Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([F:35])[CH:34]=1)[CH2:5][C@H:6]([NH:24]C(=O)OC(C)(C)C)[C@H:7]([OH:23])[CH2:8][NH:9][CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH3:21])[CH:18]=2)[N:13]([CH3:22])[CH2:12][CH2:11]1.Cl>CO.CCOCC>[NH2:24][C@@H:6]([CH2:5][C:4]1[CH:3]=[C:2]([F:1])[CH:34]=[C:33]([F:35])[CH:32]=1)[C@H:7]([OH:23])[CH2:8][NH:9][CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH3:21])[CH:18]=2)[N:13]([CH3:22])[CH2:12][CH2:11]1
Reactant: CCc1ccc2c(c1)C(NC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C)CCN2C
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CCc1ccc2c(c1)C(NC[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1)CCN2C
Temperature: 25 °C
Yield: 78 %

Procedure:
To a solution of tert-butyl (1S,2R)-1-(3,5-difluorobenzyl)-3-[(6-ethyl-1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino]-2-hydroxypropylcarbamate (0.412 g) in MeOH (5 mL) was added 2N HCl in Et2O (2.1 mL). The mixture was stirred at room temperature for fifteen minutes. The mixture was stripped of solvent under reduced pressure. The residue was partitioned between dichloromethane and aqueous sodium bicarbonate, and the organic was extracted three times, washed with brine, dried with sodium sulfate, filtered, and concentrated. A silica gel column was run for purification using 5% MeOH in dichloromethane with as the solvent solution. 0.255 g of the title product were recovered. (78% yield). MS (ESI+) for C22H29F2N3O m/z 390.18 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:28]=[CH:27][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([CH2:25][NH2:26])[CH:22]=[CH:23][CH:24]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.CN1C[CH2:39][CH2:38][C:37]1=[O:41]>ClCCl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=2)[CH2:25][NH:26][C:37](=[O:41])[CH2:38][CH3:39])=[CH:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Reactant: CN1CCCC1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)NCc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Yield: 58 %

Procedure:
N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)propionamide was prepared from (3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine and pyridine instead of N, N-diethylethanamine, 1-methylpyrrolidin-2-one, dichloromethane using Method G (58% yield). HPLC: 97%, RT=4.034 min. MS: m/z=425 [M+H]+, RT=3.34 min.
Reaction SMILES: [CH2:1]([C:3]([OH:5])=[O:4])[CH3:2].C([N:13]1[CH:18]2[CH2:19][CH2:20][CH:14]1[CH2:15][CH:16]([NH:21][S:22]([C:25]1[CH:34]=[CH:33][C:32]3[NH:31][C:30](=[O:35])[C:29]4[NH:36][CH:37]=[CH:38][C:28]=4[C:27]=3[CH:26]=1)(=[O:24])=[O:23])[CH2:17]2)C1C=CC=CC=1>C(O)C.[Pd]>[CH:14]12[NH:13][CH:18]([CH2:19][CH2:20]1)[CH2:17][CH:16]([NH:21][S:22]([C:25]1[CH:34]=[CH:33][C:32]3[NH:31][C:30](=[O:35])[C:29]4[NH:36][CH:37]=[CH:38][C:28]=4[C:27]=3[CH:26]=1)(=[O:23])=[O:24])[CH2:15]2.[CH2:1]([C:3]([O-:5])=[O:4])[CH3:2]
Reactant: O=c1[nH]c2ccc(S(=O)(=O)NC3CC4CCC(C3)N4Cc3ccccc3)cc2c2cc[nH]c12
Reactant: CCC(=O)O
Agent: [Pd]
Solvent: CCO
Product: CCC(=O)[O-]
Product: O=c1[nH]c2ccc(S(=O)(=O)NC3CC4CCC(C3)N4)cc2c2cc[nH]c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.1 %

