Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([CH:12]3[CH:16]([C:17]([OH:19])=O)[CH2:15][CH2:14][N:13]3[CH3:20])[CH:9]=[C:8]([CH3:21])[N:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:46]1[C:51]2[CH:52]=[CH:53][C:54]([CH2:56][CH2:57][NH2:58])=[CH:55][C:50]=2[O:49][CH2:48][CH2:47]1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[O:46]1[C:51]2[CH:52]=[CH:53][C:54]([CH2:56][CH2:57][NH:58][C:17]([CH:16]3[CH2:15][CH2:14][N:13]([CH3:20])[CH:12]3[C:10]3[CH:9]=[C:8]([CH3:21])[N:7]=[C:6]([N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[N:11]=3)=[O:19])=[CH:55][C:50]=2[O:49][CH2:48][CH2:47]1
Reactant: Cc1cc(C2C(C(=O)O)CCN2C)nc(-n2ccnc2)n1
Reactant: NCCc1ccc2c(c1)OCCO2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C2C(C(=O)NCCc3ccc4c(c3)OCCO4)CCN2C)nc(-n2ccnc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.8 %

Procedure:
2-(2-Imidazol-1-yl-6-methyl-pyrimidin-4-yl)-1-methyl-pyrrolidine-3-carboxylic acid (27.0 mg, 0.094 mmol) was dissolved in DMF (1 mL). Next, the HBTU (54.0 mg, 0.141 mmol) was added. The reaction was stirred at room temperature for 30 minutes prior to addition of 2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamine (17.0 mg, 0.094 mmol) and the triethylamine (50 μL). The reaction was stirred at rt for 12 h then heated to 60° C. for 16 h. After this period, the reaction mixture was transferred to a separatory funnel with ethyl acetate (20 mL). The organic layer was washed with saturated NaHCO3 (aq) (30 mL) and H2O (30 mL), respectively. The aqueous layers were back extracted with ethyl acetate and all of the organic portions were combined, dried over Na2SO4 and concentrated under vacuum. The material was purified by Flash Chromatography (10 g, 0-10% methanol/DCM gradient) to afford 3.3 mg of 2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-1-methyl-pyrrolidine-3-carboxylic acid [2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-amide. Product isolated as a mixture of diasteromers; [M+H]+ 449.84.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16]S(C(C)(C)C)=O)[C:11]([O:13][CH2:14][CH3:15])=C)=[CH:4][CH:3]=1.[O:30]1CCOCC1>>[NH2:16][C:8]1([C:11]([O:13][CH2:14][CH3:15])=[O:30])[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=2)[CH2:6][C:7]21[CH2:23][CH2:24][CH:25]([O:28][CH3:29])[CH2:26][CH2:27]2
Reactant: C1COCCO1
Reactant: C=C(OCC)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Product: CCOC(=O)C1(N)c2cc(Br)ccc2CC12CCC(OC)CC2
Yield: 38 %

Procedure:
To solution of compound 5 (100 mg, 0.26 mmol) and Lawesson'reagent (104 mg, 0.26 mmol) in dioxane (3 mL) was heated at 150° C. for 30 min in a microwave reactor. The mixture was cooled, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexanes: EtOAc=20:1) to give compound 7 (30 mg, 38%) as a light orange solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4](=[O:12])[N:3]1[CH2:13][C:14]([OH:16])=O.[Cl:17]C(Cl)OCC>C(Cl)(Cl)Cl>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4](=[O:12])[N:3]1[CH2:13][C:14]([Cl:17])=[O:16]
Reactant: O=C(O)CN1C(=O)Cc2ccccc2C1=O
Reactant: CCOC(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(Cl)CN1C(=O)Cc2ccccc2C1=O
Yield: 100.3 %

