Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([C:4]1[NH:5][CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[N:8]=1)([O-])=O.[ClH:12]>O>[Cl:12][C:4]1[NH:5][CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[N:8]=1
Reactant: O=[N+]([O-])c1c[nH]c([N+](=O)[O-])n1
Reactant: Cl
Solvent: O
Product: O=[N+]([O-])c1c[nH]c(Cl)n1
Temperature: 95 °C
Reaction time: 7 h
Yield: 77.1 %

Procedure:
5.0 g of 2,4-dinitroimidazole (purity 92.3%) was added to 30 mL of 35 mass % hydrochloric acid. The reaction liquid was warmed to 95° C. and the reaction was performed for 7 hours. After the reaction, 43 g of water was added and the resultant mixture was cooled to 0° C. for crystallization. The crystals were filtered and dried to obtain 3.31 g of 2-chloro-4-nitroimidazole (yield 77.1%). This was identified to be 2-chloro-4-nitroimidazole by
Reaction SMILES: [K].[OH:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[C:4]=1[CH:5]=[O:6].[C:16](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O.[K]>CC(C)=O>[CH3:16][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[C:4]=1[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1O
Agent: [K+]
Agent: [K]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1ccc([N+](=O)[O-])c(C=O)c1OC
Yield: 80 %

Procedure:
2-Hydroxy-3-methoxy-6-nitrobenzaldehyde potassium salt was slurried in acetone (500 mL) containing potassium carbonate (50 g) and the suspension was treated with dimethylsulfate (18.5 mL) and heated to reflux for one hour. An additional aliquot (18.5 mL) of dimethylsulfate was then added and the mixture was heated overnight. After 24 hours the red color of the potassium salt was virtually absent. The salts were removed by filtration, the filtrate was concentrated and the residue was recrystallized from isopropanol to give the title compound 40.0 g (80% from 3) mp 109°-110° C.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:15]([CH3:17])=[C:14]([CH3:18])[N:13]=[C:12](OC3C=CC=CC=3)[C:11]=2[N:10]=[C:9]1[CH2:26][CH2:27][CH3:28])(=[O:4])=[O:3].C([O-])(=O)C.[NH4+:33]>>[CH3:1][S:2]([CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:15]([CH3:17])=[C:14]([CH3:18])[N:13]=[C:12]([NH2:33])[C:11]=2[N:10]=[C:9]1[CH2:26][CH2:27][CH3:28])(=[O:4])=[O:3]
Reactant: CCCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCCS(C)(=O)=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: CCCc1nc2c(N)nc(C)c(C)c2n1CCCS(C)(=O)=O
Yield: 67.2 %

Procedure:
Using the general method of Example 89 Part H, 1-[3-(methanesulfonyl)propyl]-6,7-dimethyl-4-phenoxy-2-propyl-1H-imidazo[4,5-c]pyridine (2.1 g, 5.23 mmol) was reacted with ammonium acetate (25 g) and purified to provide 1.14 g of 1-[3-(methanesulfonyl)propyl]-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-4-amine as white needles, mp 153.5–155.0° C. 1H NMR (300 MHz, CDCl3) δ 4.83 (br s, 2H), 4.48–4.42 (m, 2H), 3.07 (t, J=7.1 Hz, 2H), 2.95 (s, 3H), 2.82–2.77 (m, 2H), 2.45 (s, 6H), 2.35–2.25 (m, 2H), 1.94–1.81 (m, 2H), 1.07 (t, J=7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 153.2, 148.3, 147.1, 138.9, 125.4, 104.0, 51.2, 42.9, 41.3, 29.5, 24.3, 22.1, 21.5, 14.0, 13.1;
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][CH2:6][CH:7]([N:18]([CH3:35])[C:19](=[O:34])[C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=1)[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)C.[OH-].[Li+]>O1CCCC1.CO.O>[CH3:35][N:18]([CH:7]([CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[CH2:6][CH2:5][C:4]([OH:36])=[O:3])[C:19](=[O:34])[C:20]1[CH:21]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1
Reactant: CCOC(=O)CCC(Cc1c[nH]c2ccccc12)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CCC(=O)O)Cc1c[nH]c2ccccc12

