Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCCOCCO)C.[BH4-].[Na+].[C:12]([CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)([CH3:15])([CH3:14])[CH3:13].S(=O)(=O)(O)O>C1(C)C(C)=CC=CC=1>[C:12]([CH:16]1[CH2:17][CH2:18][CH:19]([OH:22])[CH2:20][CH2:21]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)C1CCC(=O)CC1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CCOCCOCCO
Product: CC(C)(C)C1CCC(O)CC1
Temperature: 95 °C

Procedure:
A mixture consisting of 0.52 g (0.0039 mole) of diethylene glycol monoethyl ether and 5 ml of xylene was added dropwise to a mixture consisting of 0.65 g (0.017 mole) of sodium borohydride, 10 ml of xylene and 10 g (0.065 mole) of 4-t-butylcyclohexanone at 95° C. over 30 minutes while agitating the mixture. Subsequently, the mixture was agitated for one hour while maintaining it at 95° C. Next, after the mixture was cooled to room temperature, it was neutralized with dilute sulfuric acid. As a result, 4-t-butylcyclohexanol was quantitatively obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:12][CH:13](O)[CH:14]=[CH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>COC(OC)(C)C.C1(C)C=CC=CC=1>[CH2:12]([CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:8]1=[O:11])[CH:13]=[CH:14][CH3:15]
Reactant: C=CC(C)O
Reactant: O=C1CCc2ccc(Cl)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2ccc(Cl)cc2C1=O
Yield: 39 %

Procedure:
A solution of 20.2 g of 6-chloro-1-indanone, 25 ml of 3-buten-2-ol and 200 mg of p-toluenesulfonic acid in 25 ml of 2,2-dimethoxypropane and 200 ml of anhydrous toluene was boiled under reflux for 16 hours. The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 5:1). 10.3 g (39%) of (RS)-2-(2-buten-1-yl)-6-chloro-1-indanone were obtained as a yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[N+:15]([CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)([O-])=O>ClC1C=CC(CN)=CC=1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:15]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:13][C:12]=3[C:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[CH:18]2)=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)cc1
Agent: NCc1ccc(Cl)cc1
Product: Clc1ccc(Cn2cc(-c3ccc(Cl)cc3)c3c2CCNC3)cc1
Yield: 52.4 %

Procedure:
The title compound (260.2 mg) was prepared from 0.55 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 340 μL of 4-chlorobenzylamine, and 0.51 g of (2-nitro-vinyl)-4-chlorobenzene. MS (ESI): exact mass calculated for C20H18Cl2N2, 356.08; found, m/z 357.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.37-7.31 (m, 6H), 7.17-7.13 (m, 3H), 5.15 (s, 2H), 4.35 (s, 2H), 3.51 (t, J=6.3 Hz, 2H), 2.85 (t, J=6.3 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19](I)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21]([C:23]1[CH:24]=[N:25][C:26]([NH2:29])=[N:27][CH:28]=1)#[CH:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:22]#[C:21][C:23]4[CH:24]=[N:25][C:26]([NH2:29])=[N:27][CH:28]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2cc(C3CC3)n3ncc(I)c3n2)cc1
Reactant: C#Cc1cnc(N)nc1
Product: Nc1ncc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)cn1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-3-iodo-pyrazolo[1,5-a]pyrimidine (example C.5 step 4) (198 mg, 0.5 mmol) and 5-ethynyl-pyrimidin-2-ylamine (example D.2 step 2) (60 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (88 mg, 46%). MS (ISP) 387.1 [(M+H)+]; mp 243-246° C.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[CH2:4]([N:15]([CH2:20][C:21]([OH:23])=[O:22])[CH2:16][C:17]([OH:19])=O)[CH2:5][N:6]([CH2:11][C:12]([OH:14])=[O:13])[CH2:7][C:8]([OH:10])=O.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[O:22]=[C:21]1[O:23][C:17](=[O:19])[CH2:16][N:15]([CH2:4][CH2:5][N:6]2[CH2:7][C:8](=[O:10])[O:14][C:12](=[O:13])[CH2:11]2)[CH2:20]1
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Ca+2]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: O=C1CN(CCN2CC(=O)OC(=O)C2)CC(=O)O1

