Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:17][OH:18])[CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O.O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1)[CH:17]=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(CO)cc(OCc2ccccc2)c1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(C=O)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
To a solution of (3-(benzyloxy)-5-methoxyphenyl)methanol (6.50 g) in DMSO (100 mL) was added 2-iodoxybenzoic acid (9.00 g), and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.50 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]([C:36](O)=[O:37])([CH3:35])[CH3:34])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[F:70][C:71]1([F:77])[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]([CH3:34])([CH3:35])[C:36]([N:74]2[CH2:75][CH2:76][C:71]([F:77])([F:70])[CH2:72][CH2:73]2)=[O:37])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1
Reactant: CC(C)(Oc1ccc(Br)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Reactant: FC1(F)CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(Oc1ccc(Br)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12)C(=O)N1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.5 %

Procedure:
To a mixture of racemic(2′R, 3R, 4′S)-2′-[5-bromo-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.065 mmol), EDCI (18.7 mg, 0.098 mmol), HOBt (15 mg, 0.098 mmol) and DIPEA (75 mg, 0.6 mmol) in THF (2 mL) was added 4,4-difluoropiperidine hydrochloride (30 mg, 0.195 mmol). The mixture was stirred at room temperature overnight, purified by prep-HPLC to give the title compound as a white solid (19mg).
Reaction SMILES: [Na].N.[NH2:3][CH2:4][C@@H:5]1[CH2:19][C@H:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][CH:11]=3)[N:7]([CH3:21])[CH2:6]1.[CH3:22]I>CCOCC.C(O)C>[NH2:3][CH2:4][C@@H:5]1[CH2:19][C@H:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[N:12]([CH3:22])[CH:11]=3)[N:7]([CH3:21])[CH2:6]1
Reactant: CN1C[C@H](CN)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: CI
Agent: N
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CN1C[C@H](CN)C[C@@H]2c3cccc4c3c(cn4C)C[C@H]21

Procedure:
A mixture of 8 ml. of dry ethanol and 10 ml. of dry ether is added dropwise, within 20 minutes to the stirred solution of 1.9 g. of metallic sodium in 300 ml. of liquid ammonia. Upon this procedure the initially deep blue solution turns gradually colorless. Thereafter 2.53 g. of dried 8β-aminomethyl-6-methyl-ergoline, prepared as described in Step B above, are added, the mixture is stirred until complete dissolution occurs (for 5 minutes), and then a solution of 6.6 g. of methyl iodide in 8 ml. of dry ether is added dropwise, within 5 minutes to the mixture at -40° C. The mixture is stirred at the same temperature for an additional 30 minutes, thereafter it is warmed cautiously and ammonia is removed in vacuo. The residue is dissolved in a mixture of 100 ml. of isopropanol and 400 ml. of chloroform, 150 ml. of water are added to the solution, and the pH of the aqueous phase is adjusted to 8 with acetic acid. The mixture is shaken, the organic phase is separated, and the aqueous phase is extracted with 3×100 ml. of a 1:4 mixture of isopropanol and chloroform. The organic phases are combined, dried over sodium sulfate, filtered and evaporated. The residue is subjected to chromatography using a column filled with 40 g. of silica gel in order to remove the impurities optionally present. A 30:2:11 mixture of chloroform, water and methanol is used as eluting agent.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH2:14]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][NH:26][CH2:25][CH:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23]2)=[CH:18][CH:17]=1)[CH3:15].C(N(CC)CC)C>ClCCl>[CH2:14]([C:16]1[CH:17]=[CH:18][C:19]([CH:22]2[CH2:27][N:26]([C:2]([O:4][C:5]3[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=3)=[O:3])[CH2:25][CH:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23]2)=[CH:20][CH:21]=1)[CH3:15]
Reactant: CCOC(=O)C1CNCC(c2ccc(CC)cc2)C1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CC(c2ccc(CC)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 0° C., 1.93 g (9.57 mmol) of 4-nitrophenyl chloroformate were added slowly to 2.5 g (9.57 mmol) of ethyl 5-(4-ethylphenyl)piperidine-3-carboxylate, the compound from Example 17A, and 1.94 g (19.1 mmol) of triethylamine in 292 ml of dichloromethane. The mixture was stirred at RT for 2 h. For workup, the reaction mixture was washed first with saturated aqueous sodium hydrogencarbonate solution, then with water. The organic phase was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by means of preparative HPLC. Yield: 2.66 g (64% of theory)
