Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH2:4][CH2:3]1.Br[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([NH:26][C:27]2[N:32]=[C:31]([C:33]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]([CH3:42])[CH:34]=3)[CH:30]=[CH:29][N:28]=2)=[CH:20][C:19]=1[NH2:43].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH3:25][O:24][C:22]1[CH:23]=[C:18]([C:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=2)[C:19]([NH2:43])=[CH:20][C:21]=1[NH:26][C:27]1[N:32]=[C:31]([C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]([CH3:42])[CH:34]=2)[CH:30]=[CH:29][N:28]=1
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1cc(Br)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C2=CCN(C)CC2)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Temperature: 100 °C
Yield: 83.4 %

Procedure:
1,1 Bis(di-tert-butylphosphino)ferrocene palladium dichloride (16.74 mg, 0.03 mmol) was added to a solution containing 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (139 mg, 0.62 mmol), 4-bromo-6-methoxy-N-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 144, 220 mg, 0.52 mmol), and K3PO4 (220 mg, 1.04 mmol) in 1,4-dioxane (6 mL) and water (1.5 mL, degassed for 20 minutes prior to use). The mixture was heated at 100° C. for 1 h and then concentrated in vacuo. The resulting residue was dissolved in EtOAc. This solution was washed with water (×3), brine, and was then dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-10% methanolic ammonia in CH2Cl2 gave the title compound (191 mg, 84%) as a tan solid after trituration with diethyl ether; 1H NMR: 2.31 (3H, s), 2.37-2.43 (2H, m), 2.61 (2H, t), 3.01-3.04 (2H, m), 3.76 (3H, s), 3.89 (3H, s), 4.37 (2H, br s), 5.70-5.73 (1H, m), 6.63 (1H, s), 7.18-7.22 (2H, m), 7.25-7.29 (1H, m), 7.54 (1H, d), 7.63 (1H, s), 7.81 (1H, s), 8.31 (1H, d), 8.34 (1H, s), 8.46 (1H, d); m/z: ES+ MH+ 441.57.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][OH:8])[CH:3]=1.CN1CCOCC1.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.[CH:29]([CH:32]1[C:37]2[N:38]=[CH:39][NH:40][C:36]=2[CH2:35][CH2:34][N:33]1[C:41](OCC1SC=CN=1)=[O:42])([CH3:31])[CH3:30].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:29]([CH:32]1[C:37]2[N:38]=[CH:39][NH:40][C:36]=2[CH2:35][CH2:34][N:33]1[C:41]([O:8][CH2:7][C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1)=[O:42])([CH3:31])[CH3:30]
Reactant: CC(C)C1c2nc[nH]c2CCN1C(=O)OCc1nccs1
Reactant: Cc1cc(CO)no1
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(COC(=O)N2CCc3[nH]cnc3C2C(C)C)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 9.8 %

Procedure:
5-Methylisoxazole-3-methanol (1.64 g, 14.5 mmol) was dissolved in DCM (10 mL) at 0° C. and NMM (1.47 g, 1.40 mL, 14.5 mmol) and 4-nitrophenyl chloroformate (2.93 g, 14.5 mmol) were added. The reaction mixture was stirred at room temperature for 18 h. A solution of Intermediate 1 (1.87 g, 3.60 mmol) in DCM (20 mL) and DIPEA (1.87 g, 2.52 mL, 14.5 mmol) was added and the resulting solution was stirred for 3 d and concentrated in vacuo. The residue was dissolved in MeOH (8 mL) and 1 M aq NaOH solution (6 mL) and the reaction mixture was stirred for 18 h and concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and the organic layer was washed with 1 M aq Na2CO3 solution (6×100 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase column chromatography (LiChroprep RP-18, 40-63 μm, 460×26 mm (100 g), 30 mL per min, gradient 0% to 20% (over 5 min) to 90% (over 40 min) MeOH in water) and reverse phase HPLC (YMC ODS-A 150×20 mm, 5 μm, 25 mL per min, gradient 40% to 80% (over 7 min) then 100% (3 min) MeOH in 10% MeOH/water) to give (5-methylisoxazol-3-yl)methyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (107 mg, 9.7%) as a colourless gum.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=2)[C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:32][O:33][S:34]([O-:36])=O.[K+].[CH3:38]O>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=2)[C:15]2[CH:16]=[CH:17][C:18]([S:34]([CH3:38])(=[O:36])=[O:33])=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4].[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=2)[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:22])=[O:32])=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S([O-])OO
Reactant: CO
Reactant: CSc1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(S(C)(=O)=O)cc2)CC1
Product: CS(=O)c1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 32 %
Yield: 53 %

