Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)#[CH:22].CCN(CC)CC>CN(C=O)C.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.[Cu]I>[CH:16]1([N:5]2[C:4]3[N:3]=[C:2]([C:22]#[C:21][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]2[CH2:14][CH3:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C#Cc1ccccc1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[C@@H]1C(=O)N(C)c2cnc(C#Cc3ccccc3)nc2N1C1CCCC1

Procedure:
To a solution of Intermediate B (1.0 eq) in DMF, ethynylbenzene (compound III-139, 3.0 eq), Pd(PPh3)2Cl2 (0.2 eq), CuI (0.25 eq) and Et3N (5.0 eq) were added. The mixture was refluxed for 18 h under argon, extracted with EtOAc and purified by silica gel column to give (R)-8-cyclopentyl-7-ethyl-5-methyl-2-(phenylethynyl)-7,8-dihydropteridin-6(5H)-one (compound IV-139).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[Cl:28][CH2:29][C:30](Cl)=[O:31].C(N(CC)CC)C>ClCCl>[Cl:28][CH2:29][C:30]([N:2]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:11][CH2:10]2)=[O:8])=[CH:26][CH:27]=1)[CH3:1])=[O:31]
Reactant: CNc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)CCl)c1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-{1-[4-(N-methylamino)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (200 mg) is dissolved in dichloromethane (5 ml) and thereto is added α-chloroacetyl chloride (55 μl) under ice cooling. Continually thereto is added triethylamine (0.23 ml) and the mixture is stirred at room temperature overnight. After the solvent is concentrated, the residue is purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=1:1) and recrystallized from n-hexane/ethanol to give 1-{1-[4-(N-α-chloroacetyl-N-methylamino)benzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (0.18 g) as white powder, m.p.: 220°-222° C. (decomposed).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH:11]([C:15]2[N:16]=[CH:17][NH:18][CH:19]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1.CS(O[CH2:25][C:26]1[CH:30]=[C:29]([C:31]2[S:32][C:33]([Cl:36])=[CH:34][CH:35]=2)[O:28][N:27]=1)(=O)=O.[C:37](OCC)(=O)[CH3:38]>CN(C=O)C>[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][C@@H:11]([C:15]2[N:16]=[CH:17][N:18]([CH2:25][C:26]3[CH:30]=[C:29]([C:31]4[S:32][C:33]([Cl:36])=[CH:34][CH:35]=4)[O:28][N:27]=3)[CH:19]=2)[C:12]([O:14][CH2:37][CH3:38])=[O:13])=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)OCc1cc(-c2ccc(Cl)s2)on1
Reactant: CCOC(C)=O
Reactant: Nc1ccc(CC(C(=O)O)c2c[nH]cn2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](Cc1ccc(N)nc1)c1cn(Cc2cc(-c3ccc(Cl)s3)on2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, 0.485 g (60% in mineral oil, 19.21 mmol) of sodium hydride was added to a solution of 5.0 g (19.21 mmol) of 3-(6-aminopyridin-3-yl)-2-(1H-imidazol-4-yl)propionic acid in 200 ml of absolute DMF. The mixture was stirred for 30 min at RT, 5.643 g (19.21 mmol) of 5-(5-chlorothiophen-2-yl)isoxazol-3-ylmethyl methanesulfonate were then added and the mixture was stirred at RT for another 3 h. The reaction mixture was concentrated under reduced pressure, and the residue obtained was chromatographed on silica gel using CH2Cl2/MeOH/water/acetic acid 90:10:1:1. This gave two product-containing fractions which were purified by preparative HPLC. The fractions of value were combined and freeze-dried. The residue obtained was dissolved in ethyl acetate, washed with saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated. The material obtained in this manner (3.7 g) was separated into its enantiomers by chiral HPLC (column Chiralpak AD-H/55, 250×4.6 mm, flow rate 1 ml/min, mobile phase heptane:isopropanol:methanol 3:1:1+0.1% TFA). 0.1 g (218 μmol) of the product obtained was dissolved in 5 ml of water/acetic acid (1:1) and freeze-dried (0.108 g, 95%).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[C:7]1([C:13]2[O:17][C:16]([C:18]3[C:19]([NH2:30])=[N:20][CH:21]=[C:22]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[N:23]=3)=[N:15][N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([S:3]([N:27]1[CH2:28][CH2:29][N:24]([C:22]2[N:23]=[C:18]([C:16]3[O:17][C:13]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:14][N:15]=3)[C:19]([NH2:30])=[N:20][CH:21]=2)[CH2:25][CH2:26]1)(=[O:5])=[O:4])[CH3:2]
Reactant: Nc1ncc(N2CCNCC2)nc1-c1nnc(-c2ccccc2)o1
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(-c3nnc(-c4ccccc4)o3)n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Ethanesulfonyl chloride (37.51 mg, 27.64 μL, 0.2917 mmol) was added to a solution of 3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-piperazin-1-yl-pyrazin-2-amine (116 mg, 0.2652 mmol) and triethylamine (53.67 mg, 73.93 μL, 0.5304 mmol) in dichloromethane (5 mL) at 0° C. and the resulting solution stirred at room temperature for 1.5 hours. The mixture was diluted with dichloromethane, washed with water and the aqueous layer extracted further with dichloromethane. The organics were washed with saturated aqueous NaHCO3, dried over MgSO4 and concentrated in vacuo. The resultant residue was purified on silica gel by flash column chromatography (3% MeOH/DCM) to afford the title compound still impure. This was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound (25.2 mg, 18% Yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][OH:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:21](=[S:23])=S.CI.[NH4+:26].[OH-]>>[C:21]([O:18][CH2:17][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])(=[S:23])[NH2:26]
Reactant: S=C=S
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Product: CC(C)(C)OC(=O)N[C@@H](COC(N)=S)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
In a 500 mL flask equipped with magnetic stirrer, N-(t-butyloxycarbonyl)-(D)-phenylalaninol(0.040 mole, 10.05 g) was dissolved in 200 mL of THf and was added with NaH(0.048 mole, 1.15 g) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour, followed by the addition of CS2 (0.048 mole, 3.65 g). After being stirred for 40 min. at 0° C., MeI(0.048 mole, 6.81 g) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours, followed by the addition of 5N NH4OH (0.090 mole, 18.0 mL) for 6 hours. The resulting solution was quenched with water. The organic layer was extracted 3 times with dichloromethane, dried over magnesium sulfate and distilled in vacuo, to give a solid. This was recrystalized in a solution mixture of n-hexane and diethyl ether, to produce 11.3 g of O-thiocarbamoyl-N-(t-butyloxycarbonyl)-(D)-phenylalaninol: Yield 78%.
Reaction SMILES: O.NN.[CH3:4][NH:5][C:6](=[O:42])[C@H:7]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[NH:8][C:9](=[O:34])[C@H:10]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:11][S:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]1C(=O)C2=CC=CC=C2C1=O)(=[O:14])=[O:13]>C(O)C.C(Cl)(Cl)Cl.O>[CH3:4][NH:5][C:6](=[O:42])[C@H:7]([CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[NH:8][C:9](=[O:34])[C@H:10]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:11][S:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])(=[O:14])=[O:13]
Reactant: CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NS(=O)(=O)CCCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NS(=O)(=O)CCCCN
Temperature: 25 °C
Yield: 99.1 %