Procedure:
To a 250 ml round bottomed flask fitted with a magnetic stirrer, condenser, and a drying tube (calcium chloride), was added pyridine (dried by distillation from potassium hydroxide) (80 ml). Ethylenediaminetetraacetic acid (29.12 g) was added followed by acetic anhydride (37.6 ml). The suspension was stirred and heated at 65°-80° C. for 7 hr. The mixture was cooled overnight and the white solid filtered off. The solid was washed once with pyridine (dry 20 ml) and four times with ether (dry 4×40 ml). The white solid was dried on a manifold and stored in a desiccator.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][C@H:14]2[CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19](OC(N1CC[C@@H](OS(C2C=CC(C)=CC=2)(=O)=O)C1)=O)(C)(C)C.C[C@H]1CCCCN1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:18][C@@H:14]2[CH3:19])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Reactant: C[C@@H]1CCCN1[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: C[C@H]1CCCCN1
Product: C[C@H]1CCCCN1[C@H]1CCN(C(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared in a manner substantially the same as intermediate (iv), (2R,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-carboxylic acid tert-butyl ester, by condensing 3-(3R)-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (5 g) with (S)-2-Methyl-piperidine to get 1.5 g (38% yield) of the product as a beige oil.
Reaction SMILES: [C:1]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])[C@@H:2]([C@H:4]([C:6]([O:8][CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[OH:5])[OH:3].[H-].[Na+].Br[C:31](Br)([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:32]([O:34][CH2:35][CH3:36])=[O:33].[Cl-].[Na+]>C(COC)OC.O>[O:5]1[C@@H:4]([C:6]([O:8][CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:7])[C@H:2]([C:1]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[O:3][C:31]1([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: CC(C)(C)OC(=O)[C@H](O)[C@@H](O)C(=O)OC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(Br)(Br)C(=O)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C1(C(=O)OCC)O[C@@H](C(=O)OC(c2ccccc2)c2ccccc2)[C@H](C(=O)OC(C)(C)C)O1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 44 %