Procedure:
To a solution of 4-[(3-cyano-benzyl)-(4-methylsulfanyl-phenyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 105) (484 mg, 1.1 mmol) in MeOH (20 mL) cooled to 0° C. was added OXONE® (680 mg, 1.1 mmol) and the mixture was stirred at 0° C. for 1.5 hours. Work-up and purification afforded 4-[(3-cyano-benzyl)-(4-methanesulfonyl-phenyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (166 mg, 32%) as a white solid and 4-[(3-cyano-benzyl)-(4-methanesulfinyl-phenyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (264 mg, 53%) as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[Cl:5][CH2:6][C:7]([N:9]([C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])[CH2:10][CH2:11][CH:12]=O)=[O:8].C(=O)(O)[O-].[Na+]>C(O)C>[CH3:2][O:3][N:4]=[CH:12][CH2:11][CH2:10][N:9]([C:14]1[C:15]([CH3:21])=[CH:16][CH:17]=[CH:18][C:19]=1[CH3:20])[C:7](=[O:8])[CH2:6][Cl:5]
Reactant: CON
Reactant: Cc1cccc(C)c1N(CCC=O)C(=O)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CON=CCCN(C(=O)CCl)c1c(C)cccc1C
Temperature: 35 °C
Reaction time: 2 h

Procedure:
A 2.0-g (0.024-mol) sample of methoxyamine hydrochloride was added slowly to a slurry of 3.0 g (0.012 mol) beta-(N-chloroacetyl-2,6-dimethylphenylamino)propionaldehyde and 2.0 g (0.02 mol) sodium bicarbonate in 75 ml ethanol. The reaction mixture was stirred at about 35° C. for 2 hours, filtered and evaporated to give 2.9 g of the product as an oil. The product is tabulated in Table I as Compound No. 13-B.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:7][C:6]=2[CH:16]=1.[CH:17]1[CH:22]=[CH:21][C:20]([O:23][C:24](OC2C=CC=CC=2)=[N:25][C:26]#[N:27])=[CH:19][CH:18]=1>C(O)(C)C>[C:26](/[N:25]=[C:24](\[O:23][C:20]1[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1)/[NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][N:11]3[CH2:12][CH2:13][CH2:14][CH2:15]3)=[N:7][C:6]=2[CH:16]=1)#[N:27]
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: Nc1ccc2oc(CN3CCCC3)nc2c1
Solvent: CC(C)O
Product: N#C/N=C(/Nc1ccc2oc(CN3CCCC3)nc2c1)Oc1ccccc1

Procedure:
A solution of 5-amino-2-[(pyrrolidin-1-yl)methyl]benzoxazole (200 mg, 0.92 mmol) and diphenylcyanocarbonimidate (263 mg, 1.10 mmol) in isopropyl alcohol (3.5 mL) was stirred overnight at ambient temperature, the resulting white solid product, (Z)-phenyl N′-cyano-N-(2-(pyrrolidin-1-ylmethyl)benzo[d]oxazol-5-yl)carbamimidate, was filtered and used directly for the next step (290 mg, 87%).
Reaction SMILES: [NH2:1]/[C:2](/OCC)=[CH:3]\[C:4](=O)[C:5]([F:8])([F:7])[F:6].Cl.[NH2:14][NH2:15].C(N(CC)CC)C>C(O)C>[F:6][C:5]([F:8])([F:7])[C:4]1[CH:3]=[C:2]([NH2:1])[NH:14][N:15]=1
Reactant: CCO/C(N)=C/C(=O)C(F)(F)F
Reactant: NN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1cc(C(F)(F)F)n[nH]1

