:24]2[C:20]=1/[C:21](=[CH:28]/[C:29]1[NH:30][CH:31]=[CH:32][C:33]=1[O:34][CH3:35])/[C:22](=[O:27])[NH:23]2
Reactant: C#C[C@@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@@H](N)CO)c21
Reaction time: 2 h

Procedure:
Using Method C above, (R)-N-Boc-2,2-dimethyl-4-ethynyl-oxazolidine (141 mg, 0.62 mmol) (Example 91A above) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (80 mg, 0.21 mmol) (Starting Material 6) using (Ph3P)4Pd (24 mg, 0.02 mmol) and a catalytic amount of Cul in a mixture of DMF (4 mL) and Et3N (4 mL) as solvent at 80° C. for 8.5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, concentrated and the residue was chromatographed on a silica gel column with a 0-50% THF in hexanes gradient. The intermediate that resulted from this operation was directly dissolved in 6 mL of a 50% trifluoroacetic acid in CH2Cl2 solution that contained 0.6 mL of H2O at 0° C. and stirred for 2 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with ammonium hydroxide. The organic layer was dried over Na2SO4 and concentrated. (R)-(Z)-4-(3-Amino-4-hydroxy-1-butynyl)-1,3-dihydro-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with 0-20% MeOH in CH2Cl2 gradient and precipitation out of THF with excess pentane. (Yield 10 mg, 14%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:30]=[C:31]([CH3:41])[C:32]3[N:36]=[C:35]([CH:37]4[CH2:39][CH2:38]4)[NH:34][C:33]=3[CH:40]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:37]1([C:35]2[NH:34][C:33]3[CH:40]=[C:29]([O:28][C:24]4[N:25]=[CH:26][N:27]=[C:22]([N:17]5[CH2:18][CH2:19][CH:14]([N:10]6[CH2:9][CH2:8][C:7]7[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=7[NH:12][C:11]6=[O:13])[CH2:15][CH2:16]5)[CH:23]=4)[CH:30]=[C:31]([CH3:41])[C:32]=3[N:36]=2)[CH2:38][CH2:39]1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2[nH]c(C3CC3)nc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5nc(C6CC6)[nH]c5c4)ncn3)CC1)C(=O)N2

Procedure:
44 mg (0.16 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 40 mg (0.13 mmol) 6-(6-chloropyrimidin-4-yloxy)-2-cyclopropyl-4-methyl-1H-benzo[d]imidazole and 0.06 mL (0.32 mmol) DIPEA in 2.0 mL DMF were stirred overnight at RT. The reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were partially evaporated down i.vac. and neutralised with 4M sodium hydroxide solution. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][CH2:6][N:7]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)(=[O:20])=[O:19])[C:8]1([C:14](=[O:17])[NH:15][OH:16])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)C.C1(C)C=CC=CC=1.O.[OH-].[Na+]>ClCCl>[F:34][C:31]1[CH:30]=[CH:29][C:28]([O:27][C:24]2[CH:23]=[CH:22][C:21]([S:18]([N:7]([C:8]3([C:14](=[O:17])[NH:15][OH:16])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[CH2:6][CH2:5][C:4]([OH:35])=[O:3])(=[O:19])=[O:20])=[CH:26][CH:25]=2)=[CH:33][CH:32]=1
Reactant: CCOC(=O)CCN(C1(C(=O)NO)CCOCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)CCN(C1(C(=O)NO)CCOCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of (15.1 mmol) of the product from Step G in dichloromethane is concentrated by rotary evaporation with the addition of 75 mL of toluene. This solution is treated with 75 mL of water, cooled to 0° C., and treated with 6.05 g (151 mmol, 10 equivalents) of sodium hydroxide pellets over 10 minutes with vigorous stirring. This mixture is stirred for 15 minutes at 0° C. and warmed to ambient temperature over one hour. The aqueous phase is separated, diluted with 7.5 mL of tetrahydrofuran, cooled to 0° C., and treated with 33 mL of 6N aqueous hydrochloric acid over 20 minutes. This mixture is stirred with 75 mL of ethyl acetate at 0° C. to ambient temperature, and the ethyl acetate phase is separated and washed with water. The ethyl acetate solution was concentrated to yield the title compound.
Reaction SMILES: [CH3:1]OC1C(C=O)=CC2N(C)C(=O)CCC=2N=1.[CH2:17]([CH:19]1[NH:24][CH:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]([NH:31][CH2:32][C:33]2[CH:42]=[C:41]3[C:36]([CH2:37][CH2:38][C:39](=[O:44])[N:40]3[CH3:43])=[N:35][C:34]=2[O:45][CH3:46])[CH2:21][CH2:20]1)[CH3:18]>CCCCCCC.C(O)C>[CH3:46][O:45][C:34]1[N:35]=[C:36]2[C:41](=[CH:42][C:33]=1[CH2:32][NH:31][C@H:22]1[CH2:21][CH2:20][C@H:19]([CH2:17][CH2:18][CH3:1])[NH:24][C@H:23]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[N:40]([CH3:43])[C:39](=[O:44])[CH2:38][CH2:37]2
Reactant: COc1nc2c(cc1C=O)N(C)C(=O)CC2
Reactant: CCC1CCC(NCc2cc3c(nc2OC)CCC(=O)N3C)C(c2ccccc2)N1
Solvent: CCO
Solvent: CCCCCCC
Product: CCC[C@H]1CC[C@H](NCc2cc3c(nc2OC)CCC(=O)N3C)[C@H](c2ccccc2)N1