Procedure:
4 mg of activated Pd 10% on charcoal is added to a solution of 75 mg (0.14 mmol) of 8-(8-benzyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline 1-ethyl carboxylate dissolved in 15 mL of ethanol. The solution is stirred under a hydrogen atmosphere at room temperature for 18 hours then filtered on celite. The filtrate is evaporated and the residue is purified by chromatography on silica (eluent dichloromethane/methanol/ammonia 200/25/4) to give 20 mg (32%) of 8-(8-aza-bicyclo[3.2.1]oct-3-ylsulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a brown solid.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[N:33][O:34][CH3:35])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:26]=1.CN(C)C=O.Cl>C(N(CC)CC)C.C(Cl)Cl>[C:1]([NH:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[N:33][O:34][CH3:35])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:26]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=NOC)c1csc(N)n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=NOC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
15.1 g of trityl chloride were added over 20 minutes to a cooled mixture of 11.45 g of the product of Step A, 23 ml of dry dimethylformamide, 45 ml of dry methylene chloride and 7 ml of triethylamine and 50 ml of hydrochloric acid were added thereto with stirring. The mixture was decanted and the aqueous phase was extracted with methylene chloride. The organic extracts were washed with water, reextracted, dried and vacuum filtered. The filtrate was evaporated to dryness to obtain 30.1 g of raw anti isomer of ethyl 2-(2-tritylamino-4-thiazolyl)-2-methoxyimino-acetate.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@@H:10]([NH:21][C@H:22]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])[C:11]([NH:13][C:14]3C=CC=CC=3O)=[O:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[C:31](N1C=CN=C1)(N1C=CN=C1)=S.[NH2+]1C2C=CC=CC=2N=N1.CNC>ClCCl.O1CCCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([NH:21][C@H:22]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][CH:24]([CH3:25])[CH3:26])[C:11]([N:13]([CH3:14])[CH3:31])=[O:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)[C@H](CC(C)C)N[C@@H](C(=O)Nc1ccccc1O)c1ccc2occc2c1
Agent: CNC
Agent: c1ccc2c(c1)N=N[NH2+]2
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@H](CC(C)C)NC(C(=O)N(C)C)c1ccc2occc2c1
Reaction time: 18 h
Yield: 40.5 %

Procedure:
A solution of methyl N-{(1R)-1-(benzofuran-5-yl)-2-[(2-hydroxyphenyl)amino]-2-oxoethyl}-L-leucinate (410 mg) and 1,1′-thiocarbonyldiimidazole (196 mg) in dichloromethane (5 ml) was left to stand for 18 hours. Water (20□1) was added to the reaction mixture and this was then stirred rapidly for 30 minutes. After this, 1H-Benzotriazolium, 1-[bis(dimethylamino)methylene]-, tetrafluoroborate(1-), 3-oxide (TBTU, 710 mg) and a solution of dimethylamine in tetrahydrofuran (3 ml of 2M solution) were added. The reaction mixture was stirred for a further 18 hours and was then passed down an SPE (5 g, silica) eluting with a gradient (3:1 to 1:2 cyclohexane: ethyl acetate). The required fractions were combined and evaporated to furnish methyl N-[1-(benzofuran-5-yl)-2-(dimethylamino)-2-oxoethyl]-L-leucinate (140 mg).
Reaction SMILES: CO.[CH3:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.[F:12][C:13]([F:24])([F:23])[C:14]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)=[O:15].[BH3-]C#N.[Na+]>CO.C(O)(=O)C.C(O)(=O)C>[CH3:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH:9][CH:19]2[CH2:20][CH2:21][N:16]([C:14](=[O:15])[C:13]([F:12])([F:23])[F:24])[CH2:17][CH2:18]2)=[CH:6][CH:5]=1
Reactant: Cc1ccc(CN)cc1
Reactant: O=C1CCN(C(=O)C(F)(F)F)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(CNC2CCN(C(=O)C(F)(F)F)CC2)cc1

Procedure:
Methanol (150 ml) was added to an Erlenmeyer flask and acetic acid was added under stirring until pH 5. 4-Methylbenzylamine (3.14 g, 25.9 mmol) and N-trifluoroacetyl-4-piperidone (from reaction step 1) (5.065 g, 25.9 mmol) were added to a 250 ml round-bottomed flask and dissolved in the methanol/acetic acid (150 ml) solution previously made. The reaction mixture was stirred for 5 min and NaCNBH3 (2.46 g, 38.9 mmol) was added slowly under stirring. After 20 hours the reaction was concentrated and transferred to a reparatory funnel containing dichloromethane and distilled water. The aqueous phase was made basic by addition of Na2CO3. The aqueous phase was extracted twice with dichloromethane. The combined organic layers were collected and dried with Na2SO4. Concentration afforded, 4-(4-methylbenzylamine)-1-(trifluoroacetyl) piperidine. UV/MS 60/53 (M+ 301), tr (A, MS) 3.267.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:10])=[CH2:9])[N:3]=1.[Cl:11]N1C(=O)CCC1=O.C1C=CC=CC=1>CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH2:10][Cl:11])=[CH2:9])[N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: C=C(C)c1cccc(Cl)n1
Solvent: c1ccccc1
Solvent: CCCCCC
Product: C=C(CCl)c1cccc(Cl)n1
Temperature: 80 °C
Reaction time: 5 h
Yield: 56.5 %

