Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1OC(=O)[CH:6]=[C:5]([O:10][CH3:11])[CH:4]=1)[CH3:2].[CH3:12][O:13][C:14]([C:16]#[C:17][C:18]([O:20][CH3:21])=[O:19])=[O:15]>ClCCl>[CH3:12][O:13][C:14](=[O:15])[C:16]1[C:17](=[C:3]([CH2:1][CH3:2])[CH:4]=[C:5]([O:10][CH3:11])[CH:6]=1)[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)C#CC(=O)OC
Reactant: CCc1cc(OC)cc(=O)o1
Solvent: ClCCl
Product: CCc1cc(OC)cc(C(=O)OC)c1C(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.6 %

Procedure:
The following is based on the procedure described in Tam, T. F. and Coles P., Synthesis, 383 (1988). 6-ethyl-4-methoxy-2H-pyran-2-one (40.5 g, 263 mmol) was placed in a 500 mL round bottom flask and dimethylacetylenedicarboxylate (42 mL, 342 mmol) was added. This mixture was stirred until the solid completely dissolved. The flask was fitted with a water condenser and placed in a preheated oil bath at 180° C. for 3 hours. The reaction was allowed to cool to room temperature, diluted with dichloromethane (75 mL), and was purified by silica gel chromatography using a gradient of 5-20% ethyl acetate in hexanes. The appropriate fractions were collected and concentrated by rotary evaporation to yield compound P (44.16 g, 67%) as a clear oil. 1H NMR CDCl3 δ: 7.30 (d, 1H, J=3 Hz), 6.95 (s, 1H, J=3 Hz), 3.90 (s, 3H), 3.88 (s, 3H), 3.85 (s, 3H), 2.64 (q, 2H, J=8.0 Hz), 1.21 (t, 3H, J=8.0 Hz). ESMS m/z: 221 [M−OCH3]+, 275 [M+Na+].
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]([C:15]2[CH:20]=[C:19]([OH:21])[C:18]([Cl:22])=[CH:17][C:16]=2[F:23])[C:6](=[O:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=1)[CH3:2].[C:24](Cl)(=[O:28])[CH:25]([CH3:27])[CH3:26].N1C=CC=CC=1>C(OCC)C>[C:24]([O:21][C:19]1[CH:20]=[C:15]([N:5]2[C:6](=[O:14])[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[N:9]=[C:4]2[O:3][CH2:1][CH3:2])[C:16]([F:23])=[CH:17][C:18]=1[Cl:22])(=[O:28])[CH:25]([CH3:27])[CH3:26]
Reactant: CCOc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Reactant: CC(C)C(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOc1nc(C(F)(F)F)cc(=O)n1-c1cc(OC(=O)C(C)C)c(Cl)cc1F

Procedure:
using 2-ethoxy-1-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-trifluoromethyl-6(1H)-pyrimidinone and isobutyryl chloride with pyridine in diethyl ether there is obtained {5-[2-ethoxy-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-2-chloro-4-fluorophenyl} isobutyrate, 1NMR (CDCl3, 400 MHz): 7.38 ppm (d,1H), 7.13 ppm (d,1H), 6.58 ppm (s,1H), 4.50 ppm (m,2H), 2.87 ppm (m,1H), 1.35 ppm (d,3H), 1.34 ppm (d,3H), 1.31 ppm (t,3H);
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([OH:21])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2.C[O:23][C:24](=[O:46])[C@H:25]([CH2:44]O)[NH:26]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([O:21][CH2:44][C@@H:25]([C:24]([OH:46])=[O:23])[NH2:26])[C:7]2[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=2[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]1=2
Reactant: OC1(c2cccs2)c2ccccc2CCc2ccccc21
Reactant: COC(=O)[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Product: N[C@@H](COC1(c2cccs2)c2ccccc2CCc2ccccc21)C(=O)O

