Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([CH2:15][N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)=[O:14])[CH:7]=[CH:6]2)[CH3:2].[CH2:21](O)[CH2:22][OH:23].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:21]1[CH2:22][O:23][C:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([CH2:1][CH3:2])[CH:4]=3)[CH:9]=2)([CH2:15][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[O:14]1
Reactant: CCc1ccc2cc(C(=O)Cn3ccnc3)ccc2c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCc1ccc2cc(C3(Cn4ccnc4)OCCO3)ccc2c1

Procedure:
A mixture of 0.7 g. of 1-[(6-ethyl-2-naphthoyl)methyl]imidazole, 4 ml of ethylene glycol and 1.3 g. of anhydrous p-toluenesulfonic acid in 50 ml. of toluene is heated overnight under reflux through a Dean-Stark trap. The trap is then replaced by a separatory funnel containing 4 A molecular sieves and heating is continued for a further day. After cooling, the mixture is treated with 100 ml. of ethyl acetate, neutralized by pouring into excess aqueous potassium carbonate and the organic phase separated, washed with water, dried (MgSO4) and separated to afford 1-[2,2-ethylenedioxy-2-(6-ethyl-2-naphthyl)ethyl]imidazole. This is purified by chromatography on silica gel eluting with 10% methanol/dichloromethane and the hydrochloride salt prepared by dropwise addition of ethereal hydrogen chloride until precipitation is complete. Filtration and recrystallization from acetone/methanol gives 0.38 g. pure hydrochloride, m.p. 251° C.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([CH3:21])[CH:13]=2)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].O.O.[Sn](Cl)Cl>C(O)C>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH:8]2[CH2:7][CH2:6][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:10][CH2:9]2)=[CH:13][C:14]=1[CH3:21]
Reactant: CCCCN1CCC(Oc2ccc([N+](=O)[O-])c(C)c2)CC1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CCCCN1CCC(Oc2ccc(N)c(C)c2)CC1

Procedure:
In a manner similar to Preparation 44 react 1-butyl-4-(3-methyl-4-nitrophenoxy)piperidine with tin(II) chloride dihydrate in ethanol to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][CH:19]([C:21]2C3C(=CC=CC=3)N=C[CH:22]=2)C)=[CH:5][CH:4]=1.[C:31]1([C@H](N)CC)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.COC1C(C2C=CC(OC)=CC=2)=CC(C=O)=CC=1.C([BH3-])#N.[Na+]>>[C:31]1([C@H:19]([NH:18][CH2:17][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:8]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=3)[CH:7]=2)[CH2:21][CH3:22])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COc1ccc(-c2cc(CNC(C)c3ccnc4ccccc34)ccc2OC)cc1
Reactant: CC[C@@H](N)c1ccccc1
Agent: COc1ccc(-c2cc(C=O)ccc2OC)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC[C@@H](NCc1ccc(OC)c(-c2ccc(OC)cc2)c1)c1ccccc1
Yield: 52 %

Procedure:
The title compound was prepared by the same procedure for (6,4′-dimethoxy-biphenyl-3-ylmethyl)-(1-quinolin-4-yl-ethyl)-amine from (R)-(+)-1-phenyl-propylamine (405 mg, 3.0 mmol, Lancaster Synthesis Ltd.), 6,4′-Dimethoxy-biphenyl-3-carbaldehyde (242 mg, 1.0 mmol) and sodium cyanoborohydride (1.0 g, 16 mmol, Aldrich). The title compound was purified by column chromatography (silica gel, hexane/ethyl acetate 2/3) in form as white solid in 52% yield (187 mg, 0.52 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH3:10])=[CH:5][CH:4]=1)#[N:2].C([O-])=O.[NH4+:15].C(O)(=O)C>[Ir].CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH2:15])[CH3:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(=O)c1ccc(C#N)cc1
Reactant: [NH4+]
Agent: [Ir]
Agent: O=C[O-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(N)c1ccc(C#N)cc1
Temperature: 60 °C