Procedure:
By a procedure similar to the previous example 74: starting with cis-2-phenyl-3-amino-trans-6-(n-propyl)-piperidine (Scheme J) and 2-methoxy-5-methyl-6-oxo-5,6,7,8-tetrahydro-[1,5]naphthyridine-3-carbaldehyde (Example 74, step 5) and using the above coupling procedure (Example 74, step 6) 7-[(6-ethyl-2-phenyl-piperidin-3-ylamino)-methyl]-6-methoxy-1-methyl-3,4-dihydro-1H-[1,5]naphthyridin-2-one was obtained. Using a CHIRALPAK AD (10×50 cm) and a mobil phase of 95:5 heptane/ethanol containing 0.025% diethyl amine (flow rate=275 ml/min) 6-methoxy-1-methyl-7-[(2(S)-phenyl-6(S)-propyl-piperidin-3(S)-ylamino)-methyl]-3,4-dihydro-1H-[1,5]naphthyridin-2-one (retention time 11.479 min) was isolated as a pure enantiomer. 1H NMR (CDCl3) δ 7.40 (m, 2H), 7.30 (m, 2H), 7.22 (m, 1H), 6.95 (s, 1H), 4.20 (s, 1H), 3.72 (s, 3H), 3.80, 3.62 (d,d, 2H), 3.20 (m, 1H), 3.10 (s, 3H), 2.90 (m, 2H), 2.85 (m, 1H), 2.62 (m, 2H), 2.10 (m, 2H), 1.90 (m, 3H), 1.70 (m, 1H), 1.42 (m, 1H), 1.30 (m, 3H), 0.9 (t, 3H). Mass spectrum: m/e=423.2 (p+1). The corresponding enantiomer 6-methoxy-1-methyl-7-[(2(R)-phenyl-6(R)-propyl-piperidin-3(R)-ylamino)-methyl]-3,4-dihydro-1H-[1,5]naphthyridin-2-one (retention time 11.592 min) was also isolated. NMR and mass spectrum was identical to the above spectra.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:29])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([OH:28])[C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=1.O>C1C=CC=CC=1>[CH3:27][O:26][C:24]([CH:23]([OH:28])[CH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])[CH3:29])=[CH:17][CH:18]=1)=[O:25]
Reactant: COC(=O)C(O)Cc1ccc(OCC(C)=O)cc1
Reactant: NCC(O)c1cccc(Cl)c1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)C(O)Cc1ccc(OCC(C)NCC(O)c2cccc(Cl)c2)cc1
Yield: 68.9 %

Procedure:
A mixture of 1.16 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8), 1.71 g of methyl 3-[4-(2-oxopropoxy)phenyl]lactate (prepared as described in Preparation 6) and 40 ml of benzene was heated under reflux for 3.5 hours, whilst the water being formed during the reaction was continuously removed. After completion of the reaction, the benzene used in the reaction was removed by distillation under reduced pressure, and the residue was dissolved in 50 ml of absolute methanol. 2.04 g of sodium cyanoborohydride were added, whilst ice-cooling, to the solution, and the resulting mixture was allowed to react overnight at room temperature. At the end of this time, methanol was removed by distillation under reduced pressure, and the resulting residue was mixed with ethyl acetate and with an aqueous solution of sodium chloride. The ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent, to give 1.9 g of the title compound having an Rf=0.30 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]3[CH:37]=[CH:36][NH:35][C:32]3=[N:33][CH:34]=2)O1>>[NH:35]1[C:32]2=[N:33][CH:34]=[C:29]([C:2]3[CH:3]=[CH:4][N:5]4[C:10]([C:11]=3[CH3:12])=[C:9]([CH:13]3[CH2:15][CH2:14]3)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]4=[O:20])[CH:30]=[C:31]2[CH:37]=[CH:36]1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3cnc4[nH]ccc4c3)ccn2c1=O