Procedure:
from 10,11-dihydro-5-(2-thienyl)-5H-dibenzo[a,d]cyclohepten-5-ol (Example 2d) and Nα -(9-fluorenylmethoxycarbonyl)-L-serine methyl ester;
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[CH:4][CH:3]=1.[BH4-].[Na+].[O:12]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14]C1>[OH-].[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:18][CH:15]2[CH2:16][CH2:17][O:12][CH2:14]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C=Cc1ccc(Br)cc1
Reactant: OC1CCOCC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: CC(OC1CCOC1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
To the solution of 1-bromo-4-vinylbenzene (500 mg, 2.75 mmol) in tetrahydro-2H-pyran-4-ol (20 mL) was added mercuric trifluoroacetate (1.18 g, 2.75 mmol), the mixture was stirred for 1 hour at room temperature, then at 0° C. 3 mol/L sodium hydroxide (20 mL) was added with vigorous stirring, after 2 minute, sodium borohydride (0.5 mol/L) in sodium hydroxide (20 ml, 3 mol/L) was added. After 12 hours, the mixture was extracted with ethyl acetate (50 mL*3). The organics were washed with water (5×20 mL) and dried with sodium sulfate, the solvent was removed and purified by column chromatography (silica gel, dichloromethane/methanol=20:1). to give 3-(1-(4-bromo phenyl)ethoxy)-tetrahydrofuran (461 mg, 59%) as oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[C:10]([NH:16][C:17]1[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20])(=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14]>C(OC(=O)C)(=O)C>[N+:1]([C:26]1[C:17]([NH:16][C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14])=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])([O-:4])=[O:2]
Reactant: CCCCC(=O)Nc1ccccc1C(=O)OC
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CCCCC(=O)Nc1c(C(=O)OC)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
Fuming nitric acid (7.0 ml) was added dropwise to acetic anhydride (60 ml) under ice-cooling and there was added conc. sulfuric acid (0.2 ml). To the mixture was added methyl 2-valerylaminobenzoate (12 g), which was stirred for one hour at room temperature. To the resultant mixture was added ice-water and the mixture was then extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. The concentrate was purified by column chromatography on silica gel to give crude crystals, followed by recrystallization from isopropyl ether to afford colorless needles (3.9 g, 28%), m.p. 61-62° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=O)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[N:4][C:3]=1[C:17]([F:20])([F:19])[F:18].P(Cl)(Cl)(Cl)(Cl)[Cl:22]>P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[S:6][C:5]([N:7]=[C:8]([Cl:22])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[N:4][C:3]=1[C:17]([F:20])([F:19])[F:18]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(Nc1nc(C(F)(F)F)c(Cl)s1)c1cccc(Cl)c1
Solvent: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1nc(N=C(Cl)c2cccc(Cl)c2)sc1Cl

Procedure:
N-(5-Chloro-4-trifluoromethylthiazol-2-yl)-3-chlorobenzamide (15.5 g was mixed with phosphorous pentachloride (9.5 g) and phosphorous oxychloride (60 ml) and the mixture was refluxed for 12 hr. The excess phosphorous oxychloride was removed under reduced pressure and the residue was mixed with cold water then extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure then the residue was recrystallized from n-hexane to give N-(5-chloro-4-trifluoromethylthiazol-2-yl)-3-chlorobenzimidoyl chloride; as pale brown needles (11.0 g), m. p. 89-90° C.
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:8][C:4]=1[C:5](O)=[O:6])[CH3:2].[CH:30]1[C:43]2[C:34](=[N:35][C:36]3[C:41]([C:42]=2[NH:44][C:45]2[CH:46]=[C:47]([NH:53][C:54](=[O:58])[CH:55]([NH2:57])[CH3:56])[CH:48]=[C:49]([CH2:51][OH:52])[CH:50]=2)=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:33]=[CH:32][CH:31]=1>>[CH:40]1[C:41]2[C:36](=[N:35][C:34]3[C:43]([C:42]=2[NH:44][C:45]2[CH:46]=[C:47]([NH:53][C:54]([CH:55]([NH:57][C:5]([C:4]4[CH:8]=[C:9]([NH:14][C:15]([N:17]5[CH2:22][CH2:21][N:20]([C:23]6[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=6)[CH2:19][CH2:18]5)=[O:16])[C:10]([O:12][CH3:13])=[N:11][C:3]=4[CH2:1][CH3:2])=[O:6])[CH3:56])=[O:58])[CH:48]=[C:49]([CH2:51][OH:52])[CH:50]=2)=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:37]=[CH:38][CH:39]=1
Reactant: CCc1nc(OC)c(NC(=O)N2CCN(c3cccc(F)c3)CC2)cc1C(=O)O
Reactant: CC(N)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Product: CCc1nc(OC)c(NC(=O)N2CCN(c3cccc(F)c3)CC2)cc1C(=O)NC(C)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Yield: 53.4 %

