Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.Br[C:7]1[CH:16]=[N:15][C:10]2[O:11][CH2:12][CH2:13][NH:14][C:9]=2[CH:8]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O>[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:7]1[CH:16]=[N:15][C:10]2[O:11][CH2:12][CH2:13][NH:14][C:9]=2[CH:8]=1
Reactant: Brc1cnc2c(c1)NCCO2
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)c1ccccc1-c1cnc2c(c1)NCCO2
Reaction time: 2 h
Yield: 64.6 %

Procedure:
To 3 ml of tetrahydrofuran/0.5 ml of distilled water, 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (80.0 mg, 0.37 mmol), 2-trifluoromethyl-phenyl boronic acid (78 mg, 0.41 mmol), potassium carbonate (103 mg, 0.74 mmol) and tetrakis triphenylphosphine palladium (21 mg, 0.02 mmol) were added and then stirred at 800 for 2 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on amine silica eluting with a solvent of dichloromethane:methanol=50:1. The fractions containing the product were collected and evaporated to obtain 7-(2-trifluoromethyl-phenyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine as white solid (67 mg, 64%).
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]3[C:21]([NH2:22])=[CH:20][N:19]([C:23]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:16]3=[N:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].C[Al](C)C.CCCCCCC.[Si:53]([O:60][CH2:61][CH2:62][CH:63]1[C:71]2[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=2)[C:65](=O)[O:64]1)([C:56]([CH3:59])([CH3:58])[CH3:57])([CH3:55])[CH3:54].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1.C(Cl)Cl.O>[Si:53]([O:60][CH2:61][CH2:62][CH:63]1[C:71]2[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=2)[C:65](=[O:64])[N:22]1[C:21]1[C:15]2[C:16](=[N:17][CH:18]=[C:13]([C:10]3[CH:9]=[CH:8][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[CH:12][CH:11]=3)[N:14]=2)[N:19]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=1)([C:56]([CH3:59])([CH3:58])[CH3:57])([CH3:55])[CH3:54]
Reactant: CC(C)(C)[Si](C)(C)OCCC1OC(=O)c2ccccc21
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc3c(n2)c(N)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: C[Al](C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc3c(n2)c(N2C(=O)c4ccccc4C2CCO[Si](C)(C)C(C)(C)C)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 66 %

Procedure:
2-(4-isopropylsulfonylphenyl)-5-trityl-pyrrolo[2,3-b]pyrazin-7-amine (125 mg, 0.2237 mmol) dissolved in PhMe (3 mL) under N2. AlMe3 in heptane (671.1 μL of 1.0 M, 0.6711 mmol) added at RT and the mixture stirred for 30 mins. A solution of 3-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3H-isobenzofuran-1-one (130.8 mg, 0.4474 mmol) in DCM (3 mL) added with cooling on an ice bath and the mixture stirred overnight. Reaction mixture re-cooled and water added slowly followed by DCM. After stirring for 30 mins, mixture passed through a phase separator cartridge and filtrate concentrated. Residue taken up in THF (5 mL) and PPh3 (88.02 mg, 0.3356 mmol) then DEAD (42.26 μL, 0.2684 mmol) added at RT under N2. Reaction mixture stirred overnight, then concentrated without heating. Residue partitioned between DCM and brine. Aqueous phase extracted with DCM and combined organics dried and concentrated. Residue taken up in DCM and purified by chromatography (silica, 0-100% EtOAc-petrol gradient elution) to give the title compound as a yellow foam (123 mg, 66% over 2 steps); MS (ES+) 833.3.
Reaction SMILES: [CH2:1]1[C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[CH:7]=[CH:6][CH:5]=[C:4]3[CH2:3][CH:2]1[NH:14]C(=O)C.Cl.[OH-].[Na+]>O1CCOCC1>[CH2:3]1[C:4]2=[C:13]3[C:8](=[CH:7][CH:6]=[CH:5]2)[CH:9]=[CH:10][CH:11]=[C:12]3[CH2:1][CH:2]1[NH2:14]
Reactant: CC(=O)NC1Cc2cccc3cccc(c23)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: NC1Cc2cccc3cccc(c23)C1
Temperature: 100 °C
Yield: 90 %