Procedure:
To a solution of (E)-4-amino-4-ethoxy-1,1,1-trifluorobut-3-en-2-one, (Compound [XXIV]) (7.00 g, 38.2 mmol, 1.0 eq.) in ethanol (150 mL) in a 250 mL round bottom flask was added hydrazine hydrochloride (2.75 g, 40.16 mmol, 1.05 eq.) followed by triethylamine (4.05 g, 40.16 mmol, 1.05 eq.). The reaction mixture was heated to reflux for 16 hours. After cooling and concentration, the residue was purified by silica gel chromatography using CHCl3-MeOH (10%) as the eluant to give Compound [XXV]: LCMS m/e 152 (M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 5.32 (s, 2H) 5.51 (s, 1H) 12.12 (br. s., 1H).
Reaction SMILES: N1C=C([C:6]2[C:7]3[CH:14]=[CH:13][N:12](COCC[Si](C)(C)C)[C:8]=3[N:9]=[CH:10][N:11]=2)C=N1.[O-:23]CC.[Na+].C(O)C.C(OC(=O)C(C#N)CC(OCC)OCC)C>>[N:9]1[C:8]2[NH:12][CH:13]=[CH:14][C:7]=2[C:6]([OH:23])=[N:11][CH:10]=1
Reactant: CC[O-]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Agent: CCOC(=O)C(C#N)CC(OCC)OCC
Agent: [Na+]
Solvent: CCO
Product: Oc1ncnc2[nH]ccc12
Temperature: 45 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
Formamidine acetate (5, 1.04 Kg, 10 mol, 1.25 equiv) was added to 7.52 L of (21% wt) sodium ethoxide (EtONa) in ethanol (EtOH, 62.5 equiv) and the resulting solution was stirred for 60 minutes. 2-cyano-4,4-diethoxy-butyric acid ethyl ester (4, 1.8 Kg, 8.0 mol) was then added and the resulting reaction mixture was refluxed for seven hours. The stirring was turned off after the solution was cooled and the solids were allowed to settle. The supernatant ethanol solution was removed, leaving the solids in the bottom of the reaction flask. The ethanol was evaporated and the residue was added back to the solids remaining in the reaction flask with water and ice at a ratio of 600 mL/mol. A solution of 6 N aqueous HCl was added to the resulting solution at a ratio of 500 mL/mol at 15° C. The resulting solution was then heated at 45° C. for 45 minutes. The solution was again cooled to 15° C. and the pH was adjusted to 8.0 with the addition of aqueous ammonium hydroxide. The precipitated solids were collected by filtration, washed with water (2×225 mL/mol) and pulled dry. The solids were further washed with 1:1 ethyl acetate/heptane (500 mL/mol), then heptane (2×250 mL/mol) and dried in vacuum to afford 7H-pyrrolo[2,3-d]pyrimidin-4-ol (7, 738.6 g, 1081 g theoretical, 68.3%) as yellow to brown to yellow crystalline material. For 7: 1H NMR (DMSO-d6, 300 MHz) δ ppm 11.88 (bs, 1H), 11.80 (bs, 1H), 7.81 (s, 1H), 7.02 (dd, 1H, J=3.2, 2.3 Hz), 6.42 (dd, 1H, J=3.5, 2.3 Hz); C6H5N3O (MW, 135.12), LCMS (EI) m/e 136 (M++H) and (M++Na) m/e 158.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:6][CH2:5]2.[C:16]([OH:20])(=[O:19])[C:17]#[CH:18].C(N(CC)CC)C>C(#N)C.[Cu]I>[N:11]1([CH:7]2[C:8]3[C:4](=[CH:3][C:2]([C:18]#[C:17][C:16]([OH:20])=[O:19])=[CH:10][CH:9]=3)[CH2:5][CH2:6]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C#CC(=O)O
Reactant: Ic1ccc2c(c1)CCC2N1CCCC1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(O)C#Cc1ccc2c(c1)CCC2N1CCCC1
Reaction time: 2 h

