Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6](=[O:19])[CH2:7][CH2:8][NH:9][C:10](=[O:18])[CH2:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C(=O)CCC#CC2C=C(C)C(O)=CC=2C)CCCC1.[Cl:40][CH:41]([C:46]([CH3:48])=[O:47])[C:42](OC)=[O:43]>>[Cl:40][CH:41]1[C:42](=[O:43])[O:19][C:6]([CH2:7][CH2:8][NH:9][C:10](=[O:18])[CH2:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH2:48][C:46]1=[O:47]
Reactant: COC(=O)C(Cl)C(C)=O
Reactant: O=C(CCc1ccco1)NCCC(=O)C1CCCC1
Agent: Cc1cc(C#CCCC(=O)C2CCCC2)c(C)cc1O
Product: O=C(CCc1ccco1)NCCC1(C2CCCC2)CC(=O)C(Cl)C(=O)O1

Procedure:
The desired product was prepared analogously to example F(1), Step 2, substituting N-(3-cyclopentyl-3-oxo-propyl)-3-furan-2-yl-propionamide (300 mg, 1.1 mmol) from Step 2 above in place of 1-cyclopentyl-5-(4-hydroxy-2,5-dimethyl-phenyl)-pent-4-yn-1-one and methyl 2-chloroacetoacetate (0.7 mL, 5.7 mmol) in place of methyl acetoacetate. Yield: 103 mg, 14%. MS (ESI): 380 (M−H), 382 (M+2−H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:8]([C:18]([F:21])([F:20])[F:19])=[CH:9][C:10](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[N:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[F:22][C:23]([F:37])([F:36])[CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1)[NH2:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C)C=O>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[C:8]([C:18]([F:21])([F:20])[F:19])=[CH:9][C:10](/[CH:13]=[CH:14]/[C:15](=[O:17])[NH:25][CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=3)[C:23]([F:37])([F:36])[F:22])=[N:11][CH:12]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)/C=C/c1cc(C(F)(F)F)c(C(=O)NC2CC2)cn1
Reactant: NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(/C=C/c1cc(C(F)(F)F)c(C(=O)NC2CC2)cn1)NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2E)-3-[5-(Cyclopropylcarbamoyl)-4-(trifluoromethyl)pyridin-2-yl]acrylic acid (61 mg, 0.20 mmol) and 2,2,2-trifluoro-1-[3-trifluoromethylphenyl]ethanamine (46 mg, 0.19 mmol) were initially charged in N,N-dimethylformamide and admixed with HBTU (72 mg, 0.19 mmol) and N-methylmorpholine (57 mg, 0.57 mmol) and stirred at room temperature overnight. Subsequently, the reaction mixture was concentrated under reduced pressure, taken up in ethyl acetate and washed successively with a sodium hydrogencarbonate solution (10%) and a saturated sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was chromatographed on a preparative HPLC with water/acetonitrile as the eluent (gradient=43 min from 10% acetonitrile in water to 100% acetonitrile).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1.[CH2:17]([N:19]1[C:28]2[C:23](=[CH:24][N:25]=[C:26]([NH:29][CH3:30])[CH:27]=2)[CH:22]=[C:21]([C:31]2[C:32]([F:45])=[CH:33][C:34]([F:44])=[C:35]([NH:37][C:38](=O)[O:39]C(C)=C)[CH:36]=2)[C:20]1=[O:46])[CH3:18]>O1CCOCC1.CN1CCCC1>[CH2:17]([N:19]1[C:28]2[C:23](=[CH:24][N:25]=[C:26]([NH:29][CH3:30])[CH:27]=2)[CH:22]=[C:21]([C:31]2[C:32]([F:45])=[CH:33][C:34]([F:44])=[C:35]([NH:37][C:38]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([F:1])=[C:3]([CH2:9][N:10]4[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]4)[CH:4]=3)=[O:39])[CH:36]=2)[C:20]1=[O:46])[CH3:18]
Reactant: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(NC)cc3n(CC)c2=O)c(F)cc1F
Reactant: CN1CCN(Cc2cc(N)ccc2F)CC1
Agent: CN1CCCC1
Solvent: C1COCCO1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccc(F)c(CN4CCN(C)CC4)c3)c(F)cc2F)cc2cnc(NC)cc21
Temperature: 80 °C
Yield: 30.7 %