Procedure:
Hydrazine hydrate (56%, 18.2 ml) was added to a solution of example 17 (7.1 g) in ethanol (120 ml) and the mixture was heated at reflux for 30 min. The mixture was then cooled to RT and diluted with ethanol (300 ml), chloroform (100 ml) and water (200 ml). The layers were separated and the organic layer was dried (Na2SO4) and evaporated in vacuo. The residue was then purified by flash column chromatography, eluting with 0-10% methanol in chloroform containing 2.5% triethylamine, to give the title compound (5.39 g, 99%) as a colourless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][NH:14][CH:15]1[CH2:27][O:26][C:25]2[CH:24]=[CH:23][C:22]3[CH2:21][NH:20][C:19](=[O:28])[C:18]=3[C:17]=2[CH2:16]1.[CH3:29]CN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][N:14]([CH3:29])[CH:15]1[CH2:27][O:26][C:25]2[CH:24]=[CH:23][C:22]3[CH2:21][NH:20][C:19](=[O:28])[C:18]=3[C:17]=2[CH2:16]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C1NCc2ccc3c(c21)CC(NCCCc1c[nH]c2ccc(F)cc12)CO3
Solvent: ClCCl
Product: CN(CCCc1c[nH]c2ccc(F)cc12)C1COc2ccc3c(c2C1)C(=O)NC3
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a mixture of (3) (52 mg, 0.137 mmol) and Me3OBF4 (40 mg, 0.274 mmol) in methylene chloride (5 ml) was added Hunig's base (40 μl, 0.274 mmol). The reaction mixture was stirred at 50° C. for 2 hr, then diluted with 100 ml of methylene chloride. It was washed with H2O, saturated NaCl. The organic solution was dried over Na2SO4 and concentrated in vacuo. The residue was purified on silica gel eluting with (80% EtOAc/Hexane) to give the title compound, which was treated with 1 equivalent of etherate HCl to give HCl salt. MS (ES) m/z 394.1.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:8]([C:11]1[NH:15][N:14]=[C:13]([CH3:16])[CH:12]=1)([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.CCOC(C)=O>[CH:8]([C:11]1[CH:12]=[C:13]([CH3:16])[N:14]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[N:15]=1)([CH3:10])[CH3:9]
Reactant: Cc1cc(C(C)C)[nH]n1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1nc(C(C)C)cc1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 34 %