Procedure:
N-(2,3-Dihydro-1H-phenalen-2-yl)acetamide (0.97 mmol; 0.22 g) is solubilized in 2 cm3 of dioxane and 9 cm3 of 10% HCl are added. The mixture is maintained at 100° C. for 3 h and then at 90° C. overnight. After cooling, 10% NaOH is added until the pH is basic and the amine is extracted with CH2Cl2. The organic phase is dried over MgSO4 and evaporated under reduced pressure. The desired amine is thus isolated without further purification.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([N+:14]([O-:16])=[O:15])[CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][O:23][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[C:5]([N+:14]([O-:16])=[O:15])[CH:6]=[C:7]([O:12][CH3:13])[CH:8]=3)[N:3]=2)=[CH:20][CH:19]=1
Reactant: COc1cc([N+](=O)[O-])c2nc(Cl)ccc2c1
Reactant: OCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])c2nc(OCc3ccc(Cl)cc3)ccc2c1
Temperature: 0 °C
Yield: 84 %

Procedure:
A mixture of 48 g (0.2 mole) of 2-chloro-6-methoxy-8-nitroquinoline, 42.78 g (0.3 mole) of 4-chlorobenzyl alcohol, 27.6 g (0.2 mole) of anhydrous potassium carbonate, and 200 ml N,N-dimethyl formamide was heated under nitrogen at ca. 155°-160° for 18 hr. The mixture was cooled, diluted with ice water, stirred, collected, and washed with water. The crude solid was leached with a little 95% ethanol at 70° and then recrystallized from that solvent. A 84% yield of 2-(4-chlorobenzyloxy)-6-methoxy-8-nitroquinoline resulted; mp 129.5°-133.5°.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[C:7]([F:19])=[CH:8][C:9]([Cl:18])=[C:10]([NH:12][S:13]([CH2:16][Cl:17])(=[O:15])=[O:14])[CH:11]=1>C(C(C)=O)C(C)C>[Cl:17][CH2:16][S:13]([NH:12][C:10]1[CH:11]=[C:6]([N:5]=[C:1]=[O:2])[C:7]([F:19])=[CH:8][C:9]=1[Cl:18])(=[O:15])=[O:14]
Reactant: O=C(Cl)Cl
Reactant: Nc1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Solvent: CC(=O)CC(C)C
Product: O=C=Nc1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Temperature: 35 °C

Procedure:
To a stirred solution of 218 g (2.2 mole) of phosgene in 0.6 L of methyl isobutyl ketone at 0° C. was added 546.2 g (2 mol) of N-(5-amino-2-chloro-4-fluorophenyl)-1-chloromethanesulfonamide dissolved in 2 L of methyl isobutyl ketone. During the addition (75 minutes) the temperature was kept between −3° C. and 3° C. The temperature of the solution was raised to 35° C. and 1 L of the solvent was distilled off under reduced pressure (11.0-11.5 kPa (110-115 mbar), maximum temperature: 60° C.). This isocyanate solution was used in the next step without further purification.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:22])[C:7]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH3:20])=[CH:11][C:10](Cl)=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH2:28][CH2:27][S:26][CH2:25][CH2:24]1.CCCCCC>CS(C)=O.C(=O)([O-])[O-].[K+].[K+]>[C:1]([NH:5][C:6](=[O:22])[C:7]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH3:20])=[CH:11][C:10]([N:23]2[CH2:28][CH2:27][S:26][CH2:25][CH2:24]2)=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1C(=O)NC(C)(C)C
Reactant: C1CSCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CCSCC2)ncc1C(=O)NC(C)(C)C
Temperature: 25 °C

Procedure:
N-tert-Butyl-4-(4-fluoro-2-methyl-phenyl)-6-thiomorpholin-4-yl-nicotinamide can be then produced by dissolving N-tert-Butyl-6-chloro-4-(4-fluoro-2-methyl-phenyl)-nicotinamide in dimethylsulfoxide and potassium carbonate, followed by the addition of thiomorpholine. The resulting suspension is stirred, cooled to room temperature, and partitioned between ethyl acetate and half-saturated aqueous sodium chloride solution. The phases are then separated and the organic phase washed with half-saturated aqueous sodium chloride. The aqueous phases are then extracted with ethyl acetate. The combined organic extracts are dried and concentrated in a rotary evaporator to produce a yellow oil. This oil is heated with the dropwise addition of n-hexane to obtain a refluxing suspension, which can be cooled to room temperature and further stirred at 0° C. for about one hour. The precipitate is filtered off, washed with cold n-hexane:ethyl acetate 9:1, and dried in a vacuum oven to yield N-tert-butyl-4-(4-fluoro-2-methyl-phenyl)-6-thiomorpholin-4-yl-nicotinamide as a light beige powder.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]2[NH:6][C:7]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[C:3]=1[N+:20]([O-])=O.[H][H]>CO.[Pd]>[NH2:20][C:3]1[C:4]2[S:9](=[O:11])(=[O:10])[N:8]=[C:7]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:6][C:5]=2[CH:18]=[CH:19][C:2]=1[OH:1]
Reactant: [H][H]
Reactant: CCOC(=O)CC1=NS(=O)(=O)c2c(ccc(O)c2[N+](=O)[O-])N1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC1=NS(=O)(=O)c2c(ccc(O)c2N)N1
Yield: 99.2 %

