Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.C([O-])([O-])=O.[K+].[K+].[CH2:19]([O:21][C:22](=[O:25])[CH2:23][SH:24])[CH3:20].O>CN(C=O)C>[CH2:19]([O:21][C:22]([C:23]1[S:24][C:2]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=2[CH:4]=1)=[O:25])[CH3:20]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2s1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-chloro-5-nitro-benzaldehyde (31.01 g, 167.1 mmol) in 330 mL of anhydrous DMF at 0° C. was added K2CO3 (27.80 g, 201.1 mmol), followed by slow addition of mercapto-acetic acid ethyl ester (18.5 mL, 168.7 mmol). After stirring at 0° C. for 20 min, the resulting mixture was allowed to warm to rt and stir at rt overnight. The reaction mixture was then poured into 1.5 L of water. The solid formed was filtered and washed with 600 μL of water. After drying, 5-nitro-benzo[b]thiophene-2-carboxylic acid ethyl ester was obtained as pale solid. MS (EI): cal'd 252.0 (MH+), exp 252.1 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]#[C:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([O:20][CH3:21])[CH:12]=2)[CH2:4][CH2:3]1>CCOC(C)=O.CO>[CH3:21][O:20][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:16]=[CH:15][C:14]=1[NH2:17]
Reactant: COc1cc(C#CCN2CCN(C)CC2)ccc1[N+](=O)[O-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(CCCN2CCN(C)CC2)ccc1N
Reaction time: 8 h
Yield: 58.9 %

Procedure:
1-methyl-4-{3-[3-(methyloxy)-4-nitrophenyl]-2-propyn-1-yl}piperazine (0.309 g, 1.07 mmol) was placed in a 40 mL high vial and dissolved in 10 mL of 1 to 1 EtOAc/MeOH. 5 wt % Platinum(sulfided)/carbon (0.291 g, 0.075 mmol) was added followed quickly by a screw cap septum. The vial was evacuated and filled with N2 six times to remove any oxygen. The vial was then pressurized with H2 (balloon). The solution stirred overnight. The next morning the vessel was evacuated and filled with N2 six times to remove any H2. The solution was filtered through celite and evaporated to afford the title compound of step B (0.165 mg, 0.63 mmol, 60%). 1H NMR (400 MHz, CDCl3) δ ppm 6.55-6.64 (m, 3H), 3.83 (s, 3H), 3.56 (bs, 2H), 2.47-2.56 (m, 8H), 2.36-2.41 (m, 2H), 2.31 (s, 3H), 1.75-1.83 (m, 1H), 1.53-1.64 (m, 1H), 0.92 (t, J=7.42 Hz, 2H).
Reaction SMILES: I[C:2]([C:4]1[CH:12]=C[C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1)=[O:3].[C:13](=O)([O-])[O-].[K+].[K+].[I:19][CH3:20].C(OCC)C>CN(C)C=O>[I:19][C:20]1[CH:12]=[C:4]([CH:5]=[C:6]([O:7][CH3:8])[C:9]=1[O:10][CH3:13])[CH:2]=[O:3]
Reactant: O=C([O-])[O-]
Reactant: CI
Reactant: COc1cc(C(=O)I)ccc1O
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(I)c1OC
Temperature: 25 °C
Yield: 90.5 %