Procedure:
Methyl 8-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A′ from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (100.3 mg, 0.41 mmol).
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[C:5]([F:10])[C:4]=1[CH2:11][C:12]([OH:14])=O.[CH2:15]([C@H:22]1[CH2:26][NH:25][C@H:24]([C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[CH:32][CH:31]=2)=[O:28])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([C@H:22]1[CH2:26][N:25]([C:12](=[O:14])[CH2:11][C:4]2[C:5]([F:10])=[CH:6][CH:7]=[C:8]([F:9])[C:3]=2[F:2])[C@H:24]([C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]3[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=3)=[CH:32][CH:31]=2)=[O:28])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: O=C(O)Cc1c(F)ccc(F)c1F
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)Cc1c(F)ccc(F)c1F
Yield: 49.8 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2,3,6-trifluorophenyl)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 84, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-(2,3,6-trifluorophenyl)acetyl)pyrrolidine-2-carboxamide (16.8 mg, 49.8%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): a 9.93 (s, 1H), 7.52 (d, 2H), 7.39 (m, 1H), 7.32-7.15 (m, 9H), 7.09 (m, 1H), 6.93 (m, 2H), 4.46 (m, 1H), 3.79 (m, 3H), 3.38 (m, 1H), 2.70 (m, 3H), 1.93 (m, 2H). MS (EI) for C32H26F4N2O3. found 563.6 (MH+).
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20](Br)[S:21][C:17]=2[C:16]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:33][C:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[CH:36][N:35]=1.C(=O)([O-])[O-].[K+].[K+]>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>[C:1]([O:7][CH2:8][C@@H:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20]([C:38]3[CH:37]=[CH:36][N:35]=[C:34]([Cl:33])[CH:39]=3)[S:21][C:17]=2[C:16]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: Cc1cc2nc(Br)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(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: [K+]
Product: Cc1cc2nc(-c3ccnc(Cl)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 90 °C

Procedure:
(S)-2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (400.0 mg, 0.742 mmol), 2-chloro-4-pyridinylboronic acid (140.2 mg, 0.891 mmol), potassium carbonate (307.7 mg, 2.227 mmol), and Pd(PPh3)4 (128.7 mg, 0.111 mmol) were placed in a microwave vial and the vial was vacuum pumped and flushed with argon three times. To this mixture was added degassed 1,4-dioxane (3.5 mL) and water (0.7 mL). The reaction mixture was heated at 90° C. for 4.5 h then cooled to rt. The aqueous layer was separated and extracted three times with ethyl acetate. All organic layers were combined, dried over Na2SO4, and concentrated. Purification by flash column chromatography on silica gel (hexanes/ethyl acetate eluent) provided the final compound. LCMS-ESI+: calc'd for C30H33O2N2O3S: 571.2 (M+H+); Found: 571.1 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J=4.9 Hz, 1H), 7.93 (s, 2H), 7.77 (d, J=5.0 Hz, 1H), 7.55 (d, J=9.2 Hz, 1H), 7.50 (d, J=7.4 Hz, 1H), 7.40 (d, J=7.4 Hz, 1H), 7.29 (d, J=8.9 Hz, 1H), 4.82 (dd, J=8.9, 2.7 Hz, 1H), 4.42 (dd, J=11.2, 9.3 Hz, 1H), 4.29 (dd, J=11.5, 3.2 Hz, 1H), 2.80 (s, 3H), 1.14 (s, 9H), 0.97 (s, 9H).
Reaction SMILES: [I-:1].[NH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N+:10]1[C:14]([CH3:15])=[CH:13][S:12][C:11]=1SC>CO>[I-:1].[F:9][C:7]1[CH:6]=[CH:5][C:4]2[N:10]3[C:14]([CH3:15])=[CH:13][S:12][C:11]3=[NH+:2][C:3]=2[CH:8]=1
Reactant: CSc1scc(C)[n+]1-c1ccc(F)cc1N
Agent: [I-]
Solvent: CO
Product: Cc1csc2[nH+]c3cc(F)ccc3n12
Yield: 99.6 %

