Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C@@H:4]([OH:16])[CH2:5][C:6](=[O:15])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])#[N:2].CO.[BH4-].[Na+]>C1COCC1>[C:1]([CH2:3][C@@H:4]([OH:16])[CH2:5][C@@H:6]([OH:15])[CH2:7][C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])#[N:2]
Reactant: CC(C)(C)OC(=O)CC(=O)C[C@H](O)CC#N
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@H](O)C[C@H](O)CC#N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of tert-butyl (5R)-6-cyano-5-hydroxy-3-oxohexanoate (10 g, 0.044 mol) in THF (60 mL) was stirred under nitrogen and methanol (20 mL) was added. The reaction mixture was stirred for 15 min. and cooled to −50° C. to −55° C. Anhydrous CeCl3 (10.8 g, 0.044 mol) was added and stirred for 30 min., maintaining the temperature between −50 and −55° C. Sodium borohydride (2.5 g, 0.066 mol) was added in 6 portions maintaining the temperature between −70 and −90° C. The resulting mixture was stirred for 1 h at the same temperature. After warming the reaction mixture to room temperature (RT), it was concentrated to a residue under vacuum at about 45° C. Methanol (60 mL) was added and the resulting mixture was concentrated. The resulting residue was cooled to RT, water (50 mL) was added and the resulting aqueous mixture was extracted with ethyl acetate (100 mL×2). The combined organic layer was washed with brine solution (50 mL), and concentrated to obtain the title compound. Yield: 9 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[CH:4][N:3]=1.[OH:16]OS([O-])=O.[K+].C(=O)(O)[O-].[Na+].[OH2:27]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])(=[O:16])=[O:27])=[CH:4][N:3]=1
Reactant: O
Reactant: O=S([O-])OO
Reactant: Fc1ccccc1Sc1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: O=S(=O)(c1ccc(Cl)nc1)c1ccccc1F
Reaction time: 0.25 h
Yield: 86 %

Procedure:
The product from Step 1 (2.0 g, 8.3 mmol) and OXONE® (7.7 g, 12.5 mmol) were stirred in methanol (50 mL) at room temperature for 6 days. Saturated sodium bicarbonate was added and the suspension stirred for 15 minutes before diluting with water and extracting into ethyl acetate (×2). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo while loading onto silica. Dry flash column chromatography using 10–30% ethyl acetate/isohexane gave 2-chloro-5-[(2-fluorophenyl)sulfonyl]pyridine as a white solid (1.95 g, 86%). δH (500 MHz, d6 DMSO): 7.45–7.56 (2H, m), 7.81–7.88 (2H, m), 8.10 (1H, td, J=1.6, 7.6 Hz), 8.37–8.41 (1H, m), 8.98 (1H, d, J=2.6 Hz); m/z (ES+) 272, 274 [MH+].
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:7][C:8]1([CH2:21][NH2:22])[C:13]2[NH:14][C:15]3[C:20]([C:12]=2[CH2:11][CH2:10][O:9]1)=[CH:19][CH:18]=[CH:17][CH:16]=3.C(N(CC)CC)C>O1CCCC1>[CH3:7][C:8]1([CH2:21][NH:22][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[C:13]2[NH:14][C:15]3[C:20]([C:12]=2[CH2:11][CH2:10][O:9]1)=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: CC1(CN)OCCc2c1[nH]c1ccccc21
Reactant: CCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)NCC1(C)OCCc2c1[nH]c1ccccc21
Yield: 94.4 %