Procedure:
To a solution of 2-(1,3-dioxo-3,4-dihydroisoquinolin-2(1H)-yl)acetic acid (150 mg, 0.684 mmol) in CHCl3 (3 ml), (dichloromethoxy)ethane (1 ml, 0.684 mmol) was added, and the mixture refluxed for 3 hours. The solvent was evaporated under reduced pressure, the crude taken up with CHCl3, and the solvent evaporated again to give the title compound (163 mg, quantitative yield).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:21][N:20]([C:22]3[N:26]([CH3:27])[N:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[CH:23]=3)[CH2:19][CH2:18][C:4]=2[N:5]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10]([CH3:17])=[CH:11][NH:12]3)[N:7]=1.C(N(C(C)C)CC)(C)C.[CH3:40][C@H:41]1[CH2:46][CH2:45][CH2:44][CH2:43][NH:42]1>CN(C)C(=O)C>[CH:28]([C:24]1[CH:23]=[C:22]([N:20]2[CH2:19][CH2:18][C:2]3[N:7]=[C:6]([C:8]4[CH:16]=[CH:15][CH:14]=[C:13]5[C:9]=4[C:10]([CH3:17])=[CH:11][NH:12]5)[N:5]=[C:4]([N:42]4[CH2:43][CH2:44][CH2:45][CH2:46][C@@H:41]4[CH3:40])[C:3]=3[CH2:21]2)[N:26]([CH3:27])[N:25]=1)([CH3:29])[CH3:30]
Reactant: Cc1c[nH]c2cccc(-c3nc(Cl)c4c(n3)CCN(c3cc(C(C)C)nn3C)C4)c12
Reactant: C[C@H]1CCCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1c[nH]c2cccc(-c3nc4c(c(N5CCCC[C@@H]5C)n3)CN(c3cc(C(C)C)nn3C)CC4)c12
Temperature: 125 °C

Procedure:
To a solution of 4-chloro-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3-methyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (50 mg, 0.123 mmol) in N,N-dimethylacetamide (1.5 mL), was added diisopropylethylamine (0.15 mL, 0.86 mmol) and (S)-2-methylpiperidine (37 mg, 0.37 mmol). The reaction was stirred and heated to 125° C. for 24 h. After cooling, the mixture was directly purified via HPLC ((0.1% ammonium hydroxide in acetonitrile)/water=35%-100%). 1H NMR (400 MHz, CD2Cl2) δ ppm 8.23 (br. s., 1 H), 7.42 (d, J=8.1 Hz, 1 H), 7.33 (d, J=8.1 Hz, 1 H), 7.16-7.26 (m, 1 H), 7.04 (s, 1 H), 5.69 (s, 1 H), 4.06-4.16 (m, 1 H), 3.90-4.06 (m, 2 H), 3.67 (s, 3 H), 3.53 (d, J=13.4 Hz, 1 H), 3.29-3.40 (m, 2 H), 3.16-3.29 (m, 1 H), 3.10 (d, J=4.5 Hz, 2 H), 2.85 (dt, J=13.8, 6.9 Hz, 1 H), 2.10 (s, 3 H), 1.74-1.91 (m, 2 H), 1.65-1.74 (m, 2 H), 1.48-1.65 (m, 2 H), 1.22 (d, J=6.8 Hz, 6 H); MS (ESI+) m/z 484.4 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[NH:16][C:15]4[CH:17]=[CH:18][CH:19]=[C:20]([C:21]([NH2:23])=[O:22])[C:14]=4[N:13]=3)[N:11]=2)[CH2:3][CH2:2]1.C=O.[C:26]([BH3-])#N.[Na+]>CO.O.[Cl-].[Zn+2].[Cl-]>[CH3:26][N:1]1[CH2:2][CH2:3][CH:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[NH:16][C:15]4[CH:17]=[CH:18][CH:19]=[C:20]([C:21]([NH2:23])=[O:22])[C:14]=4[N:13]=3)[N:11]=2)[CH2:5][CH2:6]1
Reactant: NC(=O)c1cccc2[nH]c(-c3csc(C4CCNCC4)n3)nc12
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CCC(c2nc(-c3nc4c(C(N)=O)cccc4[nH]3)cs2)CC1
Reaction time: 1 h