Procedure:
A mixture of 29.8 g of 2-chloro-6-isopropenylpyridine, 29.8 g of N-chlorosuccinimide and 60 ml of benzene was stirred at 80° C. for 5 hours. After the reaction mixture was cooled to room temperature, 200 ml of n-hexane was added thereto to remove the insoluble matter through filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluted with n-hexane then n-hexane - ethyl acetate 20:1) to obtain 20.6 g of the objective compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([CH2:19][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:27][Si:28]([CH:31](Br)[C:32]#[CH:33])([CH3:30])[CH3:29]>O1CCCC1>[CH2:19]([C:20]([CH3:26])([CH2:33][C:32]#[C:31][Si:28]([CH3:30])([CH3:29])[CH3:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(C)Cc1ccccc1
Reactant: C#CC(Br)[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(CC#C[Si](C)(C)C)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2.2 ml (1.58 gm) of diisopropylamine in 20 ml of dry tetrahydrofuran, was added dropwise a solution of n-butyllithium (9.7 ml, 1.6M) at 0° C. The solution was stirred at 0° C. for 30 min, then cooled to -78° C. A solution of 2.5 gm of ethyl 3-phenyl-2-methylpropionate in 10 ml of dry tetrahydrofuran was added. After 30 min., 3 gm of trimethylsilylpropargyl bromide in 10 ml dry tetrahydrofuran was added. The mixture was warmed up to 0° C. slowly and maintained at 0° C. for 1.75 hours. The reaction mixture was quenched with 5% hydrochloric acid and partitioned between ether and 5% hydrochloric acid. The ethereal layer, washed with brine solution and water was dried and evaporated in an oil. The oil was chromatographed on silica gel (5% ethyl acetate; petroleum ether). This procedure yielded the title compound, IR: 2170, 1738 cm-1.
Reaction SMILES: [CH2:1]1[N:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]2=[N:3][CH2:2]1)=[CH:10][C:9]([S:14][C:15]1[CH:16]=[C:17]([C:21]2([OH:27])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1)=[CH:8][CH:7]=3.[H-].[Na+].[CH3:30]N(C=O)C>IC>[CH3:30][O:27][C:21]1([C:17]2[CH:16]=[C:15]([S:14][C:9]3[CH:10]=[C:11]4[C:6](=[CH:7][CH:8]=3)[N:5]3[CH2:1][CH2:2][N:3]=[C:4]3[CH:13]=[CH:12]4)[CH:20]=[CH:19][CH:18]=2)[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: CN(C)C=O
Reactant: OC1(c2cccc(Sc3ccc4c(c3)C=CC3=NCCN34)c2)CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COC1(c2cccc(Sc3ccc4c(c3)C=CC3=NCCN34)c2)CCOCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2c (42 mg, 0.11 mmol) in DMF was added sodium hydride (5 mg, 0.12 mmol). Iodomethane (one drop) was added, and the mixture was stirred at room temperature for 5 hours. The reaction was quenched with water, extracted with EtOAc, and purified by preparative HPLC to give the desired product, 2d.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]([CH3:19])[CH:12]=1)=[C:5]2C.[C:21](Cl)(=[O:23])[CH3:22].N1C=CC=C[CH:26]=1>>[C:21]([O:1][C:2]1([CH3:26])[CH:10]=[CH:9][C:8]2[C:4]([CH:5]=[C:6]([C:11]3[CH:12]=[C:13]([CH3:19])[C:14]([OH:18])=[C:15]([CH3:17])[CH:16]=3)[N:7]=2)=[CH:3]1)(=[O:23])[CH3:22]
Reactant: c1ccncc1
Reactant: Cc1cc(-c2[nH]c3ccc(O)cc3c2C)cc(C)c1O
Reactant: CC(=O)Cl
Product: CC(=O)OC1(C)C=CC2=NC(c3cc(C)c(O)c(C)c3)=CC2=C1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
0.8 g of 5-hydroxy-2-(4-hydroxy-3,5-dimethylphenyl)-3-methylindole was dissolved in 4 ml of pyridine, and under ice cooling, 0.26 g of acetyl chloride was added. The mixture was stirred at 40° C. for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with water, 2N hydrochloric acid and water, and purified by silica gel column chromatography to give 5-acetyloxy-2-(4-hydroxy-3,5-dimethylphenyl)-5-methylindole.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.Cl.[CH3:11][NH:12][CH3:13].[CH2:14]=O>C(O)(C)C>[CH3:11][N:12]([CH3:14])[CH2:13][C:3]1[C:4]2[C:9](=[N:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: CNC
Reactant: c1cnc2[nH]ccc2c1
Reactant: C=O
Agent: Cl
Solvent: CC(C)O
Product: CN(C)Cc1c[nH]c2ncccc12
Temperature: 20 °C
Reaction time: 12 h