Procedure:
A mixture of Example D2 (0.060 g, 0.269 mmol) and prop-1-en-2-yl (5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)carbamate (0.086 g, 0.208 mmol) in dioxane (2 mL) was treated with 1-methylpyrrolidine (2 drops) and heated at 80° C. overnight. The mixture was concentrated to dryness, treated with EtOAc and the resulting solid collected via filtration and purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). The organics were removed under reduced pressure, the aqueous residue treated with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over MgSO4 and concentrated to dryness to afford 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)urea (37 mg, 31% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.82 (s, 1H), 8.94 (s, 1H), 8.86 (t, J=8.5 Hz, 1H), 8.59 (s, 1H), 7.93 (dd, J=6.5, 2.8 Hz, 1H), 7.76 (m, 2H), 7.62 (s, 1H), 7.13 (t, J=9.5 Hz, 2H), 6.25 (s, 1H), 4.19 (q, J=7.1 Hz, 2H), 3.55 (s, 2H), 3.08 (d, J=4.9 Hz, 3H), 2.50 (br s, 4H), 2.30 (br s, 4H), 2.10 (s, 3H), 1.18 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 580.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH3:18])[NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[N+:15]([O-])=O)[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH3:18])[NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[NH2:15])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)[C@H](C)NCc1cccc(C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@H](C)NCc1cccc(C)c1N

Procedure:
A solution of 26.6 g of N-(3-methyl-2-nitrobenzyl)-L-alanine ethyl ester in 100 ml of absolute ethanol was hydrogenated in the presence of 2 g of 10% palladium/carbon. 6.7 liters of hydrogen were taken up in 5 hours. After completion of the hydrogenation, the catalyst was filtered off and the filtrate was evaporated to dryness. There was obtained N-(2-amino-3-methylbenzyl)-L-alanine ethyl ester in the form of a yellow oil; [α]D =-52.6° (c=1% in methanol).
Reaction SMILES: Cl.[CH3:2][CH:3]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1)[C:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[O:5].[N:22]#[C:23][NH2:24]>C(O)C>[ClH:13].[CH3:2][CH:3]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:23]([NH2:24])=[NH:22])[CH:16]=1)[C:4]([O:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1)=[O:5]
Reactant: N#CN
Reactant: CC(Cc1cccc(N)c1)C(=O)Oc1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Product: CC(Cc1cccc(NC(=N)N)c1)C(=O)Oc1ccc(Cl)cc1

Procedure:
In 200 ml of ethanol were dissolved 23.0 g of the p-chlorophenyl α-methyl-β-(m-aminophenyl)-propionate hydrochloride thus obtained and 4.2 g of cyanamide, and the resulting solution was subjected to reaction at 70° C. for 5 hours. After the reaction, the solvent was removed by distillation under reduced pressure, to obtain p-chlorophenyl α-methyl-β-(m-guanidinophenyl)-propionate hydrochloride in the form of an oily matter. This compound was dissolved in 50 ml of ethanol, and then added to saturated aqueous NaHCO3 solution, upon which colorless crystals precipitated. The crystals were collected by filtration and washed with water and acetone, to obtain p-chlorophenyl α-methyl-β-(m-guanidinophenyl)-propionate carbonate. Yield: 19.4 g (70%); melting point: 87°-90° C.; IR (cm-1); 3500-2500, 1748, 1660, 1490; MS: M+ =m/e 331 (M.W. - H2CO3).
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[C@H:3]([CH2:5][CH3:6])[CH3:4].[NH2:17][C@H:18]([C:23]([OH:25])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21].OS([O-])(=O)=O.[K+].O>CS(C)=O.C(OC(C)C)(=O)C.[Na+].[Cl-]>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([NH:17][C@H:18]([C:23]([OH:25])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:9])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: O=S(=O)([O-])O
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(=O)OC(C)C
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)O
Temperature: 60 °C
Yield: 89 %

