Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[F:19])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccccc1F
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) and 2-fluorobenzene boronic acid according to the general procedure B. Obtained as a yellow solid (1.48 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:9])=[O:8])[CH3:6])[CH3:2].ClC[C:21]1[CH:35]=[CH:34][C:24]([O:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:9])=[O:8])[CH2:6][C:21]1[CH:22]=[CH:23][C:24]([O:25][CH2:26][CH2:27][N:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[CH:34][CH:35]=1)[CH3:2]
Reactant: CCCCCCCCS(=O)(=O)C(C)C(=O)OCC
Reactant: ClCc1ccc(OCCN2CCCCC2)cc1
Product: CCCCCCCCS(=O)(=O)C(Cc1ccc(OCCN2CCCCC2)cc1)C(=O)OCC

Procedure:
2-(Octane-1-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]-propionic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-(octane-1-sulfonyl)-propionic acid ethyl ester (5.0 g, 18 mmol) and 1-[2-(4chloromethylphenoxy)-ethyl]-piperidine (5.6 g, 19.7 mmol); Yield 8.9 g (96%); amber oil, MS 495.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]23[O:16][CH2:15][C:12](CCC)([CH2:13][O:14]2)[CH2:11][O:10]3)=[CH:5][CH:4]=1)#[CH:2].ClC(OC)=O.[CH2:25]([C:28]12COC(C3C=CC(C#CC(OC)=O)=CC=3)(O[CH2:33]1)O[CH2:29]2)CC>>[C:28]([C:12]12[CH2:11][O:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[CH:2])=[CH:4][CH:5]=3)([O:14][CH2:13]1)[O:16][CH2:15]2)([CH3:33])([CH3:29])[CH3:25]
Reactant: C#Cc1ccc(C23OCC(CCC)(CO2)CO3)cc1
Reactant: CCCC12COC(c3ccc(C#CC(=O)OC)cc3)(OC1)OC2
Agent: COC(=O)Cl
Product: C#Cc1ccc(C23OCC(C(C)(C)C)(CO2)CO3)cc1

Procedure:
Using the methodology described in (ii) above and starting from 1-(4-ethynylphenyl)-4-n-propyl-2,6,7-trioxabicyclo[2,2,2]octane and methyl chloroformate, methyl 3-[4-(4-n-propyl-2,6,7-trioxabicyclo[2,2,2]oct-1-yl)phenyl]prop-2-ynoate was prepared.
Reaction SMILES: [CH3:1][C:2]1[O:16][C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:10][C@H:11]([CH2:14][OH:15])[O:12][C:13]=3[C:4]=2[CH:3]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:15][CH2:14][CH:11]2[CH2:10][O:9][C:8]3[CH:7]=[CH:6][C:5]4[O:16][C:2]([CH3:1])=[CH:3][C:4]=4[C:13]=3[O:12]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1cc2c3c(ccc2o1)OC[C@H](CO)O3
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4oc(C)cc4c3O2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 0.20 g (0.90 mmole) of [(2S)-8-methyl-2,3-dihydrofuro[3,2-f][1,4]benzodioxin-2-yl]methanol in 5.0 mL of pyridine was added 1.0 g (5.2 mmole) of p-toluenesulfonyl chloride. The mixture was stirred at room temperature under nitrogen for 15 hours. The solvent was then removed in vacuum and replaced with 200 mL of methylene chloride. The solution was washed with 100 mL portions of 2 N aqueous HCl, saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum to a brown residue. The residue was column chromatographed on silica gel with 1:1 methylene chloride/hexane as eluant and the product fractions combined and concentrated in vacuum to give 0.28 g of the (R)-enantiomer of the title compound as a pale yellow oil. 1H-NMR (CDCl3): doublet 7.79 δ (2H); doublet 7.30 δ (2H); doublet 6.86 δ (1H); doublet 6.68 δ (1H); singlet 6.29 δ (1H); multiplet 4.48 δ (1H); multiplet 4.26 δ (3H); doublet of doublets 4.06 δ (1H); singlet 2.43 δ (3H); singlet 2.41 δ (3H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH:14]2[O:26][CH2:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)=[CH:9][CH:8]=1.[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:38]([N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:15][CH:14]2[O:26][CH2:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)=[CH:9][CH:8]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CNCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1
Reactant: BrCc1ccccc1
Product: CN(CCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1)Cc1ccccc1