Procedure:
Butanoyl chloride (5.3 g) is added to stirring mixture at 0° C. of 1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indole-1-methanamine (10.0 g, described in Example 3), triethylamine (5 g) and dry tetrahydrofuran (400 ml). The temperature is allowed to rise to room temperature, the reaction mixture is filtered, and the filtrate is evaporated to give the title compound (12.5 g): ir(CHCl3) 3420, 3250, 2885 and 1660 cm-1 ; nmr(CDCl3) δ 0.75 (t), 1.57 (s), 1.62 (m), 2.08 (t), 2.87 (m), 3.91 (t), 4.10 (t), 6.12 (s), 7.0-7.7 (m) and 9.86 (s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:30]2[CH:35]=[CH:34][C:33]([CH:36]=O)=[C:32]([F:38])[CH:31]=2)[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:19]=1[CH3:20])=[O:13].[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[C:32]([F:38])[CH:31]=2)[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:19]=1[CH3:20])=[O:13]
Reactant: C1COCCN1
Reactant: CCN(c1cc(-c2ccc(C=O)c(F)c2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)c(F)c2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.5 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3′-fluoro-4′-formyl-4-methyl-[1,1′-biphenyl]-3-carboxamide (285 mg, 0.55 mmol) and morpholine (149 mg, 1.64 mmol) in dichloroethane (5 mL), acetic acid (0.2 mL, 3.29 mmol) was added and reaction stirred at room temperature for 30 minutes. Then sodium triacetoxyborohydride (349 mg, 1.64 mmol) was added to the reaction mixture at 0° C., allowed to attain room temperature and stirring continued for overnight. On completion, reaction mixture was diluted with dichloromethane, washed with water, saturated aqueous sodium bicarbonate solution and dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic and prep. HPLC purification afforded the title compound (70 mg, 20%). LCMS: 591.45 (M+1)+; HPLC: 98.96% (@ 254 nm) (Rt; 4.034; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.5 (bs, 1H), 10.1 (bs, 1H), 8.24 (s, 1H), 7.66-7.73 (m, 3H), 7.54 (s, 1H), 7.36 (s, 1H), 5.88 (s, 1H), 4.44 (s, 2H), 4.30 (m, 5H), 3.96 (m, 2H), 3.66-3.86 (m, 6H), 3.17-3.34 (m, 4H), 2.27 (s, 3H), 2.22 (s, 3H), 2.11 (s, 3H), 1.57-1.67 (m, 4H), 0.84 (t, 3H, J=6 Hz).
Reaction SMILES: [S:1]([O-:4])([O-])=[O:2].[Na+].[Na+].C(O[CH2:11][CH2:12][CH2:13][CH2:14][Cl:15])(=O)C.[ClH:16]>O>[Cl:15][CH2:14][CH2:13][CH2:12][CH2:11][S:1]([Cl:16])(=[O:4])=[O:2]
Reactant: Cl
Reactant: CC(=O)OCCCCCl
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=S(=O)(Cl)CCCCCl
Temperature: 25 °C

Procedure:
Add anhydrous sodium sulfite (16.8 g, 130 mmol) to a solution of 4-chlorobutyl acetate (20.0 g, 133 mmol) in water (50 mL) and reflux the mixture for 20 h. Cool to room temperature and add concentrated HCl (19.0 mL) and reflux for 1 h. Cool the mixture to room temperature, neutralize to about pH=7. Concentrate to about one half the volume, filter away the sodium chloride. Concentrate and dry to give the title compound.
Reaction SMILES: [CH2:1](P(CCCC)CCCC)CCC.[F:14][C:15]([F:52])([F:51])[C:16]1[CH:17]=[C:18]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[CH2:19][N:20]([C:39]1[N:40]=[N:41][NH:42][N:43]=1)[CH:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])[C:23]2[CH:34]=[CH:35][C:36]([Br:38])=[CH:37][C:22]1=2.CO>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:50][C:47]([F:48])([F:49])[C:45]1[CH:44]=[C:18]([CH:17]=[C:16]([C:15]([F:14])([F:51])[F:52])[CH:46]=1)[CH2:19][N:20]([C:39]1[N:40]=[N:41][N:42]([CH3:1])[N:43]=1)[CH:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])[C:23]2[CH:34]=[CH:35][C:36]([Br:38])=[CH:37][C:22]1=2
Reactant: CC(C)OC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)c2cc(Br)ccc21
Reactant: CCCCP(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2cc(Br)ccc21
Temperature: 25 °C

Procedure:
Add tri-n-butylphosphine to a solution of (+/−)-isopropyl 5-[(3,5-bistrifluoromethylbenzyl)-(2H-tetrazol-5-yl)amino]-7-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate, methanol and 1,1′-(azocarbonyl)dipiperidine (ADDP) in toluene at 0° C. under nitrogen and warm to room temperature. Dilute the mixture with ethyl acetate, wash with 2 N HCl and brine and dry over sodium sulfate. Remove the solvents under reduced pressure and purify the residue by flash column chromatography on silica gel to provide the title compound.
Reaction SMILES: Br[CH:2]([C:14](=[O:20])[C:15]1[S:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5].C(#N)C.C[O-].[Na+].[C:27]([OH:35])(=[S:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(O)(=O)C>[C:27]([S:34][CH:2]([C:14](=[O:20])[C:15]1[S:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])(=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: OC(=S)c1ccccc1
Reactant: O=C(c1cccs1)C(Br)CC(=O)N1CCC[C@H]1C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: O=C(SC(CC(=O)N1CCC[C@H]1C(=O)O)C(=O)c1cccs1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
As for Example 1, 1-[3-bromo-3-(2-thenoyl)propionyl]-L-proline (0.0085 mole) in 25 ml. of acetonitrile is added to a mixture of 0.015 mole of sodium methoxide and 0.015 mole of thiobenzoic acid in 25 ml. of acetonitrile. The mixture is stirred at room temperature for 16 hours, one ml. of acetic acid is added and the solvent removed under reduced pressure. The residue is partitioned between dichloromethane and water containing acetic acid. The organic layer is separated, washed with water, dried over magnesium sulfate and the solvent removed under reduced pressure to give the product of the Example as a pale yellow glass.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])[CH:2]=1.CO>[Pd].C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:2]=1
Reactant: O=C(O)C=Cc1cccnc1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: O=C(O)CCc1cccnc1
Reaction time: 8 h
Yield: 100.7 %