Procedure:
To a stirred, cooled (0° C.) solution of iodovanillin (10.0 g, 35.96 mmol.) in dimethylformamide (50 mL) was added anhydrous potassium carbonate (20.0 g, 143.86 mmol.) followed by iodomethane (3.11 mL, 50.0 mmol.). The mixture was allowed to warm to ambient temperature and stir for 14 H. The mixture was poured into diethyl ether (500 mL) and washed with water (3×150 mL). The organic phase was dried over MgSO4 and concentrated under reduced pressure to afford 3-iodo-4,5-dimethoxybenzaldehyde (9.5 g) as a yellow oil which solidified upon standing and was used without further purification.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[F:20][C:21]1[CH:22]=[N:23][C:24]([C:27]([OH:31])([C:29]#[CH:30])[CH3:28])=[N:25][CH:26]=1>>[F:19][C:3]1[C:2]([C:30]#[C:29][C:27]([C:24]2[N:25]=[CH:26][C:21]([F:20])=[CH:22][N:23]=2)([OH:31])[CH3:28])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: C#CC(C)(O)c1ncc(F)cn1
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)c1ncc(F)cn1
Yield: 1 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(5-fluoropyrimidin-2-yl)but-3-yn-2-ol to give the titled compound as a brown solid (3.5 mg, 1%).
Reaction SMILES: Cl[CH:2]([C:7](=O)[CH2:8][CH3:9])[C:3]([O:5][CH3:6])=[O:4].[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:24]=[C:23]([CH3:25])[N:22]=[N:21][C:20]=1[NH2:26].O>CN(C)C=O>[CH3:6][O:5][C:3]([C:2]1[N:21]2[N:22]=[C:23]([CH3:25])[CH:24]=[C:19]([C:13]3[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=3[CH3:11])[C:20]2=[N:26][C:7]=1[CH2:8][CH3:9])=[O:4]
Reactant: Cc1ccc(-c2cc(C)nnc2N)c(C)c1
Reactant: CCC(=O)C(Cl)C(=O)OC
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2c(-c3ccc(C)cc3C)cc(C)nn2c1C(=O)OC
Temperature: 140 °C

Procedure:
Methyl 2-chloro-3-oxopentanoate (7 mL) was added to a solution of the resulting 4-(2,4-dimethylphenyl)-6-methyl-3-pyridazinamine in N,N-dimethylformamide (60 mL), and the mixture was heated at 140° C. for 6 hours. Water was added thereto, which was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and evaporated, to give 8-(2,4-dimethylphenyl)-2-ethyl-6-methylimidazo[1,2-b]pyridazine-3-carboxylic acid methyl ester as a crude product.
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]I.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1>>[I-:1].[I-:1].[CH2:2]([N+:14]1[CH:15]=[CH:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N+:14]1[CH:15]=[CH:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=1
Reactant: c1ccc2cnccc2c1
Reactant: ICCCCCCCCCCI
Product: [I-]
Product: c1ccc2c[n+](CCCCCCCCCC[n+]3ccc4ccccc4c3)ccc2c1
Temperature: 65 °C
Yield: 92 %

Procedure:
1,10-Diiododecane (mmol) was added to a solution (30 mL) of isoquinoline, and the solution heated for 24 hours at 65° C. The resulting precipitate was filtered, and the product washed five times with dry diethyl ether. The resulting yellow solid was isolated in a 92% yield. 1H NMR (300 MHz, DMSO-D6) δ 10.07 (1H, d, C1-H), 8.78 (1H, d, C3-H), 8.58 (1H, d, C8-H), 8.48 (1H, d, C4-H), 8.36 (1H, d, C7-H), 8.26 (1H, t, C5-H), 8.07 (1H, t, C6-H), 4.69 (2H, t, C′1-CH2), 2.0 (2H, m, C′2-CH2), 1.15-1.50 (6H, m, C′3-5-CH2).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C@@H:21](O)[CH2:20]2.N1(O)C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([O:12][C@@H:21]1[CH:22]2[CH2:25][CH2:26][N:19]([CH2:24][CH2:23]2)[CH2:20]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
A mixture of (R)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid (1.00 g, 3.98 mmol), (R)-quinuclidin-3-ol (0.51 g, 3.98 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (0.64 g, 4.78 mmol), and DCC (0.98 g, 4.78 mmol) was stirred at RT overnight. Then THF was removed by vacuum, and the residue was partitioned between EtOAc and 2M K2CO3. The organic phase was dried over Na2SO4, filtered, and evaporated to dryness. The crude was purified by flash chromatography (DCM/MeOH=98/2 to 95/5) to obtain (R)—((R)-quinuclidin-3-yl) 2-(tert-butoxycarbonylamino)-2-phenylacetate (612 mg; 43% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.OO.[OH-].[Na+].C([OH:22])C>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]([NH2:15])=[O:22])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCO
Reactant: N#Cc1ccc(-c2ccc(Cl)cc2)nc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: NC(=O)c1ccc(-c2ccc(Cl)cc2)nc1
Reaction time: 1 h