Procedure:
In an analogous manner to that described in Example 44(e), by alkylating tert-butyl (3RS,4RS)-4-[4-(3-methylamino-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 57(e)] with benzyl bromide there was obtained tert-butyl (3RS,4RS)-4-[4-[3-(benzyl-methyl-amino)-propoxy]-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 595 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]2[N:12]3[N:13]=[C:14]([NH2:16])[N:15]=[C:11]3[CH:10]=[C:9]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:8]=2)=[CH:5][N:6]=1.[CH2:23]([N:25]=[C:26]=[O:27])[CH3:24]>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.C1(C)C=CC=CC=1>[CH2:23]([NH:25][C:26]([NH:16][C:14]1[N:15]=[C:11]2[CH:10]=[C:9]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:8]=[C:7]([C:4]3[S:3][C:2]([CH3:1])=[N:6][CH:5]=3)[N:12]2[N:13]=1)=[O:27])[CH3:24]
Reactant: Cc1ncc(-c2cc(-c3cccnc3)cc3nc(N)nn23)s1
Reactant: CCN=C=O
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3cnc(C)s3)n2n1
Temperature: 125 °C

Procedure:
A suspension of the product of Step 1 (160 mg, 0.52 mmol), ethylisocyanate (205 μL, 2.6 mmol), and dibutyltin diacetate (5 drops) in dry toluene (6 mL) was heated at 125° C. in a microwave reactor for 1 h. After being cooled at room temperature the precipitated solid was filtered and washed with chloroform. The crude product was purified by flash chromatography (gradient 0-2% methanol/chloroform) to give 1-ethyl-3-[5-(2-methyl-thiazol-5-yl)-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-urea as a solid. MS m/z 380 (M+H+).
Reaction SMILES: [CH2:1]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]#[CH:10].[NH2-].[Li+]>>[CH2:1]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]#[C:10][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: C#CCCCCCCCCOC1CCCCO1
Agent: [Li+]
Agent: [NH2-]
Product: CCCCC#CCCCCCCCCOC1CCCCO1
Reaction time: 20 h
Yield: 70 %

Procedure:
A mixture of 7.4 g of compound IV, 1.0 g lithium amide, and 50 ml of dry, purified dioxane was stirred and refluxed 3.5 hours under nitrogen, cooled, 4.5 g of n-butyl bromide was added dropwise and the refluxing and stirring continued for 20 hours more. The mixture was chilled in an icebath, diluted with 60 ml of water and the layers separated. The aqueous layer was extracted three times with ether, the combined organic phase was washed three times with saturated NaCl solution, the solvents were evaporated and the residue distilled to give 3.2 g (36%) of compound V which boiled at 120°-123° (0.03 mm), ND25 1.4634.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:16]=[CH:15][C:14](I)=[CH:13][C:10]=1[CH2:11][OH:12].[C:18]([C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH:27]=1)[C:25]#[N:26])#[CH:19]>O1CCCC1.[Br-].[Zn+2].[Br-].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>[F:8][C:9]1[CH:16]=[CH:15][C:14]([C:19]#[C:18][C:20]2[CH:21]=[N:22][CH:23]=[C:24]([CH:27]=2)[C:25]#[N:26])=[CH:13][C:10]=1[CH2:11][OH:12]
Reactant: OCc1cc(I)ccc1F
Reactant: C#Cc1cncc(C#N)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1cncc(C#Cc2ccc(F)c(CO)c2)c1
Temperature: 60 °C
Yield: 61.6 %