Procedure:
Under an argon atmosphere at 0° C., 0.5 g (1.59 mmol) of 1-(5-iodoindan-1-yl)pyrrolidine and 123 mL (2 mmol) of propynoic acid are dissolved in 25 mL of acetonitrile. 0.66 mL (4.79 mmol) of triethylamine, 30 mg (0.16 mmol) of copper (I) iodide, and 80 mg (0.11 mmol) of ditriphenylphosphine palladium dichloride are added to this solution and the mixture is stirred for 2 hours, while the solution is allowed to come up to ambient temperature. The purification is carried out by preparative HPLC (eluant: dichloromethane/methanol/ammonia (8:2:0.2)). Yield 0.1 g (24.5% of theory); C16H17NO2 (M=255.31); calc.: molecular ion peak (M+H)+: 256; found: molecular ion peak (M+H)+: 256.
Reaction SMILES: Br[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:10]([NH2:12])=[O:11]>CN(C)C1C=CN=CC=1.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.CC(N(C)C)=O>[C:10]([NH2:12])(=[O:11])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrC=Cc1ccccc1
Reactant: NC=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)N(C)C
Product: NC(=O)C=Cc1ccccc1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
0.249 g of bis(triphenylphosphine)-palladium(II) chloride, 6.51 g of (2-bromovinyl)benzene, 3.03 g of formamide, 4.78 g of 4-dimethylamino-pyridine and 25 ml of dimethylacetamide are placed in a 200 ml glass autoclave. The autoclave is closed, flushed with nitrogen three times and then 5 bars carbon monoxide are applied. The reaction mixture is heated to 120° C. and stirred for 18 hours. It is then cooled, and the solution is diluted with diethylether and water, and extracted. The aqueous phase is extracted by shaking 3 times with diethylether, and afterwards the organic phases are collected, dried over magnesium sulphate and concentrated. The oil obtained is chromatographed over silica gel. The yield of title compound is 26% (part of the product remains in the water phase).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:31][CH2:32][OH:33])[O:14][CH2:13][CH2:12][N:11]([C:15](=[O:30])[C:16]3[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43].O>C(Cl)Cl>[CH3:41][S:42]([O:33][CH2:32][CH2:31][C@:9]1([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:14][CH2:13][CH2:12][N:11]([C:15](=[O:30])[C:16]2[CH:17]=[C:18]([C:26]([F:28])([F:27])[F:29])[CH:19]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:21]=2)[CH2:10]1)(=[O:44])=[O:43]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCO[C@](CCO)(c2ccc(Cl)c(Cl)c2)C1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC[C@@]1(c2ccc(Cl)c(Cl)c2)CN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
5.68 g (11 mmol) of the obtained alcohol form was dissolved in methylene chloride (60 mL) and 2.3 mL (16.5 mmol) of triethylamine was added thereto under a nitrogen atmosphere. 1.02 ml (13.2 mmol) of methanesulfonyl chloride was added to the mixture under ice-cooling and the mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. Water was added to the reaction mixture and the methylene chloride layer was washed with water and a saturated NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluting solvent: hexane/ethyl acetate=3/2) to obtain 6.09 g (yield: 93%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([Cl:27])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=1CC(=C)CCC([O-])=O.[CH3:28][OH:29].[OH-:30].[Li+]>C1COCC1>[Cl:27][C:22]1[CH:23]=[C:24]([CH3:26])[CH:25]=[C:2]([Cl:1])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:18][C:19]([CH2:24][CH:25]([CH2:2][CH:3]=[CH2:22])[C:28]([OH:30])=[O:29])=[CH:20][CH:21]=1
Reactant: [OH-]
Reactant: C=C(CCC(=O)[O-])Cc1ccccc1OCCOc1c(Cl)cc(C)cc1Cl
Reactant: CO
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(Cc1ccc(OCCOc2c(Cl)cc(C)cc2Cl)cc1)C(=O)O

Procedure:
Ethyl 2-(4-{2-[(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}pent-4-enoate from the previous step (1 eq.) was dissolved in a 2:1 (v/v) THF:MeOH solution (0.06 M). To this was then added lithium hydroxide (1.0 M aqueous solution, 3.4 eq.) and the resulting solution was stirred at 50° C. for 12 h. The volatiles were then removed in vacuo. Following careful acidification of the resulting residue with 10% aq. HCl, the mixture was extracted with EtOAc. The combined organic extracts were washed with H2O and brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a viscous oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:15]([CH2:17][C:18](=[C:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:35]([O:36][CH3:37])=[C:34]3[C:29]([C:30](=[O:44])[C:31]([C:41]([OH:43])=[O:42])=[CH:32][N:33]3[CH:38]3[CH2:40][CH2:39]3)=[CH:28][C:27]=2[F:45])[CH2:22][CH2:21]1)[Cl:19])C)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:19][C:18](=[C:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:35]([O:36][CH3:37])=[C:34]3[C:29]([C:30](=[O:44])[C:31]([C:41]([OH:43])=[O:42])=[CH:32][N:33]3[CH:38]3[CH2:40][CH2:39]3)=[CH:28][C:27]=2[F:45])[CH2:22][CH2:21]1)[CH2:17][NH:15][CH3:8]
Reactant: COc1c(N2CCC(=C(Cl)CN(C)Cc3ccccc3)CC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: CC(Cl)OC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CNCC(Cl)=C1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2OC)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 27.3 %