Procedure:
6-(4-Chlorophenyl)-3-pyridinecarbonitrile (1.61 grams), 30% hydrogen peroxide (3.0 cc.), 6 N sodium hydroxide (0.3 cc.), and about 6 ml ethanol were placed in a reaction vessel and cooled slightly. The reaction temperature rose to about 50° C. and the mixture was stirred for about 1 hour. After the reaction had cooled, a solid precipitate formed and was collected by filtration. As indicated by TLC, pure product was obtained by heating the solid in refluxing acetone, yield 0.4 gram, m.p. 245°-258° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12](/[CH:16]=[CH:17]/[C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=3)[CH2:21]O)=[N:13]2)=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+].CO>ClCCCl>[Cl:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12](/[CH:16]=[CH:17]/[C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=3)[CH2:21][Cl:3])=[N:13]2)=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: ClCc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (3.6 ml., 49.3 mmol) was added rapidly to a stirred solution of 3-[2(E)-(7-chloroquinolin-2-yl)ethenyl]benzyl alcohol (Example 6a part (ii)) (11.7 g, 39.5 mmol) in 1,2-dichloroethane (300 ml) at 50° C. giving an immediate yellow precipitate. The mixture was stirred for 1 hour and cooled to room temperature then the mixture was shaken with saturated sodium bicarbonate solution (400 ml) and methanol (50 ml) to give two clear phases. The aqueous phase was extracted with dichloromethane and the combined solvent phase was dried and evaporated.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[Cl:20])[C:14](Cl)=[O:15].CCN(CC)CC>CC#N>[Cl:10][C:11]1[CH:12]=[C:13]([C:14]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[O:15])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: c1ccc2c(c1)CCN2
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(c1ccc(Cl)c(Cl)c1)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of indoline (2.0 mL, 17.8 mmol) in MeCN (45.0 mL) was added 3,4-dichlorobenzoyl chloride (4.11 g, 19.6 mmol) followed by Et3N (7.5 mL, 53.5 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h and then concentrated in vacuo. The residue was triturated with water and dried under high vacuum to give the title compound (5.2 g, 100%) as a light brown solid. 1H NMR (DMSO-d6) δ 7.89 (d, J=1.1 Hz, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.29 (d, J=7.3 Hz, 1H), 7.19 (m, 1H), 7.06 (t, J=7.2 Hz, 1H), 4.00 (t, J=8.3 Hz, 2H), 3.09 (t, J=8.3 Hz, 2H); MS(ESI+) m/z 292.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[C:5](=[O:16])[N:4]([CH2:17][CH2:18][CH3:19])[C:3]=1[C:20]([OH:22])=O.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.[F:56][C:57]1[CH:58]=[C:59]([CH:62]=[CH:63][CH:64]=1)[CH2:60][NH2:61]>C(Cl)Cl>[F:56][C:57]1[CH:58]=[C:59]([CH:62]=[CH:63][CH:64]=1)[CH2:60][NH:61][C:20]([C:3]1[N:4]([CH2:17][CH2:18][CH3:19])[C:5](=[O:16])[C:6]2[C:11]([C:2]=1[CH3:1])=[CH:10][CH:9]=[C:8]([C:12]([F:13])([F:15])[F:14])[CH:7]=2)=[O:22]
Reactant: NCc1cccc(F)c1
Reactant: CCCn1c(C(=O)O)c(C)c2ccc(C(F)(F)F)cc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCn1c(C(=O)NCc2cccc(F)c2)c(C)c2ccc(C(F)(F)F)cc2c1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 27.3 %