Procedure:
To a solution of EXAMPLE 5 (50 mg) in methanol (8 mL) was added 37 wt % formaldehyde in water (28 μL) and TEA (21 μL). The solution was stirred for 1 hour, treated with sodium cyanoborohydride (28 mg) and zinc (II) chloride (20 mg), stirred for 60 hours and was concentrated. The concentrate was purified by HPLC (Zorbax C-8, 0.1% TFA/acetonitrile/water). The salt was dissolved in dichloromethane (2 mL) and methanol (2 mL), treated with 1M hydrochloric acid in ether (4 mL) and concentrated. 1H NMR (DMSO-d6) δ 2.12-2.23 (m, 2H), 2.32-2.41 (m, 2H), 2.78 (d, J=4.6 Hz, 3H), 3.10-3.20 (m, 2H), 3.41-3.48 (m, 1H), 3.50-3.59 (m, 2H), 7.45 (t, J=7.8 Hz, 1H), 7.80-7.82 (m, 1H), 7.82-7.85 (m, 1H), 7.94 (d, J=6.7 Hz, 1H), 8.82 (brs, 1H), 8.98 (brs, 1H), 10.84 (brs, 1H).
Reaction SMILES: C([O:5][C:6](=[O:35])[CH:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C:20]2[C:21]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:19])=[C:12]([F:34])[CH:11]=1)[CH3:8])(C)(C)C.C(OC(=O)C(OC1C=CC(CNC(C2C(OC3C=CC4=NON=C4C=3)=NC=CC=2)=O)=C(F)C=1)C)(C)(C)C>>[F:34][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[CH2:16][NH:17][C:18]([C:20]1[C:21]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[N:22][CH:23]=[CH:24][CH:25]=1)=[O:19])[O:9][CH:7]([CH3:8])[C:6]([OH:35])=[O:5]
Reactant: CC(Oc1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)c(F)c1)C(=O)OC(C)(C)C
Agent: CC(Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3nonc3c2)c(F)c1)C(=O)OC(C)(C)C
Product: CC(Oc1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)c(F)c1)C(=O)O

Procedure:
The compound of Formula (5.5.4) was prepared in a manner analogous to that described in Example 3, substituting (±)-2-[3-fluoro-4-({[2-(4-fluoro-phenoxy)-pyridine-3-carbonyl]-amino}-methyl) -phenoxy]-propionic acid tert-butyl ester for the corresponding (±)-2-[4-({[2-(benzo[2,1,3]oxadiazol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-propionic acid tert-butyl ester material.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=1)=[CH:12][CH:11]=[C:10]([Cl:23])[CH:9]=2)=[O:5])[CH3:2].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8]2[C:13]([C:14]=1[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=1)=[CH:12][CH:11]=[C:10]([Cl:23])[CH:9]=2)=[O:5])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1[nH]c2cc(Cl)ccc2c1Sc1cccc(Br)c1
Product: CCOC(=O)c1c(Sc2cccc(Br)c2)c2ccc(Cl)cc2n1Cc1ccccc1

Procedure:
Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: 3-(3-bromo-phenylsulfanyl)-6-chloro-1H-indole-2-carboxylic acid ethyl ester and benzyl bromide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]3[CH2:14]N(C(OC(C)(C)C)=O)C[CH2:17][C:12]=3[NH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[O:25]1CCCC(=O)[CH2:26]1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]3[CH2:14][CH2:26][O:25][CH2:17][C:12]=3[NH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CCCOC1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(F)c(F)c3)c2C1
Product: Fc1ccc(-c2n[nH]c3c2CCOC3)cc1F

Procedure:
Intermediate 16B was prepared according to the procedure for the synthesis of intermediate 15 by replacing 1-Boc-4-piperidone with dihydro-2H-pyran-3(4H)-one LCMS (+ESI) m/z=236 [M+H]+. 1H NMR (CDCl3) δ 7.37-7.41 (m, 1H), 7.29-7.32 (m, 1H) 7.17-7.24 (m, 1H), 4.76 (s, 2H), 3.95 (t, J=5.5 Hz, 2H), 2.84 (t, J=5.5 Hz, 2H).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[C:11]([N:18]([CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)C(=O)C(F)(F)F)[CH:10]=2)[CH2:5][CH2:4]1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[F:42][C:43]1[CH:60]=[CH:59][C:58]([F:61])=[CH:57][C:44]=1[CH2:45][O:46][C:47]1[CH:48]=[C:49]2[C:53](=[CH:54][CH:55]=1)[NH:52][N:51]=[C:50]2[NH2:56]>C(Cl)Cl.N1C=CC=CC=1>[F:42][C:43]1[CH:60]=[CH:59][C:58]([F:61])=[CH:57][C:44]=1[CH2:45][O:46][C:47]1[CH:48]=[C:49]2[C:53](=[CH:54][CH:55]=1)[NH:52][N:51]=[C:50]2[NH:56][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([N:6]2[CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][CH2:5]2)=[CH:10][C:11]=1[NH:18][CH:25]1[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: CN1CCN(c2ccc(C(=O)O)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Reactant: Nc1n[nH]c2ccc(OCc3cc(F)ccc3F)cc12
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(OCc5cc(F)ccc5F)cc34)c(NC3CCOCC3)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.8 %