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)\[C:11](=[NH:15])[N:12]([OH:14])[CH3:13])[N:6]=1.[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23]>C(#N)C>[Br:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)\[C:11]2[N:12]([CH3:13])[O:14][C:22](=[O:23])[N:15]=2)[N:6]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(O)C(=N)/C(=N\OCc1csc(Br)n1)c1ccccc1
Solvent: CC#N
Product: Cn1oc(=O)nc1/C(=N\OCc1csc(Br)n1)c1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 103.9 %

Procedure:
To a solution of (2Z)-2-{[(2-bromo-1,3-thiazol-4-yl)methoxy]imino}-N-hydroxy-N-methyl-2-phenylethanimidamide (1.8 g, 4.87 mmol, 1 eq.) in acetonitrile (120 ml), was added 1,1′-carbonyldiimidazole (1.58 g, 9.75 mmol, 2 eq.). After stirring at 80° C. for 1 hour, the reaction was quenched by addition of water (100 ml) and extracted with EtOAc (2×100 ml). The organics were combined, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel to give 3-[(Z)-{[(2-bromo-1,3-thiazol-4-yl)methoxy]imino}(phenyl)methyl]-2-methyl-1,2,4-oxadiazol-5(2H)-one (2 g, 100% yield).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:12]2[C:5]([NH:6][CH:7]=[C:8]2[CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.[CH2:14]([CH:16]1[CH2:22][CH2:21][CH2:20][O:19][C:17]1=[O:18])[CH3:15]>C1(C)C(C)=CC=CC=1>[CH2:14]([CH:16]([CH2:22][CH2:21][CH2:20][OH:19])[C:17]([NH:11][CH2:10][CH2:9][C:8]1[C:12]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:13]=2)[NH:6][CH:7]=1)=[O:18])[CH3:15]
Reactant: NCCc1c[nH]c2ccc(Br)cc12
Reactant: CCC1CCCOC1=O
Solvent: Cc1ccccc1C
Product: CCC(CCCO)C(=O)NCCc1c[nH]c2ccc(Br)cc12
Yield: 80 %

Procedure:
0.48 g. (2.0 mmoles) of 5-bromo-tryptamine and 0.30 g. (2.3 mmoles) of 2-ethyl-pentanolide are dissolved in 5 ml. of abs. xylene, and the solution is refluxed for 4 hours. The reaction mixture is evaporated in vacuo, the residue is triturated twice with 3 ml. each of petroleum ether, thereafter it is dried in a desiccator. 0.59 g. (80%) of N-(α-ethyl-δ-hydroxyl-valeroyl)-5-bromo-tryptamine are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[N:8][NH:7][C:6]1=[S:13].[CH3:19]I.[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[N:8][N:7]=[C:6]1[S:13][CH3:19]
Reactant: CI
Reactant: Cc1n[nH]c(=S)n(Cc2cc(F)ccc2Cl)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1nnc(C)c(=O)n1Cc1cc(F)ccc1Cl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a suspension of 4-(2-chloro-5-fluorobenzyl)-6-methyl-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)-one (29, 3.06 g, 10.72 mmol) in ethanol (50 mL) was added MeI (2.44 g, 17.1 mmol) followed by NaOH (429 mg, 10.72 mmol). The mixture was stirred at RT for 40 min to produce a clear yellow solution. The reaction was diluted with water (200 mL), and extracted with EtOAc (100 mL×3). The extracts were washed with brine, dried over MgSO4, and concentrated to give the crude product (3.195 g). This was crystallized from ethyl acetate-petroleum ether to give 4-(2-chloro-5-fluorobenzyl)-6-methyl-3-(methylthio)-1,2,4-triazin-5(4H)-one (30). MS: m/z, 300 (100%, M+1), 302 (35%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[Cl:9].[OH-].[K+].[C:12]([OH:16])(=[O:15])[CH2:13][SH:14].ClSC(Cl)(C1C=CC=CC=1)C([O-])=O.ClC1C(Cl)=C(S)C=CC=1>CN1CCCC1=O>[Cl:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[CH:13]([SH:14])[C:12]([OH:16])=[O:15]
Reactant: O=C(O)CS
Reactant: Clc1ccc(Cl)c(Br)c1
Agent: O=C([O-])C(Cl)(SCl)c1ccccc1
Agent: Sc1cccc(Cl)c1Cl
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(O)C(S)c1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
To a 500 ml flask equipped with a thermometer, a condenser and a stirrer were added 45.2 g (0.2 mol) of 1-bromo-2,5-dichlorobenzene, 23.7 g (0.4 mol) of 95% potassium hydroxide, 18.4 g (0.2 mol) of thioglycolic acid and 320 g of N-methyl-2-pyrrolidone, followed by stirring at 140° to 150° C. for 2 hours. Assay of the reaction solution by high performance liquid chromatography identified the solution as a mixture of dichlorophenylthioglycolate and dichlorothiophenol salt. Then, after distilling off the solvent, 300 g of water and 50 g of toluene were added for layer separation. To the water layer was added 45 g of concentrated hydrochloric acid, and the mixture was cooled to room temperature. The resulting crystal was filtered and dried to yield 28.7 g of 2,5-dichlorophenylthioglycolic acid. Its melting point was 129° to 131° C., and the yield was 60.5%. The results are given in Table 2.