Procedure:
2 g (5.23 mmol) of 3-(2-amino-4-fluorophenyl)-4-methyl-2-(methylsulfanyl)-1,3-thiazol-3-ium iodide obtained in stage B1 were solubilised in MeOH (200 mL) and the solution refluxed for 12 h. Then MeOH was evaporated to yield 7-fluoro-3-methyl[1,3]thiazolo[3,2-a]benzimidazol-9-ium iodide (4b) (pale yellow powder, 1.74 g, 99%). Mp=240° C.; 1H NMR (300 MHz, CD3OD) δ=2.83 (3H, d, 0.1=1.3, CH3), 7.03 (1H, q, J=1.3, H5), 7.20-7.27 (1H, m, Ar), 7.47-7.51 (1H, m, Ar), 8.06-8.11 (1H, m, Ar); 13C NMR (75 MHz, CD3OD) δ=14.1, 103.5 (d, J=27), 109.9, 112.1 (d, J=27), 114.0 (d, J=10), 126.9, 133.3, 143.6 (d, J=10), 158.3, 162.0 (d, J=242); HRMS m/z C10H8N2FS [M−I]+ calcd: 207.0387, found: 207.0388. Stage C: Preparation of 7-fluoro-3,9-dimethyl[1,3]thiazolo[3,2-a]benzimidazol-9-ium iodide
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13](=O)[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:26]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([Cl:26])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(=O)[nH]c(-c3ccc(C(C)(C)C)cc3)cc2c1
Product: COc1ccc2c(Cl)nc(-c3ccc(C(C)(C)C)cc3)cc2c1
Yield: 28 %

Procedure:
A solution of 3-(4-(tert-butyl)phenyl)-6-methoxyisoquinolin-1(2H)-one (0.7 g, 2.277 mmol) in POCl3 (7 ml) was refluxed for overnight. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified by solid sodium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (10% ethyl acetate in pet ether) to get desired compound (0.21 g, 28.0%) as solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.34(s, 1H), 8.18-8.16 (d, J=8 Hz, 1H), 8.08-8.06 (d, J=8 Hz, 2H), 7.57-7.55 (d, J=8 Hz, 2H), 7.41 (s, 1H), 7.40-7.38 (d, J=8 Hz, 1H), 3.97 (s, 3H), 1.34 (s, 9H); MS: MS m/z 362.2 (M++1).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:23][CH2:22][N:21]3[C:14](=[CH:15][C:16]4[CH2:17][C:18]([CH3:25])([CH3:24])[CH2:19][C:20]=43)[C:13]2=[O:26])=[CH:10][C:9]([F:27])=[CH:8][C:7]=1[C:28]1[CH:33]=[C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH2:46][C@@H:45]([CH3:47])[N:44]([CH:48]4[CH2:51][O:50][CH2:49]4)[CH2:43][C@@H:42]3[CH3:52])=[CH:37][N:36]=2)[C:31](=[O:53])[N:30]([CH3:54])[CH:29]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[CH3:52][C@H:42]1[CH2:43][N:44]([CH:48]2[CH2:51][O:50][CH2:49]2)[C@H:45]([CH3:47])[CH2:46][N:41]1[C:38]1[CH:39]=[CH:40][C:35]([NH:34][C:32]2[C:31](=[O:53])[N:30]([CH3:54])[CH:29]=[C:28]([C:7]3[C:6]([CH2:5][OH:4])=[C:11]([N:12]4[CH2:23][CH2:22][N:21]5[C:20]6[CH2:19][C:18]([CH3:24])([CH3:25])[CH2:17][C:16]=6[CH:15]=[C:14]5[C:13]4=[O:26])[CH:10]=[C:9]([F:27])[CH:8]=3)[CH:33]=2)=[N:36][CH:37]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4C[C@@H](C)N(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2ccc(Nc3cc(-c4cc(F)cc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4CO)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Temperature: 30 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
A mixture of 116a (150 mg, 0.20 mmol) and lithium hydroxide (48 mg, 2.0 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at 30° C. for 1 h. The mixture was evaporated under reduced pressure. The resulting residue was extracted with ethyl acetate (2×10 mL). The combined organic layer was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 116 (57 mg, 41%) as white solid. MS: [M+H]+ 696.3. 1H NMR (500 MHz, CDCl3) δ 8.60 (dd, J=2.0, 6.5 Hz, 1H), 8.02 (d, J=2.5 Hz, 1H), 7.88 (s, 1H), 7.50-7.49 (m, 1H), 7.37 (d, J=8.5 Hz, 1H), 7.16 (d, J=9.0 Hz, 1H), 6.96 (dd, J=2.5, 9.0 Hz, 1H), 6.83-6.81 (m, 2H), 4.77-4.74 (m, 2H), 4.66-4.62 (m, 2H), 4.57-4.55 (m, 1H), 4.33-4.31 (m, 1H), 4.23-4.14 (m, 3H), 3.92-3.89 (m, 1H), 3.78-3.76 (m, 1H), 3.71 (s, 3H), 3.22-3.20 (m, 1H), 2.93-2.91 (m, 1H), 2.75-2.73 (m, 2H), 2.58 (s, 2H), 2.52 (s, 3H), 1.97-1.90 (m, 2H), 1.28 (s, 6H), 0.91 (d, J=5.5 Hz, 6H).