Procedure:
A solution of 161 (160 mg, 0.24 mmol) was dissolved in 1,2-dichloroethane (4 mL) and was treated with 1-chloroethyl chloroformate (0.8 mL, 7.3 mmol) under nitrogen. After 5 min, the reaction mixture was warmed to reflux temperature and the reaction mixture was allowed to stir for 3 h. The resulting mixture was allowed to cool to room temperature, and then it was concentrated in vacuo. The residue was dissolved in tetrahydrofuran (5 mL), adjusted to pH>7 by the addition of NaHCO3 and water at room temperature and stirred overnight. The resulting mixture was concentrated in vacuo and the residue purified by HPLC (reverse phase C-18 column, 35-90% acetonitrile/water containing 0.1% trifluoroacetic acid) to afford the trifluoroacetic acid salt of 72 (37 mg, 27%) as a yellow solid. MS 450 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[NH2:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[N:22]=[CH:21][C:20]=1[C:31]([NH:33][CH2:34][C:35]([CH2:41][NH2:42])([OH:40])[C:36]([F:39])([F:38])[F:37])=[O:32].C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C)C=O>[NH2:18][C:19]1[N:23]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[N:22]=[CH:21][C:20]=1[C:31]([NH:33][CH2:34][C:35]([CH2:41][NH:42][C:4]([C:3]1[C:7]([Br:11])=[CH:8][CH:9]=[CH:10][C:2]=1[Br:1])=[O:6])([OH:40])[C:36]([F:39])([F:38])[F:37])=[O:32]
Reactant: O=C(O)c1c(Br)cccc1Br
Reactant: NCC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1c(C(=O)NCC(O)(CNC(=O)c2c(Br)cccc2Br)C(F)(F)F)cnn1-c1ccc(F)cc1
Reaction time: 0.75 h
Yield: 90.8 %

Procedure:
To a solution of 2,6-dibromobenzoic acid (28 mg, 0.1 mmol) in anhydrous tetrahydrofuran (1 ml) was added anhydrous dimethylformamide (4 μl) followed by oxalyl chloride (100 μl of a 1 ml solution of 87 μl of oxalyl chloride in THF; 0.1 mmol). The mixture effervesced and was stirred under nitrogen for 45 minutes. A solution of 5-amino-N-[2-(aminomethyl)-3,3,3-trifluoro-2-hydroxypropyl]-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (25.3 mg, 0.07 mmole) in anhydrous tetrahydrofuran (0.5 ml) and diisopropylethylamine (52 μl, 0.3 mmol) was added. It was then stirred under nitrogen at 21° C. for 3 days. It was blown down, partitioned between dichloromethane (5 ml) and 2M hydrochloric acid (2 ml). The organic layer was blown down and the residue purified on a 5 g SPE silica cartridge. Elution with dichloromethane then cyclohexane:ethyl acetate (10:1), (5:1), (3:1), (2:1) (3 times) and finally (1:1) (3 times). The title product was eluted in the third (2:1) fraction and the first (1:1) fraction. These fractions were combined and evaporated to give the title product (39.6 mg).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([O-:4])=[O:3].[C:7]([C:10]1[CH:27]=[CH:26][C:13]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])=[C:12]([CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:11]=1[O:34][CH3:35])(=[O:9])[CH3:8].N(CCO)(CCO)[CH2:37]CO>C(Cl)Cl>[C:7]([C:10]1[CH:27]=[CH:26][C:13]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]([NH:22][C:1](=[O:5])[C:2]([O:4][CH3:37])=[O:3])[CH:23]=[CH:24][CH:25]=2)=[C:12]([CH2:28][CH2:29][C:30]([F:31])([F:33])[F:32])[C:11]=1[O:34][CH3:35])(=[O:9])[CH3:8]
Reactant: OCCN(CCO)CCO
Reactant: COc1c(C(C)=O)ccc(OCCCOc2cccc(N)c2)c1CCC(F)(F)F
Reactant: O=C([O-])C(=O)Cl
Solvent: ClCCl
Product: COC(=O)C(=O)Nc1cccc(OCCCOc2ccc(C(C)=O)c(OC)c2CCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 3.45 ml of metjhyl chlorooxalate in 10 ml of methylene chloride is added dropwise to a solution of 9.2 g of 3-{3-[4-acetyl-3-methoxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-aniline and 4.3 ml of triethanolamine in 90 ml of methylene chloride in the course of 10 minutes. After stirring at room temperature for 5 hours, the mixture is poured onto water and extracted with methylene chloride. Evaporation of the extracts and recrystallisation of the residue from ether gives methyl N-{{3-{3-[4-acetyl-3-methoxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-phenyl}}-oxamate.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][C@H:4]([NH2:8])[C:5]([OH:7])=[O:6].C(N1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])(OCC)=O>C([O-])([O-])=O.[Na+].[Na+]>[O:19]=[C:18]1[C:17]2[C:16](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15](=[O:24])[N:8]1[C@@H:4]([CH2:3][CH:2]=[CH2:1])[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: C=CC[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C=CC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.1 %