Procedure:
Dissolve zinc (II) bromide (374 mg, 14.3 mmol) in tetrahydrofuran (30 mL) and treat with triethylamine (7.96 mL, 57.1 mmol). After 5 min add 2-fluoro -5-iodobenzyl alcohol, (prepared as described in PREPARATION 33), (3.00 g, 11.9 mmol), 5-ethynylnicotinonitrile, (prepared as described in PREPARATION 4), (1.83 g, 14.3 mmol) and tetrakis(triphenylphosphine)palladium (0) (688 mg, 0.595 mmol) to the reddish solution. Heat to 60° C. for 2 h, cool to room temperature, and filter through diatomaceous earth. Purify by silica gel chromatography, eluting with 75:25 to 60:40 hexanes:ethyl acetate, to give the title compound as a yellow crystalline solid (1.85 g, 62%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])[N:20]=[CH:19][C:18]=3[N:31]=2)=[CH:11][C:10]=1[F:32])[C:2]1[CH:7]=[CH:6]C=CC=1.[F:33]C1(CO)CC1>>[F:32][C:10]1[CH:11]=[C:12]([C:15]2[O:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])[N:20]=[CH:19][C:18]=3[N:31]=2)[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1([F:33])[CH2:6][CH2:7]1
Reactant: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCc4ccccc4)c(F)c3)nc2cn1
Reactant: OCC1(F)CC1
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCC4(F)CC4)c(F)c3)nc2cn1

Procedure:
Using N-((2S)-1-((2-(4-(benzyloxy)-3-fluorophenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide and (1-fluorocyclopropyl)methanol, and in the same manner as in Step A and Step B of Example 4, the title compound was obtained.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([CH2:12][O:13][C:14](=[O:29])[NH:15][CH2:16][CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][NH2:28])[CH:25]=3)[NH:20][CH:19]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>N1C=CC=CC=1>[C:6]1([CH2:12][O:13][C:14](=[O:29])[NH:15][CH2:16][CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][NH:28][S:2]([CH3:1])(=[O:4])=[O:3])[CH:25]=3)[NH:20][CH:19]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCc1ccc2[nH]cc(CCNC(=O)OCc3ccccc3)c2c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)NCc1ccc2[nH]cc(CCNC(=O)OCc3ccccc3)c2c1
Reaction time: 1 h

Procedure:
Methanesulphonyl chloride (0.3 ml) was added in 3 portions over 3 h to a stirred, ice-cold solution of phenylmethyl[2-[5-(aminomethyl)-1H-indol-3-yl]ethyl]carbamate (0.45 g) in dry pyridine (15 ml). After a further 1 h, the mixture was partitioned between ice-cooled hydrochloric acid (1N, 300 ml) and ethyl acetate (200 ml). The organic layer was washed with brine (80 ml) and potassium carbonate solution (ca. 40%; 50 ml), dried (Na2SO4) and evaporated in vacuo to leave a yellow gum (0.45 g). Chromatography on silica gel (MFC: 18 g), eluting with increasing concentrations of ether in dichloromethane, gave the title compound (0.3 g) as an almost colourless oil.
Reaction SMILES: O[C@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C@@H:4]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[O:19])[CH2:3]1.CCN(S(F)(F)[F:38])CC>C(Cl)Cl>[F:38][CH:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:4]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[O:19])[CH2:3]1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C(OCc1cccc(C(F)(F)F)c1)[C@H]1C[C@@H](O)CN1Cc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: O=C(OCc1cccc(C(F)(F)F)c1)C1CC(F)CN1Cc1cccc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 54.4 %

Procedure:
A solution of (2R,4R)-3-(trifluoromethyl)benzyl 4-hydroxy-1-(3-(trifluoromethyl)benzyl)pyrrolidine-2-carboxylate (D81) (200 mg, 0.45 mmol) in DCM (20 ml) cooled at −20° C. was treated with DAST (0.148 ml, 1.11 mmol) and the mixture was first stirred 1 h at −20° C. then 18 hrs at RT. The reaction was quenched with NaHCO3 sat. sol. and the aqueous phase extracted with DCM (3×5 ml), dried over MgSO4 and evaporated. The residue was purified by Biotage SNAP-Si column (25 g) eluting with petroleum ether/EtOAc from 90/10 to 80/20. Collected fractions, after solvent evaporation afforded the title compound (D82) (110 mg)
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(NC(C)C)(C)C.[CH:15]([OH:18])([CH3:17])[CH3:16]>>[CH:15]([O:18][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1)([CH3:17])[CH3:16]
Reactant: CC(C)O
Reactant: Clc1ncccn1
Solvent: CC(C)NC(C)C
Product: CC(C)Oc1ncccn1
Temperature: 130 °C