Procedure:
1H-Pyrrolo[2,3-b]pyridine (94, 5.0 g, 42 mmol), dimethylamine hydrochloride (3.8 g, 46 mmol), formaldehyde (1.4 g, 46 mmol) and isopropyl alcohol (220.0 mL) were combined in a pressure tube. The reaction mixture was stirred at 20° C. for 12 hours and then refluxed for 2 hours. The clear solution was evaporated to dryness in vacuo. Water (40 mL) and concentrated hydrochloric acid (4 mL) were added to the residue. The mixture was extracted with ether and then made strongly basic with potassium carbonate. The basified aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel chromatography to give the compound (109, 5.0 g, 68%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]=O)[CH:5]=[C:4]([CH3:10])[N:3]=1.[NH2:11][C:12]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[C:13]=1[C:14]([NH2:16])=[O:15].S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.O>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:16][C:14](=[O:15])[C:13]3[C:12](=[CH:20][C:19]([F:21])=[CH:18][C:17]=3[F:22])[N:11]=2)[CH:5]=[C:4]([CH3:10])[N:3]=1
Reactant: NC(=O)c1c(N)cc(F)cc1F
Reactant: Cc1cc(C=O)cc(C)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(-c2nc3cc(F)cc(F)c3c(=O)[nH]2)cc(C)n1
Temperature: 115 °C
Reaction time: 16 h

Procedure:
To a solution of 2,6-dimethyl-pyridine-4-carbaldehyde (5.0 g, 36.5 mmol) and 2-amino-4,6-difluorobenzamide (6.28 g, 36.5 mmol) in N,N-dimethyl acetamide (80 mL) were added sodium hydrogen sulfite (7.95 g, 43.8 mmol) and p-toluenesulfonic acid (0.7 g, 3.65 mmol). The reaction mixture was stirred at 115° C. for 16 hours under nitrogen. The reaction mixture was cooled to room temperature, diluted with water, the precipitate was collected by filtration, washed with sat. NaHCO3 and brine, and dried in vacuo to give 2-(2,6-dimethylpyridin-4-yl)-5,7-difluoro-3H-quinazolin-4-one as a white solid. Yield: 2.82 g (26.8%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[O:18][C:19]1[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[CH:23][C:20]=1[C:21]#[N:22].[H-].[Na+].CN(C)[CH:40]=[O:41]>>[CH3:12][N:11]1[C:4]2[N:5]([C:6](=[O:8])[N:7]=[C:2]([O:28][CH2:27][C:24]3[CH:25]=[CH:26][C:19]([O:18][C:17]4[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=[C:15]([F:14])[CH:16]=4)=[C:20]([CH:23]=3)[C:21]#[N:22])[CH:3]=2)[CH2:9][CH:10]1[CH3:13].[F:33][C:32]([F:35])([F:34])[C:40]([OH:41])=[O:8]
Reactant: CC1Cn2c(cc(Cl)nc2=O)N1C
Reactant: CN(C)C=O
Reactant: N#Cc1cc(CO)ccc1Oc1cc(F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Product: CC1Cn2c(cc(OCc3ccc(Oc4cc(F)cc(C(F)(F)F)c4)c(C#N)c3)nc2=O)N1C
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (30 mg, 0.15 mmol) and 2-(3-fluoro-5-(trifluoromethyl)phenoxy)-5-(hydroxymethyl)be-nzonitrile (47 mg, 0.15 mmol) in N,N-dimethylformamide (DMF) (1 mL) was added NaH (12 mg, 0.30 mmol). The reaction mixture was stirred at rt for 30 min., then quenched with water. Purification via mass-directed autopreparation afforded the title product with trifluoroacetic acid salt as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([C:12](=[O:15])[CH2:13][CH3:14])[CH:9]=[CH:8][C:5]=1[C:6]#N)([O-:3])=[O:2].[OH2:16].S(=O)(=O)(O)O.[OH-:22].[Na+]>C(O)(=O)C>[N+:1]([C:4]1[CH:11]=[C:10]([C:12](=[O:15])[CH2:13][CH3:14])[CH:9]=[CH:8][C:5]=1[C:6]([OH:22])=[O:16])([O-:3])=[O:2]
Reactant: CCC(=O)c1ccc(C#N)c([N+](=O)[O-])c1
Reactant: O
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
2-nitro-4-propionylbenzonitrile (5g) was suspended in acetic acid (15 ml), then water (5 ml) and concentrated sulfuric acid (5 ml) were added and the mixture was stirred at 110° C. for 6 hours 30 minutes. The reaction solution was gradually cooled down to room temperature, then water and a 5N aqueous sodium hydroxide solution were added, and the mixture was extracted with ethyl acetate. Next, the organic layer was extracted with water and 5N sodium hydroxide aqueous solution, then the obtained aqueous layer was adjusted by 50% sulfuric acid to pH 1. The resulting mixture was extracted with ethyl acetate. The obtained organic layer was concentrated in vacuo. Toluene was added to the concentrated residue which was then concentrated in vacuo to obtain a crude product of the title compound (4.6 g). The compound was used for the next process without purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1([C:28]([OH:30])=O)[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])[CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCCl.CCN(C(C)C)C(C)C.[C:44]1([NH2:50])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1([C:28](=[O:30])[NH:50][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:27])[CH3:25])=[O:20])[CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: C[Si](C)(C)CCOC(=O)N1CCCC(CNC(=O)OCc2ccccc2)(C(=O)O)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: C[Si](C)(C)CCOC(=O)N1CCCC(CNC(=O)OCc2ccccc2)(C(=O)Nc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.1 %