Procedure:
A solution of 30 g of 4-[N-methyl-N-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(1H-indol-3-yl)-pentanoic acid ethyl ester and 3.7 g of lithium hydroxide in 210 ml of tetrahydrofuran/methanol/water=2/2/1 is stirred at room temperature for 3 hours and then concentrated by evaporation. The residue is dissolved in 300 ml of water, extracted with ether, acidified to pH=2 with 0.1N hydrochloric acid and extracted three times with ether. The combined organic phases originating from the extraction of the acidic aqueous phase are washed with water and saturated NaCl solution, dried (magnesium sulfate) and concentrated by evaporation. In this way the title compound is obtained in the form of a yellow foam.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:13][CH:14]([C:19]([CH3:21])=[O:20])[CH2:15][C:16]([OH:18])=[O:17].N1CCCCC1>C1(C)C=CC=CC=1.O1CCCC1>[C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:21][C:19](=[O:20])[CH:14]([CH3:13])[CH2:15][C:16]([OH:18])=[O:17])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)C(C)CC(=O)O
Reactant: CC(=O)Nc1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C=CC(=O)C(C)CC(=O)O)cc1
Yield: 51.6 %

Procedure:
A solution of 8.2 g (0.05 mol) of 4-acetamidobenzaldehyde, 7.2 g (0.055 mol) of β-methyl levulinic acid, 6.3 g (0.075 mol) of piperidine in a mixture of 125 ml of toluene and 75 ml of tetrahydrofuran is heated under relux with a Dean Stark apparatus for two hours. The solution is evaporated under vacuo and the residue is taken up with dilute aqueous K2CO3 solution. The insoluble material is extracted with ether and discarded. The pH of the solution is adjusted to 5.6 and the gummy material is extracted with ethyl acetate. The extract is washed with saturated sodium chloride solution, dried, and evaporated. The residue is crystallized from 2-propanol to give 7.1 g of 6-[4(acetylamino) phenyl]-3-methyl-4-oxo-5-hexenoic acid, mp 189°-190° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[N:23]=[N:24][C:25]([C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)=[C:26]([CH3:29])[C:27]=2[CH3:28])[CH2:18][CH2:17]1)C)(C)(C)C>C(Cl)Cl>[CH3:28][C:27]1[C:26]([CH3:29])=[C:25]([C:30]2[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=2)[N:24]=[N:23][C:22]=1[N:19]1[CH2:18][CH2:17][CH:16]([NH:14][CH3:13])[CH2:21][CH2:20]1
Reactant: Cc1c(-c2ccncc2)nnc(N2CCC(N(C)C(=O)OC(C)(C)C)CC2)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC1CCN(c2nnc(-c3ccncc3)c(C)c2C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 88.8 %

Procedure:
Add CH2Cl2 (20 mL) and trifluoroacetic acid (20 mL) to tert-butyl-1-(4,5-dimethyl-6-(pyridine-4-yl)pyridazin-3-yl)piperidin-4-yl(methyl)carbamate (1.19 g, 2.99 mmol). Stir at ambient temperature for 3 d. Concentrate under reduced pressure to give a residue. Partition the residue between CH2Cl2 and 1 N NaOH. Separate the layers, and extract the aqueous layer twice with CH2Cl2. Combine the organic extracts, dry over Na2SO4, filter, and concentrate under reduced pressure to obtain the title compound (790 mg, 89%). ES/MS m/z 298.2 (M+1).
Reaction SMILES: C([NH:8][C@@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(OC(C)(C)C)=O.[ClH:20].[CH2:21]([O:28][C:29](=[O:35])[C@@H:30]1[CH2:34][CH2:33][CH2:32][NH:31]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[NH2:8][C@@H:9]([C:17]([N:31]1[CH2:32][CH2:33][CH2:34][C@H:30]1[C:29]([O:28][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:35])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1.[ClH:20]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 119.9 %