Reaction SMILES: [NH2:1][C:2]1[C:12]([Cl:13])=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[Br:14]>Cl.CCO>[NH2:1][C:2]1[C:12]([Cl:13])=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Br:14]
Reactant: CCOC(=O)c1cc(Cl)c(N)c(Br)c1
Agent: Cl
Solvent: CCO
Product: Nc1c(Cl)cc(C(=O)O)cc1Br

Procedure:
A solution of 21.0 g (75.4 mmol) ethyl 4-amino-3-bromo-5-chloro-benzoate in 200 mL 4 M HCl and 100 mL EtOH was refluxed overnight. After cooling the precipitate formed was suction filtered and dried.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([N:7]2[C:11]3[N:12]=[C:13]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[N:14]=[C:15]([C:16]4[CH:17]=[N:18][C:19]([NH2:22])=[N:20][CH:21]=4)[C:10]=3[CH2:9][CH2:8]2)[CH2:4]1.CCN(C(C)C)C(C)C.[CH:39]([S:42](Cl)(=[O:44])=[O:43])([CH3:41])[CH3:40]>C(Cl)Cl>[CH3:29][C@H:24]1[CH2:25][O:26][CH2:27][CH2:28][N:23]1[C:13]1[N:14]=[C:15]([C:16]2[CH:21]=[N:20][C:19]([NH2:22])=[N:18][CH:17]=2)[C:10]2[CH2:9][CH2:8][N:7]([CH:5]3[CH2:6][N:3]([S:42]([CH:39]([CH3:41])[CH3:40])(=[O:44])=[O:43])[CH2:4]3)[C:11]=2[N:12]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: C[C@H]1COCCN1c1nc(-c2cnc(N)nc2)c2c(n1)N(C1CNC1)CC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N1CC(N2CCc3c(-c4cnc(N)nc4)nc(N4CCOC[C@@H]4C)nc32)C1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 53.1 %

Procedure:
To a suspension of 5-{7-(azetidin-3-yl)-2-[(3S)-3-methylmorpholin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}pyrimidin-2-amine dihydrochloride (100 mg, 0.20 mmol) in DCM (5.0 mL) was added DIPEA (0.2 mL, 1.15 mmol). After a few minutes, the mixture became almost homogeneous, and a fine precipitation began to form. The reaction mixture was cooled to 0° C. and isopropylsulfonyl chloride (0.023 mL, 0.21 mmol) was added. The mixture was stirred at 0° C. for 45 min resulting in an amber solution. The mixture was concentrated to a minimum volume and the residue was purified by SFC column to give 50.4 mg (51%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 2 H), 6.98 (s, 2 H), 4.80 (p, J=7.2 Hz, 1 H), 4.68-4.59 (m, 1H), 4.29-4.21 (m, 3 H), 3.98 (dt, J=7.9, 4.4 Hz, 2 H), 3.88 (dd, J=11.1, 3.0 Hz, 1 H), 3.72-3.65 (m, 3 H), 3.56 (dd, J=11.3, 2.9 Hz, 1 H), 3.40 (dt, J=11.7, 2.8 Hz, 1 H), 3.28-3.21 (m, 1H, partially overlapped with water), 3.15 (t, J=8.2 Hz, 2 H), 3.07 (dt, J=12.9, 3.7 Hz, 1 H), 1.24 (d, J=6.8 Hz, 6 H), 1.16 (d, J=6.7 Hz, 3 H). m/z (APCI+) for C21H30N8O3S 475.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[N+:17]([O-])=O)[C:5](OC)=[O:6]>[Pd].CO>[CH3:1][O:2][C:3]([CH:4]1[C:9]2[C:10](=[CH:11][CH:12]=[C:13]([O:15][CH3:16])[CH:14]=2)[NH:17][C:5]1=[O:6])=[O:20]
Reactant: COC(=O)C(C(=O)OC)c1cc(OC)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1C(=O)Nc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To 2-(5-methoxy-2-nitro-phenyl)-malonic acid dimethyl ester and 5% Pd—C (7.0 g) in 1 l of flask, MeOH (490 ml) is added at ambient temperature. The reaction mixture is stirred under H2 at room temperature for 15 h. The catalysts are removed by filtration and MeOH is evaporated down to give crude 5-methoxy-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid methyl ester.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C[Si](C)(C)[N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26]Cl)=[CH:22][N:21]=1>C1CCCCC1.O1CCCC1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:13]2[CH2:14][CH2:15][NH:11][C:12]2=[O:16])=[CH:22][N:21]=1