Procedure:
Ethyl bromoacetate (1.00 mL, 9.03 mmol) was added to 5-isopropyl-3-methyl-1H-pyrazole (1.07 g, 8.60 mmol) and potassium carbonate (3.57 g, 25.9 mol) in DMF (10 mL). The mixture was stirred at room temperature for 17 hours then EtOAc (20 mL) and aqueous HCl (20 mL, 1 M) were added. The organic phase was dried over magnesium sulphate then evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:EtOAc 4:1) to afford the title compound as a yellow oil in 34% yield, 607 mg.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[C:2]=[S:3].[CH3:24][O:25][CH:26]([O:30][CH3:31])[CH2:27][NH:28][CH3:29]>ClCCl>[CH3:24][O:25][CH:26]([O:30][CH3:31])[CH2:27][N:28]([CH3:29])[C:2]([NH:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[S:3]
Reactant: COc1ccc(N2CCN(c3ccc(N=C=S)cc3)CC2)cc1
Reactant: CNCC(OC)OC
Solvent: ClCCl
Product: COc1ccc(N2CCN(c3ccc(NC(=S)N(C)CC(OC)OC)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A mixture of 15 parts of 1-(4-isothiocyanatophenyl)-4-(4-methoxyphenyl)piperazine, 6.5 parts of 2,2-dimethoxy-N-methylethanamine and 195 parts of dichloromethane was stirred for 1 hour at room temperature. The reaction mixture was evaporated and the residue was triturated in 4-methyl-2-pentanone. The product was filtered off and dried, yielding 19.4 parts (95%) of N-(2,2-dimethoxyethyl)-N'-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-N-methylthiourea; mp. 155.0° C. (40).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([I:23])[CH:18]=2)[N:3]=1.[NH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27][CH2:26]1>>[ClH:1].[ClH:1].[NH2:24][CH:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([I:23])[CH:18]=3)[N:3]=2)[CH2:27][CH2:26]1
Reactant: CCC(C)n1cnc2c(NCc3cccc(I)c3)nc(Cl)nc21
Reactant: N[C@H]1CC[C@H](N)CC1
Product: CCC(C)n1cnc2c(NCc3cccc(I)c3)nc(NC3CCC(N)CC3)nc21
Product: Cl
Yield: 124 %

Procedure:
The operation is carried out as in Stage 3 of Example 9 starting from 279 mg of the product obtained in Stage 1 above and 720 mg of trans-1,4-diaminocyclohexane. After purification under the same conditions as for Example 9, salification is carried out with 10 ml 1.4N HCl/Ethanol followed by evaporating to dryness. In this way 232 mg of expected product is obtained in the form of crystals.
Reaction SMILES: CCC([O-])(C)C.[K+].[Cl:8][C:9]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:10]=1[C:11]([O:13]C)=O.[C:23](#[N:25])[CH3:24]>C1(C)C=CC=CC=1.Cl.O.CCOC(C)=O>[Cl:8][C:9]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:10]=1[C:11](=[O:13])[CH2:24][C:23]#[N:25]
Reactant: CC#N
Reactant: COC(=O)c1cc(C(F)(F)F)ccc1Cl
Agent: CCC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#CCC(=O)c1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83.4 %