Procedure:
To a suspension of Boc-D-phenylalanine (42.4 g, 160 mmol) in methylene chloride was added proline benzyl ester hydrochloride (38.7 g, 160 mmol), 1-hydroxybenzotriazole hydrate (21.6 g, 160 mmol) and diisopropylethylamine (83 mL, 480 mmol). Once the solution was homogeneous, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (40 g, 200 mmol) was added. This mixture was allowed to stir at room temperature for 16 hrs and was then concentrated in vacuo. The residue was dissolved in ethyl acetate (500 mL) and this solution was washed twice with saturated aqueous ammonium chloride (400 mL), twice with saturated aqueous bicarbonate (400 mL), and twice with brine (400 mL). The organic solution was dried (MgSO4), filtered and concentrated in vacuo to give 74.6 g (103%) of a straw colored syrup. This syrup was dissolved in p-dioxane (400 mL) and anhydrous HCl gas was bubbled through for 15 minutes and was allowed to stir for 3 hr at room temperature. The solution was concentrated in vacuo to give a yellow foam coating the sides of the flask. The foam was washed several times with diethyl ether and the solvent was decanted. The foam was dried under high vacuum to give 61 g (98%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH3:10]O.[ClH:12]>>[ClH:12].[CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: CO
Reactant: CNCCCCC(=O)O
Agent: Cl
Product: CNCCCCC(=O)OC
Temperature: 60 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
A stirred solution of 1-methyl-2-piperidinone (4.40 mL, 40.0 mmol) in aqueous sodium hydroxide (4 M, 11.0 mL, 44.0 mmol) was heated at 100° C. for 15 h. The reaction mixture was cooled to room temperature and then acidified to pH 2 with concentrated hydrochloric acid. The mixture was then concentrated under reduced pressure to give crude 5-methylaminopentanoic acid as a pinkish white solid. To the crude 5-methylaminopentanoic acid was added MeOH (40.0 mL, 987 mmol) and concentrated hydrochloric acid (0.33 mL, 4.0 mmol). The resulting cloudy solution was heated at 60° C. for 39 h at which time LC-MS showed remaining starting material. Additional concentrated hydrochloric acid (0.33 mL, 4.0 mmol) was added and the resulting mixture was heated at 60° C. for 33 h and then at 65° C. for an additional 24 h. LC-MS showed remaining starting material. The reaction mixture was concentrated under reduced pressure and a solution of hydrogen chloride in MeOH (1.25 M) was added to the residue. The resulting mixture was heated at 60° C. for 72 h at which time no remaining starting material was observed by LC-MS. The reaction mixture was partially concentrated under reduced pressure and the solid material that formed was removed by filtration, washing with MeOH. The filtrate was then concentrated under reduced pressure to provide methyl 5-methylaminopentanoate hydrochloride (7.57 g, 100% yield) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])=[CH:4][C:3]=1[CH:21]=[O:22].[CH2:23](O)[CH2:24][CH2:25][OH:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[N:10]([CH3:19])[C:9]2=[O:20])=[CH:4][C:3]=1[CH:21]1[O:26][CH2:25][CH2:24][CH2:23][O:22]1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C=O)c2)c1=O
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C3OCCCO3)c2)c1=O

Procedure:
A solution of 3.5 g of 3-[4-chloro-3-formylphenyl]-2,4-dioxo-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine, 0.8 g of 1,3-propanediol and 0.2 g of p-toluenesulfonic acid in 100 ml of anhydrous dichloromethane was boiled for 5 hours under a water separator. The solution was washed with 10% strength sodium bicarbonate solution and water, dried over sodium sulfate and evaporated down. The residue was chromatographed over silica gel (7:3 cyclohexane/ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]([CH3:19])[CH:12]=3)[O:8][C:6]=2[N:7]=1.Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:25]([O:24][C:22](=[O:23])[CH2:21][O:18][C:14]1[C:13]([CH3:19])=[CH:12][C:11]([C:9]2[O:8][C:6]3[N:7]=[C:2]([Cl:1])[N:3]=[CH:4][C:5]=3[N:10]=2)=[CH:16][C:15]=1[CH3:17])([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1cc(-c2nc3cnc(Cl)nc3o2)cc(C)c1O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3cnc(Cl)nc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1 g of 4-(5-chloro-oxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethyl-phenol in 5 ml of dimethylformamide was added slowly to a suspension of 1.2 ml of tert-butyl bromoacetate and 1.3 g of potassium carbonate in 15 ml of dimethylformamide. The mixture was stirred at room temperature for 30 min and then heated to 50° C. for 4 h. After cooling, the solids were removed by filtration and the solvents were distilled off in vacuo to give 1.4 g of the crude title compound as a pale yellow solid.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].CON(C)[C:15](=[O:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].Cl>C1COCC1>[CH3:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:15](=[O:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCC(=O)N(C)OC
Reactant: CCCCCCCCCBr
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)CCCCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
Polished shaved magnesium (3.2 g, 134 mmol) was heated, and thereafter, an anhydrous THF solution (68 ml) of 1-bromononane (12.9 ml, 67.5 mmol) was slowly added dropwise thereto. After heating to reflux for 1.5 hours, the reaction solution was cooled to a room temperature, and it was then added dropwise to a THF (80 mL) solution of the N-methoxy-N-methyldecanamide (4.8 g, 22.5 mmol) obtained by the method described in Production Example D-1-1. After the obtained mixture had been stirred for 30 minutes, 1 N hydrochloric acid was added to the reaction solution, followed by extraction with diethyl ether two times. Anhydrous magnesium sulfate was added to the organic layer to dry it, and the resultant was filtrated and was then concentrated. The obtained residue was purified using column chromatography (hexane:dichloromethane=8:1), so as to obtain 10-nonadecanone (6.0 g, 95%) as a ketone body in the form of a white amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=2)[CH:4]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: COc1ccc(O)cc1
Product: COc1ccc(O)c(Cc2ccc(F)cc2)c1