Procedure:
4-(4-Methylpiperazin-1-yl)-2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzoic acid hydrochloride (590 mg, 1.31 mmol) in dry DCM (10 mL), under nitrogen, was cooled with an ice bath and treated first with a drop of DMF and then with oxalyl chloride (2.62 mmol, 0.228 mmol). After stirring for 4 hours at room temperature, the solution was evaporated and the solid was dried under vacuum. The crude acid chloride was dissolved in 20 mL of dry pyridine, cooled with an ice bath and treated drop-wise with 5-[(2,5-difluorobenzyl)oxy]-1H-indazol-3-amine (300 mg, 1.09 mmol) in 15 mL of pyridine. The reaction was left overnight at 4° C. Volatiles were evaporated and the residue was diluted with water (300 mL) and extracted with EtOAc (3×300 mL). Organic phases were collected, dried over sodium sulfate and evaporated. Crude product was diluted with MeOH (10 mL) and heated at 80° C. in the presence of triethylamine (2.5 mL). After 3 hours, volatiles were evaporated and the residue was dissolved in DCM (100 mL), washed with NaHCO3 satured solution, water and brine. The organic layer was dried over sodium sulfate, filtered and evaporated under vacuum. Crude product was purified by flash chromatography over silica gel (DCM/MeOH 92:8) affording 470 mg (yield 75%) of title compound
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.B(O)(O)[C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.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:8][C:7]1[C:2]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccnc1Cl
Reactant: Cc1ccc(B(O)O)cc1
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: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2ncccc2Cl)cc1
Yield: 87 %

Procedure:
{circle around (2)} 100 g (0.676 mol) of 2,3-dichloropyridine was dissolved in 500 mL of ethanol, and 91.87 g (0.676 mol) of p-tolylboronic acid and 78 g (0.0676 mol) of Pd(PPh3)4 were sequentially added. A solution of 86 g (0.811 mol) of sodium carbonate in 500 mL of distilled water was placed in the reactor, and the mixture was heated to reflux for 4˜6 hours so as to allow it to react. After completion of the reaction, the reaction solution was concentrated under reduced pressure to remove ethanol, and then extracted with ethyl acetate. The extract was treated with magnesium sulfate, filtered, and concentrated under reduced pressure, yielding 3-chloro-2-para-tolylpyridine as represented below in a 87% yield.
Reaction SMILES: [OH-].[Na+].C(O)C.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22]3[CH:23]=[C:24]([CH:32]=[CH:33][CH:34]=3)[O:25][CH2:26][C:27]([O:29]CC)=[O:28])[N:14]=2)=[CH:9][CH:8]=1.Cl>O.O1CCOCC1>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22]3[CH:23]=[C:24]([CH:32]=[CH:33][CH:34]=3)[O:25][CH2:26][C:27]([OH:29])=[O:28])[N:14]=2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)COc1cccc(-n2nc(-c3ccc(F)cc3)c3cccnc32)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)COc1cccc(-n2nc(-c3ccc(F)cc3)c3cccnc32)c1
Yield: 64.6 %