Procedure:
Potassium tert-pentoxide 1.7 M in toluene (7.35 mL, 12.5 mmol) was added drop wise to a solution of methyl 2-chloro-5-(trifluoromethyl)benzoate (2.0 g, 8.38 mmol) and ACN (1.32 mL, 25.15 mmol) in anhydrous toluene (30 mL). The mixture was stirred at room temperature for 20 min, then diluted with HCl 1 N (20 mL), water (75 mL) and EtOAc (100 mL). The organic layer was separated, washed with water (50 mL×2) and brine (50 mL×2), dried over sodium sulfate and concentrated. Column chromatography on silica gel (0 to 20% EtOAc/hexane) provided the title compound (1.73 g, 83%).
Reaction SMILES: [NH2:1][C:2]1([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:22](Cl)(=[O:26])[O:23][CH2:24][CH3:25]>ClCCl>[CH2:24]([O:23][C:22]([NH:1][C:2]1([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1)=[O:26])[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NC1(c2ccc(C(=O)OC)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 4-(1-aminocyclopropyl)benzoate (1.84 g) and triethylamine (2.82 mL) were dissolved in dichloromethane (40 mL), ethyl chlorocarbonate (1.01 mL) was added under ice-cooling, and the mixture was stirred at the same temperature for 30 min and at room temperature for 1 hr. After completion of the reaction, the solvent was evaporated, to the residue was added 0.5N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (0.86 g).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:10]([NH2:11])[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)=[O:4].Cl.[CH3:20][C:21]1[CH:30]=[C:29]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH3:1][O:2][C:3]([CH:5]1[CH:10]([NH:11][S:39]([C:36]2[CH:37]=[CH:38][C:33]([O:32][CH2:31][C:29]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=[C:21]([CH3:20])[CH:30]=3)=[CH:34][CH:35]=2)(=[O:40])=[O:41])[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1N
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Temperature: 25 °C
Yield: 55 %

Procedure:
To a mixture of 4-amino-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (1.3 g, 5 mmol] and 4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl chloride hydrochloride (1.9 g, 5.50 mmol) in CH2Cl2 (20 mL) was added saturated aqueous NaHCO3 (20 mL) at 0° C. The solution was allowed to warm to 25° C. over 19 h. The reaction was then further diluted in CH2Cl2 (100 mL) and water (30 mL). The organic layer was washed with water (2×50 mL). The organic layer was dried over MgSO4, filtered and concentrated to provide a crude oil (2.6 g). The crude product was purified by Biotage Flash 40M chromatography, eluting with 1:1 ethyl acetate-hexanes, to afford 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester as a white solid (1.6 g, 55%). MS: 570 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](/[CH:10]=[CH:11]/[C:12](O)=[O:13])=[CH:7][C:6]=2[CH:15]=1.CCN(CC)CC.ClC(OCC(C)C)=O.[N-:31]=[N+:32]=[N-:33].[Na+]>CC(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](/[CH:10]=[CH:11]/[C:12]([N:31]=[N+:32]=[N-:33])=[O:13])=[CH:7][C:6]=2[CH:15]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)/C=C/c1cc2cc(Cl)ccc2s1
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)/C=C/c1cc2cc(Cl)ccc2s1
Reaction time: 1 h

Procedure:
To a suspension of (2E)-3-(5-chloro-1-benzothien-2-yl)acrylic acid in acetone (0.2 M) at 0° C. were added Et3N (1.3 equiv) followed by isobutyl chloroformate (1.3 equiv). After stirring for 1 h, H2O solution (2 M) of NaN3 (1.3 equiv) was then added. The resulting mixture was stirred for a period of 0.5 h at 0° C. and 30 min at room temperature. H2O was then added followed by filtration and wash with H2O to provide the title compound.
Reaction SMILES: [N:1]1([C:7]2[S:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27].CCN(C(C)C)C(C)C>CN1CCCC1=O>[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[S:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:8]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: Cc1ccccc1CCl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2nsc(N3CCN(Cc4ccccc4C)CC3)n2)cc1
Temperature: 165 °C

Procedure:
A mixture of 5-(piperazin-1-yl)-3-p-tolyl-1,2,4-thiadiazole (17.3 mg, 66.4 μmol), 1-(chloromethyl)-2-methylbenzene (14.0 mg, 99.7 μmol) and DIPEA (42.9 mg, 58.0 μl) in 0.8 mL N-Methyl-2-pyrrolidinone was heated in the microwave oven 165° C. for 12.5 min. The resulting reaction mixture solution was purified by preparative HPLC on reversed phase eluting with a gradient formed from MeCN, water and NEt3 to yield after evaporation of the product containing fractions 17.5 mg (72%) of the title compound as yellow viscous oil. MS (m/e): 365.3 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:14]=2)=[CH:6][CH:5]=1)([O-])=O>CCO.CN(C=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14]2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1C=C(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of tert-butyl 4-(4-nitrophenyl)-2,3-dihydro-1H-pyrrole-1-carboxylate (I134 and I135) (0.442 g, 1.52 mmol) in EtOH (10 mL) and DMF (10 mL) was added to a solution of 10% Pd/C (255 mg) in DMF (10 mL). The reaction was stirred at room temperature for 17 hours under an atmosphere of hydrogen. The reaction was filtered through a pad of celite and washed through with EtOAc (130 mL). The solvent was removed in vacuo to yield a brown oil which was purified by column chromatography on silica gel (0-50% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I136) (0.307 g, 77%) as a brown oil; 1H NMR (400 MHz, CDCl3) δ 7.02 (d, J=8.4 Hz, 2H), 6.64 (d, J=8.4 Hz, 2H), 3.85-3.49 (m, 4H), 3.43-3.29 (m, 1H), 3.29-3.15 (m, 2H), 2.18 (d, J=6.5 Hz, 1H), 1.97-1.85 (m, 1H), 1.47 (d, J=4.7 Hz, 9H). LCMS Method C: rt 4.88 min; m/z 163.2 [M-Boc+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])=[O:10])=[CH:4][CH:3]=1.C1C(=O)N([Br:23])C(=O)C1>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])=[O:10])=[CH:6][C:7]=1[Br:23]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(CC(=O)NCCCO)cc1
Product: Nc1ccc(CC(=O)NCCCO)cc1Br