Procedure:
The same reaction procedure to the example 1 were carried out using 2-ethyl-5-{[4-(3-fluorophenyl)-piperazine-1-carbonyl]-amino}-6-methoxy-n icotinic acid and N-[3-(acridine-9-yl-amino)-5-hydroxymethyl-phenyl]-2-aminopropaneamide to give the titled compound.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[F:18])[N:11]2[CH:19]=[N:20][C:21]([C:22]3[N:26]=[C:25]([CH:27]4[CH2:29][CH2:28]4)[O:24][N:23]=3)=[C:10]2[CH2:9]1)=O)(C)(C)C.Cl>CO>[CH:27]1([C:25]2[O:24][N:23]=[C:22]([C:21]3[N:20]=[CH:19][N:11]4[C:12]5[C:17](=[C:16]([F:18])[CH:15]=[CH:14][CH:13]=5)[NH:8][CH2:9][C:10]=34)[N:26]=2)[CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1Cc2c(-c3noc(C4CC4)n3)ncn2-c2cccc(F)c21
Agent: Cl
Solvent: CO
Product: Fc1cccc2c1NCc1c(-c3noc(C4CC4)n3)ncn1-2
Reaction time: 8 h

Procedure:
A mixture of 5 -(tert-butyloxycarbonyl)-3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-6-fluoro-4,5-dihydroimidazo[1,5-a]quinoxaline (I, EXAMPLE 51, 3.39 g) and 50 ml of methanol saturated with HCl(g) is stirred at 20°-25° overnight. The solvent is then removed under reduced pressure and the residue is partitioned between dichloromethane and aqueous sodium bicarbonate. The organic phase is separated and dried over sodium sulfate and taken to dryness to give the title compound, NMR (CDCl3) 1.23, 1.35, 2.26, 4.32, 4.86, 6.80, 6.95, 7.22 and 8.06 δ.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=2)=[C:11]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:10]=1)([CH3:8])[CH3:7])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[CH3:62][N:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1>ClCCl>[CH3:29][O:28][CH2:27][CH2:26][CH2:25][O:24][C:11]1[CH:10]=[C:9]([C:6]([CH3:7])([CH3:8])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:30])[CH:14]=[CH:13][C:12]=1[C:15]1[CH:16]=[CH:17][C:18]([C:21]([N:66]2[CH2:67][CH2:68][N:63]([CH3:62])[CH2:64][CH2:65]2)=[O:23])=[CH:19][CH:20]=1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)CC(C)(C)c1ccc(-c2ccc(C(=O)O)cc2)c(OCCCOC)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CC(C)(C)c1ccc(-c2ccc(C(=O)N3CCN(C)CC3)cc2)c(OCCCOC)c1
Reaction time: 18 h
Yield: 42.8 %

Procedure:
In a round bottom flask, under an atmosphere of argon, 4′-(3-ethoxy-1,1-dimethyl-3-oxopropyl)-2′-(3-methoxypropoxy)biphenyl-4-carboxylic acid (1.0 g, 2.4 mmol) was dissolved in dichloromethane (40 mL). EDCl (0.55 g, 2.9 mmol), HOBT (0.39 g, 2.9 mmol) and diisopropylethylamine (2.10 mL, 12.1 mmol) were added at room temperature. After consumption of all the acid, N-methylpiperazine (0.27 mL, 2.4 mmol) was added and the mixture was stirred for 18 hrs. The organic layer was washed twice with water. The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (dichloromethane/ethanol, 95/5) to yield 0.51 g (43%) of the desired product as a yellow oil.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[OH:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1>>[C:6]([C:5]1[C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=[CH:11][C:4]=1[O:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)#[N:7]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Product: CC(C)(C)OC(=O)N1CCC(COc2cccc([N+](=O)[O-])c2C#N)CC1

Procedure:
Prepared as in Example 111c from 2,6-dinitrobenzonitrile and tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate in 73% as a tan solid. 1H NMR (400 MHz, MeOD) δ 1.24 (qd, J=12.8, 4.4 Hz, 2H), 1.41 (s, 9H), 1.78 (br d, J=12.1 Hz, 2H), 2.02 (m, 2H), 2.77 (m, 2H), 4.00 (br d, J=13.1 Hz, 2H), 4.15 (d, J=6.3 Hz, 2H), 7.74 (dd, J=7.5, 1.5 Hz, 1H), 7.91 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:16])[C:8]([CH3:10])([CH3:9])[O:7][B:6]([C:11]2[CH:12]=[N:13][NH:14][CH:15]=2)[O:5]1.[F:17][CH:18]([F:21])[CH2:19]I>CN(C=O)C.[Cl-].[Na+].O>[F:17][CH:18]([F:21])[CH2:19][N:14]1[CH:15]=[C:11]([B:6]2[O:7][C:8]([CH3:9])([CH3:10])[C:4]([CH3:16])([CH3:3])[O:5]2)[CH:12]=[N:13]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: FC(F)CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OB(c2cnn(CC(F)F)c2)OC1(C)C
Reaction time: 0.25 h