Procedure:
3.92 g of tert-butyl diphenylmethyl L-tartarate was dissolved in 10 ml of dimethoxyethane, and 844 mg of 60% sodium hydride was added at 0° C. , followed by stirring at the same temperature for 45 minutes. Then, a solution of 3.37 g of diethyl dibromomalonate in 5 ml of dimethoxyethane, was added, followed by stirring under heating at 80° C. for 12 hours. The reaction solution was cooled to room temperature and then poured into water. The aqueous layer was saturated with sodium chloride and extracted with ethyl ether. The obtained organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/1→5/1) to obtain 1.73 g (yield: 44%) of the above identified compound as white solid.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[Cl:25][C:26]1[CH:32]=[C:31]([CH3:33])[C:29]([NH2:30])=[C:28]([O:34][CH3:35])[CH:27]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:19][C:18]1[C:4]2[N:3]=[C:2]([NH:30][C:29]3[C:31]([CH3:33])=[CH:32][C:26]([Cl:25])=[CH:27][C:28]=3[O:34][CH3:35])[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=1
Reactant: COc1cc(Cl)cc(C)c1N
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: CCOC(=O)CCCn1c(Nc2c(C)cc(Cl)cc2OC)nc2c(Cl)ccc(C(CC)CC)c21
Yield: 22.8 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 470 mg, 1.27 mmol), 4-chloro-2-methoxy-6-methylaniline (650 mg, 3.81 mmol) and p-toluenesulfonic acid (241 mg, 1.27 mmol) and xylene (5.0 mL) was irradiated by microwave at 150° C. for 4 hr. After cooling, the reaction mixture was extracted with ethyl acetate (×3). The organics were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound (120 mg, 0.289 mmol, 18.7%) as a brown amorphous.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:12](=[O:13])[CH2:11][CH:10](C(N)=O)[CH2:9]2)=[CH:5][CH:4]=1.C(OI(OC(=O)C)C1C=CC=CC=1)(=O)C.Cl.CC#[N:37]>O>[NH2:37][CH:10]1[CH2:9][N:8]([CH2:7][C:6]2[CH:17]=[CH:18][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:12](=[O:13])[CH2:11]1
Reactant: CC#N
Reactant: COc1ccc(CN2CC(C(N)=O)CC2=O)cc1
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: Cl
Solvent: O
Product: COc1ccc(CN2CC(N)CC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
To a solution of 1-(4-methoxy-benzyl)-5-oxo-pyrrolidine-3-carboxylic acid amide (50.0 g, 201 mmol) in 560 mL of CH3CN and 560 mL of H2O was added bis(acetyloxy)(phenyl)-λ3-iodane (84.0 g, 261 mmol). The color of the mixture turned to light red. After being stirred at room temperature overnight, the reaction mixture was diluted with 1000 mL of H2O and acidified to pH 2 with concentrated HCl, then extracted with DCM (300 mL×3). The aqueous layer was then basified to pH 10 with 1 N aqueous solution of KOH and then extracted with DCM (400 mL×3). The combined organic layers were dried over Na2SO4 and then concentrated in vacuo to afford 4-amino-1-(4-methoxybenzyl)pyrrolidin-2-one as light yellow oil (28.0 g, yield: 63.2%), which solidified after being cooled down to room temperature and was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][S:20]([CH3:19])(=[O:22])=[O:21])[CH:5]=[CH:4][N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccnc(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a chilled (0° C.) solution of (2-bromopyridin-4-yl)-methanol (3.00 g, 16.0 mmol) and DIPEA (8.3 mL, 48 mmol) in dichloromethane (30 mL) is added methanesulfonyl chloride (1.30 mL, 16.8 mmol). The resulting mixture is warmed to room temperature. After 1 hour, the mixture is diluted with dichloromethane (20 mL) and washed with saturated aqueous ammonium chloride (3×10 mL), saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL), dried over MgSO4, filtered and concentrated to afford crude methanesulfonic acid 2-bromopyridin-4-ylmethyl ester, which is used without purification.
Reaction SMILES: Cl[CH:2]([C:13](=O)[CH2:14][CH2:15][CH3:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[CH3:18][S:19][CH2:20][C:21]([NH2:23])=[S:22]>C1CCCCC1.C(OCC)(=O)C>[CH3:18][S:19][CH2:20][C:21]1[S:22][C:2]([CH2:3][C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=2)=[C:13]([CH2:14][CH2:15][CH3:16])[N:23]=1
Reactant: CSCC(N)=S
Reactant: CCCC(=O)C(Cl)Cc1ccc([N+](=O)[O-])cc1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CCCc1nc(CSC)sc1Cc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Yield: 86.8 %

Procedure:
A mixture of 5 g of 2-chloro-1-(4-nitrophenyl)-hexan-3-one (0.02 mol) and 2.6 g of (methylthio)thioacetamide (0.022 mol) is heated at 60° C. for 24 h. The reaction is followed by TLC (7/3 cyclohexane/ethyl acetate). The reaction medium is then treated according to the process of Example 45 to give 5.6 g of 2-methylthiomethyl-5-(4-nitrobenzyl)-4-propylthiazole in the form of an orange oil.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[OH:55][CH2:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[O:64][CH3:65]>ClCCl.CO>[Br:1][C:62]1[CH:61]=[CH:60][C:59]([O:64][CH3:65])=[C:58]([CH2:57][CH2:56][OH:55])[CH:63]=1
Reactant: [Br-]
Reactant: COc1ccccc1CCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(Br)cc1CCO
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
35.72 g of tetrabutylammonium tribromide are added in portions to a solution of 10.7 g of 2-(2-hydroxyethyl)-anisole in 195 ml of dichloromethane and 130 ml of methanol. The reaction mixture is stirred for 150 minutes at room temperature and is then concentrated by evaporation in a rotary evaporator. The residue is partitioned between diethyl ether and water. The organic phases are combined, dried over magnesium sulfate and concentrated by evaporation, and the residue is purified by means of FC (dichloromethane), yielding the title compound: Rf (dichloromethane)=0.26; HPLC Rt =13.04 minutes.
Reaction SMILES: N1C=CN=C1.[NH:6]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:7]([C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([NH2:18])=O)=[O:13])[C@H:8]([CH2:10][CH3:11])[CH3:9].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:16]([C@@H:15]1[CH2:19][CH2:20][CH2:21][N:14]1[C:12](=[O:13])[C@H:7]([C@H:8]([CH2:10][CH3:11])[CH3:9])[NH:6][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])#[N:18]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(N)=O
Agent: c1c[nH]cn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C#N
Reaction time: 1 h
Yield: 94 %