Procedure:
726 mg (5.0 mmol) of 4′-cyanoacetophenone (MW: 145.16), 946 mg (15.0 mmol) of ammonium formate (MW: 63.06) and 5.90 mg (0.01 mmol, S/C=500) of the iridium catalyst Ir-7 (MW: 590.13) were introduced in a 20-mL Schlenk tube, and subjected to argon-gas replacement. To this, 5 mL of dehydrated methanol and 286 μL (5.0 mmol) of acetic acid were added and stirred while heating at 60° C. for 3 hr. After distillation of the solvent, a saturated sodium hydrogen carbonate solution was added, then a product was extracted with methylene chloride, the organic layer was washed with water, and the product was dried with sodium sulfate. The drying agent was removed by filtration and the methylene chloride was distilled away to give a crude product DL-1-(4′-cyanophenyl)ethylamine. Its conversion rate was 100% based on NMR measurement, with 95% of DL-1-(4′-cyanophenyl)ethylamine, 1% of 1-(4′-cyanophenyl)ethanol, and 4% of other by-products. Since no compound in which reduction of cyano groups occurred was generated, we confirmed that reductive amination reaction was carried out in a functional-group-selective manner.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]#[N:11])=[CH:4][CH:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:12]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]#[N:11])=[CH:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CCCc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCc1ccc(OCc2ccccc2)cc1
Temperature: 90 °C
Yield: 100.7 %

Procedure:
3-(4-Hydroxyphenyl)propionitrile (1.47 g, 0.01 mol) was dissolved in DMF (24 ml), and to this solution were successively added benzyl bromide (1.31 ml, 0.011 mol, 1.1 eq) and anhydrous potassium carbonate (4.15 g, 0.030 mol, 3.0 eq). The mixture was stirred under heating at 90° C. for 3 hours. This reaction mixture was cooled to room temperature, and water (100 ml) was added. The mixture was extracted twice with ethyl acetate (100 ml). The organic layers were combined, washed with saturated brine (200 ml) and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give 3-(4-benzyloxyphenyl)propionitrile (2.39 g, 100%) as a colorless solid.
Reaction SMILES: [C:1]1([C:7]([CH:9]2[CH:14]3[CH2:15][CH:11]4[CH:12]([CH2:13]3)[CH:10]24)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2-].[Na+].Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[CH:11]12[CH2:15][CH:14]3[CH2:13][CH:12]1[CH:10]2[C:9]3=[C:7]([O:8][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCCN1CCOCC1
Reactant: O=C(c1ccccc1)C1C2CC3C(C2)C31
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(C(OCCN2CCOCC2)=C2C3CC4C(C3)C24)cc1

Procedure:
A solution of 19.83 g. (0.1 mol) of tricyclo-(2.2.1.02.6)hept-3-yl phenyl ketone in 45 ml. of anhydrous toluene was added while stirring and boiling to a suspension of 3.9 g. (0.1 mol) of sodium amide in 45 ml. of anhydrous toluene, followed by etherification with a solution of 14.96 g. (0.1 mol) of N-(2-chloroethyl)-morpholine in 45 ml. of anhydrous toluene in the same way as in Example 3.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[CH2:15]([OH:19])[CH2:16]CC.CC1C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C(O)CO>[Br:1][CH2:2][C:3]1([C:5]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=2)[O:19][CH2:15][CH2:16][O:4]1
Reactant: CCCCO
Reactant: O=C(CBr)c1ccc2ccccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: OCCO
Product: BrCC1(c2ccc3ccccc3c2)OCCO1
Reaction time: 8 h

Procedure:
To a stirred solution of 74.4 parts of 2-bromo-1-(2-naphthalenyl)-1-ethanone in 240 parts of a butanol are added successively 3 parts of 4-methylbenzenesulfonic acid and 270 parts of benzene. Then there are added dropwise 28 parts of 1,2-ethanediol. Upon completion, stirring is continued overnight at reflux temperature. The reaction mixture is evaporated. The residue is dissolved in 2,2'-oxybispropane and the solution is stirred with a diluted sodium hydroxide solution. The layers are separated and the aqueous phase is extracted with 2,2'-oxybispropane. The extra ct is neutralized with water, dried, filtered and evaporated. The oily residue is crystallized from methanol. The product is filtered off and recrystallized from methanol, yielding 41 parts of 2-(bromomethyl)-2-(2-naphthalenyl)-1,3-dioxolane; mp. 64° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:17]=1[O:18][C:19]1[CH:30]=[CH:29][C:22]([C:23]([N:25]([O:27][CH3:28])[CH3:26])=[O:24])=[CH:21][CH:20]=1>>[Cl:35][C:33]1[CH:32]=[CH:31][C:17]([O:18][C:19]2[CH:30]=[CH:29][C:22]([C:23]([N:25]([O:27][CH3:28])[CH3:26])=[O:24])=[CH:21][CH:20]=2)=[C:16]([NH:15][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:34]=1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Reactant: CON(C)C(=O)c1ccc(Oc2ccc(Cl)cc2N)cc1
Product: CCCc1ccc2c(Nc3cc(Cl)ccc3Oc3ccc(C(=O)N(C)OC)cc3)ccnc2n1