Procedure:
NaH (60%, 128 mg) was added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (313 mg, 1.61 mmol) in DMF (4 mL). After stirring for 15 minutes, 1,1-difluoro-2-iodoethane (372 mg, 1.94 mmol) in DMF (1 mL) was added. The resulting solution was stirred at 80° C. under microwave irradiation for 60 minutes. The reaction mixture was diluted with brine and extracted with EtOAc. The combined organic layers were washed with water, dried with Na2SO4, and concentrated in vacuo to afford the title compound as a yellow oil that was used directly in the next step (210 mg, 50%).
Reaction SMILES: [CH2:1]([O:4][N:5]=[CH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]=1)[CH:2]=[CH2:3].B1C2CCCC1CCC2.[OH:32]O.[OH-].[Na+]>O1CCCC1>[OH:32][CH2:3][CH2:2][CH2:1][O:4][N:5]=[CH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]=1
Reactant: OO
Reactant: C=CCON=Cc1cn(Cc2ccccc2)c2ccccc12
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OCCCON=Cc1cn(Cc2ccccc2)c2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
To a solution of 1-benzyl-1H-indole-3-carbaldehyde O-allyl-oxime (2.965 g, 10.2 mmol) in tetrahydrofuran (50 mL) cooled to 0° C. was added 9-BBN (0.5 M in THF)(50.0 mL, 25.0 mmol). The reaction was stirred at 0° C. for 1 hour and then warmed to room temperature over 30 minutes. Hydrogen peroxide (12 mL) was carefully added followed by a 10% NaOH solution (20 mL) and stirring continued at room temperature for 25 minutes. The reaction was quenched by the addition of saturated sodium bisulfite and extracted with ethyl acetate. The combined organic were washed with saturated sodium bisulfite and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography through silica gel using ethyl acetate/hexanes (10/90 to 40/60) to give 1-benzyl-1H-indole-3-carbaldehyde O-(3-hydroxy-propyl)-oxime (1.298 g, 41%) as a white solid. mp=76.4-77.7° C.; mass spectrum (+ES, M+H) m/z 309. 1H NMR (400 MHz, CDCl3); δ 8.33 (s, 1H), 8.01 (d, 1H), 7.92 (s, 1H), 7.49 (d, 1H), 7.22 (m, 7H), 5.44 (s, 2H), 4.47 (t, 1H), 4.13 (t, 2H), 3.52 (q, 2H), 1.82 (m, 2H). Elemental analysis: Calcd. for C19H20N2O2: C, 74.0; H, 6.54; N, 9.08. Found: C, 73.74; H, 6.46; N, 8.95.
Reaction SMILES: [C:1]1([C:7]2[C:12]3[O:13][CH:14]=[CH:15][C:11]=3[C:10](=O)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:19])=O>ClC(Cl)C>[Cl:19][C:10]1[N:9]=[N:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:12]2[O:13][CH:14]=[CH:15][C:11]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]nc(-c2ccccc2)c2occc12
Solvent: CC(Cl)Cl
Product: Clc1nnc(-c2ccccc2)c2occc12
Temperature: 100 °C
Reaction time: 3 h

