Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:3]=1[CH2:4][NH:5][CH2:6][C@@H:7]([OH:22])[C@@H:8]([NH:18][C:19](=[O:21])[CH3:20])[CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1.BrN(Br)CC1C=CC=CC=1.C1COCC1.[I-].[CH2:44]([Zn+])[C:45]([CH3:48])([CH3:47])[CH3:46]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[Br:27][C:24]1[CH:23]=[C:3]([CH:2]=[C:26]([CH2:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH:25]=1)[CH2:4][NH:5][CH2:6][C@@H:7]([OH:22])[C@@H:8]([NH:18][C:19](=[O:21])[CH3:20])[CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1
Reactant: CC(C)(C)C[Zn+]
Reactant: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNCc1cc(Br)ccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: BrN(Br)Cc1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNCc1cc(Br)cc(CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To dibromobenzylamine (1S,2R) N-[3-(2,5-Dibromo-benzylamino)-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-acetamide (0.504 g, 1.0 mM, 1 eq) was added 0.5 M THF solution of neopentylzinc iodide (20 mL, 10 eq) and 0.082 g, (0.1 mM, 0.1 eq) of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (Pd(dppf)Cl2 CH2Cl2). A reaction mixture was stirred overnight at room temperature. The reaction was quenched with a saturated aqueous solution of NH4Cl (20 mL) and extracted with ethyl acetate (3×30 mL). Combined organic layers were washed with brine, dried and concentrated.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12](=O)[C:11]=3[C:20]([O:22]CC)=[O:21])=[CH:4][C:3]=2[O:2]1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([Mg]Br)[CH:30]=[CH:31][CH:32]=1>C1COCC1>[CH3:25][O:26][C:27]1[CH:32]=[C:31]([CH:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]([C:5]3[CH:6]=[CH:7][C:8]4[O:9][CH2:1][O:2][C:3]=4[CH:4]=3)[CH:11]2[C:20]([OH:22])=[O:21])[CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1=O
Reactant: COc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: COc1cccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)c1
Reaction time: 0.25 h
Yield: 124.6 %

Procedure:
To a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxylate (100 mg, 0.31 mmol) in THF (2 ml) under an argon atmosphere at 0° C. was added a solution of freshly prepared 3-methoxyphenyl magnesium bromide (0.31 mmol). After stirring for 15 min, additional 3-methoxyphenyl magnesium bromide (0.06 mmol) was added. Stirring was continued for 45 min, at which time thin layer chromatographic analysis indicated that the reaction was incomplete. Additional 3-methoxyphenyl magnesium bromide (0.12 mmol) was added. After stirring for 2 h more, the mixture was partitioned between 3M HCl and EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3, H2O and saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 15% EtOAc/hexanes to afford the title compound (150 mg, 100%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O-:20])=[O:19])[CH2:14][CH:13]2[O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)=[CH:8][CH:7]=1.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:33]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:9]([CH3:12])([CH3:10])[CH3:8])=[O:19])[CH2:14][CH:13]2[O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)=[CH:8][CH:7]=1)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C([O-])N1CCC(c2ccc(OCCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: O=C(Cl)c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOC(=O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22(k), by acylating (3RS,4RS)-4-[4-(3-hydroxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with benzoyl chloride there was obtained tert-butyl (3RS,4RS)-4-[4-(3-benzoyloxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; Rf : 0.84 (SiO2, hexane:ethyl acetate=1:1).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[CH3:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][C:19]=1[CH:27]=O.N1CCCCC1>C(O)C>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:27][C:19]1[NH:20][C:21]2[C:26]([C:18]=1[CH3:17])=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:5])=[O:4]
Reactant: Cc1c(C=O)[nH]c2ccccc12
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C=C2C(=O)Nc3ccc(S(=O)(=O)N(C)C)cc32)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
A mixture of 5-dimethylaminosulfonyl-2-oxindole (96 mg), 3-methylindole-2-carbaldehyde (56 mg) (prepared according to Synthetic Communications, 1986, 16, 1799) and piperidine (30 mg) in ethanol (1 mL) was held in a sealed tube at 90° C. overnight. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum oven to give 76 mg (57% yield) of 3-(3-methyl-1H-indol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid dimethylamide (mixture of isomers).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=O)[CH2:8][CH:9]([C:11]3[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=3)[CH2:10][C:5]=2[O:4][CH:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:7]1[C:6]2[C:2]([CH3:1])=[CH:3][O:4][C:5]=2[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[CH2:8]1)[C:19]([NH2:21])=[NH:20]
Reactant: N=C(N)NN
Reactant: Cc1coc2c1C(=O)CC(c1ccc(Br)cc1)C2
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1coc2c1C(=NNC(=N)N)CC(c1ccc(Br)cc1)C2
Yield: 63.9 %