Procedure:
A mixture of 3-(pyridin-3-yl)propenoic acid (10.0 g, 67 mmol), 10% palladium-activated carbon (1 g), methanol (100 mL) and ethanol (100 mL) was stirred overnight under hydrogen atmosphere. The resultant reaction mixture was filtered, evaporated, and dried to give 3-(pyridin-3-yl)propionic acid (10.2 g, quantitative).
Reaction SMILES: CN([CH:4]=[O:5])C.[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]2[C:14]([NH2:19])=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:7]=1>O>[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH:19][C:4]2=[O:5])[CH:7]=1
Reactant: Nc1ccccc1Nc1cccnc1
Reactant: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2ccccc2n1-c1cccnc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N,N′-Carbonyldiimidazole (0.57 g) was added to a DMF solution (5 ml) of N-pyridine-3-ylbenzene-1,2-diamine (0.5 g). The mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture and the precipitated insoluble matter was separated, washed with water, and dried to give the title compound (0.5 g) as a pale whitish purple powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[C:6]([C:7]([OH:9])=O)[CH:5]=1.Cl.[CH3:18][N:19](C)[CH2:20][CH2:21][CH2:22]N=C=NCC.ON1C2C=CC=CC=2N=N1.C(NC)CC.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:12]=[C:11]([NH2:13])[CH:10]=[C:6]([C:7]([N:19]([CH3:18])[CH2:20][CH2:21][CH3:22])=[O:9])[CH:5]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Agent: CCCNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCN(C)C(=O)c1cc(N)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Mix 5-nitro-isophthalic acid monomethylester (3.0 g, 13.32 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.20 g, 16.65 mmol), and 1-hydroxybenzotriazole (2.25 g, 16.65 mmol) in dichloromethane (100 mL) at room temperature for 20 min. Add propylmethylamine (1.46 g, 16.65 mmol) and triethylamine (3.36 g, 33.3 mmol). Stir at room temperature for 1 h, dilute with ethyl acetate, wash with 10% aqueous potassium carbonate, 1 N citric acid, saturated aqueous sodium chloride and concentrate. Dissolve in ethanol (100 mL), add a slurry of 10% Pd/C (300 mg) in ethanol (10 mL) and place under a hydrogen atmosphere using a balloon and stir overnight. Flush with nitrogen, filter and concentrate to give the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:27])[F:28])=[CH:21][CH:20]=4)[CH2:16][NH:15][CH2:14]3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cccc(-c2noc(C3CNCC(c4ccc(OC(F)(F)F)cc4)C3)n2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
425 mg (0.84 mmol) of the compound from Example 177A were initially charged in 55 ml of dichloromethane and, at RT, reacted with 0.65 ml (955 mg, 8.37 mmol) of trifluoroacetic acid. The reaction mixture was stirred at RT for 20 h and then concentrated under reduced pressure. The residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. Yield: 340 mg (80% of theory, 80% pure)
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]([C:15]([O:17]CC(Cl)(Cl)Cl)=O)C(OC(Cl)(Cl)Cl)=O)=[CH:5][CH:4]=[N:3]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:31]=[C:32]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[S:33][CH:34]=2)=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:31]=[C:32]([N:35]3[CH2:36][CH2:37][N:38]([C:15]([NH:7][C:6]4[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=4)=[O:17])[CH2:39][CH2:40]3)[S:33][CH:34]=2)=[CH:26][CH:25]=1
Reactant: Cn1nccc1N(C(=O)OCC(Cl)(Cl)Cl)C(=O)OC(Cl)(Cl)Cl
Reactant: Fc1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cn1nccc1NC(=O)N1CCN(c2nc(-c3ccc(F)cc3)cs2)CC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 39.5 %