Procedure:
Alkylation of 4-methoxyphenol with 4-fluorobenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-methoxy-2-(4′-fluorobenzyl)phenol. This material was converted to compound 69 and compound 70 by the procedure similar to that in Example 18 method B.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:8]=1[O:9][CH3:10])=[O:2].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH2:31][C:32](Cl)=[O:33])[CH:25]=1>>[CH:1]([C:3]1[CH:4]=[C:5]([S:20]([NH:23][C:32](=[O:33])[CH2:31][CH2:30][C:26]2[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=2)(=[O:22])=[O:21])[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:8]=1[O:9][CH3:10])=[O:2]
Reactant: O=C(Cl)CCc1cccnc1
Reactant: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1cccc([N+](=O)[O-])c1
Product: COc1c(C=O)cc(S(=O)(=O)NC(=O)CCc2cccnc2)cc1-c1cccc([N+](=O)[O-])c1

Procedure:
Proceeding as in Reference 21, but substituting 5-formyl-6-methoxy-3′-nitro-biphenyl-3-sulfonamide and 3-pyridin-3-ylpropanoyl chloride, gave 5-formyl-6-methoxy-3′-nitro-N-(3-pyridin-3-ylpropanoyl)-biphenyl-3-sulfonamide.
Reaction SMILES: [OH-].C[N+:3](C)(C)[CH2:4][C:5]1C=CC=C[CH:6]=1.[C:13]1([CH2:19][NH:20][CH2:21][CH:22]2[CH2:27][CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[O:23]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O(CC)CC>C(#N)C=C>[O:23]1[C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2[CH2:26][CH2:27][CH:22]1[CH2:21][N:20]([CH2:19][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:6][CH2:5][C:4]#[N:3]
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: c1ccc(CNCC2CCc3ccccc3O2)cc1
Agent: [OH-]
Solvent: C=CC#N
Solvent: CCOCC
Product: N#CCCN(Cc1ccccc1)CC1CCc2ccccc2O1
Reaction time: 96 h
Yield: 28.6 %

Procedure:
3 ml of N,N,N-trimethylbenzenemethanaminium hydroxide was added dropwise to a stirred mixture of 60 g (±)-3,4-dihydro-N-(phenylmethyl)-2H-1-benzopyran-2-methanamine in 350 ml of 2-propenenitrile. After stirring for 4 days at reflux temperature, the reaction mixture was cooled and poured into 1,1'-oxybisethane. The whole was filtered over diatomaceous earth and the filtrate was evaporated, yielding 21 g (28.6%) of (±)-3-[[(3,4-dihydro-2H1-benzopyran-2-yl)methyl](phenylmethyl)amino]propanenitrile as crude residue (interm. 21).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[C:5]([N+:12]([O-])=O)=[C:4]([F:15])[CH:3]=1.C(OCC)(=O)C>O.Cl.[Fe]>[NH2:12][C:5]1[C:6]2[S:10][C:9]([CH3:11])=[N:8][C:7]=2[C:2]([Cl:1])=[CH:3][C:4]=1[F:15]
Reactant: Cc1nc2c(Cl)cc(F)c([N+](=O)[O-])c2s1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc2c(Cl)cc(F)c(N)c2s1
Temperature: 80 °C

Procedure:
6 g of iron powder were added to a suspension of 8 g (32 mmol) of 4-chloro-6-fluoro-2-methyl-7-nitrobenzothiazole in 100 ml of water and 9 ml of concentrated hydrochloric acid, which suspension had been heated to 80° C., after which the mixture was refluxed for 3 hours. 200 ml of ethyl acetate were then added to the reaction mixture. The solid was filtered off. The remaining organic phase was washed with water, dried over magnesium sulfate and finally evaporated down. Yield: 4.5 g.
Reaction SMILES: [CH:1]1([CH:4]=O)[CH2:3][CH2:2]1.[CH3:6][C:7]([S@@:10]([NH2:12])=[O:11])([CH3:9])[CH3:8].S([O-])([O-])(=O)=O.[Mg+2].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl>[CH:1]1(/[CH:4]=[N:12]/[S:10]([C:7]([CH3:9])([CH3:8])[CH3:6])=[O:11])[CH2:3][CH2:2]1
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=CC1CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)S(=O)/N=C/C1CC1
Reaction time: 8 h