Procedure:
A solution of 360 mg (1.1 mmol) 4-methyl-1-oxo-2-propyl-7-(trifluoromethyl)-1,2-dihydroisoquinoline-3-carboxylic acid in DCM (20 ml) was cooled to 0° C. and 870 mg (2.3 mmol) HATU and 0.8 ml (4.6 mmol) DIPEA were added. After stirring at 0° C. for 10 min, 0.2 ml (1.7 mmol) 3-fluoro-benzylamine was added and the RS was stirred at RT for 1 h. The mixture was then diluted with DCM (40 ml) and the organic layer was separated, washed with a sat. aq. NaHCO3-sol. (25 ml), a sat. aq. NH4Cl-sol. (20 ml), water (20 ml) and brine (20 ml), dried over Na2SO4 and concentrated in vacuo. The residue obtained was purified by CC (acetone/hexan 1:9) to yield 120 mg (0.3 mmol, 25%) N-(3-fluorobenzyl)-4-methyl-1-oxo-2-propyl-7-(trifluoromethyl)-1,2-dihydroisoquinoline-3-carboxamide (example 2). [M+H]+ 421.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C@@H:5]1[CH2:9][C@H:8](Cl)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH3:2].[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[C@@H:5]1[CH2:9][C@@H:8]([N:19]=[N+:20]=[N-:21])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1C[C@@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Reaction time: 64 h

Procedure:
The chloro ester 4a (5.5 g, 19.8 mmol) and NaN3 (5.5 g, 84.6 mmol) were dissolved 200 ml of DMF in a 75° C. oil bath and stirred at this temp. for 64 h, then worked up using method B. This gave 4.5 g (80% crude yield)of an oil, which was used directly in the next step. 1H NMR (CDCl3) δ1.28 (t, 3H), 1.41/1.46 (2s, 9H), 2.17 (m, 1H), 2.32 (m, 1H), 3.52 (m, 1H), 3.70 (dd, 1H), 4.18 (m, 3H), 4.34 (m, 1H). FAB MS; MH+ calc. for C12H21N4O4 =235.1563, found 285.1574.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[C:12]([O:13][CH3:14])=[CH:11][C:10]([N+:15]([O-])=O)=[CH:9][N:8]=2)[CH:6]=1.C(O)C.C(O)(=O)C.[OH-].[Na+]>[Fe].O>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:8]=[CH:9][C:10]([NH2:15])=[CH:11][C:12]=2[O:13][CH3:14])[CH:6]=1
Reactant: COc1cc([N+](=O)[O-])cnc1-n1cnc(Cl)c1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(N)cnc1-n1cnc(Cl)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
Step O (2): Iron powder-325 mesh (2.19 g, 39.3 mmol) was added to a flask charged with a mixture of 2-(4-chloro-1H-imidazol-1-yl)-3-methoxy-5-nitropyridine (5.0 g, 19.64 mmol), absolute ethanol (50 mL), and glacial acetic acid (20 mL). A water-cooled reflux condenser was attached to the flask and the heterogeneous mixture was heated to 100° C. with vigorous stirring for 30 min. The reaction mixture was allowed to cool to rt and was neutralized upon addition to a chilled and vigorously stirred solution of 5 M NaOH. The resulting mixture was poured into a reparatory funnel and extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 6-(4-chloro-1H-imidazol-1-yl)-5-methoxypyridin-3-amine (3.12 g, 71% yield). LC-MS (M+H)+ 225.1. 1H NMR (500 MHz, chloroform-d) δ ppm 8.06 (d, J=1.83 Hz, 1 H) 7.53 (dd, J=13.28, 1.98 Hz, 2 H) 6.70 (d, J=2.44 Hz, 1 H) 3.90 (s, 3 H) 3.86 (br. s., 2 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O.C(O)(=O)C.C([BH3-])#N.[Na+].C1COCC1>C1COCC1.CO>[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][NH:5][CH2:4][C:3]([O:2][CH3:1])=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: COC(=O)CN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)CNCc1cccc(O)c1
Temperature: 25 °C
Yield: 45 %