Reactant: C[Si](C)(C)N1CCCC1=O
Reactant: ClCc1ccc(Cl)nc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: O=C1NCCC1Cc1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere at a temperature of from −78° C. to −60° C., 180 ml of a 1.5 molar solution of lithium diisopropylamide (LDA) in cyclohexane are added dropwise to 31.4 g of N-trimethylsilylpyrrolid-2-one in 150 ml of tetrahydrofuran (THF) and the reaction mixture is stirred at the same temperature for a further one hour. Then, at from −78° C. to −60° C., 25.5 g of 2-chloro-5-chloromethylpyridine in 40 ml of THF are added, and the mixture is stirred for a further 16 hours at that temperature and then for a further three hours at room temperature. The reaction mixture is poured onto a mixture of ice/water and extracted with ethyl acetate, and the organic phase is separated off. The ethyl acetate phase is dried over sodium sulfate and concentrated to dryness by evaporation in vacuo. The residue is purified on silica gel using ethyl acetate/hexane (7:1) as eluant. The title compound having a melting point of 117-118° C. (compound 1.3) is obtained.
Reaction SMILES: O.NN.[CH3:4][C:5]1[C:19]([O:20][CH3:21])=[CH:18][C:8]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:16][OH:17])=[O:10])=[C:7]([N+:22]([O-])=O)[C:6]=1[O:25][CH3:26].[H][H]>CO.[Ni]>[NH2:22][C:7]1[C:6]([O:25][CH3:26])=[C:5]([CH3:4])[C:19]([O:20][CH3:21])=[CH:18][C:8]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][OH:17])=[O:10]
Reactant: COc1cc(C(=O)N2CCCC2CO)c([N+](=O)[O-])c(OC)c1C
Reactant: [H][H]
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)N2CCCC2CO)c(N)c(OC)c1C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
Hydrazine hydrate (1.26 g, 39.37 mmol) was added dropwise to a solution of 190 (2.13 g, 6.56 mmol) in methanol (50 mL) gently refluxing over Raney nickel (1 g, slurry). The resulting vigorous evolution of hydrogen gas subsided after approximately 10 minutes and the reaction was deemed to be complete by TLC after 2 h. The reaction mixture was filtered through celite and the solvent evaporated. Distilled water (100 mL) was added to the residue, and the aqueous mixture was extracted with EtOAc (3×100 mL) and the combined organic phase washed with H2O (3×100 mL) and brine (3×100 mL) and dried over anhydrous MgSO4. Evaporation of the solvent afforded the product as a brown glass (191) (1.91 g, 6.50 mmol) which was protected directly as the troc-carbamate.
Reaction SMILES: [ClH:1].[CH3:2][NH:3][C:4](=[O:22])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14]CC2C=CC=CC=2)=[CH:10][CH:9]=1)[NH2:6].[H][H]>CO.[Pd]>[ClH:1].[CH3:2][NH:3][C:4](=[O:22])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)[NH2:6]
Reactant: CNC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNC(=O)[C@@H](N)Cc1ccc(O)cc1
Reaction time: 4 h
Yield: 104.6 %

Procedure:
To a solution of O-benzyl-L-tyrosine N-methylamide HCl (1.13 g) in methanol (50 ml) was added 10% Pd/C and the mixture was stirred in an atmosphere of hydrogen at room temperature and atmospheric pressure for 4 h. The catalyst was then filtered and the solvent was removed in vacuo to yield L-tyrosine N-methylamide HCl as a foam (0.85 g).