Procedure:
0.15 g of 7-phenyl-furano[2,3-d]pyridazine-4-(5H)-one and 10 ml of phosphorus oxychloride were dissolved in 10 ml of dichloroethane, and the solution was stirred at 100° C. for 3 hours. The reaction solution was concentrated, and a 1-N aqueous KOH solution was added thereto under cooling with ice. The solution was extracted with chloroform and dried. The solvent was distilled off, thereby obtaining 0.10 g of 4-chloro-7-phenyl-furano[2,3-d]pyridazine.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[C:15]([CH3:17])[C:14]([CH:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22][CH:21]=2)[OH:19])=[C:13]([O:30][CH3:31])[CH:12]=1)[CH3:2].[H-].[Na+].I[CH2:35][CH3:36]>CN(C=O)C>[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:11]1[N:16]=[C:15]([CH3:17])[C:14]([CH:18]([O:19][CH2:35][CH3:36])[CH:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22][CH2:21]2)=[C:13]([O:30][CH3:31])[CH:12]=1)[CH3:10]
Reactant: CCI
Reactant: CCc1cccc(CC)c1-c1cc(OC)c(C(O)C2=CCCc3ccccc32)c(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(c1c(OC)cc(-c2c(CC)cccc2CC)nc1C)C1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of [6-(2,6-diethyl-phenyl)-4-methoxy-2-methyl-pyridin-3-yl]-(3,4-dihydro-naphthalen-1-yl)-methanol (75 mg, 0.18 mmol) in DMF (1 mL) is added to a suspension of NaH (22 mg, 0.90 mmol) in DMF (5 mL). The mixture is stirred for 1 hour at room temperature. Iodoethane (0.14 mL, 1.8 mmol) is added and the resulting mixture is stirred for 18 hours at room temperature, quenched with water, and extracted with ether. The combined extracts are washed with saturated brine, dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel to give 6-(2,6-diethyl-phenyl)-3-[ethoxy-(1,2,3,4-tetrahydronaphthalen-1-yl)-methyl]-4-methoxy-2-methyl-pyridine as a colorless oil. 1H NMR (CDCl3) 7.71-7.68 (m, 1H), 7.32-7.26 (m, 1H), 7.21-7.10 (m, 5H), 6.67 (s, 1H), 5.04 (d, 1H), 3.80 (s, 3H), 3.51-3.46 (m, 1H), 3.36-3.19 (m, 2H), 2.89-2.2.72 (m, 2H), 2.75 (s, 3H), 2.47-2.38 (m, 4H), 1.90-1.81 (m, 1H), 1.69-1.59 (m, 2H), 1.41-1.1.32 (m, 1H), 1.17-1.08 (m, 9H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([N:12]3[CH2:15][C:14]([F:17])([F:16])[CH2:13]3)=[CH:10][N:9]=[C:8]([C:18]([OH:20])=O)[CH:7]=2)[CH2:3][CH2:2]1.[NH2:21][C:22]1([CH2:28][C:29]([NH2:31])=[O:30])[CH2:25][S:24](=[O:27])(=[O:26])[CH2:23]1>>[NH2:31][C:29](=[O:30])[CH2:28][C:22]1([NH:21][C:18]([C:8]2[CH:7]=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[C:11]([N:12]3[CH2:13][C:14]([F:16])([F:17])[CH2:15]3)=[CH:10][N:9]=2)=[O:20])[CH2:23][S:24](=[O:26])(=[O:27])[CH2:25]1
Reactant: NC(=O)CC1(N)CS(=O)(=O)C1
Reactant: O=C(O)c1cc(OCC2CC2)c(N2CC(F)(F)C2)cn1
Product: NC(=O)CC1(NC(=O)c2cc(OCC3CC3)c(N3CC(F)(F)C3)cn2)CS(=O)(=O)C1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 4-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (example 53e) and 2-(3-amino-1,1-dioxo-thietan-3-yl)acetamide (example 160d) as starting materials and isolated (35 mg, 42%); MS (ESI, m/z): 445.3 (M+H+).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:7][CH:6]=1)#[N:4].CN(C)C=O.Br[CH2:27][CH2:28][CH2:29][Cl:30]>O1CCCC1>[Cl:30][CH2:29][CH2:28][CH2:27][N:13]([CH2:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([C:3]#[N:4])=[CH:10][CH:9]=1)[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18]
Reactant: ClCCCBr
Reactant: CC(C)(C)OC(=O)NCCc1ccc(C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCCCl)CCc1ccc(C#N)cc1
Reaction time: 0.25 h

Procedure:
At room temperature, 0.23 g (9.03 mmol) of sodium hydride (95%) was added to a solution of 1.482 g (6.02 mmol) of tert.-butyl [2-(4-cyanophenyl)ethyl]carbamate in 25 ml of tetrahydrofuran/25 ml of dimethylformamide. The mixture was stirred for a further 15 minutes. 1.49 ml (15.04 mmol) of 1-bromo-3-chloropropane were then added, and the reaction mixture was stirred at room temperature overnight. With ice bath cooling, the mixture was then quenched with water, and extracted with ethyl acetate. The organic extracts were washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated to dryness. The crude product obtained in this manner was purified by column chromatography on silica gel (mobile phase: petroleum ether/ethyl acetate 4:1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([S:17](C)(=O)=O)[NH:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:4].[Li+].[OH-]>C1COCC1.O>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7](=[S:17])[NH:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:4]
Reactant: COC(=O)c1nc(S(C)(=O)=O)[nH]c1-c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1[nH]c(=S)[nH]c1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 107.5 %