Procedure:
To a stirred solution of cyclopropane carboxaldehyde (26.1 ml, 347 mmol) in DCM (347 ml) were added (S)-(−)-2-methyl-2-propanesulfinamide (21.0 g, 173 mmol), magnesium sulfate (104 g, 866 mmol), and PPTS (2.177 g, 8.66 mmol). The reaction mixture was left to stir overnight, filtered through a fritted funnel, concentrated, and purified by chromatography to provide the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH2:21]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([BH-](CC)CC)C.[Li+]>C1COCC1>[Si:14]([O:13][C@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([CH3:21])[CH2:10]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1COS(C)(=O)=O
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (2S,4R)-tert-butyl-4-(tert-butyldimethylsilyloxy)-2-((methylsulfonyloxy)methyl)pyrrolidine-1-carboxylate (5.34 g, 13.0 mmol) in THF (30 mL) was cooled to about 0° C. and a solution of lithium triethylborohydride (1M in THF, 52 mL) was added dropwise. The ice-bath was removed and the reaction mixture was stirred at ambient temperature for about 2 hours. The reaction mixture was cooled to about 0° C. and additional lithium triethylborohydride solution (10 mL) was added. The reaction mixture was stirred at ambient temperature for about 1 h and then the reaction was quenched by a dropwise addition of water. EtOAc (100 mL) was added and the layers were separated. The organic phase was washed with water (75 mL), IN phosphoric acid (2×100 mL), water (100 mL), aqueous sodium bicarbonate (100 mL) and brine (100 mL) then dried over magnesium sulfate and concentrated to give (2R,4R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-methylpyrrolidine-1-carboxylate that was used without further purification.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][C:15]([C:21]([NH2:23])=[O:22])=[C:14]2Cl.Cl.[CH3:26][O:27][CH:28]1[CH2:31][CH:30]([NH2:32])[CH2:29]1>CC(N(C)C)=O.O>[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][C:15]([C:21]([NH2:23])=[O:22])=[C:14]2[NH:32][C@H:30]1[CH2:31][C@@H:28]([O:27][CH3:26])[CH2:29]1
Reactant: NC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: COC1CC(N)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Product: CO[C@H]1C[C@@H](Nc2c(C(N)=O)cnc3ccc(Br)cc23)C1
Temperature: 100 °C
Reaction time: 18 h
Yield: 68.3 %

Procedure:
DIPEA (13.76 mL, 78.80 mmol) was added to a mixture of 6-bromo-4-chloroquinoline-3-carboxamide (7.5 g, 26.27 mmol) and 3-methoxycyclobutan-1-amine hydrochloride (3.98 g, 28.89 mmol) in DMA (35 mL) and the resulting mixture stirred at 100° C. for 18 h. The reaction mixture was diluted with water (250 mL) and the precipitate was collected by filtration, washed with water (50 mL) and dried under vacuum to afford the desired material (6.28 g, 68.3%) as a tan solid, which was used without further purification. NMR Spectrum: 1H NMR (400 MHz, DMSO-d6) δ 2.45-2.55 (2H, m), 2.76-2.88 (2H, m), 3.17 (3H, s), 3.66 (1H, q), 4-4.16 (1H, m), 7.67 (1H, s), 7.80 (1H, dd), 7.93 (1H, dd), 8.15 (1H, s), 8.59 (1H, s), 8.69 (1H, s), 9.34 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=350, 352.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][C:7](=[O:9])[CH2:8][CH:4]2[CH2:3][NH:2]1.[N:10]1([C:15](Cl)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]1.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[N:10]1([C:15]([N:2]2[CH2:3][CH:4]3[CH2:8][C:7](=[O:9])[CH2:6][CH:5]3[CH2:1]2)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C1CC2CNCC2C1
Reactant: O=C(Cl)N1CCCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CC2CN(C(=O)N3CCCC3)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
Hexahydro-cyclopenta[c]pyrrol-5-one triflutate 1f (478 mg, 2 mmol) was dissolved in 20 mL dichloromethane, and pyrrolidine-1-carbonyl chloride (0.276 mL, 2.5 mmol) and triethylamine (0.84 mL, 6 mmol) were then added to the solution in an ice-water bath. Upon completion of the addition, the reaction mixture was stirred overnight at room temperature, 10% citric acid solution was then added to the mixture to adjust to pH 4. The mixture was extracted with dichloromethane (50 mL×3). The combined organic extracts were washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 2-(pyrrolidine-1-carbonyl)-hexahydro-cyclopenta[c]pyrrol-5-one 8a (0.26 g, yield 58.5%) as a colorless oil.