Procedure:
Glycine methyl ester (500 mg, 4 mmol) and 3-hydroxybenzaldehyde (480 mg, 4 mmol) were dissolved in 5 mL THF/Methanol (1:1). Acetic acid (240 mg, 4 mmol), and 1M sodium cyanoborohydride in THF (4.8 mL, 4.8 mmol) were slowly added into the reaction. The reaction was irradiated in the microwave reactor at 85° C. for 15 minutes, cooled to room temperature and the salts were removed by filtration. The clear solution was concentrated and the residue was purified by reversed phase HPLC (10 to 95% Acetonitrile in H2O:25 minute gradient) to give the title compound as a clear gel. Yield 45%. MS M+H calculated 196.1; found 196.1.
Reaction SMILES: [C:1]1([C@@H:7]2[C:11]([CH3:13])([CH3:12])[O:10][C:9](=[O:14])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:20](Cl)(=[O:24])/[CH:21]=[CH:22]/[CH3:23].C(OCC)(=O)C>O1CCCC1>[C:20]([N:8]1[C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]([CH3:12])([CH3:13])[O:10][C:9]1=[O:14])(=[O:24])/[CH:21]=[CH:22]/[CH3:23]
Reactant: CC1(C)OC(=O)N[C@@H]1c1ccccc1
Reactant: C/C=C/C(=O)Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C/C=C/C(=O)N1C(=O)OC(C)(C)[C@H]1c1ccccc1
Reaction time: 2 h
Yield: 99.3 %

Procedure:
Reaction of the auxiliary (15) (0.416 g, 2.19 mmol) in solution in tetrahydrofuran (10 ml) at -78° C. with butyllithium (1.3M, 1.69 ml, 2.20 mmol) and crotonyl chloride (0.229 ml, 2.40 mmol) for 30 minutes and then at room temperature for 2 hours, with work-up and flash column chromatography using 20% ethyl acetate/40-60 petroleum ether as eluant furnished the title compound (25) as a solid (0.564 g, 100%) ; mp 104° C.; νmax (CDCl3) 1687 and 1769 cm-1 ; [α]D24 (c 1 in CDCl3)=-82.6; (Found: C, 69.60; H, 6.64; N, 5.35. C15H17NO3 requires C, 69.48; H, 6.61; N, 5.40%); δH (CDCl3 ; 200 MHz) 0.99 (3H, s, C(CH3)2), 1.60 (3H, s, C(CH3)2), 1.93 (3H, d, J=5.4, CH3CHCH), 5.13 (1H, s, CHPh), 7.02-7.40 (7H, m, ArCH and CH3 CH=CH); δC (125 MHz; CDCl3) 18.39 (CH3), 23.60 (CH3), 28.81 (CH3), 67.09 (CH), 82.87 (C), 122.14 (CH), 126.08 (CH), 126.19 (CH), 128.71 (CH), 129.08 (CH), 136.61 (C), 147.31 (CH), 153.50 (CO), 165.07 (CO); m/z (CI+, NH3) 260 (M+ +1).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[O:11][CH:12]=[C:13]([CH3:15])[N:14]=1)=S.[N:16]#[C:17][NH2:18].[Pb]>>[C:17]([NH:18][C:3]([NH:2][CH3:1])=[N:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[O:11][CH:12]=[C:13]([CH3:15])[N:14]=1)#[N:16]
Reactant: CNC(=S)NCCCSc1nc(C)co1
Reactant: N#CN
Agent: [Pb]
Product: CNC(=NCCCSc1nc(C)co1)NC#N

Procedure:
Reaction of N-methyl-N'-[3-(4-methyl-2-oxazolyl)thiopropyl]thiourea with lead cyanamide by the procedure of Example 121 gives the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N-:4][C:5](=O)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.B.[Na].C(O)(=O)C.Cl>O1CCCC1.O>[OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1
Reactant: O=C(CCc1ccc([N+](=O)[O-])cc1)[N-]CCO
Agent: B
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(CCCNCCO)cc1
Reaction time: 1 h