Procedure:
Imidazole (84 mg, 1.24 mmol) was added to a solution of BocIleProNH2 in dry pyridine (10 cm3), under a nitrogen atmosphere. The solution was cooled to −35° C., before the dropwise addition of POCl3 (0.25 cm3, 2.48 mmol). The reaction was stirred at −30° C. to −20° C. for 60 min. The solution was then evaporated and the crude residue subjected to column chromatography (silica gel) to yield 180 mg (94%) of 2-(S)-cyano-1-[N-(t-butoxycarbonyl) isoleucyl]pyrrolidine as a colourless oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[N:23]1[CH2:27][CH2:26][CH:25]([C:28](O)=[O:29])[C:24]1=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:28]([CH:25]1[CH2:26][CH2:27][N:23]([C:17]2[C:16]([F:15])=[CH:21][CH:20]=[CH:19][C:18]=2[F:22])[C:24]1=[O:31])=[O:29]
Reactant: O=C(O)C1CCN(c2c(F)cccc2F)C1=O
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2c(F)cccc2F)C1=O
Yield: 18.6 %

Procedure:
This compound was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), 1-(2,6-difluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (0.107 g; 0.445 mmol), HATU (0.166 g; 0.437 mmol) and N,N-diisopropylethylamine (0.186 mL; 1.06 mmol) in DMF (5 mL). The crude material was purified by flash chromatography on silica gel (eluent: 2 to 20% of ethyl acetate in dichloromethane) to give 0.033 g (20%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(2,6-difluorophenyl)-2-oxopyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1)#[N:2].Cl.[Cl:24][S:25](O)(=[O:27])=[O:26]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([S:25]([Cl:24])(=[O:27])=[O:26])=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: O=S(=O)(O)Cl
Reactant: N#Cc1ccc(CCC(=O)N2CCCc3ccccc32)cc1
Agent: Cl
Product: N#Cc1ccc(CCC(=O)N2CCCc3cc(S(=O)(=O)Cl)ccc32)cc1
Temperature: 60 °C

Procedure:
(0.04 mol) of 1-[3-(4-cyano-phenyl)-propionyl]-1,2,3,4-tetrahydro-quinoline are dissolved in 16 ml of chlorosulphonic acid at 0° C. The thickly liquid mass is heated to 60° C. and hydrochloric acid develops. Then the mixture is carefully added to ice and extracted with methylene chloride, dried and concentrated by rotary evaporation.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:14][CH2:15][CH:16]([CH2:21][CH3:22])[CH2:17][CH2:18][CH2:19][CH3:20])=[C:9]([N+:11]([O-])=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O.NN>CC(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:14][CH2:15][CH:16]([CH2:21][CH3:22])[CH2:17][CH2:18][CH2:19][CH3:20])=[C:9]([CH:10]=1)[NH2:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCC(CC)CSc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: NN
Solvent: CC(C)O
Solvent: O
Product: CCCCC(CC)CSc1ccc(C(C)(C)C)cc1N