Procedure:
A mixture of trichloromethyl 2,2,2-trichloroethyl (1-methyl-1H-pyrazol-5-yl)imidodicarbonate (255 mg, 0.570 mmol), 4-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]piperazine (300 mg, 1.14 mmol) and diisopropylethylamine (0.198 ml, 1.14 mmol) in dimethyl sulfoxide (3.8 ml) was stirred at 70° C. for 18 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over magnesium sulfate anhydrous, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 87.1 mg (39.6%) of the desired product as a solid.
Reaction SMILES: [C:1]([C:4]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][C:7]([O:8][CH2:9][C:10]2([NH:13][C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:12][CH2:11]2)=[C:6]([O:29][CH3:30])[CH:5]=1)(=[O:3])[CH3:2].CO[CH:33](OC)[N:34]([CH3:36])[CH3:35]>CN(C=O)C.O>[CH3:33][N:34]([CH3:36])[CH:35]=[CH:2][C:1]([C:4]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][C:7]([O:8][CH2:9][C:10]2([NH:13][C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:12][CH2:11]2)=[C:6]([O:29][CH3:30])[CH:5]=1)=[O:3]
Reactant: COc1cc(C(C)=O)c([N+](=O)[O-])cc1OCC1(NC(=O)OCc2ccccc2)CC1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)C=CN(C)C)c([N+](=O)[O-])cc1OCC1(NC(=O)OCc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
A mixture of the compound of Example 2 (1.7 g, 4.1 mmol) and N,N-dimethylformamide dimethylacetal (0.9 g, 8.2 mmol) in DMF (6 mL) was stirred at 100° C. for 2 h. After cooling at room temperature, the reaction mixture was diluted with water (30 mL) and extracted with AcOEt (3×50 mL). The combined organic phases were washed with brine (2×50 mL), dried and evaporated to give 1-[(4-(3-dimethylaminopropenoyl)-2-methoxy-5-nitrophenoxy)methyl]-N-benzyloxycarbonyl-1-aminocyclopropane (1.9 g, yield: 95%) as a yellow solid.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:9]([OH:14])[C:10]([O:12][CH3:13])=[O:11])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].CS([C:37]1[N:42]=[C:41]([O:43][CH3:44])[CH:40]=[C:39]([CH3:45])[N:38]=1)(=O)=O>CN(C=O)C.O>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:9]([O:14][C:37]1[N:42]=[C:41]([O:43][CH3:44])[CH:40]=[C:39]([CH3:45])[N:38]=1)[C:10]([O:12][CH3:13])=[O:11])(=[O:3])[CH3:2]
Reactant: COc1cc(C)nc(S(C)(=O)=O)n1
Reactant: COC(=O)C(O)C(OCCOC(C)=O)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Oc1nc(C)cc(OC)n1)C(OCCOC(C)=O)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
4 g (11.1 mmol) of methyl 3-(2-acetoxyethoxy)-2-hydroxy-3,3-di-phenylpropionate were dissolved in 20 ml of DMF under N2, 770 mg (5.6 mmol) of K2CO3 and 2.24 g (11.1 mmol) of 2-methanesulfonyl-4-methoxy-6-methylpyrimidine were added, and the mixture was stirred at 80° C. for 2 h. It was subsequently diluted with 20 ml of H2O and extracted twice with 30 ml of diethyl ether, the organic phase was dried over MgSO4 and concentrated, and the residue was purified by chromatography on silica gel with ethyl acetate/cyclohexane mixtures. 4.8 g (90%) of a colorless oil were obtained.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.B([O-])([O-])O[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.C(=O)([O-])O.[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[N:18]1[CH:19]=[CH:20][C:15]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: [O-]B([O-])Oc1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1ccc(-c2ccncc2)cc1
Reaction time: 3 h
Yield: 56.3 %

Procedure:
To a mixture of ethyl 4-bromobenzoate (2.29 g), 4-pyridyl borate (1.23 g), 1 M sodium hydrogen carbonate solution (30 ml) and 1,2-dimethoxyethane (40 ml) was added tetrakis(triphenylphosphine)palladium (0.3 g) and the mixture was stirred for 3 hours with reflux under nitrogen atmosphere. To the mixture was added water and the solution was extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography, and eluted with hexane-ethyl acetate (2:1) to give the title compound as crystals (1.15 g, 50.7%).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[CH2:18][CH:17]([CH2:19][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:22][CH2:21]3)[C:15](=[O:16])[C:10]2=[CH:11][C:12]=1[O:13][CH3:14]>C(OCC)(=O)C>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[CH2:18][CH:17]([CH2:19][CH:20]3[CH2:21][CH2:22][N:23]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:24][CH2:25]3)[C:15](=[O:16])[C:10]2=[CH:11][C:12]=1[O:13][CH3:14].[N+:1]([O-:4])([O-:3])=[O:2]
Reactant: O=[N+]([O-])O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCOC(C)=O
Product: O=[N+]([O-])[O-]
Temperature: 25 °C