Procedure:
1.00 equivalent of Boc-Ile-NCA (Mw=257.3) was added to 1.10 equivalents of H-Leu-OH (Mw=131.2) in suspension in DMSO. The suspension was then heated at 60±5° C. at least 2 hours. After checking the conversion rate by HPLC, the reaction mixture was diluted with isopropyl acetate, washed by KHSO4 (Mw=136; 1.00 equivalent) in NaCl 5% (weight) aqueous, NaCl 5% (weight) aqueous and water. After evaporation of isopropyl acetate in vacuo, the excess of water was eliminated by azeotropic distillation with isopropyl acetate. The peptide precipitated during the concentration. The concentrated suspension was then diluted in cyclohexane. The precipitate was stirred at room temperature for at least 10 min, filtered and finally dried in vacuum at 45° C. The dried precipitate yielded 89% of Boc-Ile-Leu-OH as a white solid (based on NMR content).
Reaction SMILES: [CH3:1][C:2]([OH:19])([CH3:18])[CH2:3][N:4]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[N:5]1.[Cl:20][C:21]1[N:26]=[C:25](Cl)[CH:24]=[CH:23][N:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1COCC1>O>[Cl:20][C:21]1[N:26]=[C:25]([C:7]2[CH:6]=[N:5][N:4]([CH2:3][C:2]([CH3:1])([OH:19])[CH3:18])[CH:8]=2)[CH:24]=[CH:23][N:22]=1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Clc1ccnc(Cl)n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)Cn1cc(-c2ccnc(Cl)n2)cn1
Temperature: 120 °C
Yield: 58.1 %

Procedure:
To a mixture of the product from Step 1 (84 mg, 0.31 mmol), 2,4-dichloropyrimidine (47 mg, 0.31 mmol), potassium phosphate, tribasic (167 mg, 0.79 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)-dichloride dichloromethane complex (26 mg, 0.031 mmol) was added THF (2 mL) and water (0.2 mL). The mixture was heated to 120° C. for 15 minutes under microwave irradiation, cooled to room temperature, quenched with 1:1 water:brine, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography on silica gel (Biotage 10 G, eluting with 0:100 to 100:0 ethyl acetate:hexanes) afforded 1-[4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl]-2-methylpropan-2-ol (44 mg, 0.18 mmol, 56% yield) as a yellow solid. MS ESI: [M+H]+ m/z 253.0.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:14])=[CH:4][C:3]=1[Cl:23].FC(F)(F)C([O:28][CH2:29][C:30]([CH3:36])([CH3:35])[C:31](=[O:34])[CH2:32]Br)=O>CO>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:32][C:31](=[O:34])[C:30]([CH3:36])([CH3:35])[CH2:29][OH:28])[CH2:19][CH2:18]2)=[O:14])=[CH:4][C:3]=1[Cl:23]
Reactant: CCc1cn2c(N)c(Cl)cc(C(=O)NCC3CCNCC3)c2n1
Reactant: CC(C)(COC(=O)C(F)(F)F)C(=O)CBr
Solvent: CO
Product: CCc1cn2c(N)c(Cl)cc(C(=O)NCC3CCN(CC(=O)C(C)(C)CO)CC3)c2n1
Temperature: 25 °C
Reaction time: 120 h
Yield: 24.5 %

Procedure:
A mixture of 5-amino-6-chloro-2-ethyl-N-(piperidin-4-ylmethyl)imidazo[1,2-a]-pyridine-8-carboxamide (Example 4, step 4, 530 mg, 1.57 mmol) and 4-bromo-2,2-dimethyl-3-oxobutyl trifluoroacetate (Example 6, step 1, 777 mg, 2.67 mmol) in methanol (15 mL) was stirred at room temperature for 5 days. The reaction mixture was concentrated in vacuo. The residue was basified with aqueous potassium carbonate (20 mL) and extracted with dichloromethane (3×30 mL). The combined extract was washed with brine, dried over magnesium sulfate, and evaporated. Flash column chromatography (NH-silica gel) of the residue eluting with dichloromethane/methanol (200:1 to 50:1) afforded a white solid. This was recrystallized from ethanol to afford 173 mg (25%) of the title compound as a white solid.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.Br[C:8]1[CH:13]=[CH:12][N:11]2[C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=[C:10]2[N:9]=1.C(N(CC)CC)C>O>[N:9]1[C:10]2[N:11]([C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[CH:12]=[CH:13][C:8]=1[N:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1
Reactant: Brc1ccn2c(n1)nc1ccccc12
Reactant: OC1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: OC1CN(c2ccn3c(n2)nc2ccccc23)C1
Temperature: 25 °C
Yield: 99 %