Procedure:
The product of Example 352D (61 mg, 0.1852 mmol) in methanol (5 mL) was hydrogenated at 1 atmosphere hydrogen pressure (balloon) with 10% palladium on carbon (9 mg, 15 weight %) for 45 minutes. The reaction was filtered through a PTFE membrane filter (0.45 μm) and the catalyst thoroughly washed with warm methanol (50 mL). The filtrate was concentrated under reduced pressure to give the title compound as a beige solid (55 mg, 99%). MS (ESI−) m/z 298 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 1.21 (t, J=7.17 Hz, 3 H) 3.61 (s, 2 H) 4.15 (q, J=6.99 Hz, 2 H) 5.22 (s, 2 H) 6.40 (d, J=8.46 Hz, 1 H) 6.93 (d, J=8.46 Hz, 1 H) 9.82 (s, 1 H) 11.86 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[C:15]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][C:8](=[O:12])[N:9]2[CH3:15])=[CH:4][CH:3]=1
Reactant: CC1(C)CC(=O)Nc2cc(Br)ccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CN1C(=O)CC(C)(C)c2ccc(Br)cc21
Reaction time: 18 h

Procedure:
7-bromo-4,4-dimethyl-3,4-dihydroquinolin-2(1H)-one (210 mg, 0.83 mmol) and K2CO3 (335 mg, 2.42 mmol) were taken up in DMF (5 mL). Iodomethane (0.15 mL, 2.4 mmol) was added and the resulting mixture was stirred for 18 h. Water was added, and the resulting solids were filtered and washed with additional water to provide crude 7-bromo-1,4,4-trimethyl-3,4-dihydroquinolin-2(1H)-one that was used without further purification.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:17][C:16]([SH:18])=[N:15][N:14]=2)=[CH:9][CH:8]=1.[OH-].[K+].[F:21][C:22]([F:29])([F:28])[C:23]([F:27])=[C:24](F)[F:25]>C(Cl)(Cl)Cl>[F:25][C:24]([S:18][C:16]1[S:17][C:13]([C:10]2[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][CH:11]=2)=[N:14][N:15]=1)=[C:23]([F:27])[C:22]([F:29])([F:28])[F:21]
Reactant: Sc1nnc(-c2ccc(Cl)cc2)s1
Reactant: FC(F)=C(F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: FC(Sc1nnc(-c2ccc(Cl)cc2)s1)=C(F)C(F)(F)F
Temperature: 60 °C

Procedure:
60 ml of dimethylformamide and 6.85 g of 5-(4-chlorophenyl)-2-mercapto-1,3,4-thiadiazole and 0.7 g of potassium hydroxide are stirred in an autoclave. 20 g of hexafluoropropylene are pressed in, and the reaction mixture is heated for 19 hours at 60° C. (10-12·105Pa). After cooling and release of pressure, the solution is poured into ice-water, the product is taken up in chloroform, the chloroform solution is washed with 1n sodium hydroxide solution, and the solvent is removed in vacuo, affording as reside the title compound in the form of an crystals with a melting point of 69°-70° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1F)[CH:22]=[O:23]>O.C(OCC)(=O)C>[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]1)[CH:22]=[O:23]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cn(-c2ccc(C=O)cc2F)cn1
Temperature: 90 °C
Reaction time: 6 h
Yield: 17.6 %