Procedure:
To a solution of 3-((((benzyloxy)carbonyl)amino)methyl)-1-((2-(trimethylsilyl)ethoxy)carbonyl)piperidine-3-carboxylic acid (2462.00 mg; 5.64 mmol; 1.00 eq.) in DCE (4.0 ml) bis(2-oxo-1,3-oxazolidin-3-yl)phosphinic chloride (1435.59 mg; 5.64 mmol; 1.00 eq.) was added. After stirring for 15 mins at RT, DIEA (1.52 ml; 8.46 mmol; 1.50 eq.) and Phenylamine (525.18 mg; 5.64 mmol; 1.00 eq.) were added. The reaction mixture was stirred overnight at RT. The reaction mixture was added 50 ml of DCM, washed with brine, dried and concentrated. The residue was subjected to SNAP column (100 g) for purification, eluted with 20-50% EtOAc in hexane to yield the title compound (2600 mg, yield 90.1%)
Reaction SMILES: [OH-].[K+].C(O)C.[NH2:6][C:7]1[CH:8]=[C:9]([OH:16])[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14].Cl[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>O>[N:21]1[CH:22]=[CH:23][C:18]([O:16][C:9]2[CH:10]=[CH:11][C:12]([N+:13]([O-:15])=[O:14])=[C:7]([CH:8]=2)[NH2:6])=[CH:19][CH:20]=1
Reactant: Nc1cc(O)ccc1[N+](=O)[O-]
Reactant: Clc1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cc(Oc2ccncc2)ccc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
A solution of 0.1 m. of potassium hydroxide in water is added to an ethanol (100 ml.)-water (175 ml.) mixture containing 15.4 g. (0.1 m.) of 3-amino-4-nitrophenol. The mixture is then heated to 50°C. at which point a solution of 0.1 m. of 4-chloropyridine in 75 ml. of ethanol is added dropwise over a 45 minute period. Then the mixture is heated at reflux for 18 hours, cooled and worked up to give a crystalline yellow solid, m.p. 170°-175°C. of 5-(4-pyridyloxy)-2-nitroaniline.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[S:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.[C:11](Cl)(=[O:15])[CH2:12][CH2:13][CH3:14].Cl>N1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[CH3:1][C:2]1([CH3:10])[S:7][C:6](=[O:8])[CH:5]([C:11](=[O:15])[CH2:12][CH2:13][CH3:14])[C:4](=[O:9])[CH2:3]1
Reactant: CC1(C)CC(=O)CC(=O)S1
Reactant: CCCC(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccncc1
Product: CCCC(=O)C1C(=O)CC(C)(C)SC1=O
Yield: 42.3 %