Procedure:
Azetidin-3-ol hydrochloride (0.022 g, 0.202 mmol), 2-bromobenzo[4,5]imidazo[1,2-a]pyrimidine (0.05 g, 0.202 mmol) and Triethylamine (0.028 ml, 0.202 mmol) were heated to 100° C. for 10 minutes in a microwave. Let the reaction cool to room temperature. Diluted with water and vacuum filtered ppt. Washed with water to afford 1-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)azetidin-3-ol (0.048 g, 0.200 mmol, 99% yield).
Reaction SMILES: [NH2:1][C@H:2]([CH2:25][CH3:26])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[C:18]3[C:19]4([CH2:22][O:23][C:17]=3[C:16]([CH3:24])=[CH:15][CH:14]=2)[CH2:21][CH2:20]4)=[CH:10][CH:11]=1)=[O:4].Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:25]([C@H:2]1[NH:1][C:28](=[O:30])[N:5]([C:6]2[CH:7]=[N:8][C:9]([O:12][C:13]3[C:18]4[C:19]5([CH2:22][O:23][C:17]=4[C:16]([CH3:24])=[CH:15][CH:14]=3)[CH2:21][CH2:20]5)=[CH:10][CH:11]=2)[C:3]1=[O:4])[CH3:26]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC[C@@H](N)C(=O)Nc1ccc(Oc2ccc(C)c3c2C2(CC2)CO3)nc1
Solvent: ClCCl
Product: CC[C@H]1NC(=O)N(c2ccc(Oc3ccc(C)c4c3C3(CC3)CO4)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 72.5 %

Procedure:
To a solution of (2R)-2-amino-N-[6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxy-3-pyridyl]butanamide (Intermediate 17, 40 mg, 0.11 mmol) in dry DCM (5 ml) TEA (0.042 ml, 0.3 mmol) was added and the reaction mixture was cooled to 0° C. A solution of triphosgene (23.7 mg, 0.08 mmol) in dry DCM (3 ml) was slowly added and the reaction mixture was stirred for 15 minutes at the same temperature. The reaction was quenched with water (10 ml) and two phases were separated. The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 75:25 to cyclohexane/ethyl acetate 25:75 as eluents affording the title compound (22 mg) as a white solid.
Reaction SMILES: [N:1]1([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][CH2:7]2)[CH2:3][CH2:2]1.Br[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[C:26]1([N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:4]3([CH2:3][CH2:2][N:1]([C:15]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[O:16])[CH2:6][CH2:5]3)[CH2:7]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Brc1ccccc1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CNc1ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CCC2(CC1)CN(c1ccccc1)c1ccccc12
Temperature: 100 °C
Reaction time: 5 h
Yield: 86.3 %

Procedure:
To a solution of benzyl spiro[indoline-3,4′-piperidine]-1′-carboxylate (1.5 g, 4.65 mmol) in 1-4, dioxane (5 mL) is added bromobenzene (0.803 g, 5.115 mmol), 4,5-(diphenyl-phosphino)-9,9-dimethyl xanthene (0.807 g, 1.395 mmol) and cesium carbonate (4.54 g, 13.95 mmol) at 0° C. The reaction mixture is purged with nitrogen gas for 15 minutes and palladium acetate (0.062 g, 0.279 mmol) is added. The mixture is stirred at 100° C. for 5 hours, filtered, diluted with ammonium chloride solution, extracted with EtOAc, dried with sodium sulphate, and concentrated under reduced pressure. The crude material is purified by silica gel chromatography, eluting with hexane:ethyl acetate (9.0:1.0) to give the title compound (1.6 g, 86.48%). ESI/MS m/z 399.4 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[F:17][C:18]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:19]=1[CH2:20][N:21]([CH3:42])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:34]2[CH2:39][CH2:38][CH:37]([CH:40]=O)[CH2:36][CH2:35]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1)=[O:23].C(O)(=O)C.C([BH3-])#N.[Na+]>>[F:17][C:18]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:19]=1[CH2:20][N:21]([CH3:42])[C:22]([NH:24][C:25]1[CH:26]=[CH:27][C:28]([S:31]([N:34]2[CH2:39][CH2:38][CH:37]([CH2:40][NH:1][CH2:2][C@@H:3]([C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[OH:4])[CH2:36][CH2:35]2)(=[O:32])=[O:33])=[CH:29][CH:30]=1)=[O:23]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CN(Cc1cc(F)ccc1F)C(=O)Nc1ccc(S(=O)(=O)N2CCC(C=O)CC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(Cc1cc(F)ccc1F)C(=O)Nc1ccc(S(=O)(=O)N2CCC(CNC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Yield: 37.4 %