Procedure:
A 2-chloropyrimidine was dissolved in isopropyl alcohol to which was added diisopropylamine. The reaction was heated in a sealed tube for ten days at 130° C. The cooled reaction mixture was concentrated, and the product purified via silica gel column chromatography to yield the 2-isopropoxypyrimidine.
Reaction SMILES: Cl.C([O:4][C:5](=O)[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]([N:17]2[C:21]([NH2:22])=[CH:20][C:19]([C:23]([CH3:26])([CH3:25])[CH3:24])=[N:18]2)[CH:8]=1)C.[NH3:28].CO>>[NH2:22][C:21]1[N:17]([C:9]2[CH:8]=[C:7]([CH2:6][C:5]([NH2:28])=[O:4])[C:16]3[C:11]([CH:10]=2)=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:18]=[C:19]([C:23]([CH3:26])([CH3:24])[CH3:25])[CH:20]=1
Reactant: CCOC(=O)Cc1cc(-n2nc(C(C)(C)C)cc2N)cc2ccccc12
Reactant: N
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1cc(N)n(-c2cc(CC(N)=O)c3ccccc3c2)n1
Yield: 41 %

Procedure:
[3-(5-amino-3-t-butyl-pyrazol-1-yl)naphthalen-1-yl]acetic acid ethyl ester hydrochloride (see WO 2006/071940, 1.60 g, 4.55 mmol) was treated with ammonia in methanol (7 M, 13 mL, 91 mmol) and the reaction mixture was heated in a sealed tube for 6 days. The solvent was removed in vacuo and the residue was chromatographed to provide 2-(3-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)naphthalen-1-yl)acetamide (610 mg, 41% yield). MS (ESI) m/z: 323.3 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([OH:16])=O)[CH:13]=[C:8]2[C:7]([CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:6]1.CN1CCOCC1.Cl.[CH3:36][NH:37][OH:38]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([N:37]([OH:38])[CH3:36])=[O:16])[CH:13]=[C:8]2[C:7]([CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:6]1
Reactant: COCCOCc1cn(Cc2ccc(F)cc2F)c2cnc(C(=O)O)cc12
Reactant: CNO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COCCOCc1cn(Cc2ccc(F)cc2F)c2cnc(C(=O)N(C)O)cc12
Temperature: 4 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To a solution of 1-(2,4-difluorobenzyl)-3-[(2-methoxyethoxy)methyl]-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid 782 mg 2.078 mmol) in anhydrous DMF (10 ml) was added CDMT (438 mg 2.439 mmol 1.2 eq.) and NMM (N-methyl morpholine) (0.28 ml 2.493 mmol 1.2 eq.). The mixture, under nitrogen, was stirred for 2.0 hours, during which it slowly darkened to a deep orange. N-Methylhydroxylamine hydrochloride (868 mg 10.389 mmol 5.0 eq) was added and stirring continued for 10 hours. The reaction was judged to be complete by HPLC-MS analysis and the volatiles were removed in vacuo (ca. 2 torr) to give a golden yellow oil. This oil was dissolved in EtOAc (30 mL) and washed with water (3×20 mL) and brine (20 mL). The organic phase was separated, dried (Na2SO4), and concentrated in vacuo to afford the crude product which was purified by recrystallisation in hot IPA (20 ml) with cooling at 4° C. overnight to give 556 mg (66%) of 1-(2,4-difluorobenzyl)-N-hydroxy-3-[(2-methoxyethoxy)methyl]-N-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxamide as a pale tan powder. LC-MS (Eclipse XDB-C8, 0.8 mL/min, gradient 80:20 to 5:95H2O (+0.1% HOAc):CH3CN—3 minutes, APCI, +mode): RT—1.08 min, m/e=344.2 (M+H+, base).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][NH:12][CH2:13]2.C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CC(N(C)C)=O>[C:31]([N:12]1[CH2:11][CH2:10][C:9]2[C:14](=[CH:15][C:16]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])=[CH:17][C:8]=2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:13]1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)C(=O)Nc1cc2c(c(-c3ccccc3Cl)c1)CCNC2
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CC(C)C(=O)Nc1cc2c(c(-c3ccccc3Cl)c1)CCN(C(=O)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 27 %