Procedure:
In 5 ml of water was dissolved 0.97 g of sodium hydroxide, whereto 100 ml of ethanol was added. Thereto was added a solution of 8.0 g of ethyl 3-[3-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl]phenoxyacetate dissolved in 60 ml of dioxane while stirring. After the mixture was stirred at room temperature for 4 hours, about 500 ml of water was added thereto and the mixture was neutralized with dilute hydrochloric acid. The resulting crystals were collected by filtration and recrystallized from dioxane to give 4.8 g of 3-[3-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl]phenoxyacetic acid, m.p. 225°-226° C.
Reaction SMILES: C(NCCO)C1C=CC=CC=1.C([O:14][C:15](=[O:51])[C:16]([CH2:38][CH2:39][N:40]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:41][CH2:42][OH:43])([NH:30]C(OC(C)(C)C)=O)[CH2:17][CH2:18][CH2:19][CH2:20][B:21]1[O:25]C(C)(C)C(C)(C)[O:22]1)C.[ClH:52]>O>[ClH:52].[ClH:52].[NH2:30][C:16]([CH2:38][CH2:39][N:40]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:41][CH2:42][OH:43])([CH2:17][CH2:18][CH2:19][CH2:20][B:21]([OH:22])[OH:25])[C:15]([OH:51])=[O:14]
Reactant: CCOC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)(CCN(CCO)Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: OCCNCc1ccccc1
Solvent: O
Product: NC(CCCCB(O)O)(CCN(CCO)Cc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
2-Amino-2-{2-[benzyl-(2-hydroxyethyl)-amino]-ethyl}-6-borono-hexanoic acid dihydrochloride is prepared in a manner analogous to that set forth in Example 16, except 2-(benzylamino)ethanol is used as the amine in step 6. The final step is as follows: a solution of 2-{2-[benzyl-(2-hyrdoxyethyl)-amino]-ethyl}-2-tert-butoxycarbonylamino-6-(4,4,5,5-tetramethyl-[1,3,2]-dioxa-borolan-2-yl)-hexanoic acid ethyl ester (111 mg) in 6 N hydrochloric acid (6 mL) was stirred at 95° C. overnight. After cooling to room temperature, the reaction mixture was transferred to a separatory funnel, diluted with deionized water (5 mL) and washed with dichloromethane (3×). The aqueous layer was frozen in liquid nitrogen and lyophilized to give the title compound as a colorless foam (48 mg); 1H NMR (D2O, 300 MHz) δ 7.35 (s, 5H), 4.11-4.25 (m, 2H), 3.76 (s, 2H), 3.06-3.34 (m, 4H), 2.18 (m, 2H), 1.76 (m, 1H), 1.43 (m, 1H), 1.18 (m, 4H) and 0.56 (m, 2H); MS (+CI): m/z for C17H29BN2O5: expected 352.2. found 371.2 (M+H+H2O)+353.2 (M+H)+, 335.2 (M+H—H2O)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]([C:7]2[CH:12]=[N:11][C:10]([Cl:13])=[CH:9][N:8]=2)[N:6]=1.[Cl:19][C:20]1[C:24]([Cl:25])=[C:23]([CH3:26])[NH:22][C:21]=1[C:27]([NH:29][C@H:30]1[CH2:35][CH2:34][NH:33][CH2:32][C@H:31]1[O:36][CH3:37])=[O:28].C(N(CC)C(C)C)(C)C.O>CN1CCCC1=O>[Cl:13][C:10]1[N:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:33]3[CH2:34][CH2:35][C@H:30]([NH:29][C:27]([C:21]4[NH:22][C:23]([CH3:26])=[C:24]([Cl:25])[C:20]=4[Cl:19])=[O:28])[C@H:31]([O:36][CH3:37])[CH2:32]3)[S:3][C:4]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:8][CH:9]=1
Reactant: CCOC(=O)c1sc(Br)nc1-c1cnc(Cl)cn1
Reactant: CO[C@@H]1CNCC[C@@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)nc1-c1cnc(Cl)cn1
Temperature: 52.5 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
Ethyl 2-bromo-4-(5-chloropyrazin-2-yl)-1,3-thiazole-5-carboxylate (Intermediate 47, 120 mg, 0.3960 mM) was added to a solution of 3,4-dichloro-N-[(3R,4S)-3-methoxypiperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide (WO2006087543, 127 mg, 0.4158 mM) and N,N-diisopropylethylamine (159.6 mg, 1.247 mM) in N-methyl 2-pyrrolidinone (1.0 mL) and the resulting reaction mixture was stirred at 50-55° C. for 1 h. The reaction mixture was cooled to room temperature and then poured into water (40 mL). The resulting solid was collected by filtration and dried to afford ethyl 4-(5-chloropyrazin-2-yl)-2-[(3R,4S)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate 140 mg (90%) of as an off-white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[CH:7][C:8]([OH:10])=[O:9]>C(O)C.[Pd]>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: O=C(O)C=Cc1nccs1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCc1nccs1
Reaction time: 6 h
Yield: 93.6 %