Procedure:
The title compound was prepared from N-[5-(2-amino-1-{R}-hydroxyethyl)-2-hydroxyphenyl]-methanesulfonamide (0.130 g, 0.53 mmol), 1-(2,5-difluoro-benzyl)-3-[4-(4-formyl-piperidine-1-sulfonyl)-phenyl]-1-methyl-urea (0.8 mmol), glacial acetic acid (0.029 mL, 0.5 mmol) and sodium cyanoborohydride (0.031 g, 0.5 mmol) according to the general procedure used for example 84 (Step E) to give the final product (0.135 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:45]=[CH:46][CH:47]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([O:32][CH3:33])=[C:25]([S:27]([NH:30][CH3:31])(=[O:29])=[O:28])[CH:26]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[C:8]([CH3:44])=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:45]=[CH:46][CH:47]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([O:32][CH3:33])=[C:25]([S:27]([NH:30][CH3:31])(=[O:28])=[O:29])[CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:44])=[N:7]1
Reactant: CNS(=O)(=O)c1cc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cccc(F)c4)c2C)cn3S(=O)(=O)c2ccc(C)cc2)ccc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1cc(-c2cnc3[nH]cc(-c4c(C)nn(Cc5cccc(F)c5)c4C)c3c2)ccc1OC
Yield: 35.9 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 5-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxy-N-methylbenzenesulfonamide (80 mg, 0.118 mmol) was hydrolyzed by lithium hydroxide (143 mg, 0.593 mmol), THF/Methanol/water (1/1/0.5 mL) to afford 22 mg (36.06% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.47-8.46 (d, 1H), 8.029-8.024 (d, 1H), 7.89-7.86 (m, 2H), 7.41 (s, 1H), 7.38-7.30 (m, 2H), 7.05-6.96 (m, 2H), 6.90-6.85 (m, 1H), 5.36 (s, 2H), 4.00 (s, 3H), 2.53 (s, 3H), 2.21 (s, 3H), 2.18 (s, 3H). MS: m/z=520.1 (M+1), HPLC Purity: 93.81% (Method B).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:16][OH:17])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])=[CH:4][CH:3]=1.Cl.Cl[CH2:20][CH2:21][NH2:22].[OH-].[K+]>CN(C)C=O>[ClH:1].[NH2:22][CH2:21][CH2:20][O:17][N:16]=[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15]
Reactant: N#CCCCCCC(=NO)c1ccc(Cl)cc1
Reactant: NCCCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#CCCCCCC(=NOCCN)c1ccc(Cl)cc1
Temperature: 10 °C