Procedure:
50 g of the previously obtained N-(2-hydroxyethyl)-3-(4-nitrophenyl)propionylamide and 31.8 g of sodium boron hydride were suspended in 500 ml of tetrahydrofuran, and 50.5 g of acetic acid was added dropwise thereto under ice cooling conditions. After completion of the addition, the solution was heated under reflux for 2 hours and then ice-cooled again, and 500 ml of water was added dropwise thereto. Afterward, 4N hydrochloric acid was added to the solution so as to adjust its pH to a level of from 5 to 6, and tetrahydrofuran was then distilled off under reduced pressure. Next, 425 ml of 4N hydrochloric acid was added to the resultant aqueous solution, and the solution was stirred at 60°-70° C. for 1 hour and then allowed to stand for cooling, so that the temperature of the solution was returned to room temperature. After washed with chloroform, the aqueous solution was adjusted to a pH of 11 by the use of a 16% aqueous sodium hydroxide solution, and extraction was carried out twice with 500 ml of chloroform. The chloroform extracts were joined and concentrated under reduced pressure, and the resultant residue was crystallized from 900 ml of toluene to obtain 38.6 g of crystalline N-(2-hydroxyethyl)-3-(4-nitrophenyl)propylamine, which had a melting point of from 82.5° to 84.5° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[O-]CC.[Na+].C([O:13][C:14](=O)[C:15]([C:24]#[N:25])=[C:16]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH3:17])C>C(O)C>[CH3:17][C:16]1([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:3]([C:1]#[N:2])[C:4](=[O:5])[NH:6][C:14](=[O:13])[CH:15]1[C:24]#[N:25]
Reactant: CCOC(=O)C(C#N)=C(C)c1cccnc1
Reactant: N#CCC(N)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC1(c2cccnc2)C(C#N)C(=O)NC(=O)C1C#N
Reaction time: 16 h

Procedure:
Cyanoacetamide was stirred with sodium ethoxide in ethanol for 30 minutes. 2-Cyano-3-pyridin-3-yl-but-2-enoic acid ethyl ester was added and allowed to sit for 16 hours. The solution was acidified to pH 4 and partially concentrated under reduced pressure, causing precipitation of product. The product was filtered and allowed to dry. MS (ESI+) for C13H10N4O2 mz 255.2 (M+H)+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2C3CN(C(C4CCCCC4)=O)[CH2:13][C:14](=[O:15])[N:9]3[CH2:8][CH2:7][C:5]=2[CH:6]=1.C1(CCN)C=CC=CC=1.[Cl:33]CC(Cl)=O>>[Cl:33][CH2:13][C:14]([NH:9][CH2:8][CH2:7][C:5]1[CH:4]=[CH:3][CH:2]=[CH:1][CH:6]=1)=[O:15]
Reactant: O=C(C1CCCCC1)N1CC(=O)N2CCc3ccccc3C2C1
Reactant: O=C(Cl)CCl
Agent: NCCc1ccccc1
Product: O=C(CCl)NCCc1ccccc1

Procedure:
KR2002076486 describes a process for preparation of praziquantel by reacting phenylethylamine with chloroacetyl chloride to obtain 2-chloro-N-phenethylacetamide. The compound 2-chloro-N-phenethylacetamide is then reacted with pthalimide to give 2-pthalimido-N-phenethylacetamide, which is then treated with hydrazine monohydrate to give 2-amino-N-phenylethylacetamide. On further treatment with bromoacetal, 2-amino-N-phenylethylacetamide gives 2-[2,2-dimethoxyethyl)amino]-N-(2-phenylethyl)acetamide. This compound on further cyclization and acylation using cyclohexanoylchloride forms praziquantel.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[O:9]1[CH2:12][C:11](=[O:13])[CH2:10]1>C1COCC1>[Br:8][C:6]1[CH:7]=[C:2]([C:11]2([OH:13])[CH2:12][O:9][CH2:10]2)[CH:3]=[N:4][CH:5]=1
Reactant: O=C1COC1
Reactant: Brc1cncc(Br)c1
Solvent: C1CCOC1
Product: OC1(c2cncc(Br)c2)COC1
Temperature: -10 °C
Reaction time: 1 h
Yield: 27.8 %

Procedure:
To a cooled (−20° C.) solution of 3,5-dibromopyridine (1.2 g, 5.0 mmol) in THF (2 mL) is added a solution of isopropylmagnesium chloride-lithium chloride complex in THF (1.7 M, 2.9 mL, 4.9 mmol). The resultant mixture is stirred warming to −10° C. for 30 min. The mixture is recooled to −20° C. and 3-oxetanone (432 mg, 6.0 mmol) is added. After stirring for 1 h, the reaction is quenched with saturated aqueous ammonium chloride solution and is extracted with EtOAc. The combined organic extracts are washed with water and brine, dried (MgSO4) and concentrated under reduced pressure. Purification by silica gel column (0-10% MeOH in DCM) provided 3-(5-bromo-pyridin-3-yl)-oxetan-3-ol (320 mg).