Procedure:
The product from Example 2g (75 mg, 0.36 mmol) was reacted with the product from Example 128b (111 mg, 0.36 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (76.3 mg, 36%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.88-1.03 (m, 3H) 1.70-1.91 (m, 2H) 2.88-3.00 (m, 2H) 3.18 (s, 3H) 3.42 (s, 3H) 6.71 (d, J=7.35 Hz, 1H) 6.94 (d, J=8.82 Hz, 2H) 7.36 (d, J=8.82 Hz, 1H) 7.50 (d, J=8.82 Hz, 2H) 7.59-7.66 (m, 1H) 7.71-7.79 (m, 2H) 8.53 (d, J=6.99 Hz, 1H) 8.84 (d, J=8.82 Hz, 1H) 10.89 (s, 1H) 14.54 (s, 1H); MS (ESI+) m/z 477 (M+H−TFA)+.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)(O)=[O:2].O.[NH2:13][C:14]1[NH:18][N:17]=[N:16][N:15]=1>CN(C=O)C>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([NH:13][C:14]2[N:15]=[N:16][NH:17][N:18]=2)=[O:2])=[CH:5][CH:6]=1)=[O:9]
Reactant: Nc1nnn[nH]1
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(C(=O)Nc2nn[nH]n2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.4 %

Procedure:
To a solution of 4-carboxybenzaldehyde (40.2 g, 0.27 mol) in DMF (400 mL) was added N-ethyl-N′-3-dimethylaminopropylcarbodiimide (65.5 g, 0.33 mol) followed by 5-aminotetrazol monohydrate (36.6 g, 0.35 mol). The mixture was stirred for 24 hours at ambient temperature. The reaction volume was then reduced to one half by rotary evaporation, and water (800 mL) was added. The precipitate was collected by filtration, washed with cold acetonitrile and dried overnight in a vacuum oven to afford 46.0 g (80%) of 4-formyl-N-(2H-tetrazol-5-yl)benzamide.
Reaction SMILES: C([O:5][C:6](=[O:26])[CH2:7][O:8][C:9]1[CH:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[C:12]([N+:19]([O-:21])=[O:20])=[C:11]([C:22]([O:24][CH3:25])=[O:23])[CH:10]=1)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:22]([C:11]1[CH:10]=[C:9]([CH:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[C:12]=1[N+:19]([O-:21])=[O:20])[O:8][CH2:7][C:6]([OH:26])=[O:5])([O:24][CH3:25])=[O:23]
Reactant: COC(=O)c1cc(OCC(=O)OC(C)(C)C)cc(C(=O)OC)c1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)c1cc(OCC(=O)O)cc(C(=O)OC)c1[N+](=O)[O-]

Procedure:
To a solution of 3.28 g. of tert-butyl-(3,5-dicarbomethoxy-4-nitrophenoxy)acetate in 20 ml. of benzene are added 100 mg. of p-toluenesulfonic acid monohydrate. The solution is stirred and refluxed for 30 min. After this time, the reaction is cooled and the precipitate collected. Yield 2.4 g.; m.p. 151°-152° C.
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][CH:12]3[CH2:16][CH2:15][NH:14][CH2:13]3)=[CH:10][C:4]=2[O:3]1.C(N(CC)CC)C.C1([O:31][C:32](=O)[NH:33][C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)C=CC=CC=1>C(#N)C>[N:36]1[CH:37]=[CH:38][CH:39]=[C:34]([NH:33][C:32]([N:14]2[CH2:15][CH2:16][CH:12]([CH2:11][C:9]3[CH:8]=[CH:7][C:5]4[O:6][C:2]([F:1])([F:17])[O:3][C:4]=4[CH:10]=3)[CH2:13]2)=[O:31])[CH:35]=1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: FC1(F)Oc2ccc(CC3CCNC3)cc2O1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1cccnc1)N1CCC(Cc2ccc3c(c2)OC(F)(F)O3)C1
Temperature: 35 °C
Yield: 38.8 %