Procedure:
5.0 mmol. (1.25 gr) of 4'-chloro-6-cyanocaprophenone oxime, melting point 58°-59° C, 5.2 mmol (0.60 gr) of 2-chloroethylaminehydrochloride and 0.7 gr of KOH powder were sequentially added to 12.5 ml of dimethyl-formamide (DMF) while stirring at 10° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([NH:11][S:12]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:13])[S:8][C:7]=2[CH:21]=1.CC(C)([O-])C.[K+].[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[F:37])[CH2:32]Br>C1COCC1.CCOC(C)=O>[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[F:37])[CH2:32][N:11]([C:9]1[S:8][C:7]2[CH:21]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[CH:10]=1)[S:12]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:13]
Reactant: Fc1ccc(CBr)cc1F
Reactant: COc1ccc2cc(NS(=O)(=O)c3cccnc3)sc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2cc(N(Cc3ccc(F)c(F)c3)S(=O)(=O)c3cccnc3)sc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a solution of compound 141-F (0.488 g; 1.52 mmol) in THF (15 mL) was added 1M potassium tert-butoxide (2.28 mL; 2.28 mmol) and the reaction mixture was stirred at ambient temperature for 30 min. 3,4-Difluorobenzyl bromide (0.409 g; 1.97 mmol), dissolved in THF (1.0 mL), was added drop-wise, and the reaction was stirred at ambient temperature for 18 h. The reaction was diluted with EtOAc, washed with 2N HCl, water, brine, dried over Na2SO4, filtered, the solvent evaporated under reduced pressure. The crude residue was purified by flash column chromatography (SiO2) eluting with a heptane-EtOAc gradient to afford an oily semi-solid, which was further purified by reverse-phase semi-prep HPLC (Gemini, C-18 column; 100×30 mm I.D.; 5μ) eluting with a 55% to 75% MeCN—H2O gradient to afford compound 141-G as a white solid (0.447 g, 66%). 1H-NMR (DMSO-d6): δ 3.76 (s, 3H), 4.89 (s, 2H), 6.93-6.96 (m, 1H), 7.11 (s, 1H), 7.19-7.20 (m, 1H), 7.34-7.43 (m, 3H), 7.60-7.62 (d, 1H), 7.70-7.73 (m, 1H), 8.21-8.24 (m, 1H), 8.93-8.96 (m, 2H); MS: m/z 447.0 (MH+).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[N:10]1[CH2:14][CH2:13][CH2:12]C1.C(N)(=[O:18])C=C>C(O)(=O)C.O>[NH:10]1[C:14](=[O:18])[CH2:13][CH2:12][C:3]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[CH2:1][C:2]1=2
Reactant: C=CC(N)=O
Reactant: C1=C(N2CCCC2)Cc2ccccc21
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCC2=C(Cc3ccccc32)N1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-(1H-inden-2-yl)-pyrrolidine (5.34 g) and acrylamide (6.15 g) is stirred in argon atmosphere at 100° C. for 30 min. The temperature is then rised to 130° C. and stirring continued for another 15 min. After cooling to room temperature, water (50 mL) and acetic acid (5 drops) are added and the mixture is stirred for 30 min. The mixture is filtered and the organic phase of the filtrate is separated and washed with brine. After drying (MgSO4) and evaporating the solvent, the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 1:1→0:1) to give a brown solid that is triturated with ethyl acetate and dried to afford the title compound. Yield: 1.12 g (21% of theory); Mass spectrum (ESI+): m/z=186 [M+H]+.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8]1([CH3:18])[O:14][CH:13]([CH3:15])[CH2:12][C:11]([CH3:17])([CH3:16])[O:10][O:9]1)=O)C.[NH2:19][NH2:20].C(OCC)(=O)CCC(C)=O>OC(C)CC(OO)(C)C>[CH3:18][C:8]1([CH2:7][CH2:6][C:4]([NH:19][NH2:20])=[O:3])[O:14][CH:13]([CH3:15])[CH2:12][C:11]([CH3:17])([CH3:16])[O:10][O:9]1
Reactant: CCOC(=O)CCC1(C)OOC(C)(C)CC(C)O1
Reactant: NN
Agent: CC(O)CC(C)(C)OO
Agent: CCOC(=O)CCC(C)=O
Product: CC1CC(C)(C)OOC(C)(CCC(=O)NN)O1
Yield: 88 %

Procedure:
3-(1,4,4,6-Tetramethyl-2,3,7-trioxacycloheptyl)propionhydrazide was prepared by reacting 3-(ethoxycarbonylethyl)-3,5,7,7-tetramethyl-1,2,4-trioxacycloheptane with 9 molar excess of 54% aqueous hydrazine. 3-(Ethoxycarbonylethyl)-3,5,7,7-tetramethyl-1,2,4-trioxacycloheptane was initially prepared in an assay of 89% and a corrected yield of 88% by reacting ethyl levulinate with 10% molar excess of 3-hydroxy-1,1-dimethylbutyl hydroperoxide using 70% aqueous sulfuric acid as a catalyst/dehydrating agent.