Procedure:
Nitric acid (0.45 ml, dissolved in 35 ml of 2-propanol) is slowly added to a solution of Donepezil (3.79 g) in ethyl acetate (70 ml) with stirring at room temperature. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound. Melting point: 213.7° C.
Reaction SMILES: O1CCO[CH:2]1[C:6]1[O:10][C:9]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:16]([NH:21][CH3:22])=[CH:17][N+:18]([O-:20])=[O:19])=[CH:8][CH:7]=1.Cl.[CH3:24][NH:25][CH3:26].Cl.CNC.[BH4-].[Na+]>O.C(O)(=O)C>[CH3:24][N:25]([CH2:2][C:6]1[O:10][C:9]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:16]([NH:21][CH3:22])=[CH:17][N+:18]([O-:20])=[O:19])=[CH:8][CH:7]=1)[CH3:26]
Reactant: CNC
Reactant: CNC(=C[N+](=O)[O-])NCCSCc1ccc(C2OCCO2)o1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.3 %

Procedure:
To a solution of N-[2-[[5-(1,3-dioxolan-2-yl)-2-furanylmethyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine (2.21 g) and dimethylamine hydrochloride (20 g) in water (5 ml) was added 2 N hydrochloric acid (5 ml). After 10 min, dimethylamine (33% in ethanol) (2 ml) was added, the solution cooled to 18° and sodium borohydride (1 g) added portionwise. The suspension was acidified with acetic acid (2.5 ml) and after 15 mins was heated at 60° for 15 mins. The suspension was evaporated to low bulk and an excess of anhydrous sodium carbonate and tetrahydrofuran (100 ml) added. The suspension was refluxed for 2 hours and after 2 hours at room temperature was filtered and the filtrate evaporated in vacuo. The oily residue was chromatographed (silica/methanol) and the appropriate eluate evaporated in vacuo to give the title compound (0.45 g) which was crystallised from methyl isobutyl ketone, m.p. 64°-67° .
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][C@H:4]([CH3:8])[NH:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:42][C:43]1[CH:51]=[CH:50][C:46]([C:47](O)=[O:48])=[CH:45][N:44]=1>CN(C=O)C>[NH2:42][C:43]1[N:44]=[CH:45][C:46]([C:47]([N:3]2[C@@H:4]([CH3:8])[CH2:5][O:6][CH2:7][C@@H:2]2[CH3:1])=[O:48])=[CH:50][CH:51]=1
Reactant: C[C@H]1COC[C@H](C)N1
Reactant: Nc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1COC[C@H](C)N1C(=O)c1ccc(N)nc1
Reaction time: 18 h
Yield: 34 %

Procedure:
To a solution of (3S,5S)-3,5-dimethylmorpholine (115 mg, 1.0 mmol) in DMF (2 mL) was added HATU (380 mg, 1.0 mmol), DIPEA (260 mg, 2.0 mmol), and 6-aminonicotinic acid (138 mg, 1.0 mmol) at room temperature. After stirring for 18 h, the reaction mixture was filtered and purified with Combiflash (A: 1% NH4HCO3/water, B: acetonitrile) to afford 324a (80 mg, 34%) as a yellow solid. MS (ESI): 236.1 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[I-:10].[K+].II.[CH3:14][N:15]1[CH2:20][CH2:19][CH2:18][N:17]=[C:16]1[SH:21]>CO.O>[IH:10].[CH3:14][N:15]1[CH2:20][CH2:19][CH2:18][N:17]=[C:16]1[S:21][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CN1CCCN=C1S
Reactant: [I-]
Agent: II
Agent: [K+]
Solvent: CO
Solvent: O
Product: CN1CCCN=C1Sc1c[nH]c2ccccc12
Product: I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 11.7 g of indole in 100 ml of methanol is added portionwise to a stirred solution of 50 g potassium iodide and 25.4 g of iodine in 150 ml of water at room temperature. This mixture is further treated with a solution of 13 g of 1-methyl-1,4,5,6-tetrahydro-2-pyrimidinethiol in 150 ml of methanol. The reaction mixture is then stirred at room temperature for 2 hours, filtered and the filtrate concentrated to one-fourth of the original volume and cooled. A crystalline precipitate is formed. This is filtered and recrystallised from a mixture of methanol, ethyl acetate and ether to yield 3-(1-methyl-1,4,5,6-tetrahydro-2-pyrimidinylthio)-indole hydriodide which melts at 207°.