Procedure:
To a solution consisting of 3-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-pyrrolidine (111 mg, 0.399 mmol), triethylamine (0.1 mL, 0.72 mmol) and acetonitrile (2 mL) was added pyridin-3-yl-carbamic acid phenyl ester (90.1 mg, 0.421 mmol). The mixture was heated at 35° C. for 18 h, cooled to rt and then concentrated. The crude residue was purified (FCC) to give the title compound (56 mg, 39%). MS (ESI): mass calcd. For C18H17F2N3O3, 361.12. m/z found, 362.2 [M+H]+. 1H NMR (CD3OD): 8.63-8.59 (m, 1H), 8.16-8.13 (m, 1H), 7.97-7.92 (m, 1H), 7.35-7.30 (m, 1H), 7.16-7.09 (m, 2H), 7.06-7.02 (m, 1H), 3.66-3.53 (m, 2H), 3.48-3.38 (m, 1H), 3.19-3.11 (m, 1H), 2.85-2.72 (m, 2H), 2.62-2.50 (m, 1H), 2.11-2.02 (m, 1H), 1.78-1.66 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([CH3:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.O[CH2:13][C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([CH3:11])[N:8]([CH2:13][C@@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1cc2c(Cl)ncnc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(Cl)ncnc2n1C[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To the solution of 4-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 5.97 mmol, 1.0 eq) and (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.32 g, 6.57 mmol, 1.1 eq) and PPh3 (3.03 g, 11.94 mmol, 2.0 eq) in THF (50 mL), DIEA (2.08 g, 11.94 mmol, 2.0 eq) was added at 0° C. The resulted mixture was stirred and warmed to RT for 12 h. Solvent was removed and purified by column chromatography (eluting with 10% EtOAc in PE) to afford (S)-tert-butyl 2-((4-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carboxylate as a white solid (2.08 g, 100% in yield).
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([Cl:17])[CH:11]=2)=[O:8])[O:4][N:3]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[Cl:17][C:12]1[CH:11]=[C:10]([NH:9][C:7]([C:5]2[O:4][N:3]=[C:2]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:6]=2)=[O:8])[CH:15]=[CH:14][C:13]=1[F:16]
Reactant: C1COCCN1
Reactant: O=C(Nc1ccc(F)c(Cl)c1)c1cc(Br)no1
Product: O=C(Nc1ccc(F)c(Cl)c1)c1cc(N2CCOCC2)no1
Yield: 42 %

Procedure:
A solution of 3-bromo-N-(3-chloro-4-fluorophenyl)isoxazole-5-carboxamide (7.5 mg, 0.024 mmol) in morpholine (1.0 mL) was heated at 180° C. in the microwave for 15 minutes. Purification by preparative LCMS (pH 10 buffer) gave the desired product (3.2 mg, 42%). MF=C14H14ClFN3O3; LCMS calculated for C14H14ClFN3O3 (M+H)+: m/z=326.
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[C:12]([I:14])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=O)C.Cl.[CH3:16]O>>[NH2:4][C:5]1[CH:13]=[C:12]([I:14])[CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH3:16])=[O:8]
Reactant: CC(=O)Nc1cc(I)ccc1C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(I)cc1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 16.1 g of 2-acetylamino-4-iodobenzoic acid (m.p. 233°-5° C; synthesized in accordance with U.S. Pat. No. 4,762,838) in 325 ml of absolute methanol is saturated at 0° C. with dry hydrogen chloride gas. The mixture is heated to the boil for 15 hours, cooled to room temperature, resaturated using dry hydrogen chloride gas, and allowed to stand at room temperature for 24 hours. The solvent is evaporated in vacuo, the residue is taken up in dichloromethane, and the organic phase is washed with a saturated aqueous sodium hydrogen carbonate solution until free from acid. The organic phase is dried over Na2 SO4, and evaporated in vacuo. This gives 13.8 g of methyl 2-amino-4-iodobenzoate of m.p. 63°-7° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[OH-].[Na+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C)C=O>[C:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:11][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:10])[CH3:9]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: CCOC(=O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Br)cc1C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
To a solution of 1-(5-bromo-2-hydroxyphenyl)ethan-1-one (10 g, 46.50 mmol) in N,N-dimethylformamide (80 mL) was added sodium hydroxide (2.23 g, 92.92 mmol) and then stirred for 1 hour at room temperature. Ethyl 2-bromoacetate (8.24 g, 49.34 mmol) was added dropwise and stirred overnight at room temperature. The reaction mixture was quenched by the addition of water (200 mL), adjusted to pH 5 with HCl (3N), extracted with ethyl acetate (50 mL×3), dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue which was purified by silica gel chromatography (5% ethyl acetate in petroleum ether) to afford ethyl 2-(2-acetyl-4-bromophenoxy)acetate as a light yellow oil (8.9 g, 64%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:15][NH:14][C:13](=S)[C@H:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1.[NH2:25][CH2:26][C:27](=O)[C:28]([CH3:31])([CH3:30])[CH3:29].C(N(CC)CC)C>C(O)C.[Hg](Cl)Cl>[C:28]([C:27]1[N:14]2[CH2:15][C@H:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])[CH2:10][CH2:11][C@@H:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:13]2=[N:25][CH:26]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)C(=O)CN
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=S
Agent: Cl[Hg]Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C(C)(C)C)cnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 119.2 %