Procedure:
9.6 g (0.07 mol) of zinc chloride are first added to 5 g (0.035 mol) of 6,6-dimethyltetrahydrothiopyran-2,4-dione in 100 ml of pyridine, after which 3.7 g (0.03 mol) of butyryl chloride are added dropwise. When the addition is complete, the mixture is heated to the reflux temperature for 4 hours, and the cooled reaction mixture is poured into 200 ml of semi-concentrated hydrochloric acid, the mixture is extracted several times with dichloromethane, the combined organic phases are dried over magnesium sulphate, and the solvent is removed in vacuo. 2.9 g (36.6% of theory) of 6,6-dimethyl-3-butyryltetrahydrothiopyran-2,4-dione are obtained as an oil.
Reaction SMILES: C1(C)C=CC=CC=1.CCCCCC.C([Li])CCC.[C:19](=[O:21])=[O:20].O.Br[C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][N:25]=1>>[Br:30][C:27]1[CH:28]=[CH:29][C:24]([C:19]([OH:21])=[O:20])=[N:25][CH:26]=1
Reactant: Brc1ccc(Br)nc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCCC
Product: O=C(O)c1ccc(Br)cn1
Temperature: -78 °C
Reaction time: 3 h
Yield: 49.9 %

Procedure:
To a toluene solution (300 ml) at −78° C. in which 2,5-dibromopyridine (4.7 g) was dissolved, n-butyl lithium hexane solution (1.6 M) was added dropwise, followed by stirring at −78° C. for 3 hours. To the reaction mixture, dry ice (ca. 50 g) was added, and followed by further stirring at room temperature for 10 hours. Water (100 ml) was added, and the aqueous layer washed with ethyl acetate (100 ml×2) was neutralized with 5M−HCl aqueous solution under ice cooling, and the resulting precipitate was filtered and dried, to obtain 5-bromo-pyridine-2-carboxylic acid as a colorless powder (2.0 g, 50%). Then, 5-bromo-pyridine-2-carboxylic acid (202 mg), N-methylpiperazine (124 μl), WSCI (230 mg), HOBt (149 mg) and triethylamine (140 μl) were dissolved in acetonitrile (10 ml), followed by stirring at room temperature for 10 hours. To the reaction mixture, water (10 ml) was added, followed by extraction with ethyl acetate (10 ml). The organic layer was washed with saturated aqueous sodium chloride solution, followed by drying over sodium sulfate. After filtering off the sodium sulfate, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by amino silica gel column chromatography (dichloromethane), to obtain (5-bromo-pyridin-2-yl)-(4-methyl-piperazin-1-yl)-methanone as a yellow oil (70 mg, 25%).
Reaction SMILES: B.O1CCCC1.[C:7]([O:11][C:12]([N:14]1[CH2:22][CH2:21][CH:17]([C:18](O)=[O:19])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].O.C([O-])([O-])=O.[K+].[K+]>O1CCCC1>[C:7]([O:11][C:12]([N:14]1[CH2:22][CH2:21][CH:17]([CH2:18][OH:19])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CO)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
Borane-tetrahydrofuran (1M, 25 mL, 25 mmol) was added slowly to N-tert-butoxycarbonylisonipecotic acid (5.73 g, 25 mmol), as prepared in the preceding step, in tetrahydrofuran (50 mL) at 0° C. (ice-bath) over 30 min. The mixture was stirred at 0° C. overnight and then warmed up to room temperature for 6 h. Water (10 mL) was added slowly and then K2CO3 (5 g in 50 mL water) was added. The mixture was extracted with ethyl acetate (3×50 mL). The organic phase was washed sequentially with saturated NaHCO3 (2×50 mL) and brine (2×50 mL), and dried over Na2SO4. The solvent was removed in vacuo, and the residue was purified by flash column chromatography (1:1 hexane/ethyl acetate) to give the title compound as white crystals (4.55 g, 84%). 1H-NMR (300 MHz, CDCl3) δ 1.13 (m, 2H), 1.42 (s, 9H), 1.67 (m, 4H), 2.67 (t, 2H, J=12.5 Hz), 3.46 (d, 2H, J=3.0 Hz), and 4.09 (d, 2H, J=3.6 Hz).