Procedure:
N-[5-(2-Chloro-phenyl)-1,2,3,4-tetrahydro-isoquinolin-7-yl]2-methylpropanamide (39 mgs, 0.12 mmoles) was dissolved in dimethylacetamide (1 ml) followed by the addition of triethylamine (20 ul, 0.144 mmoles) and finally benzoyl chloride (16.7 ul, 0.144 mmoles). The reaction was stirred at room temperature for 1.5 hours and purified by C18 reverse phase automated HPLC (14 mgs, 27% yield, 100% pure, CO-AAWO0025).
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].[F:6][C:7]1[CH:8]=[C:9]([CH:15]([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:16]([OH:18])=O)[CH:10]=[CH:11][C:12]=1[S:13][CH3:14].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(#N)C.C(OCC)(=O)C.C(N(CC)CC)C>[F:6][C:7]1[CH:8]=[C:9]([CH:15]([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:16]([N:4]([O:3][CH3:2])[CH3:5])=[O:18])[CH:10]=[CH:11][C:12]=1[S:13][CH3:14]
Reactant: CNOC
Reactant: CSc1ccc(C(CC2CCOCC2)C(=O)O)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CON(C)C(=O)C(CC1CCOCC1)c1ccc(SC)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
A solution of N-methoxymethanamine hydrochloride (467 mg) in acetonitrile (16 mL) was neutralized with triethylamine (1.82 mL), and 2-[3-fluoro-4-(methylsulfanyl)phenyl]-3-(tetrahydro-2H-pyran-4-yl)propanoic acid (1.30 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (918 mg) and 1-hydroxybenzotriazole (73.4 mg) were added under ice-cooling. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate, and washed with water and saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (1.33 g, yield 89%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio).
Reaction SMILES: C[O:2][C:3]([N:5]1[CH2:9][CH:8]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH:7]2[N:20]([C:23](=[O:39])[CH:24]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:21][CH2:22][CH:6]12)=O.[C:40]1([CH2:46]C(Cl)=O)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[C:35]([O:34][C:32](=[O:33])[NH:31][CH:24]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:23]([N:20]1[CH2:21][CH2:22][CH:6]2[N:5]([C:3](=[O:2])[CH2:46][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:9][CH:8]([C:10]3[C:18]4[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH:7]12)=[O:39])([CH3:38])([CH3:37])[CH3:36]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COC(=O)N1CC(c2c[nH]c3cc(F)ccc23)C2C1CCN2C(=O)C(NC(=O)OC(C)(C)C)C1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2C(=O)Cc1ccccc1)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 66.4 %