Procedure:
The sulfone 10 (19.8 g, 66.4 mmol) was treated with a mixture of LiOH (4.8 g, 200 mmol) in THF (240 mL) and water (80 mL) at 85° C. for 3 h. The resulting mixture was cooled to rt and then concentrated under reduced pressure. The aqueous solution was diluted with water (150 mL) and extracted with ethyl acetate (50 mL×2, discarded). The aqueous solution was acidified with 1N HCl aq. to pH 1 and then extracted with ethyl acetate (150 mL×3). The combined extracts were washed with brine (50 mL×2), dried over anhydrous MgSO4, filtered, and evaporated to afford crude product 7 (18.0 g) as a white solid. ESI MS m/z 285.2 (M+H)+. The crude product was suspended in a mixture of MTBE (50 mL) and dichloroethane (200 mL) and stirred at rt for 72 h. The remaining solid was collected by filtration, dried over vacuum to afford pure 5-(4-Fluoro-phenyl)-2-methanesulfonyl-1H-imidazole-4-carboxylic acid (S-17) as a white solid (14 g, 74%) with 96% purity by UV254 nm and 100% purity by ELS.
Reaction SMILES: [NH2:1][C:2]([N:8]([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10][CH3:11])=[C:3]([C:6]#[N:7])[C:4]#[N:5].C(N(CC)CC)C.[SH2:22]>N1C=CC=CC=1>[NH2:1][C:2]([N:8]([CH2:9][CH2:10][CH3:11])[CH2:12][CH2:13][CH3:14])=[C:3]([C:4]#[N:5])[C:6](=[S:22])[NH2:7]
Reactant: S
Reactant: CCCN(CCC)C(N)=C(C#N)C#N
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCCN(CCC)C(N)=C(C#N)C(N)=S
Reaction time: 48 h
Yield: 29.1 %

Procedure:
An attempt at conversion by the method of Example IV, part D, was unsuccessful. Thus a mixture of 28 g of 3-amino-2-cyano-3-(dipropylamino)propenenitrile, 14.7 g of triethylamine and 100 ml of pyridine in a pressure bottle was cooled to -70° and 10 g of hydrogen sulfide were added. The bottle was capped and allowed to stand at ambient temperature during two days, then heated at 80° for about 16 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in a minimum of toluene containing a trace of ethanol. The solid which separated on cooling was collected to obtain 9.6 g of 3-amino-2-cyano-3-(dipropylamino)propenethioamide, m.p. 141°-144°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: Cl.C([O:4][CH:5](OCC)[C:6]1[CH:7]=[C:8]([C:12]([CH3:24])([CH3:23])[CH2:13][NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:9]([CH3:11])[N:10]=1)C.COC(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[CH:5]([C:6]1[CH:7]=[C:8]([C:12]([CH3:24])([CH3:23])[CH2:13][NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:9]([CH3:11])[N:10]=1)=[O:4]
Reactant: CCOC(OCC)c1cc(C(C)(C)CNC(=O)c2ccccc2)n(C)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: Cn1nc(C=O)cc1C(C)(C)CNC(=O)c1ccccc1
Reaction time: 8 h
Yield: 76.5 %

Procedure:
Hydrochloric acid (40 mL of 1 M) was added to a solution of N-[1-(5-diethoxymethyl-2-methyl-2H-pyrazol-3-yl)-1,1-dimethylethyl]benzamide (8.7 g, 24 mmol) in tetrahydrofuran (40 mL), and the reaction was stirred for ten minutes. tert-Butyl methyl ether and 2 M aqueous sodium carbonate (20 mL) were added. The aqueous layer was extracted twice with tert-butyl methyl ether, and the combined organic fractions were dried over magnesium sulfate and filtered. Hexane was added, and the cloudy mixture was stored overnight in the refrigerator. Crystals formed and were isolated in two crops by filtration to provide 5.24 g of N-[1-(5-formyl-2-methyl-2H-pyrazol-3-yl)-1,1-dimethylethyl]benzamide as a white powder, mp 150-151° C.