Procedure:
4-Methylimidazole (46.4 g) and potassium carbonate (78.0 g) were added to a DMF solution (533 mL) of 3,4-difluorobenzaldehyde (40.0 g) at room temperature. This reaction solution was stirred at 90° C. for 6 hr and then was allowed to cool to room temperature. To the reaction solution, ethyl acetate and water were added. The organic layer was separated, washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: heptane-ethyl acetate system) and further solidified with tert-butylmethylether to give 10.1 g of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [N:1]([CH2:4][C:5]([CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])([CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH3:6])=[N+]=[N-].[H][H]>O1CCCC1.[OH-].[OH-].[Pd+2]>[NH2:1][CH2:4][C:5]([CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH3:6]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOCC(C)(CN=[N+]=[N-])COCCCCCCCCCCCCCCCCCCCCCC
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCCCCCOCC(C)(CN)COCCCCCCCCCCCCCCCCCCCCCC
Yield: 64.7 %

Procedure:
1-Azido-2,2-bis(docosyloxymethyl)propane (12.8 g; 16.8 mmol) and palladium hydroxide on carbon (6.0 g) in tetrahydrofuran (100 ml) was stirred under the hydrogen atmosphere at 50° C. for 3 h. The reaction solution was filtered through celite, and the filtrate was evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography (60 g of gel, chloroform/methanol, 10:1) to obtain the title compound (8 g, 65%) as white powder.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Cl[C:15]1[C:20]([C:21]#[N:22])=[N:19][CH:18]=[CH:17][N:16]=1>O1CCCC1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][C:15]1[C:20]([C:21]#[N:22])=[N:19][CH:18]=[CH:17][N:16]=1
Reactant: N#Cc1nccnc1Cl
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1nccnc1Oc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
12.8 g (80 mmol) of 3-trifluoromethylphenol are added to a suspension of 2.2 g (90 mmol) of sodium hydride in 40 ml of tetrahydrofuran. The reaction mixture is heated to the boil. After 1 hour, a solution of 11.2 g (80 mmol) of 2-chloro-3-cyanopyrazine in 40 ml of tetrahydrofuran is added and the mixture is heated at the boil for a further 4 hours. After the mixture has cooled to room temperature, the solvent is distilled off under reduced pressure. The residue is taken up in diethyl ether and the solution is extracted with 5% strength, aqueous sodium hydroxide solution, washed with distilled water, dried over magnesium sulfate, filtered and freed from the solvent under reduced pressure. The crude product is purified by chromatography (silica gel, cyclohexane/ethyl acetate 20/1 (v/v)). 4.6 g (51%) of a yellow, crystalline solid of melting point 68-70° C. are obtained.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][CH2:6][C:7]#[CH:8])=[O:4].[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C(Cl)Cl>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([CH2:2][C:3]([NH:5][CH2:6][C:7]#[CH:8])=[O:4])[CH2:12][CH2:11]1
Reactant: C#CCNC(=O)CBr
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: C#CCNC(=O)CN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.9 %

Procedure:
To a solution of 2-bromo-N-(prop-2-yn-1-yl)acetamide (0.7 g, 3.98 mmol) in DCM (10 mL) added N-methyl piperazine (0.66 mL, 5.96 mmol) drop wise. Reaction mixture stirred at rt for 16 h, diluted with DCM and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude residue was triturated with ether-pentane, affording the title compound (0.38 g, 49%); LCMS: m/z=196.15 (M+1); 1H NMR (300 MHz, DMSO-d6) δ 8.06 (d, J=6.1 Hz, 1H), 3.86 (dd, J=5.9, 2.5 Hz, 2H), 3.07 (t, J=2.5 Hz, 1H), 2.91 (s, 2H), 2.47-2.25 (m, 8H), 2.15 (s, 3H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([O-:20])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].[Li+].Br[CH2:33][CH2:34][N:35]([CH3:37])[CH3:36].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([O:20][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)[O-])cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: CN(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)OCCN(C)C)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 5 %

Procedure:
To a solution of lithium 4-((2S,4R)-1-acetyl-4-((isopropoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (for a preparation see Intermediate 20) (246 mg, 0.591 mmol) and 2-bromo-N,N-dimethylethanamine (135 mg, 0.886 mmol) in DMF (5 mL) was added potassium carbonate (122 mg, 0.886 mmol). The resulting mixture was stirred at room temperature for 2 h, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in a 1:1 MeOH/DMSO mixture and purified by MDAP (formate). The appropriate fractions were combined and concentrated in vacuo to give 2-(dimethylamino)ethyl 4-((2S,4R)-1-acetyl-4-((isopropoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (14.5 mg, 5%) as a viscous colourless oil. LCMS (Formate, 2 min), Rt=0.72 min, MH+=482.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[NH:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])([O-])=O>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CCNc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CCNc1c(N)cccc1N
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.5 %