Procedure:
A solution containing amine 50 (296 mg, 0.61 mmol) in DCM (8 mL) was cooled to 0° C. TEA (145 mg, 1.43 mmol) was added followed by phenylacetyl chloride (105 mg, 0.68 mmol) and the reaction mixture was warmed to ambient temperature. After 40 min, the reaction mixture was diluted with DCM and the resulting organic solution was washed successively with 1M HCl and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (1:1 hexanes/EtOAc to 1:2 hexanes/EtOAc) to afford 244 mg (66%) of 56 as an off-white-colored foam. 1H NMR (300 MHz, CDCl3), mixture of amide rotamers: δ8.27 (s, 0.7H), 8.20 (s, 0.3H), 8.02 (dd, J=5.1, 8.4 Hz, 0.7H), 7.35-7.27 (m, 5H), 6.96-6.89 (m, 2H), 6.53 (s, 0.3H), 6.14 (s, 0.7H), 5.34 (d, J=9.3 Hz, 0.7H), 4.77 (d, J=5.1 Hz, 0.3H), 4.51-4.38 (m, 2H), 4.34-4.28 (m, 1H), 4.12 (app q, J=6.9 Hz, 1H), 4.04-3.89 (m, 2H), 3.77 (s, 1H), 3.51-3.42 (m, 0.7H), 3.30-3.20 (m, 0.3H), 2.60-2.53 (m, 1H), 1.76-1.63 (m, 6H), 1.44 (s, 9H), 1.19-1.05 (m, 5H) ppm. Mass spectrum, m/z [603.4] (M+H)+.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C@@H:8]([CH:12]([CH2:17][CH2:18][CH3:19])[C:13]([O:15]C)=[O:14])[C@@H:7]1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1.[Li+].[OH-].O1CCOCC1.Cl>C1COCC1.O>[F:39][C:2]([F:1])([F:38])[C:3]1[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:37])[F:36])=[CH:30][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C@@H:8]([CH:12]([CH2:17][CH2:18][CH3:19])[C:13]([OH:15])=[O:14])[C@@H:7]1[C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=1
Reactant: CCCC(C(=O)OC)[C@@H]1CCCN(Cc2cc(C(F)(F)F)ccc2C(F)(F)F)[C@H]1c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: O
Product: CCCC(C(=O)O)[C@@H]1CCCN(Cc2cc(C(F)(F)F)ccc2C(F)(F)F)[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Yield: 74.1 %

Procedure:
A solution of the ester from Step 1 (0.098 g, 0.17 mmol) and LiOH (0.082 g, 3.4 mmol) in THF (3 ml) and water (3 ml) was heated at 60° C. for 16 hrs. Then dioxane (3 ml) was added and the reaction was heated at 100° C. for 16 hrs. The reaction mixture was acidified to pH6 with 2N HCl and extracted with EtOAc. The combined extracts were washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (silica, 1-2% MeOH/DCM) to give the acid (0.070 g, 74%). 1H NMR (400 MHz, CD3OD): δ 0.84 (3H, t, J 7.2), 0.86-0.97 (1H, m), 1.21-1.47 (3H, m), 1.61-1.83 (5H, m), 2.17 (1H, dt, J 3.0, 11.7), 2.28-2.34 (1H, m), 2.83 (1H, d, J 11.6), 3.37-3.57 (3H, m), 7.65 (5H, m), 7.75 (1H, d, J 8.2), 8.19 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=2[F:26])[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:32].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=2[F:26])[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH2:17][O:32]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCCCC(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(c1ccc(Cl)cc1)C(CCCCC1CO1)c1c(F)ccc(F)c1F

Procedure:
[7-(4-chloro-benzenesulfonyl)-7-(2,3,6-trifluoro-phenyl)-1-heptene (0.65 g, 1.6 mmole) and mCPBA (77%, 0.71 g, 3.2 mmole) were stirred in 50 mL DCM for 5 hours. 2 g Na2S2O3 in 100 mL water were added to quench excess mCPBA. The organic layer was separated, washed with 1N NaOH solution (50 mL), brine (50 mL), dried over Na2SO4 and concentrated. The product was purified by column chromatography using EtOAc/Hexane as eluent (Gradient from 0/100 to 40/60 in 40 minute, 0.52 g, 77%). 1H NMR (CDCl3, 400 MHz) δ 7.63 (d, j=8.05 Hz, 2H), 7.45 (d, j=8.05 Hz, 2H), 7.15 (m, 1H), 6.83 (m, 0.5H), 6.74 (m, 0.5H), 4.58 (dd, j=5.1 and 6.5 Hz, 1H), 2.84 (m, 1H), 2.71 (t, j=4.4 Hz, 1H), 2.41 (dd, j=2.9 and 5.1 Hz), 2.45 (m, 1H), 2.34 (m, 1H), 1.25-1.55 (m, 6H).