Procedure:
A mixture of 3-methyl-6-(4-bromophenyl)-4,5,6,7-tetrahydrobenzofuran-4-one (0.30 g), aminoguanidine hydrochloride (0.11 g), concentrated hydrochloric acid (0.049 ml), water (0.049 ml) and ethanol (30 ml) was refluxed for 2 hours. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 4-guanidinoimino-3-methyl-6-(4-bromophenyl)-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 35) (0.25 g) as colorless crystals.
Reaction SMILES: [H-].[Na+].[CH3:3][OH:4].Cl[C:6]1[C:11]([C:12]([OH:14])=[O:13])=[C:10]([CH3:15])[CH:9]=[C:8]([Cl:16])[N:7]=1.Cl>C1COCC1>[Cl:16][C:8]1[N:7]=[C:6]([O:4][CH3:3])[C:11]([C:12]([OH:14])=[O:13])=[C:10]([CH3:15])[CH:9]=1
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)O
Reactant: CO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nc(Cl)cc(C)c1C(=O)O
Temperature: 70 °C
Yield: 120.5 %

Procedure:
To a suspension of 9.3 g (231 mmol, 60% w/w in mineral oil) NaH in THF (200 ml) was added a solution of 3.8 ml (93 mmol) Methanol in THF (200 ml) while the temperature was kept at 10-20° C. Subsequently a solution of 20.0 g (97 mmol) of 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid in THF (200 ml) was added and the RM was heated to 70° C. for 16 h. After cooling to RT the mixture was acidified with a 2M aq. HCl to pH 3-4 and was then extracted with EtOAc (2×600 ml). The combined organic layers were washed with water and brine, dried over MgSO4 and concentrated in vacuo. The obtained crude 22.6 g 6-chloro-2-methoxy-4-methyl-pyridine-3-carboxylic acid was used in subsequent reactions without further purification.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH2:9][C:10]([NH:12][C:13]1[NH:14][C:15]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)=[CH:16][C:17]=1[C:18]([NH2:20])=[O:19])=[O:11].O>CN(C)C=O>[NH2:9][C:10]([NH:12][C:13]1[NH:14][C:15]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)=[C:16]([Cl:1])[C:17]=1[C:18]([NH2:20])=[O:19])=[O:11]
Reactant: NC(=O)Nc1[nH]c(-c2ccc(Br)cc2)cc1C(N)=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)Nc1[nH]c(-c2ccc(Br)cc2)c(Cl)c1C(N)=O
Yield: 51 %

Procedure:
N-Chlorosuccinimide (48 mg, 0.36 mmol) was added to a solution of 2-aminocarbonylamino-5-(4-bromophenyl)pyrrole-3-carboxamide (Compound No. 1-1, 97 mg, 0.30 mmol) in anhydrous N,N-dimethylformamide (2 mL), and the mixture was stirred overnight at 50° C. After cooling, water (4 mL) was added thereto, the precipitated solid was filtered off, and washed with water (5 mL). The obtained solid was dried under reduced pressure to give the target compound (54 mg) as a pale brown solid (Yield 51%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[C:7]([N+:13]([O-])=O)=[N:8][C:9]([Br:12])=[CH:10][CH:11]=1.Cl.C(=O)(O)[O-].[Na+]>CO.[Fe]>[CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[C:7]([NH2:13])=[N:8][C:9]([Br:12])=[CH:10][CH:11]=1
Reactant: COC(=O)COc1ccc(Br)nc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Product: COC(=O)COc1ccc(Br)nc1N
Temperature: 60 °C
Reaction time: 1 h