Procedure:
Mix and suspend 3-thiazol-2-yl-acrylic acid (580 mg, 3.74 mmol) and 5% Pd/C (270 mg) in ethanol (200 mL). Purge the mixture with nitrogen. Then purge with hydrogen for 30 minutes and stir under 1 atmosphere of hydrogen for 6 hours. Filter the reaction mixture through Celite® and wash the filter cake with additional ethanol. Concentrate the filtrate to afford 550 mg (94%) of 3-thiazol-2-yl-propionic acid as a white solid. MS: m/e=158 (MH+).
Reaction SMILES: Br[C:2]1[C:7]([CH:8]([OH:18])[CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:19]([O:21][C:22](=[O:48])[CH2:23][C:24]1([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36](B4OC(C)(C)C(C)(C)O4)=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)[CH2:26][CH2:25]1)[CH3:20]>>[CH2:19]([O:21][C:22](=[O:48])[CH2:23][C:24]1([C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:38]=[CH:37][C:36]([C:2]4[C:7]([CH:8]([OH:18])[CH2:9][CH2:10][CH2:11][C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)=[CH:6][CH:5]=[CH:4][N:3]=4)=[CH:35][CH:34]=3)=[CH:31][CH:32]=2)[CH2:25][CH2:26]1)[CH3:20]
Reactant: OC(CCCc1ccccc1)c1cccnc1Br
Reactant: CCOC(=O)CC1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4ncccc4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 2, using the following starting materials: 1-(2-bromo-pyridin-3-yl)-4-phenyl-butan-1-ol and {1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.B(O)(O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([NH2:33])=[O:32])[CH:26]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:25]5[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=5)[C:31]([NH2:33])=[O:32])[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: NC(=O)c1cccc(B(O)O)c1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cccc(C(N)=O)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.106 mmol) and benzamide-3-boronic acid (ABCR, Karlsruhe, Germany, 21 mg, 0.129 mmol) to give the title compound as a white solid. (HPLC: tR 2.34 min (Method A); M+H=413 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.98 (s, 1H), 8.19-8.16 (m, 1H), 8.14-8.10 (m, 1H), 8.09-8.04 (m, 1H), 8.02-7.95 (m, 2H), 7.89-7.83 (m, 1H), 7.65-7.59 (m, 2H), 7.58-7.47 (m, 2H), 3.94 (s, 3H), 3.58 (s, 3H), 1.93 (s, 3H))
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[CH:10]3)[CH2:3][CH2:2]1.[H][H]>[Pt]=O.C(O)(=O)C>[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[CH:10]3)[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: C1=C(c2ccc3[nH]ccc3c2)CCNC1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: c1cc2cc(C3CCNCC3)ccc2[nH]1
Yield: 37.9 %

Procedure:
A mixture of 5-(3,6-dihydro-2H-pyridin-4-yl)-1H-indole (3.4 g), platinum oxide (0.2 g) and acetic acid (50 mL) was shaken at room temperature for 24 h and under 3 atmospheres of hydrogen. The mixture was filtered, and the solvent was removed in vacuo. The residue was purified by flash chromatography on silicagel (eluent: 4 M ammonia in methanol) to give the title compound (1.3 g).
Reaction SMILES: O.[Na].Cl[CH2:4][CH2:5][CH:6]([C:14]1[NH:18][C:17](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([O:33][CH3:34])[CH:22]=2)=[N:16][N:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.C(OCC)(=[O:37])C.O.C(=O)(O)[O-].[Na+]>CN(C=O)C>[F:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]2([OH:37])[C:14]3[N:15]([N:16]=[C:17](/[CH:19]=[CH:20]/[C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]5)=[C:23]([O:33][CH3:34])[CH:22]=4)[N:18]=3)[CH2:4][CH2:5]2)=[CH:12][CH:11]=1
Reactant: COc1cc(/C=C/c2nnc(C(CCCl)c3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1
Reactant: CCOC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(/C=C/c2nc3n(n2)CCC3(O)c2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
Sodium hydrate (containing mineral oil at 40%, 15 mg) was added to a solution of 3-[3-chloro-1-(4-fluorophenyl)propyl]-5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-4H-[1,2,4]triazole (86 mg) in DMF (1 mL), and the reaction solution was stirred at room temperature for 13 hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain 3 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Br)(Br)[Br:12]>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][Br:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrP(Br)Br
Reactant: OCCCC1CCCCC1
Solvent: ClCCl
Product: BrCCCC1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.2 %

Procedure:
To the chilled (0° C.) 3-cyclohexyl-1-propanol (5 g, 35.15 mmol) was added slowly a solution of phosphorus tribromide (1.1 mL, 17.6 mmol) in dichloromethane (2 mL). Upon completion of the addition, the reaction mixture was allowed to warm up to room temperature and was stirred for 4 hours. The reaction was quenched by addition of saturated sodium bicarbonate aqueous solution (5 mL) and 10% NaOH (10 mL). The resulting mixture was extracted with diethyl ether (3×50 mL), the combined organic extracts were dried over sodium sulfate and the solvent was evaporated in vacuo to provide an oil. Vacuum distillation yielded 3.4 g (47% yield) of the title compound.