Procedure:
Under hydrogen gas atmosphere, a mixture of ethyl N-(2,6-dinitrophenyl)-beta-alaninate (Reference Example 24; 1.39 g, 4.92 mmol), 10% palladium on carbon (50% wet, 280 mg) and tetrahydrofuran (50 mL) was stirred at room temperature for 6 hr. The reaction mixture was filtered and concentrated in vacuo to give the title compound as an oil (1.00 g, 4.50 mmol, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[S:20][C:21]([C:24]([O:26]C)=[O:25])=[CH:22][N:23]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[S:20][C:21]([C:24]([OH:26])=[O:25])=[CH:22][N:23]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1cnc(NC(=O)c2nnn(Cc3ccc(Cl)c(Cl)c3)c2C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(=O)Nc2ncc(C(=O)O)s2)nnn1Cc1ccc(Cl)c(Cl)c1
Yield: 83.2 %

Procedure:
A mixture of methyl 2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-1,3-thiazole-5-carboxylate (Example 4) (0.403 g, 0.95 mmol) and a 1N NaOH solution (10 mL, 9.5 mmol) in EtOH was stirred at reflux for 2 hours. The solvent was evaporated and the residue was acidified with a 1N HCl solution. The precipitate formed was filtered and dried to give the title compound as a white solid (326 mg, 83%). LC/MS: m/z 412 (M+H)+. Rt: 2.48 min.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3([N:20]([CH3:21])[CH2:19][CH2:18][N:17]4[C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=[C:16]34)[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:29]1[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30]1>>[OH:34][CH:31]1[CH2:32][CH2:33][N:29]([C:2]2[C:7]([C:8]([N:10]3[CH2:11][CH2:12][C:13]4([N:20]([CH3:21])[CH2:19][CH2:18][N:17]5[C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=[C:16]45)[CH2:14][CH2:15]3)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:30]1
Reactant: CN1CCn2c(C(F)(F)F)ccc2C12CCN(C(=O)c1cccnc1Cl)CC2
Reactant: OC1CCNC1
Product: CN1CCn2c(C(F)(F)F)ccc2C12CCN(C(=O)c1cccnc1N1CCC(O)C1)CC2
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of (2-Chloro-3-pyridyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone (0.1 mol) and pyrrolidin-3-ol (0.3 mmol) DMF (0.5 mL) was stirred at 80° C. for 16 h. Additional pyrrolidin-3-ol (0.5 mmol) was added and the mixture was stirred at 150° C. for 16 h. The mixture was filtered and was subjected to preparatory-HPLC (10-90% ACN in water) to give (2-(3-hydroxypyrrolidin-1-yl)pyridin-3-yl)(2′-methyl-6′-(trifluoromethyl)-3′,4′-dihydro-2′H-spiro[piperidine-4,1′-pyrrolo[1,2-a]pyrazine]-1-yl)methanone. ESI-MS m/z calc. 463.5, found 464.3 (M+1)+; Retention time: 0.75 minutes (3 min run).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:20]([OH:22])=O)[CH2:3]1.Cl.[CH3:24][N:25]([CH2:39][C@H:40]1[CH2:44][CH2:43][NH:42][CH2:41]1)[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1)=[O:27].C(N(C(C)C)CC)(C)C.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[O:8])[C@H:4]([C:20]([N:42]2[CH2:43][CH2:44][C@H:40]([CH2:39][N:25]([CH3:24])[C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])[CH2:41]2)=[O:22])[CH2:3]1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CN(C[C@H]1CCNC1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C[C@H]1CCN(C(=O)[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 99.1 %

Procedure:
To a solution of (2S,4R)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)proline (4.65 g) in anhydrous dimethylformamide (60 ml), (3S)-3-[N-methyl-N-(4-nitrobenzyloxycarbonyl)aminomethyl]pyrrolidine hydrochloride (4.95 g), diisopropylethylamine (5.23 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.03 g) and 1-hydroxybenzotriazole (2.23 g) were added. The resulting mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated by evaporation under reduced pressure. The residue was dissolved in ethyl acetate. The resulting solution was washed with water and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was subjected to chromatography through a silica gel column. From the fractions eluted with ethyl acetate/methanol=9/1, (2S,4R)-4-hydroxy-2-[(3S)-3-[N-methyl-N-(4-nitrobenzyloxycarbonyl)aminomethyl]pyrrolidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (8.70 g) was obtained as a powder.