Procedure:
(6-Bromo-2-nitropyridin-3-yloxy)acetic acid methyl ester (10.9 g, 37.5 mmol) was dissolved in methanol (90 mL). Concentrated HCl (10 mL) was then added followed by iron (6.4 g, 110 mmol). The reaction mixture was stirred at 60° C. for 1 hour. Then, the reaction mixture was cooled to room temperature and neutralized with solid sodium bicarbonate. The insoluble iron salts were removed by centrifugation. Silica gel was then added to the supernatant and the solvents were removed under reduced pressure. The resulting crude material was purified by column chromatography (SiO2, EtOAc/hexanes) to give (2-amino-6-bromopyridin-3-yloxy)acetic acid methyl ester. Yield 4.0 g (15 mmol, 40%). LCMS (ESI): calc. C8H9BrN2O3=260, 262; obs. M+H=261, 263.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[N:13][CH:14]=2)[C:5](=[O:28])[N:4]([CH3:29])[CH:3]=1.Cl.O1CCOCC1>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[N:13][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[C:5](=[O:28])[N:4]([CH3:29])[CH:3]=1
Reactant: Cn1cc(Br)nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)c1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1cc(Br)nc(Nc2ccc(N3CCNCC3)nc2)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.8 %

Procedure:
To a solution of 197c (500 mg, 1.08 mmol) in dichloromethane (10 mL) was added 4.0 M HCl/dioxane (10 mL). The reaction mixture was stirred at room temperature for 5 h. It was then concentrated under reduced pressure to afford 197d (358 mg, 91%). MS-ESI: [M+H]+ 365.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[OH:15].[CH2:16]([O:18][C:19](=[O:24])[CH:20]=[C:21](Cl)[CH3:22])[CH3:17]>O1CCCC1>[CH2:16]([O:18][C:19](=[O:24])/[CH:20]=[C:21](/[O:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:8]=1[F:7])\[CH3:22])[CH3:17]
Reactant: Oc1cccc(F)c1F
Reactant: CCOC(=O)C=C(C)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1cccc(F)c1F
Temperature: 23 °C
Yield: 66.1 %

Procedure:
Potassium t-butoxide (11.2 g, 0.100 mol) was added to a stirred solution of 2,3-difluoro-phenol (6.58 g, 0.051 mol) in tetrahydrofuran (30 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191 7.50 g, 0.050 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(2,3-difluoro-phenoxy)-but-2-enoic acid ethyl ester (8.01 g, 66%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=O.S(Cl)(Cl)=O.[CH2:16]([C@@H:23]1[CH2:28][C@@H:27]([N:29]([CH2:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=[CH:39][CH:38]=2)[C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])[CH2:26][CH2:25][NH:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N>C(Cl)Cl.CO>[CH2:16]([C@@H:23]1[CH2:28][C@@H:27]([N:29]([CH2:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=[CH:39][CH:38]=2)[C:30](=[O:35])[C:31]([F:33])([F:34])[F:32])[CH2:26][CH2:25][N:24]1[C:5](=[O:7])[C:4]1[CH:8]=[C:9]([Cl:11])[CH:10]=[C:2]([Cl:1])[CH:3]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: N
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(c1cc(Cl)cc(Cl)c1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1

Procedure:
1.11 g (5.85 mmol) of 3,5-dichlorobenzoic acid are reacted in analogy to Example 2j first with 0.63 ml (8.77 mmol) of thionyl chloride and subsequently with 1 g (2.34 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine to give the product. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.65, FD-MS: M+ =599.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13](Cl)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:44]2[CH:45]=[C:46]([NH:50][C:51]([CH:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)=[O:52])[CH:47]=[CH:48][CH:49]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13]([C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([NH:50][C:51]([CH:53]5[CH2:54][CH2:55][O:56][CH2:57][CH2:58]5)=[O:52])[CH:45]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cccc(NC(=O)C3CCOCC3)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(Cl)nc43)cc2)CCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5cccc(NC(=O)C6CCOCC6)c5)nc43)cc2)CCC1
Temperature: 80 °C
Yield: 50.6 %