Procedure:
To a solution of L-2-amino-4-pentenoic acid (9.88 g) in an aqueous Na2CO3 (9.11 g, 150 mL) at RT was added N-carboethoxyphthalimide (18.8 g). The reaction mixture was stirred for 6 h at RT, gradually becoming homogeneous. The reaction mixture was transferred to a separatory funnel and extracted with DCM (3×). The basic aqueous layer was made acidic with 2N HCl and extracted with DCM (3×). The combined DCM layer was washed with brine, dried (Na2SO4), filtered and evaporated. The crude product was purified via column chromatography (2% MeOH/DCM) to give a viscous oil (20.0 g), which crystallized upon standing. 1H NMR (300 MHz, CDCl3) δ 2.93-3.11 (m, 2H), 4.97-5.11 (m, 3H), 5.65-5.79 (m, 1H), 7.71-7.75 (m, 2H), 7.83-7.88 (m, 2H). MS APCI-m/z=246 (M+1). LCMS 1.91 min., Method A.
Reaction SMILES: [C:1]([O:5][C@H:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=1[Cl:40]>>[C:1]([O:5][C@H:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[Cl:40])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(CBr)c(Cl)c1
Reactant: COC(=O)[C@H](OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Product: Cc1nc2c(ccn2Cc2ccc(F)cc2Cl)c(-c2ccc3c(c2)CCCO3)c1[C@@H](OC(C)(C)C)C(=O)O
Temperature: 40 °C

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from (R)-methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 1-(bromomethyl)-2-chloro-4-fluorobenzene, but finally purified on a ChiralPak ADH column (250×30 mm i.d., 5 um; ChiralTechnologies, West Chester, Pa.) under supercritical conditions maintained at 40° C., 140 bar, with MeOH modified CO2 (25% Isopropanol, 75% CO2) delivered at a combined flow rate of 90 g/min on a PIC Preplab 200 SFC system (Avignon, France). Triggered collections were made using a Knauer selectable wavelength UV-Vis detector at 230 nm (Rt=3.67 minutes): 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.49-7.42 (m, 1 H), 7.25-7.15 (m, 2 H), 7.13-7.06 (m, 2 H), 6.96-6.88 (m, 2 H), 6.30 (dd, J=3.5, 11.9 Hz, 1 H), 5.70-5.63 (m, 1 H), 5.61-5.51 (m, 2 H), 4.32-4.25 (m, 2 H), 2.95-2.79 (m, 2 H), 2.76 (d, J=1.6 Hz, 3 H), 2.15-2.04 (m, 2 H), 1.07-0.87 (s, 9 H); LC/MS (m/z) ES+=537.31 (M+1).