Reaction SMILES: C(O[Si](OCC)(OCC)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([Si](OCC)(OCC)OCC)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)C.Cl>C(O)C>[C:8]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1
Reactant: CCO[Si](OCC)(OCC)c1ccc(-c2ccc([Si](OCC)(OCC)OCC)cc2)cc1
Agent: Cl
Solvent: CCO
Product: c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
First, trimethyloctadecylammonium chloride (surfactant: 1.83 g, 5.26 mol) was dissolved in a mixed liquid of water (100 ml) and a 6M aqueous solution of sodium hydroxide (10 g) to obtain a mixed solution. Then, 4,4′-bis(triethoxysilyl)biphenyl (2.00 g, 4.18 mol) was added dropwise into the obtained mixed solution while stirring at room temperature. Thereafter, the irradiation with ultrasonic waves for 20 minutes and the stirring were repeated to the mixed solution. Subsequently, the solution was stirred for 24 hours at room temperature to obtain a reaction solution. After that, the reaction solution was left at rest at a temperature condition of 98° C. for 48 hours. Then, the reaction solution was heated to obtain a silica porous material modified by a biphenyl group (BiPh-HMM) containing the surfactant. Subsequently, BiPh-HMM containing the surfactant was suspended in a mixed liquid containing ethanol (260 ml) and concentrated hydrochloric acid (11.7 g). Thereafter, the suspended liquid was stirred while heating at a temperature condition of 70° C. for 7 hours to extract the surfactant from the BiPh-HMM. After that, the suspended liquid was filtered. Then, the obtained white powders were washed with ethanol and dried in vacuum to obtain BiPh-HMM crystalline powders.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[O:26]=[C:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:30]1[CH2:31][CH2:32][C:27](=[O:26])[CH2:28][CH2:29]1)=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: O=C1CCNCC1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCC(=O)CC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from 2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, 4-oxopiperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.04 minutes; C22H20Cl2N4O3 (459.33); mass spectrum: (M−H)−=458/460/462 (chlorine isotope).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[OH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25].C([O-])([O-])=O.[K+].[K+]>CC#N>[F:25][C:24]([F:26])([F:27])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Reactant: Oc1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1cc(-c2ccc(COc3ccccc3C(F)(F)F)cc2)no1
Temperature: 90 °C
Yield: 77.4 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 2-hydroxybenzotrifluoride (29 mg, 0.179 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 90° C. for 16 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(2-trifluoromethyl-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (30 mg, 77%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.39 (s, 1H), 8.02 (s, 1H), 7.94 (d, J=8.5 Hz, 2H), 7.54-7.68 (m, 5H), 7.34 (d, J=8.5 Hz, 1H), 7.10 (t, J=7.7 Hz, 1H), 5.35 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17](S(C)=O)[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[NH2:24][C@@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:24][C@@H:25]5[C:33]6[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=6)[CH2:27][C@H:26]5[OH:34])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2s1
Reactant: N[C@@H]1c2ccccc2C[C@H]1O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1Cc2ccccc2[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2s1
Temperature: 130 °C
Yield: 3.7 %

Procedure:
A stirred mixture of 6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole from Example 29 (210 mg, 0.3 mmol), (1R,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (92 mg, 0.6 mmol), and DIEA (267 μL, 1.5 mmol) in DMA (3 mL) was heated at 130° C. for 120 h in a sealed tube. The mixture was cooled to rt and subjected to purification by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford (1R,2R)-1-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol (5.4 mg, 4%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.36-8.54 (m, 3H), 7.71 (s, 1H), 7.35 (m, 1H), 7.11-7.30 (m, 5H), 5.51 (s, 2H), 5.18 (t, J=7.0 Hz, 1H), 4.30 (m, 1H), 3.16 (dd, J=7.2, 15.8 Hz, 1H), 2.74 (dd, J=7.3, 15.4 Hz, 1H). LCMS (ESI) m/z 492 and 494 (M+H)+.