Procedure:
To a suspension of tert-butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (50 mg) and N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]tetrahydro-2H-pyran-4-carboxamide (67 mg) and potassium phosphate (65 mg) and PdCl2(dppf)CH2Cl2 (8 mg) in dioxane (2 mL) and H2O (0.2 mL) was degassed for 5 minutes and then heated to 80° C. for 18 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (2 times: 0-10% methanol in chloroform then 0-10% methanol in ethyl acetate) gave the product (34 mg, 51%).
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH:29]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C.O>[CH2:16]([O:15][C:13]([C:12]1[CH:18]=[CH:19][C:9]([O:8][C:3]2[C:2]([C:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH:29]=3)=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:10][CH:11]=1)=[O:14])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CCOC(=O)c1ccc(Oc2ncccc2Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(Oc2ncccc2C2=CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 135 °C

Procedure:
Four glass microwave reaction vessels were charged with ethyl 4-(3-bromopyridin-2-yloxy)benzoate (1.025 g, 3.18 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.195 g, 3.86 mmol), sodium carbonate (1.725 g, 16.28 mmol) and trans-dichlorobis(triphenyl-phosphine)palladium (II) (0.140 g, 0.199 mmol). DME (6 mL), Water (3 mL) and Ethanol (2 mL) were added and the reaction mixtures were sealed under argon and heated in a Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 135° C. for 15 min. The reaction mixtures were combined and partitioned between EtOAc/water. The aqueous layer was extracted with EtOAc (3×) and the combined organic layers were evaporated onto silica gel and purified by flash chromatography (Isco (120 gram)) eluting with EtOAc:hexanes (0:1→1:4) to give a light-yellow crystalline solid. MS m/z: 425.1 [M+1].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][S:13]([CH3:12])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccccc1O
Product: COC(=O)c1ccccc1OS(C)(=O)=O

Procedure:
2-Methanesulfonyloxybenzoic acid methyl ester is prepared according to the general procedure outlined in Example 4, Step B, using 2-hydroxybenzoic acid methyl ester and methanesulfonyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[O:12]1[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:18][CH:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)[CH:3]=1
Reactant: NC1CCOCC1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Br)cc1NC1CCOCC1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
To a solution of 4-bromo-2-fluoro-1-nitrobenzene (1.1 g, 4.95 mmol) and tetrahydro-2H-pyran-4-amine (500 mg, 4.95 mmol) in DMF (6 mL) was added K2CO3 (1.37 g, 9.9 mmol) and the mixture stirred in sealed tube at 85° C. for 16 h. After cooling, water (100 mL) was added to the mixture and extracted with DCM (3×50 mL). The combined organic layers were washed with water (2×50 mL), brine (50 mL) and dried over anhydrous Na2SO4 then filtered and concentrated to yield the title compound which was directly used for next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]([NH2:24])=[O:23])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=3)[C:6]=2[CH:21]=1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34].O>ClCCl>[CH3:32][S:33]([O:20][CH2:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([N:7]2[C:6]3[CH:21]=[C:2]([Cl:1])[C:3]([C:22]([NH2:24])=[O:23])=[CH:4][C:5]=3[N:9]=[C:8]2[CH2:10][CH3:11])=[CH:17][CH:16]=1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1nc2cc(C(N)=O)c(Cl)cc2n1-c1ccc(CCO)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2cc(C(N)=O)c(Cl)cc2n1-c1ccc(CCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.7 %