Procedure:
In a typical example of a specific production method, ferric chloride hexahydrate and an activated carbon are added to a 2-propanol solution of 5-tert-butyl-2-(2-ethylhexylthio)nitrobenzene, and the mixture is refluxed under heating for 10 minutes. To this solution is added, dropwise, an aqueous 80% solution of hydrazine monohydrate. After the addition is finished, the reaction is continued under refluxing until the raw material disappears. Then, the reaction solution is cooled, and the catalyst and the activated carbon are separated by filtration. Toluene is added to the filtrate, and the toluene solution is then washed with water, washed with an acid, neutralized, washed with water, and then concentrated, to obtain 5-tert-butyl-2-(2-ethylhexylthio)aniline.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH:18](O)[CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.CCN(S(F)(F)[F:34])CC>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH:18]([F:34])[CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC(O)CC(CNc2nc(Cl)cc3nccnc23)C1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(F)CC(CNc2nc(Cl)cc3nccnc23)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-((7-chloropyrido[4,3-b]pyrazin-5-ylamino)methyl)-5-hydroxypiperidine-1-carboxylate (1.97 g, 5.0 mmol) in dichloromethane was added DAST (4.03 g, 25 mmol). The reaction mixture was stirred at room temperature for 2 hours, then diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by chromatography to give the title compound. MS (m/z): 396 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)Cl>[CH2:24]([O:23][C:21]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:22])[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
(R)-Pyrrolidine-2-carboxylic acid tert-butyl ester (16.11 g, 94.1 mmol) in DCM (250 ml) under an inert atmosphere of argon is treated with triethyl amine (26 ml, 188 mmol) and then cooled to 0° C. with a ice bath. To this cooled solution is added dropwise ethyl chloroformate (8.99 ml, 94.1 mmol) and the reaction mixture is left to stir at 0° C. for 3 hours. The reaction mixture is washed with 1M HCl (2×100 ml), water, brine, dried over MgSO4 and concentrated in vacuo to yield the titled compound as a clear oil.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[O:4].Cl.[NH:7]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C@H:8]([C:16](O)=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>O.CN(C=O)C>[NH:7]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C@H:8]([C:16]([NH:1][NH:2][C:3]([NH2:5])=[O:4])=[O:17])[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: NNC(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 24 h

Procedure:
In 5 ml of water is dissolved 2.50 g (22 mM) of NH2NHCONH2.HCl, the solution is neutralized with 3.14 ml of TEA, and 40 ml of DMF is added. To this solution are added 3.0 g of Z-Phe-OH, 2.0 g of HONB and 2.3 g of DCC. The mixture is stirred for 24 hours, the precipitated DCU filtered off, the solvent distilled off and the residue dissolved in 200 ml of ethyl acetate. The solution is washed with aqueous sodium hydrogen carbonate and water in that order and dried over anhydrous sodium sulfate. The solvent is then distilled off, the residue is treated with ether, and crystals are collected by filtration. Yield 2.7 g; m.p. 119°-121° C., [α]D21.5 -14.4° (c=1.01, DMF), Rf1 0.29.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:40])[CH:5]=[C:6]([Cl:39])[C:7]=1[CH2:8][C@@H:9]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:33])[F:32])=[C:26]([O:34][CH2:35][CH:36]2[CH2:38][CH2:37]2)[CH:25]=1)[O:10][C:11](=[O:23])[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1.CCOC(C)=O>C1COCC1.C([O-])(O)=O.[Na+]>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][NH:12][C:11]([O:10][C@H:9]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:32])[F:33])=[C:26]([O:34][CH2:35][CH:36]3[CH2:38][CH2:37]3)[CH:25]=2)[CH2:8][C:7]2[C:2]([Cl:1])=[CH:3][N+:4]([O-:40])=[CH:5][C:6]=2[Cl:39])=[O:23])=[CH:19][CH:18]=1
Reactant: O=C(NCc1ccc([N+](=O)[O-])cc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(CNC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To a stirred solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(4-nitrobenzylcarbamoyloxy)ethyl)pyridine 1-oxide (200 mg, 0.334 mmol) in THF (10 ml), SnCl2 dihydrate (603 mg, 2.67 mmol) was added, and the mixture was stirred at 60° C. for 5 hours, then the mixture was diluted with NaHCO3 sat (pH=7) followed by the addition of EtOAc and filtered trough a celite pad. The inorganic phase was extracted with EtOAc. The combined organic layers were rinsed with brine, dried over Na2SO4 and evaporated affording the desired product (190 mg, 0.334 mmol, 100% yield, MS/ESI+ 568.3 [MH]+).
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH:14]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]1.C(=O)(O)[O-].[Na+]>C(O)C>[OH:20][CH:17]1[CH2:18][CH2:19][N:14]([CH:2]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:15][CH2:16]1
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: OC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(c1ccccc1)N1CCC(O)CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 96.2 %

Procedure:
To a solution of ethyl bromo(phenyl)acetate (5.0 g) in ethanol (20 mL) was added 4-piperidinol (5.05 g) and the mixture was stirred at 60° C. for 4 hours. The mixture was poured into dilute sodium bicarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethylacetate (3:7) to afford ethyl (4-hydroxypiperidin-1-yl)(phenyl)acetate (5.21 g) as a yellow oil.