Procedure:
Mercury(II) chloride (10 mg, 0.036 mmol) was added to a solution of tert-butyl [(3R,6S)-6-(2,3-difluorophenyl)-2-thioxoazepan-3-yl]carbamate (10 mg, 0.028 mmol), hydrobromide salt of 1-amino-3,3-dimethylbutan-2-one (11 mg, 0.056 mmol), and triethylamine (10 μL, 0.07 mmol) in ethanol (1 mL) at 70° C. After 18 h, the reaction was allowed to cool to ambient temperature. The mixture was filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→95% dichloromethane/methanol) gave the title compound (14 mg). MS 420.2 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([N:33]=[C:34]=[O:35])(=[O:32])=[O:31]>>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH:33][C:34]([NH:22][CH2:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([N:13]2[C:6]3=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]3[N:4]=[C:3]2[CH2:1][CH3:2])=[CH:19][CH:18]=1)=[O:35])(=[O:32])=[O:31]
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCN)cc1
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccccc2Cl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 10 of Example 1 from 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine (step 9 of Example 1) and 2-chlorobenzenesulfonyl isocyanate.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([O:21][CH3:22])[CH:16]=1)=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([O:21][CH3:22])[CH:16]=1)=[O:11]
Reactant: CCOC(=O)[C@H](Cc1ccnc(OC)c1)NC(=O)CNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H](Cc1ccnc(OC)c1)NC(=O)CN
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 100-mL round-bottomed flask was added ethyl N-(tert-butoxycarbonyl)glycyl-3-(2-methoxy-4-pyridinyl)alaninate (2.3 g, 6.03 mmol) and trifluoroacetic acid (8 mL, 108 mmol) in DCM (8 mL). The reaction mixture was stirred at 0° C. for 2 h. The solvent was removed in vacuo to give crude ethyl glycyl-3-(2-methoxy-4-pyridinyl)alaninate as a colorless tar, which was used without further purification.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:18][C:19]1[CH:24]=[C:23](Cl)[CH:22]=[CH:21][N:20]=1>CN(C=O)C>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:23]2[CH:22]=[CH:21][N:20]=[C:19]([Cl:18])[CH:24]=2)=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cc(Oc2ccc(OCc3ccccc3)cc2)ccn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirring RT suspension of NaH (0.739 g of a 60% by weight oil dispersion, 18.48 mmol) in DMF (20 mL) was added 4-benzyloxy phenol (3.70 g, 18.48 mmol). The mix was stirred 10 min before cooling to 0° C. and adding 2,4-dichloropyridine (2.734 g, 18.48 mmol). The reaction was warmed to RT. After stirring for 60 h, the reaction was quenched with saturated aqueous NaHCO3 and then basified with 2N NaOH. The crude was extracted twice with Et2O. The organic layers were washed three times with 2 N NaOH, once with brine, then combined and dried over Na2SO4, filtered and dried in vacuo. The crude residue was eluted on a silica gel column with a hexanes/EtOAc system to yield title compound, isolated as the major regioisomer.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25])(=[O:17])=[O:16])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:49]([O:51][C:52](=[O:56])[CH2:53][NH:54][CH3:55])[CH3:50]>CN(C=O)C.C(Cl)(Cl)Cl>[CH2:49]([O:51][C:52](=[O:56])[CH2:53][N:54]([C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][NH:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25])(=[O:16])=[O:17])[CH3:55])[CH3:50]
Reactant: CCOC(=O)CNC
Reactant: CC(C)(C)OC(=O)N[C@@H](CNS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CN(C)C(=O)[C@H](CNS(=O)(=O)c1ccccc1[N+](=O)[O-])NC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 91.6 %

Procedure:
To a solution of compound A (10.0 g, 25.7 mmol) in DMF (100 mL) was added HOBt (5.2 g, 38.5 mmol) and the reaction mixture was cooled to −10° C. To this reaction mixture, EDC-HCl (5.4 g, 28.2 mmol) was added in portions over 10 min and stirred at −10° C. for 20 min. To the reaction mixture, Sarcosine ethyl ester (256.8 mmol) in CHCl3 (300 mL) was added drop wise over 30 min. The reaction mixture was stirred at this temperature for 30 min followed by stirring at ambient temperature overnight. Solvents were then removed in vacuo, and the residue was dissolved in EtOAc (500 mL), washed with water (3×300 mL), saturated aqueous NaHCO3 (2×300 mL) and brine (100 mL). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo to afford compound B (11.5 g, 91%) as a cream solid. LC-MS [M+H] 489.5 (C19H28N4O9S+H, calc: 489.3). Purity >95% (UV/254 nm). Compound B was used without further purification.