Procedure:
The title compound was prepared from 2-(4-amino-phenyl)-N-(3-hydroxy-propyl)-acetamide (as prepared in the previous step) and NBS according to the procedure in Example 7, step (c). Mass spectrum (ESI, m/z): Calcd. for C11H15BrN2O2, 287.0 (M+H). found 287.0.
Reaction SMILES: COC1C=CC(C[N:8]2[C:26](=[O:27])[N:25]3[CH:21]([CH2:22][CH:23]([O:28][C:29]4[CH:34]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:32]=[C:31]([O:41][CH3:42])[N:30]=4)[CH2:24]3)[C:20](=[O:43])[NH:19][C:18]3([C:44]([NH:46][S:47]([C:50]4([CH3:53])[CH2:52][CH2:51]4)(=[O:49])=[O:48])=[O:45])[CH:16]([CH2:17]3)[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=CC=1.C(Cl)Cl.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O>[CH3:42][O:41][C:31]1[N:30]=[C:29]([O:28][CH:23]2[CH2:22][CH:21]3[N:25]([C:26](=[O:27])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][CH:16]4[C:18]([C:44]([NH:46][S:47]([C:50]5([CH3:53])[CH2:52][CH2:51]5)(=[O:48])=[O:49])=[O:45])([NH:19][C:20]3=[O:43])[CH2:17]4)[CH2:24]2)[CH:34]=[C:33]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:32]=1
Reactant: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)NS(=O)(=O)C3(C)CC3)NC(=O)C3CC(Oc4cc(-c5ccccc5)nc(OC)n4)CN3C2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1nc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5(C)CC5)CC4C=CCCCCCNC(=O)N3C2)cc(-c2ccccc2)n1
Yield: 16 %

Procedure:
Compound 4a was dissolved in a 1:2 mixture of TFA:DCM (12 ml) and stirred at RT for 1 h. NaHCO3 was added and the organic layer was dried, filtered and evaporated. The afforded residue was purified by preparative HPLC which gave the pure title compound (36 mg, 16% over two steps), MS (M+H)+639.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5]O)[OH:4].C(O)CO>CC(O)C>[OH:1][CH2:2][C:3](=[O:4])[CH3:5].[CH2:2]([OH:1])[CH:3]([OH:4])[CH3:5]
Reactant: OCC(O)CO
Solvent: OCCO
Solvent: CC(C)O
Product: CC(=O)CO
Product: CC(O)CO
Yield: 0.01 %

Procedure:
20 wt % glycerol was dehydrated at nitrogen ambient pressure at 220° C. using 80 g of 2-propanol as solvent. 0.01 g/ml of 13% Cu+7% Cr+80% SiO2 catalyzed the reaction for 3 h to give glycerol conversion of 8% with 100% selectivity to hydroxyacetone, <0.01% 1,2-propylene glycol, <0.01% ethylene glycol and <0.01% to other products.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1([CH2:17][CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]1=[O:16].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[ClH:19].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]2([CH2:17][CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:28][CH2:27]1
Reactant: CCC1(CCCCCBr)C(=O)Nc2ccccc21
Reactant: Clc1ccccc1N1CCNCC1
Product: CCC1(CCCCCN2CCN(c3ccccc3Cl)CC2)C(=O)Nc2ccccc21
Product: Cl

Procedure:
The title compound is prepared according to process H by applying processing method 2 starting from 3-(5-bromopentyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(2-chlorophenyl)-piperazine.