Procedure:
A mixture of 6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-carboxamide (Example 111, step 4, 500 mg, 1.45 mmol), triethylamine (293 mg, 2.90 mmol) and methansulfonyl chloride (322 mg, 2.9 mmol) in dichloromethane (20 ml) was stirred at room temperature for 6 h. The reaction mixture was poured into water, and extracted with dichloromethane (50 ml). The organic layer was washed with brine (50 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by TLC with hexane/ethyl acetate (1:1) to afford 304 mg (50%) of the title compound as white solids.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH2:9]([NH2:11])[CH3:10]>ClCCl.CCN(CC)CC>[CH2:9]([NH:11][C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:7])[CH3:10]
Reactant: CCN
Reactant: O=C(Cl)c1cccs1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)c1cccs1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
Neat thiophene-2-carbonyl chloride (1.46 g, 10 mmol) is added dropwise to a solution of ethylamine (70% wt/water) in Dichloromethane (8 mL) and Et3N at 0° C. Additional ethylamine (2.5 ml, 70% wt/water) is added to the reaction mixture and the reaction is stirred at 0° C. for 2 hrs and the warmed to room temperature for 2 h. The reaction mixture is transferred to a separatory funnel and the organic layer is washed sequentially with aqueous 1N HCl solution, water and saturated aqueous NaHCO3 solution. The organic phase is collected, dried over Na2SO4, filtered and concentrated to give the title compound (1.4 g, 90%).
Reaction SMILES: [ClH:1].[F:2][C:3]([F:14])([F:13])[CH:4]([OH:12])[CH2:5][CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8].[CH3:15]O>>[ClH:1].[F:2][C:3]([F:13])([F:14])[CH:4]([OH:12])[CH2:5][CH2:6][C@@H:7]([C:9]([O:11][CH3:15])=[O:10])[NH2:8]
Reactant: N[C@@H](CCC(O)C(F)(F)F)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)[C@@H](N)CCC(O)C(F)(F)F

Procedure:
1.4 ml of saturated hydrochloric acid in methanol were added to 150 mg (0.7 mmol) of rac-6,6,6-trifluoro-5-hydroxynorleucine (stereoisomer mixture), and the mixture was stirred under reflux overnight. The reaction solution was concentrated, another 1.5 ml of saturated hydrochloric acid in methanol were added and the mixture was stirred under reflux overnight. The reaction solution was concentrated and the residue was dried under high vacuum. This gave 185 mg (99% of theory) of the target compound.
Reaction SMILES: N1C=CC=CC=1.[C:7](Cl)(=[O:9])[CH3:8].[Br:11][C:12]1[C:13]([F:20])=[CH:14][C:15]([CH3:19])=[C:16]([CH:18]=1)[NH2:17].Cl>C(Cl)(Cl)Cl.O.C(Cl)Cl>[Br:11][C:12]1[C:13]([F:20])=[CH:14][C:15]([CH3:19])=[C:16]([NH:17][C:7](=[O:9])[CH3:8])[CH:18]=1
Reactant: CC(=O)Cl
Reactant: Cc1cc(F)c(Br)cc1N
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cc(Br)c(F)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Pyridine (1.0 mL) and acetyl chloride (0.67 mL) were sequentially added to a methylene chloride (17 mL) solution of 5-bromo-4-fluoro-2-methylaniline (1.74 g), followed by stirring at room temperature for 1 hour. Water, 1 mol/L hydrochloric acid, and chloroform were added to the reaction mixture. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Hexane was added to the obtained residue, and the solid substance was collected by filtration to obtain 1.83 g of N-(5-bromo-4-fluoro-2-methylphenyl)acetamide as a white solid.
Reaction SMILES: Cl.[CH2:2]([O:5][C:6](=[O:16])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:8])[CH2:3][CH3:4].C(N(CC)CC)C.[Cl:24][C:25]1=[C:26]([Cl:32])[C:27]([O:29][C:30]1=O)=[O:28]>O1CCCC1.C(O)(=O)C>[Cl:24][C:25]1[C:30](=[O:29])[N:8]([C@@H:7]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:6]([O:5][CH2:2][CH2:3][CH3:4])=[O:16])[C:27](=[O:28])[C:26]=1[Cl:32]
Reactant: CCCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCOC(=O)[C@H](Cc1ccccc1)N1C(=O)C(Cl)=C(Cl)C1=O

Procedure:
The hydrochloride thus obtained (1.0 g) was dissolved in 25 ml of tetrahydrofuran and allowed to react with 1.2 ml of triethylamine at room temperature for 30 minutes, the precipitated crystals were separated by filtration, and the filtrate concentrated under a reduced pressure to give a colorless oily product. This oily product and 700 mg of dichloromaleic anhydride were dissolved in 6 ml of acetic acid and refluxed for 3 hours, and after completion of the reaction, the reaction mixture was concentrated under a reduced pressure, the residue was dissolved in ethyl acetate, washed with water, and dried over magnesium sulfate, followed by evaporation of the solvent. The residue obtained was purified by silica gel chromatography (eluant: n-hexane-ethyl acetate=9/1) to give 1.41 g of the desired compound as a colorless oily product (yield: 97%).